Crystalline forms of N-(6-amino-5-methylpyridin-3-yl)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide, pharmaceutical compositions, and methods of use thereof

Abstract

Crystalline forms and pharmaceutical compositions of the PRMT5 inhibitor of formula (I), methods for preparing the PRMT5 inhibitor of formula (I) and its crystalline form, methods for preparing pharmaceutical compositions of the PRMT5 inhibitor of formula (I), and methods of using the PRMT5 inhibitor of formula (I) or crystalline solid form and pharma- ceutically acceptable compositions thereof. TIFF2025501503000207.tif42165

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 291,007, filed December 17, 2021, and U.S. Provisional Application No. 63 / 419,221, filed October 25, 2022, which applications are incorporated herein by reference in their entirety for all purposes. [Background technology]

[0002] Developing pharmaceutical compositions containing one or more novel active ingredients requires various considerations, such as the route of administration (e.g., gastrointestinal, parenteral, topical, etc.), dosage form (e.g., solid—tablet, capsule, etc.; liquid—solution, suspension, syrup, etc.), active ingredient(s) content (e.g., 1 mg to 1,000 mg), non-therapeutic ingredient(s) (e.g., excipients), and their respective amounts, each of which may involve additional considerations such as stability, degradability, photosensitivity, solubility, taste when administered via the gastrointestinal tract, palatability, pH, skin irritation, microbial growth, etc. Advancement of novel active ingredients (e.g., PRMT5 inhibitors) through stringent regulatory agencies requires the discovery and development of pharmaceutical compositions that take these and other considerations into account.

[0003] Thus, a need exists for pharmaceutical compositions comprising compounds (eg, PRMT5 inhibitors) that exhibit desirable properties for treating diseases or disorders (eg, cancer) in human patients. Summary of the Invention

[0004] In some embodiments, N-(6-amino-5-methylpyridin-3-yl)-2-((2R,5S)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound of formula (I)) [ka] A crystalline form of

[0005] In some embodiments, N-(6-amino-5-methylpyridin-3-yl)-2-((2R,5S)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound of formula (I)) [ka] wherein the X-ray powder diffraction (XRPD) pattern of the crystalline form comprises one or more peaks at 2θ angles selected from 6.4±0.2, 8.9±0.2, 12.7±0.2, 14.0±0.2, 19.1±0.2, 19.9±0.2, 22.6±0.2 degrees (Form A).

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

[0007] In certain embodiments, the pharmaceutical composition comprises crystalline Form A of the compound of formula (I).

[0008] In some embodiments, (a) Formula (I): [ka] or a pharmaceutically acceptable salt thereof; (b) a bulking agent (e.g., microcrystalline cellulose); (c) a glidant (e.g., colloidal silicon dioxide); and (d) a disintegrant (e.g., croscarmellose sodium); and (e) a lubricant (e.g., magnesium stearate); A pharmaceutical composition comprising:

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

[0010] In some embodiments, a dosage form is provided comprising the pharmaceutical composition described herein.

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

[0012] In some embodiments, a method is provided for treating an MTAP deficiency and / or an MTA storage disorder in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition described herein comprising a therapeutically effective amount of a compound of Formula (I).

[0013] In some embodiments, N-(6-amino-5-methylpyridin-3-yl)-2-((2R,5S)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound of formula (I)): [ka] or a salt thereof, the process comprising: Formula (II): [ka] by hydrogenating a compound of formula (III-a): [ka] and forming a compound of formula (I) In the formula, R 1 is a chiral auxiliary.

[0014] In some embodiments, N-(6-amino-5-methylpyridin-3-yl)-2-((2R,5S)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound of formula (I)): [ka] or a salt thereof, the process comprising: Formula (VI): [ka] with a compound of formula (VII): [ka] whereby a compound of formula (Ia): [ka] and forming a compound of formula (I) In the formula, R 6 , R 7 , R 8 , and R 9 are each independently H or a nitrogen protecting group; Optionally, R 8 , R 9 , or R 8 and R 9 are nitrogen protecting groups, the process further comprises a deprotection step to remove the nitrogen protecting groups from the compound of formula (Ia), thereby producing a compound of formula (I) or a salt thereof. [Brief explanation of the drawings]

[0015] [Figure 1A] 1 is an example of a powder X-ray diffraction pattern of crystalline form A of compound of formula (I).

[0016] [Figure 2A] 1 is an example of a thermogravimetric analysis (TGA) thermogram of a compound of formula (I).

[0017] [Figure 2B] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline Form A of compound of formula (I) under a heat-cool-heat protocol, showing a melting peak at about 168°C.

[0018] [Figure 2C] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline Form A of compound of formula (I) under a heat-cool-heat protocol, showing a glass transition temperature (Tg) of 94.6° C.

[0019] [Figure 3A] FIG. 1 shows the change in water content (bold curve) and relative humidity (thin curve) as a function of time in an example DVS experiment for compound of formula (I) (crystalline form A).

[0020] [Figure 3B] 1 shows the change in water content as a function of relative humidity in an example DVS study of compound of formula (I) (crystalline form A).

[0021] [Figure 4A] Figure 1 shows survival curves at different concentrations of the PRMT5 inhibitor of Formula (I) in a pair of genetically identical, except for MTAP, HAP1 (CML - chronic myeloid leukemia) cell lines, one with intact MTAP and the other engineered by CRISPR-mediated MTAP gene knockout, as determined by CellTiter-Glo assay. Data are presented as mean ± SD.

[0022] [Figure 4B] 1 shows a plot of the pharmacodynamic activity of the PRMT5 inhibitor of Formula (I) that inhibits PRMT5 in a pair of genetically identical HAP1 cell lines except for MTAP. Normalized SDMA levels are shown for the MTAP WT and MTAP null cell lines. Data are normalized to the DMSO control for each cell line and are presented as mean ± SD.

[0023] [Figure 4C] Figure 1 shows survival curves for different concentrations of the PRMT5 inhibitor of formula (I) in a pair of genetically identical, except for MTAP, SW1573 (NSCLC - non-small cell lung cancer) cell lines, one lacking endogenous MTAP and the other reconstituted with exogenous MTAP, as determined by CellTiter-Glo assay. Data are presented as mean ± SD.

[0024] [Figure 5A] Figure 1 shows survival curves at different concentrations of the PRMT5 inhibitor of Formula (I) in a pair of genetically identical, but MTAP-exclusive, LN18 (GBM-glioblastoma) cell lines, one engineered by deletion of endogenous MTAP and the other engineered by reconstituting exogenous MTAP, as determined by CellTiter-Glo assay. Data are presented as mean ± SD.

[0025] [Figure 5B] Figure 1 shows a plot of EC50 values ​​for 12 glioblastoma cancer cell lines (5 MTAP WT and 7 MTAP null) treated for 7 days with a 9-point dose escalation of the PRMT5 inhibitor of Formula (I); antiproliferative activity was determined by CellTiter-Glo assay. A variable slope (4-parameter) curve was fitted for each cell line, and the concentration giving half-maximal efficacy was determined and plotted on the y-axis.

[0026] [Figure 6A] 1 shows a graph of tumor volume as a function of time for an MTAP-null HCT116 xenograft model administered with a PRMT5 inhibitor of formula (I).

[0027] [Figure 6B] 1 shows a graph of tumor volume as a function of time for an MTAP wild-type HCT116 xenograft model administered with a PRMT5 inhibitor of formula (I).

[0028] [Figure 7]1 shows a graph of normalized single SDMA-modified protein levels at 30 mpk and 90 mpk BID doses of the PRMT5 inhibitor of Formula (I) in a genetically identical HCT116 xenograft model, except for MTAP. Single SDMA-modified substrates were quantified by immunoblot and normalized to the loading control derived from tumors treated 8 hours after the final dose; n=4 tumors / group. Data are presented as mean ± SEM.

[0029] [Figure 8] 1 shows a waterfall plot of 199 cancer cell lines representing multiple cancer lineages including NSCLC, PDAC, bladder, CNS, and hematological malignancies profiled with the PRMT5 inhibitor of formula (I) in a 7-day CellTiter-Glo assay.

[0030] [Figure 9A] Figure 1 shows the lineage-independent response to treatment with the PRMT5 inhibitor of formula (I). Waterfall plots are shown for the activity of the PRMT5 inhibitor of formula (I) administered at 120 mpk BID in MTAP-deficient CDX and MTAP-deficient PDX models representative of the tumor tissues shown. For tumors where tumor volume final is greater than or equal to tumor volume initial, -TGI% is reported (values ​​between -100 and 0). For models where tumor volume final is less than tumor volume initial, tumor volume initial% -100 is reported (values ​​between -200 and -100). "Status quo" is defined as 100% TGI, and "complete response" is defined as tumor volume initial% equal to -100%.

[0031] [Figure 9B] Representative end-point PD analysis of Western blots (probing SDMA and ACTB as a control) of PRMT5 inhibitor of formula (I)-treated PDX tumors administered BID at the levels indicated are shown.

[0032] [Figure 10]1 shows a graph of the free concentration of a PRMT5 inhibitor of formula (I) in a series of cerebrospinal fluid (CSF, a surrogate for free brain concentration) and plasma samples from cynomolgus monkeys (N=3 / group).

[0033] [Figure 11A] Plots are shown for 111 glioblastoma samples from TCGA Firehouse Legacy that were profiled for MGMT methylation (HM27 and HM450) and expression status (z-score relative to diploid samples; RNA-Seq V2 RSEM). For further analysis, an MGMT methylation threshold of >0.2 was defined.

[0034] [Figure 11B] MGMT methylation levels in GBM samples from FIG. 11A separated by MTAP status are shown.

[0035] [Figure 11C] MGMT status from GBM samples from FIG. 11A separated by MTAP status is shown.

[0036] [Figure 11D] Shown are examples of 7-day antiproliferative assays and Western blots from MTAP-deficient GBM cell lines from Figure 11A. Cell lines are color-coded by MGMT status according to MGMT immunoblot.

[0037] [Figure 11E] An example of a Western blot from the MTAP-deficient GBM cell line from Figure 11A is shown.

[0038] [Figure 12A] FIG. 1 shows a graph of tumor volume for the subcutaneous LN18 MTAP-null GBM CDX mouse model administered the PRMT5 inhibitor of Formula (I) at 10 mg / kg, 30 mg / kg, and 60 mg / kg BID; data are plotted as mean ± SEM; n=8 mice / group.

[0039] [Figure 12B] PK / PD plots of plasma concentrations and single SDMA-modified proteins (% of vehicle) normalized to ACTB for the subcutaneous LN18 MTAP-null GBM CDX mouse model dosed with the PRMT5 inhibitor of Formula (I) at 3 mg / kg, 10 mg / kg, 30 mg / kg, and 60 mg / kg BID; data are plotted as mean ± SEM; n=8 mice / group.

[0040] [Figure 12C] FIG. 1 shows a graph of tumor volume for a subcutaneous U87MG MTAP-null GBM CDX mouse model administered the PRMT5 inhibitor of formula (I) at 30 mg / kg and 120 mg / kg BID; data are plotted as mean ± SEM; n=5 mice / group.

[0041] [Figure 12D] FIG. 1 shows a graph of tumor volume for a subcutaneous MTAP-null GBM PDX mouse model administered the PRMT5 inhibitor of formula (I) at 30 mg / kg and 120 mg / kg BID; data are plotted as mean ± SEM; n=5 mice / group.

[0042] [Figure 12E] 1 shows a graph of tumor size measured by bioluminescence (BLI) for an orthotopic U87MG MTAP null GBM CDX mouse model treated with 120 mpk BID of the PRMT5 inhibitor of formula (I) or vehicle.

[0043] [Figure 12F] Kaplan-Meier curves of survival probability for the orthotopic U87MG MTAP null GBM CDX mouse model treated with 120 mpk BID of the PRMT5 inhibitor formula (I) or vehicle.

[0044] [Figure 12G]1 shows examples of weekly bioluminescence images at the indicated time points for an orthotopic U87MG MTAP null GBM CDX mouse model treated with 120 mpk BID of the PRMT5 inhibitor of formula (I) or vehicle up to day 34.

[0045] [Figure 13A] 1 shows a graph of tumor volume for cholangiocarcinoma PDX tumor-bearing mice administered 30 mpk and 120 mpk BID of the PRMT5 inhibitor of formula (I) for the indicated periods; n=3 mice / group, and data are shown as mean±SEM.

[0046] [Figure 13B] 1 shows a graph of tumor volume for NSCLC (adenocarcinoma) PDX tumor-bearing mice administered 30 mpk and 120 mpk BID of the PRMT5 inhibitor of formula (I) for the indicated time periods; n=3 mice / group, and data are shown as mean±SEM.

[0047] [Figure 13C] 1 shows a graph of tumor volume for bladder cancer PDX tumor-bearing mice administered 30 mpk and 120 mpk BID of the PRMT5 inhibitor of formula (I) for the indicated periods; n=3 mice / group, and data are shown as mean±SEM.

[0048] [Figure 13D] 1 shows a graph of tumor volume for DLBCL OCI-Ly19 CDX tumor-bearing mice administered 30 mpk and 120 mpk BID of the PRMT5 inhibitor of formula (I) for the indicated periods; n=3 mice / group, and data are shown as mean±SEM.

[0049] [Figure 13E] 1 shows a graph of tumor volume for NSCLC (squamous cell carcinoma) PDX tumor-bearing mice administered 30 mpk and 120 mpk BID of the PRMT5 inhibitor of formula (I) for the indicated time periods; n=3 mice / group, and data are shown as mean±SEM.

[0050] [Figure 14A] FIG. 1 shows a graph of tumor volume for LU99 (lung cancer) MTAP null / KRAS G12C CDX tumor-bearing mice administered 30 mpk and 90 mpk BID of the compound of formula (I) or 18 mpk QD of sotorasib, and a combination of 30 mpk and 90 mpk BID of the compound of formula (I) and 18 mpk QD of sotorasib for the indicated time periods; n=8 mice / group, and data are shown as mean±SEM.

[0051] [Figure 14B] FIG. 1 shows a graph of tumor volume for LU99 (lung cancer) MTAP null / KRAS G12C CDX tumor-bearing mice administered 30 mpk and 90 mpk BID of the compound of formula (I) or 100 mpk QD of sotorasib, and a combination of 30 mpk and 90 mpk BID of the compound of formula (I) and 100 mpk QD of sotorasib for the indicated time periods; n=8 mice / group, and data are shown as mean±SEM.

[0052] [Figure 15] Graphs of tumor volume are shown for LU99 (lung cancer) MTAP null subcutaneous CDX tumor-bearing mice administered 80 mpk BID of the compound of formula (I), 50 mpk QD of palbociclib, 50 mpk QD of abemaciclib, a combination of 80 mpk BID of the compound of formula (I) and 50 mpk QD of palbociclib, and a combination of 80 mpk BID of the compound of formula (I) and 50 mpk QD of abemaciclib for the indicated periods; n=8 mice / group.

[0053] [Figure 16A] 1 shows that the combination of AG-270 (a MAT2A inhibitor) and the compound of formula (I) enhances the loss of cell viability in a 7-day survival assay in the MTAP-null SW1573 (NSCLC) cancer cell line.

[0054] [Figure 16B]1 shows that the combination of AG-270 (a MAT2A inhibitor) and a compound of formula (I) enhances the loss of cell viability in a 7-day survival assay in the MTAP-null LN18 (GBM) cancer cell line.

[0055] [Figure 16C] 1 shows that the combination of AG-270 (a MAT2A inhibitor) with a compound of formula (I) enhances the loss of cell viability in a 7-day survival assay in the MTAP-null RT112 / 84 (bladder) cancer cell line. DETAILED DESCRIPTION OF THE INVENTION

[0056] As generally described herein, the present disclosure provides PRMT5 inhibitors (e.g., MTA-uncompetitive PRMT5 inhibitors) (e.g., compounds represented by Formula (I): [ka] and crystalline forms thereof), methods for preparing the pharmaceutical compositions, and methods for treating medical conditions, diseases, and disorders (e.g., proliferative diseases such as cancer) using the pharmaceutical compositions.

[0057] definition As used in this disclosure, the following words and phrases are generally intended to have the meanings indicated below unless expressly stated otherwise or indicated otherwise by the context in which they are used.

[0058] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0059] Throughout the description, where compositions and kits are described as having, including, or comprising particular components, or processes and methods are described as having, including, or comprising particular steps, it is additionally contemplated that there are compositions and kits of the invention that consist essentially of the recited components or consist of the recited components, and that there are processes and methods of the invention that consist essentially of or consist of the recited processing steps.

[0060] In this application, when an element or component is described as being included in and / or selected from a list of described elements or components, it is understood that the element or component can be any one of the described elements or components, or the element or component can be selected from a group consisting of two or more of the described elements or components.

[0061] Furthermore, it is to be understood that elements and / or features of the compositions or methods described herein, whether express or implied herein, can be combined in various ways without departing from the spirit and scope of the invention. For example, when reference is made to a particular compound, that compound can be used in various embodiments of the compositions and / or methods of the invention, unless otherwise understood from the context. When elements are presented as lists (e.g., in Markush group format), each subgroup of elements is also disclosed, and any element(s) can be removed from the group. In other words, although embodiments have been described and expressed within this application in a manner that allows for clear and concise description and depiction of the application, it is intended and understood that the embodiments can be combined or separated in various ways without departing from the present teachings and invention(s). For example, it will be understood that all features described and expressed herein may be applicable to all aspects of the invention(s) described and expressed herein.

[0062] The articles "a" and "an" are used in this disclosure to refer to one or to more than one (i.e., at least one) of the grammatical object of the article, unless the context is inappropriate. As an example, in certain contexts, an "element" may mean one element, and / or in certain contexts, may mean a plurality of elements. As another example, in certain contexts, a "bulking agent" may mean one bulking agent, and / or in certain contexts may mean a plurality of bulking agents (e.g., a mixture of two or more bulking agents).

[0063] The term "and / or" is used in this disclosure to mean either "and" or "or," unless otherwise specified.

[0064] The phrase "at least one of," unless otherwise understood from context and usage, should be understood to include each of the listed objects following the phrase individually, as well as various combinations of two or more of the listed objects. The phrase "and / or" in connection with more than two listed objects should be understood to have the same meaning, unless otherwise understood from context.

[0065] Use of the terms "include," "includes," "including," "have," "has," "having," "contain," "contains," or "containing," including grammatical equivalents thereof, should generally be understood as open-ended and non-exclusive (e.g., not excluding additional, unrecited elements or steps), unless specifically stated otherwise or understood otherwise from context.

[0066] When the term "about" is used before a quantitative value, the present invention also includes the specific quantitative value itself, unless otherwise specifically stated. As used herein, the term "about" refers to a ±10% variation from the nominal value, unless otherwise specified or inferred from the context.

[0067] At various places throughout this specification, variables or parameters are disclosed in groups or ranges. It is expressly intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, an integer in the range of 0 to 40 is expressly intended to individually disclose 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 an integer in the range of 1 to 20 is expressly intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0068] The use of any example or exemplary language (e.g., "such as" or "including") herein is intended merely to better illustrate the invention and does not impose limitations on the scope of the invention unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0069] As a general matter, unless otherwise specified, compositions specifying percentages are by weight. Furthermore, if a definition of a variable is not provided, the preceding definition of the variable takes precedence.

[0070] As used herein, "XRPD" refers to powder X-ray diffraction. An XRPD pattern is an xy graph with 2θ (diffraction angle) plotted on the x-axis and intensity plotted on the y-axis. These are diffraction peaks that can be used to characterize crystalline materials. Diffraction peaks are typically expressed and referred to by their position on the x-axis rather than their intensity on the y-axis because diffraction peak intensity can be particularly sensitive to sample orientation (see Pharmaceutical Analysis, Lee & Web, pp. 255-257 (2003)). Therefore, intensity is not typically used by those skilled in the art 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 diffraction peaks on the x-axis. However, this variability can typically be taken into account when reporting diffraction peak positions for characterization purposes. Such variability in the position of diffraction peaks along the x-axis can come from several sources. One such source can be sample preparation. Samples of the same crystalline material prepared under different conditions may yield slightly different diffractograms. Factors such as particle size, water content, solvent content, temperature, and orientation can all affect how a sample diffracts X-rays. Another source of variability comes from instrument parameters. Different powder X-ray diffractometers are operated using different parameters and may produce slightly different diffraction patterns from the same crystalline material. Similarly, different software packages process XRPD data differently, which can also lead to variability. These and other sources of variability are known to those skilled in the art. Because of such sources of variability, the value of each X-ray diffraction peak may be preceded by the term "about" or an appropriate range (e.g., ±0.1°, ±0.2°, ±0.3°, ±0.4°, ±0.5°, etc.) to account for experimental variability.

[0071] Crystalline forms (such as those of the compound of Formula (I)) are readily analyzed by XRPD. Data obtained from powder X-ray diffraction can be used in multiple ways to characterize a crystalline form. For example, the entire powder X-ray diffraction pattern output from a diffractometer can be used to characterize a crystalline form (e.g., of a compound of Formula (I)). However, smaller subsets of such data may also be suitable and used to characterize such a crystalline form. Indeed, in many cases, even a single powder X-ray diffraction peak can be used to characterize such a crystalline form. With respect to the crystalline form of the compound of Formula (I), any one or more of the peaks in the powder X-ray diffraction pattern of FIG. 1A can be used to characterize the crystalline form of the compound of Formula (I) disclosed herein.

[0072] The term "characteristic peaks", when made in reference to peaks in an XRPD pattern of a crystalline form of a given chemical substance (e.g., a crystalline form of a compound of Formula (I)), refers to a particular set of diffraction peaks spanning a range of 2θ values ​​(e.g., 0°-40°) that are collectively characteristic of that particular crystalline form.

[0073] As used herein, "crystal" refers to a solid phase of a given chemical substance that has a well-defined three-dimensional structural order. The atoms, ions, and / or molecules are arranged in a regular and periodic manner within a repeating three-dimensional lattice. In various embodiments, a crystalline material can include one or more different crystalline forms.

[0074] As used herein, the terms "crystalline form," "crystalline solid form," "crystal form," "solid form," and related terms herein refer to crystalline modifications of a given substance (e.g., a compound of Formula (I)), including single-component crystalline forms and multiple-component crystalline forms, and including, but not limited to, polymorphs, solvates, hydrates, and salts.

[0075] The term "substantially crystalline" refers to a solid form in which at least a certain weight percent may be crystalline. The certain weight percent 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 certain embodiments, the certain weight percent of crystallinity is at least 90%. In certain other embodiments, the certain weight percent 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 FIG. 1A).

[0076] The term "substantially pure" refers to a composition of a particular crystalline solid form (e.g., a crystalline form of the compound of Formula (I)) in which at least a particular weight percentage may be free from impurities and / or other solid forms. The particular weight percentage may include 70%, 75%, 80%, 85%, 90%, 95%, 99%, or any percentage between 70% and 100%. In certain embodiments, 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 1A (Form A)). In certain embodiments, the compound of Formula (I) may be a substantially pure crystalline form having the XRPD pattern shown in Figure 1A (Form A).

[0077] As used herein, the term "anhydrous" or "anhydrous" when referring to a crystalline form (e.g., a crystalline form of a compound of Formula (I)) means that water molecules do not form part of the unit cell of the crystalline form. However, an anhydrous crystalline form may contain water molecules that do not form part of the unit cell of the anhydrous crystalline form (e.g., as residual solvent molecules remaining after the formation of the crystalline form). In a preferred embodiment, water may constitute about 0.5% by weight of the total composition of a sample of the anhydrous form. In a more preferred embodiment, water may constitute about 0.2% by weight of the total composition of a sample of the anhydrous form. In some embodiments, a sample of an anhydrous crystalline form of a compound of Formula (I) does not contain water molecules, e.g., does not contain detectable amounts of water.

[0078] As used herein, the term "desolvated" or "non-solvated," when used in reference to a crystalline form (e.g., a crystalline form of a compound of Formula (I)), means that solvent molecules do not form part of the unit cell of the crystalline form. However, a non-solvated crystalline form may contain solvent molecules that do not form part of the unit cell of the non-solvated crystalline form (e.g., as residual solvent molecules remaining after production of the crystalline form). In a preferred embodiment, the solvent may constitute 0.5% by weight of the total composition of a sample of the non-solvated form. In a more preferred embodiment, the solvent may constitute 0.2% by weight of the total composition of a sample of the non-solvated form. In some embodiments, a sample of a non-solvated crystalline form of a compound of Formula (I) does not contain solvent molecules, e.g., does not contain detectable amounts of solvent.

[0079] As used herein, the terms "polymorph," "polymorphic form," "polymorphs," "polymorphic forms," ​​and related terms herein refer to two or more crystalline forms consisting essentially of the same molecule(s) or ions (e.g., a compound of Formula (I)). Different polymorphs may exhibit different physicochemical properties, including but not limited to, melting temperature, solubility, dissolution rate, and physical stability, as a result of differences in the arrangement or conformation of the molecules or ions in the crystalline lattice.

[0080] The term "solvate," when used in reference to a crystalline form of a compound of formula (I), means that solvent molecules (e.g., organic solvents and water) form part of the unit cell of the crystalline form. Solvates that include water as the solvent are also referred to herein as "hydrates."

[0081] As used herein, "dissolution profile" refers to dissolution testing of a drug substance or drug product at multiple time points. Dissolution profiles of a drug substance (e.g., a compound of Formula (I)) or drug product (e.g., a pharmaceutical composition described herein) can be performed for characterization and quality control to ensure release of the drug at a specified rate range in a well-defined dissolution aqueous medium, where the drug at least sinks, or in a biologically relevant medium (such as simulated gastric or intestinal fluid) corresponding to either fasted or fed conditions. In certain cases, although not always applicable, dissolution testing can predict or provide insight into the in vivo bioavailability of a drug substance. Dissolution testing can be performed using USP test protocols and dissolution apparatus.

[0082] As used herein, "granulation" refers to the process of forming granules from powdered or particulate materials. As used herein, "dry granulation" refers to the process of forming granules in the absence of a liquid solution, which may be useful for preparing granules of materials that are sensitive to heat, moisture, or solvents. For example, roller compaction is a dry granulation process. As used herein, "wet granulation" refers to the formation of granules using a binder or liquid solution to bind the particles together. Examples of wet granulation are high shear granulation and fluidized bed granulation.

[0083] As used herein, a "pharmaceutical composition" or "pharmaceutical formulation" refers to a combination of a therapeutically active agent and inert or active pharmaceutically acceptable excipients that make the composition particularly suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0084] "Pharmaceutically acceptable" refers to a compound, molecular entity, composition, material, and / or dosage form that does not produce an adverse, allergic, or other untoward reaction when administered to animals or humans, as appropriate, or that has been approved or is approvable by a federal or state regulatory agency or its counterpart in a country other than the United States, or that the compound, molecular entity, composition, material, and / or dosage form is listed in the United States Pharmacopeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0085] As used herein, "pharmaceutically acceptable salt" refers to any salt of acidic or basic groups that may be present in the compounds of the present disclosure (e.g., compounds of Formula (I)), which salts are compatible with pharmaceutical administration.

[0086] As 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-2-sulfonic acid, and benzenesulfonic acid. Other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, can be used in the preparation of salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts.

[0087] Examples of bases include, but are not limited to, alkali metal (e.g., sodium and potassium) hydroxides, alkaline earth metal (e.g., magnesium and calcium) hydroxides, ammonia, and NW 4+ A compound of the formula (wherein W is C 1~4 alkyl), and the like.

[0088] Examples of salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include combinations of anions of the compounds of the present disclosure with suitable cations (Na + , K + , Ca 2+ , NH 4+ , and NW 4+ (where W can be a C 1~4 alkyl group) etc.) and the like.

[0089] For therapeutic use, salts of the compounds of the present disclosure are contemplated to be pharmaceutically acceptable. On the other hand, salts of pharmaceutically unacceptable acids and bases may also be useful, for example, in the preparation or purification of pharmaceutically acceptable compounds.

[0090] As used herein, "pharmaceutically acceptable excipients" refers to substances that aid in the administration and / or absorption of an active agent by a subject and that can be included in the compositions of the present disclosure without causing significant adverse toxicological effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include binders, diluents, carriers, adjuvants, fillers (e.g., friable diluents or fillers and ductile diluents or fillers), disintegrants, lubricants, coatings, sweeteners, flavorings, gelatin, carbohydrates (such as lactose, amylose, or starch), fatty acid esters, hydroxypropylmethylcellulose, polyvinylpyrrolidine, and coloring agents, and the like. For examples of excipients, see Gennaro, Remington's Pharmaceutical Sciences, 18 th Ed., Mack Publ. Co., Easton, PA (1990) or Shesky, Hancock, Moss and Goldfarb, Handbook of Pharmaceutical Excipients, 9 th See Ed. Pharmaceutical Press, London, UK (2020).

[0091] Examples of diluents or bulking agents 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., dibasic calcium phosphate, hydroxyapatite, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium sulfate, magnesium carbonate, magnesium oxide, bentonite, kaolin), calcium lactate, starch (e.g., pregelatinized starch), crystalline cellulose, silicified crystalline cellulose, polysaccharides, celluloses (e.g., hydroxypropyl cellulose, hypromellose, carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose), dextrin, maltodextrin, alginate, collagen, polyvinylpyrrolidone, polyvinyl acrylate, polyethylene oxide, and polyethylene glycol. As used herein, sugar is defined to include sugar alcohols.

[0092] Examples of disintegrants include, but are not limited to, alginic acid, alginates, primogel, celluloses (e.g., hydroxypropyl cellulose), polacrilin potassium, sodium starch glycolate, sodium croscarmellose, polyplasdones (e.g., crospovidone), and starches (e.g., corn starch, pregelatinized starch, hydroxypropyl starch, and carboxymethyl starch).

[0093] Examples of binders include, but are not limited to, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose (e.g., low viscosity hydroxypropyl methylcellulose), sugar, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, polydextrose, chitosan, carrageenan, carbophil, crystalline cellulose, tragacanth gum, guar gum, gellan gum, gelatin, and starch (e.g., corn starch).

[0094] Examples of wetting agents include, but are not limited to, poloxamers (e.g., poloxamer 407), sodium dodecyl sulfate, sodium lauryl sulfate (SLS), sodium stearyl fumarate (SSF), polydimethylsiloxane, polysorbates (e.g., polyoxyethylene 20 sorbitan mono-oleate (Tween® 20)), sorbitan monooleate, sorbitan trioleate, sorbitan laurate, sorbitan stearate, sorbitan monopalmitate, lecithin, sodium taurocholate, ursodeoxycholate, polyethoxylated castor oil, cetyltrimethylammonium bromide, nonoxynol, α-tocopherol polyethylene glycol 1000 succinate, and sodium docusate.

[0095] Examples of lubricants and glidants include, but are not limited to, waxes, glycerides, light mineral oil, 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.

[0096] Examples of glidants include, but are not limited to, colloidal silicon dioxide, talc, kaolin, bentonite, and activated carbon / charcoal.

[0097] Examples of colorants include, but are not limited to, titanium dioxide, aluminum lake, iron oxide, and carbon black.

[0098] Examples of coatings include, but are not limited to, film-forming polymers (e.g., hypromellose, methylcellulose, ethylcellulose, cellulose acetate, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, Eudragit / acrylate), and plasticizers (e.g., triacetin, polyethylene glycol, propylene glycol).

[0099] Pharmaceutical compositions for oral administration (e.g., pharmaceutical compositions of compounds of Formula (I) described herein) may take the form of bulk liquid solutions or suspensions or bulk powders. More commonly, however, the compositions are provided in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unit dosages for human subjects and other mammals, each containing a predetermined amount of active substance calculated to produce the desired therapeutic effect, together with suitable pharmaceutical excipients. Typical unit dosage forms include pills, tablets, capsules, or the like, for solid compositions.

[0100] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., males or females 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, such as mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

[0101] As used herein, "solid dosage form" means a pharmaceutical dose(s) in solid form (e.g., tablet, capsule, granule, powder, minitab, sachet, stick pack, reconstitutable powder, dry powder inhaler, lozenge, and chewable).

[0102] As used herein, "administering" refers to oral, pulmonary, suppository, intramuscular, intrathecal, intranasal, or subcutaneous administration, or implantation of a sustained-release device (e.g., mini-osmotic pump) to a subject. Administration is by any route, including transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or intramuscular). Parenteral administration includes, for example, intramuscular and subcutaneous administration. Other modes of delivery include, but are not limited to, the use of liposomal formulations. "Co-administering" refers to administering a composition described herein at the same time as, immediately before, or immediately after the administration of one or more additional therapies (e.g., anti-cancer agents, chemotherapeutic agents, or treatments for neurodegenerative diseases). Compounds of Formula (I) can be administered alone or co-administered to a patient. Co-administration is intended to include simultaneous or sequential administration of compounds, individually or in combination (multiple compounds or agents). Thus, the preparations may also be combined with other active substances if desired (eg, to reduce metabolic degradation).

[0103] The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0104] As used herein, and unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate an effect that occurs while a subject is afflicted with a specified disease, disorder, or condition and that reduces the severity of the disease, disorder, or condition, or delays or slows the progression of the disease, disorder, or condition ("therapeutic treatment"), as well as an effect that occurs before a subject begins to suffer from a specified disease, disorder, or condition ("prophylactic treatment"). In one embodiment, the compounds provided herein are contemplated for use in methods of therapeutic treatment, in which an effect occurs while a subject is afflicted with a particular disease, disorder, or condition and that reduces the severity of the disease, disorder, or condition, or slows or slows the progression of the disease, disorder, or condition. In an alternative embodiment, the compounds provided herein are contemplated for use in methods of prophylactic treatment, in which an effect occurs before a subject begins to suffer from a particular disease, disorder, or condition, and prevents the disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition, or prevents the recurrence of the disease, disorder, or condition.

[0105] In general, an "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response (e.g., to treat a disease or disorder described herein). As one of ordinary skill in the art would understand, the effective amount of a compound of the present disclosure may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the treatment modality, and the age, health, and condition of the subject. An effective amount encompasses therapeutic and prophylactic treatment (i.e., encompasses a "therapeutically effective amount" and a "prophylactically effective amount").

[0106] As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic effect in the therapeutic treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent alone or in combination with other treatments that provides a therapeutic effect in the therapeutic treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids the symptoms or pathogenesis of a disease or condition, or enhances the therapeutic effectiveness of another therapeutic agent.

[0107] As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound is 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. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of a disease, disorder, or condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic effectiveness of another prophylactic agent.

[0108] Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are listed in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed., endpapers, and specific functional groups are generally defined as described therein. Further, in addition to general principles of organic chemistry, specific functional moieties and reactivities are defined in accordance with the principles of organic chemistry, as set forth in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999, Smith and March, March's Advanced Organic Chemistry, 5 thEdition, John Wiley&Sons, Inc., New York, 2001, Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989, and Carruthers, Some Modern Methods of Organic Synthesis, 3. rd Edition, Cambridge University Press, Cambridge, 1987.

[0109] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Wilen et al., Tetrahedron 33:2725 (1977), Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). Further included are compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0110] "Enantiomeric excess" ("ee") or "% enantiomeric excess" ("%ee") of a composition, as used herein, refers to the excess of one enantiomer relative to the other enantiomer present in the composition. For example, a composition may contain 90% of one enantiomer, e.g., the S enantiomer, and 10% of the other enantiomer, i.e., the R enantiomer. ee=(90-10) / 100=80%.

[0111] Thus, a composition containing 90% of one enantiomer and 10% of the other is said to have an enantiomeric excess of 80%.

[0112] "Diastereomeric excess" ("de") or "% diastereomeric excess" ("% de") of a composition, as used herein, refers to the excess of one diastereomer over one or more different diastereomers present in the composition. For example, a composition may contain 90% of one diastereomer and 10% of one or more different diastereomers. de=(90-10) / 100=80%.

[0113] Thus, a composition containing 90% of one diastereomer and 10% of one or more different diastereomers is said to have a diastereomeric excess of 80%.

[0114] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1~6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 , and C 5~6It is intended to encompass alkyl. As described herein, it should also be understood that any of the moieties defined below may be substituted with various substituents, and that each definition is intended to include such substituted moieties within its scope as set forth below. Unless otherwise stated, the term "substituted" is defined as set forth below. It should further be understood that the terms "group" and "radical" can be considered interchangeable when used herein. The articles "a" and "an" may be used herein to refer to one or to more than one (i.e., at least one) of the grammatical object of the article. By way of example, "an analogue" means one analogue or more than one analogue.

[0115] The term "unsaturated bond" refers to a double or triple bond.

[0116] The terms "unsaturated" or "partially unsaturated" refer to a moiety that contains at least one double or triple bond.

[0117] The term "saturated" refers to a moiety that does not contain double or triple bonds, i.e., contains only single bonds.

[0118] The affixation with the suffix "-ene" indicates that the group is a divalent moiety, for example, alkylene is a divalent moiety of alkyl, alkenylene is a divalent moiety of alkenyl, alkynylene is a divalent moiety of alkynyl, heteroalkylene is a divalent moiety of heteroalkyl, heteroalkenylene is a divalent moiety of heteroalkenyl, heteroalkynylene is a divalent moiety of heteroalkynyl, carbocyclylene is a divalent moiety of carbocyclyl, heterocyclylene is a divalent moiety of heterocyclyl, arylene is a divalent moiety of aryl, and heteroarylene is a divalent moiety of heteroaryl.

[0119] "Aliphatic" refers to an alkyl, alkenyl, alkynyl, or carbocyclyl group, as defined herein.

[0120] "Cycloalkylalkyl" refers to an alkyl radical in which the alkyl group is substituted with a cycloalkyl group. Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl.

[0121] "Heterocyclylalkyl" refers to an alkyl radical in which the alkyl group is substituted with a heterocyclyl group. Typical heterocyclylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like.

[0122] "Aralkyl" or "arylalkyl" is a subset of alkyl and aryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group.

[0123] "Alkyl" refers to the radical of a straight or branched chain saturated hydrocarbon group having from 1 to 20 carbon atoms ("C 1~20 In some embodiments, the alkyl group has 1 to 12 carbon atoms ("C 1~12 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1~10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1~9 In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1~8 In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1~7In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1~6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1~5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1~4 In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1~3 In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2~6 alkyl). C 1~6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each alkyl group is independently optionally substituted, i.e., unsubstituted (unsubstituted alkyl) or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1~10 In certain embodiments, the alkyl group is a substituted C 1~10 It is an alkyl. Common abbreviations for alkyl are Me(-CH3), Et(-CH2CH3), i Pr(-CH(CH3)2), n Pr(-CH2CH2CH3), n Bu(-CH2CH2CH2CH3), or iBu(-CH2CH(CH3)2).

[0124] "Alkylene" refers to an alkyl group in which two hydrogens are removed to provide a divalent radical, which may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), butylene (-CHCHCHCHCH-), pentylene (-CHCHCHCHCHCH-), hexylene (-CHCHCHCHCHCHCH-), and the like. Exemplary substituted alkylene groups, e.g., those substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH)-, (-C(CH)-), substituted ethylene (-CH(CH)CH-, -CHCH(CH)-, -C(CH)CH-, -CHC(CH)-), substituted propylene (-CH(CH)CHCH-, -CHCH(CH)CH-, -CHCHCH(CH)CH-, -CHCHCH(CH)-, -C(CH)CHCH-, -CHC(CH)CH-, -CHCHC(CH)-), and the like. When a range or number of carbons is provided for a particular alkylene group, it is understood that the range or number refers to the range or number of carbons in a linear divalent carbon chain. An alkylene group can be unsubstituted or substituted with one or more substituents described herein.

[0125] "Alkenyl" refers to the radical of a straight- or branched-chain hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C 2~20 In certain embodiments, the alkenyl does not contain any triple bonds. In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C 2~10 In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2~9In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each alkenyl group is independently optionally substituted, i.e., unsubstituted (unsubstituted alkenyl) or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2~10 In certain embodiments, the alkenyl group is a substituted C 2~10 It is alkenyl.

[0126] "Alkynyl" refers to the radical of a straight- or branched-chain hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ("C 2~20 In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, alkynyl groups have 2 to 10 carbon atoms ("C 2~10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). C 2~4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each alkynyl group is independently optionally substituted, i.e., unsubstituted (unsubstituted alkynyl) or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2~10 In certain embodiments, the alkynyl group is a substituted C 2~10 It is alkynyl.

[0127] The term "heteroalkyl," as used herein, refers to an alkyl group, as defined herein, that further includes one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) in the parent chain, where one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~10 In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~9 In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~8 In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~7 In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("heteroC 1~6In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("heteroC 1~5 In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms ("heteroC 1~4 In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("heteroC 1~3 In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom ("heteroC 1~2 In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC1 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms ("heteroC 2~6 Unless otherwise specified, each heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted ("substituted heteroalkyl") with one or more substituents. In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1~10 In certain embodiments, the heteroalkyl group is a substituted heteroC 1~10 Exemplary heteroalkyl groups include -CHOH, -CHOCH, -CHNH, -CHNH(CH), -CHN(CH), -CHCHOH, -CHCHOCH, -CHCHNH, -CHCHNH(CH), -CHCHN(CH).

[0128] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C 6~14In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl", e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14 "Aryl" (e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, and the radical or point of attachment is on the aryl ring, in which case the number of carbon atoms continues to designate the number of carbon atoms in the aryl ring system. In particular, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6~14 In certain embodiments, the aryl group is a substituted C 6~14 It is aryl.

[0129] In certain embodiments, the aryl group is substituted with one or more groups selected from halo, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxy, C1-C8 alkoxy, and amino.

[0130] Representative examples of substituted aryl include the following: [ka] are listed, In the formula, R 56 and R 57 may be hydrogen, and one of R 56 and R 57At least one of the following is C1-C8 alkyl, C1-C8 haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , N.R. 58 SOR 59 , N.R. 58 SO2R 59 , COO alkyl, COO aryl, CONR 58 R 59 ,CONR 58 OR 59 , N.R. 58 R 59 , SO2NR 58 R 59 , S-alkyl, So alkyl, SO alkyl, S aryl, So aryl, SO aryl, or R 56 and R 57 may combine to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group consisting of N, O, or S. R 60 and R 61 are independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, substituted C6-C 10 It is aryl, 5- to 10-membered heteroaryl, or substituted 5- to 10-membered heteroaryl.

[0131] "Fused aryl" refers to an aryl having two of its ring carbons in common with a second aryl or heteroaryl ring, or a carbocyclyl or heterocyclyl ring.

[0132] "Heteroaryl" refers to the radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement), having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon or nitrogen atom, depending on valence. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring; in such cases, unless otherwise specified, the number of ring members continues to designate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, and the point of attachment is on either the aryl or heteroaryl ring, where the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the ring with a heteroatom (e.g., 2-indolyl) or on the ring without a heteroatom (e.g., 5-indolyl).

[0133] In some embodiments, a heteroaryl group is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, a 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each heteroaryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5- to 14-membered heteroaryl. In some embodiments, the heteroaryl group is a bicyclic 8- to 12-membered aromatic ring system having ring carbon atoms and 1 to 6 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("8- to 12-membered bicyclic heteroaryl"). In some embodiments, the heteroaryl group is an 8- to 10-membered bicyclic aromatic ring system having ring carbon atoms and 1-6 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur (an "8- to 10-membered bicyclic heteroaryl").In some embodiments, a heteroaryl group is a 9- to 10-membered bicyclic aromatic ring system having ring carbon atoms and 1 to 6 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("9- to 10-membered bicyclic heteroaryl"). Unless otherwise specified, each heteroaryl group is independently unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0134] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0135] Representative examples of heteroaryls include: [ka] are listed, wherein each Z is a carbonyl, N, NR 65 , O, and S; R 65 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl.

[0136] In the structures described herein, it is understood that a substituent attached to a polycyclic (e.g., bicyclic or tricyclic) cycloalkyl, heterocyclyl, aryl, or heteroaryl having bonds across more than one ring means that the substituent can be attached at any position on each of the rings.

[0137] A "heteroaralkyl" or "heteroarylalkyl" is a subset of "alkyl" and refers to an alkyl group substituted with a heteroaryl group, where the point of attachment is on the alkyl portion.

[0138] The term "carbocyclyl" or "carbocyclic" refers to a ring system having 3 to 14 ring carbon atoms ("C 3~14 "Carbocyclyl" refers to the radical of a non-aromatic monocyclic, bicyclic, or tricyclic or polycyclic hydrocarbon ring system having 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3~7 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms ("C 4~6In some embodiments, the carbocyclyl group has 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 carbocyclyl). Exemplary C 3~6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. 3~8 The carbocyclyl group includes the above-mentioned C 3~6 In addition to carbocyclyl groups, examples include, but are not limited to, cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. 3~10 The carbocyclyl group includes the above-mentioned C 3~8 In addition to the carbocyclyl group, cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ) and the like, but are not limited to these.

[0139] As the foregoing examples illustrate, in certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., containing fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic carbocyclyl") or tricyclic systems ("tricyclic carbocyclyl")), and can be saturated or contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, and the point of attachment is on the carbocyclyl ring, in which case the number of carbons continues to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each carbocyclyl group is independently unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, the carbocyclyl group is an unsubstituted C 3~14 In certain embodiments, the carbocyclyl group is a substituted C 3~14 It is a carbocyclyl.

[0140] The term "cycloalkyl," as used herein, refers to a saturated cyclic, bicyclic, tricyclic, or polycyclic hydrocarbon group having 3 to 14 carbons (e.g., C3-C6) containing the indicated number of rings and carbon atoms. 14 Monocyclic, C4~C 14 Bicyclic, C5~C 14 Tricyclic, or C6-C 14 In some embodiments, a "cycloalkyl" is a monocyclic cycloalkyl. In some embodiments, a monocyclic cycloalkyl has 3 to 14 ring carbon atoms. ("C 3~14 In some embodiments, a monocyclic cycloalkyl group has 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a monocyclic cycloalkyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a monocyclic cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6In some embodiments, a monocyclic cycloalkyl group has 4 to 6 ring carbon atoms ("C 4~6 In some embodiments, a monocyclic cycloalkyl group has 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a monocyclic cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10 Monocyclic cycloalkyl). Monocyclic C 5~6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3~6 Examples of cycloalkyl groups include the above-mentioned C 5~6 In addition to cycloalkyl groups, cyclopropyl (C3) and cyclobutyl (C4) are mentioned. 3~8 Examples of cycloalkyl groups include the above-mentioned C 3~6 Cycloalkyl groups include cycloheptyl (C7) and cyclooctyl (C8).

[0141] In some embodiments, a "cycloalkyl" is a bicyclic cycloalkyl. In some embodiments, a bicyclic cycloalkyl has 4 to 14 ring carbon atoms. ("C 4~14 In some embodiments, the bicyclic cycloalkyl group has 4 to 12 ring carbon atoms ("C 4~12 In some embodiments, a bicyclic cycloalkyl group has 4 to 10 ring carbon atoms ("C 4~10 In some embodiments, a bicyclic cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10 In some embodiments, a bicyclic cycloalkyl group has 6 to 10 ring carbon atoms ("C 6~10 In some embodiments, the bicyclic cycloalkyl group has 8 to 10 ring carbon atoms ("C 8~10 In some embodiments, the bicyclic cycloalkyl group has 7 to 9 ring carbon atoms ("C 7~9Bicyclic cycloalkyls). Examples of bicyclic cycloalkyls include bicyclo[1.1.0]butane (C4), bicyclo[1.1.1]pentane (C5), spiro[2.2]pentane (C5), bicyclo[2.1.0]pentane (C5), bicyclo[2.1.1]hexane (C6), bicyclo[3.1.0]hexane (C6), spiro[2.3]hexane (C6), bicyclo[2.2.1]heptane (norbornane) (C7), bicyclo[3.2.0]heptane (C7), bicyclo[3.1.1]heptane (C7), bicyclo[3.1.1]heptane (C7), bicyclo[4.1.0]heptane (C7), spiro[2 .4]heptane (C7), spiro[3.3]heptane (C7), bicyclo[2.2.2]octane (C8), bicyclo[4.1.1]octane (C8), octahydropentalene (C8), bicyclo[3.2.1]octane (C8), bicyclo[4.2.0]octane (C8), spiro[2.5]octane (C8), spiro[3.4]octane (C8), bicyclo[3.3.1]nonane (C9), octahydro-1H-indene (C9), bicyclo[4.2.1]nonane (C9), spiro[3.5]nonane (C9), spiro[4.4]nonane (C9), bicyclo[3.3.2]decane (C 10 ), bicyclo[4.3.1]decane (C 10 ), spiro[4.5]decane (C 10 ), bicyclo[3.3.3]undecane (C 11 ), decahydronaphthalene (C 10 ), bicyclo[4.3.2]undecane (C 11 ), spiro[5.5]undecane (C 11 ) and bicyclo[4.3.3]dodecane (C 12 In some embodiments, the "cycloalkyl" is a tricyclic cycloalkyl. In some embodiments, the tricyclic cycloalkyl has 6 to 14 ring carbon atoms. ("C 6~14 In some embodiments, a tricyclic cycloalkyl group has 8 to 12 ring carbon atoms ("C 8~12 In some embodiments, a tricyclic cycloalkyl group has 10 to 12 ring carbon atoms ("C10~12 Tricyclic cycloalkyls are examples of tricyclic cycloalkyls, such as adamantine (C 12 ) are listed.

[0142] Unless otherwise specified, each cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents. In certain embodiments, a cycloalkyl group is an unsubstituted C 3~14 In certain embodiments, the cycloalkyl group is a substituted C 3~14 It is cycloalkyl.

[0143] "Heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms ("3- to 10-membered heterocyclyl"), each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, depending on valence. Heterocyclyl groups may be either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, with the point of attachment being on either the carbocyclyl or heterocyclyl ring, or in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the heterocyclyl ring, where the number of ring members continues to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, a heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, a heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0144] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms ("5- to 10-membered heterocyclyl"), where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms ("5- to 8-membered heterocyclyl"), where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms ("5- to 6-membered heterocyclyl"), where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur, hi some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0145] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclic rings) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7 tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. A "nitrogen-containing heterocyclyl" group refers to a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom, such as, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines such as N-methylpiperazine. Specific examples include azetidine, piperidone, and piperazone.

[0146] "Hetero," when used to describe a compound or a group present on a compound, means that one or more carbon atoms in the compound or group have been replaced with a nitrogen, oxygen, or sulfur heteroatom. Hetero may apply to any of the hydrocarbyl groups described above, such as alkyl, e.g., heteroalkyl; cycloalkyl, e.g., heterocyclyl; aryl, e.g., heteroaryl; cycloalkenyl, e.g., cycloheteroalkenyl, etc., having 1 to 5, especially 1 to 3, heteroatoms.

[0147] "Acyl" is the radical -C(=O)R 20 In the formula, R 20 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl as defined herein. "Alkanoyl" refers to a group in which R 20 is an acyl group where the aryl group is a group other than hydrogen. Representative acyl groups include formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), --C(=O)-C1-C8 alkyl, and --C(=O)-(CH2). t (C6~C 10 aryl), -C(=O)-(CH2) t (5-10 membered heteroaryl), -C(=O)-(CH2) t (C3~C 10 cycloalkyl), and -C(=O)-(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4. In certain embodiments, R 21 is C1-C8 alkyl substituted with halo or hydroxy, or C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10Aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0148] The term aminoalkyl refers to a substituted alkyl group in which one or more of the hydrogen atoms is independently replaced with an -NH2 group.

[0149] The term hydroxyalkyl refers to a substituted alkyl group in which one or more of the hydrogen atoms is independently replaced with an -OH group.

[0150] The terms "alkylamino" and "dialkylamino" refer to the -NH(alkyl) and -N(alkyl) radicals, respectively. In some embodiments, alkylamino is -NH(C1-C4 alkyl). In some embodiments, alkylamino is methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, or tert-butylamino. In some embodiments, dialkylamino is -N(C1-C6 alkyl). In some embodiments, dialkylamino is dimethylamino, methylethylamino, diethylamino, methylpropylamino, methylisopropylamino, methylbutylamino, methylisobutylamino, or methyltertbutylamino.

[0151] The term "aryloxy" refers to an -O-aryl radical. In some embodiments, the aryloxy group is phenoxy.

[0152] The term "haloalkoxy" refers to an alkoxy structure substituted with one or more halo groups or combinations thereof. For example, the term "fluoroalkoxy" includes haloalkoxy groups where halo is fluorine. In some embodiments, haloalkoxy groups are difluoromethoxy and trifluoromethoxy.

[0153] "Alkoxy" refers to the group -OR 29 In the formula, R 29 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e., those having 1 to 6 carbon atoms. Still more particular alkoxy groups have 1 to 4 carbon atoms.

[0154] In certain embodiments, R 29 is amino, substituted amino, C6-C 10 Aryl, aryloxy, carboxyl, cyano, C3-C 10 It is a group having one or more substituents selected from the group consisting of cycloalkyl, 4- to 10-membered heterocyclyl, halogen, 5- to 10-membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2-, and aryl-S(O)2-, for example, 1 to 5 substituents, particularly 1 to 3 substituents, and particularly 1 substituent. Exemplary "substituted alkoxy" groups include -O-(CH2) t (C6~C 10 aryl), -O-(CH2) t (5-10 membered heteroaryl), -O-(CH2) t (C3~C 10 cycloalkyl), and -O-(CH2) t(4-10 membered heterocyclyl), where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may itself be substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Particular exemplary "substituted alkoxy" groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2N(CH3)2.

[0155] "Amino" refers to the radical -NH2.

[0156] An "oxo group" refers to -C(=O)-.

[0157] "Substituted amino" refers to a group of the formula -N(R 38 )2, where R 38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group; R 38 At least one of R is not hydrogen. 38 is hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, or C3-C 10 Cycloalkyl, or C1-C8 alkyl substituted with halo or hydroxy, C3-C8 alkenyl substituted with halo or hydroxy, C3-C8 alkynyl substituted with halo or hydroxy, or -(CH2) t (C6~C 10 aryl), -(CH2) t (5-10 membered heteroaryl), -(CH2) t (C3~C 10cycloalkyl), or -(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 8, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy, or both R 38 The groups are linked to form an alkylene group.

[0158] Exemplary "substituted amino" groups include -NR 39 -C1-C8 alkyl, -NR 39 -(CH2) t (C6~C 10 aryl), -NR 39 -(CH2) t (5-10 membered heteroaryl), -NR 39 -(CH2) t (C3~C 10 cycloalkyl), and -NR 39 -(CH2) t (4-10 membered heterocyclyl), where t is an integer of 0 to 4, for example, 1 or 2, and each R 39 independently represent H or C1-C8 alkyl, and any alkyl groups present may themselves be substituted with halo, substituted or unsubstituted amino, or hydroxy, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl groups present may themselves be substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. For the avoidance of doubt, the term "substituted amino" includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino, as defined below. Substituted amino includes both mono- and di-substituted amino groups.

[0159] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an "amino protecting group"). Nitrogen protecting groups include -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -C 1~10 Alkyl (e.g., aralkyl, heteroaralkyl), -C 2~10 Alkenyl, -C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 and 5- to 14-membered heteroaryl groups, each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl may have 0, 1, 2, 3, 4, or 5 R dd groups, and R aa , R bb , R cc and R dd is as defined herein. Nitrogen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3 rdedition, John Wiley & Sons, 1999, which is incorporated herein by reference. Each R aa But -C 1~10 Alkyl, -C 1~10 Perhaloalkyl, -C 2~10 Alkenyl, -C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R aa groups join to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may be joined by 0, 1, 2, 3, 4, or 5 R dd independently substituted with groups, Each R bb But hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)(N(R cc )2)2, -C 1~10 Alkyl, -C 1~10Perhaloalkyl, -C 2~10 Alkenyl, -C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R bb groups join to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may be joined by 0, 1, 2, 3, 4, or 5 R dd are independently substituted with groups, and X - is the counter ion. Each R cc But hydrogen, -C 1~10 Alkyl, -C 1~10 Perhaloalkyl, -C 2~10 Alkenyl, -C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R cc groups join to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may be joined by 0, 1, 2, 3, 4, or 5 R dd independently substituted with groups, Each R dd But halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 +X - 、-N(OR ee )R ff 、-SH、-SR ee 、-SSR ee 、-C(=O)R ee 、-CO2H、-CO2R ee 、-OC(=O)R ee 、-OCO2R ee 、-C(=O)N(R ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee 、-NR ff CO2R ee 、-NR ff C(=O)N(R ff )2、-C(=NR ff )OR ee 、-OC(=NR ff )R ee 、-OC(=NR ff )OR ee 、-C(=NR ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee 、-SO2N(R ff )2、-SO2R ee 、-SO2OR ee 、-OSO2R ee 、-S(=O)R ee 、-Si(R ee )3、-Osi(R ee )3、-C(=S)N(R ff )2、-C(=O)SR ee 、-C(=S)SR ee 、-SC(=S)SR ee 、-P(=O)(OR ee )2、-P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee )2、-C 1~6 アルキル、-C 1~6 ペルハロアルキル、-C2~6 Alkenyl, -C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is selected from 0, 1, 2, 3, 4, or 5 R gg groups or two geminal R dd The substituents may combine to form =O or =S, and X - is the counterion, Each R ee But -C 1~6 Alkyl, -C 1~6 Perhaloalkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is selected from 0, 1, 2, 3, 4, or 5 R gg independently substituted with groups, Each R ff But hydrogen, -C 1~6 Alkyl, -C 1~6 Perhaloalkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10aryl and 5- to 10-membered heteroaryl, or two R ff groups join to form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may be joined by 0, 1, 2, 3, 4, or 5 R gg independently substituted with groups, Each R gg are independently halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 Alkyl)3 + X - , -NH(C 1~6 alkyl)2 + X - , -NH2(C 1~6 alkyl) + X - , -NH3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C 1~6alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C 1~6 alkyl), -OC(=NH)OC 1~6 Alkyl, -C(=NH)N(C 1~6 alkyl)2, -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl)2, -OC(NH)NH(C 1~6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1~6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, -SO2C 1~6 Alkyl, -SO2OC 1~6 Alkyl, -OSO2C 1~6 Alkyl, -SOC 1~6 Alkyl, -Si(C 1~6 alkyl)3, -Osi(C 1~6 alkyl)3-C(=S)N(C 1~6 alkyl)2, -C(=S)NH(C 1~6 alkyl), -C(=S)NH2, -C(=O)S(C 1~6 alkyl), -C(=S)SC 1~6 Alkyl, -SC(=S)SC 1~6 Alkyl, -P(=O)(OC 1~6 alkyl)2, -P(=O)(C 1~6 alkyl)2, -OP(=O)(C 1~6 alkyl)2, -OP(=O)(OC 1~6 alkyl)2, -C 1~6 Alkyl, -C 1~6 Perhaloalkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or two geminal R gg The substituents may combine to form =O or =S, and X - is the counter ion.

[0160] For example, an amide group (e.g., —C(═O)R aa Nitrogen protecting groups such as acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0161] Carbamate groups (e.g., -C(=O)OR aaNitrogen protecting groups such as methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilyl ethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, Bamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclo methylcarbamate, cyclopropylmethylcarbamate, p-decyloxybenzylcarbamate, 2,2-dimethoxyacylvinylcarbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isobornylcarbamate, isobutylcarbamate, isonicotinylcarbamate Bamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,Examples include, but are not limited to, 6-tri-t-butylphenylcarbamate, 4-(trimethylammonium)benzylcarbamate, and 2,4,6-trimethylbenzylcarbamate.

[0162] Sulfonamide groups (e.g., -S(=O)R aaNitrogen protecting groups such as p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), These include, but are not limited to, 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide. Other nitrogen protecting groups include phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adducts (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-ones, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-ones, 1-substituted 3,5-Dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr) ), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, Np-nitrobenzylideneamine, N-sa Licylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentaacylchromium or tungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosamines, amine N-oxides, diphenylphosphinamide (Dpp), dimethylthiophos Examples of suitable sulfonamides include, but are not limited to, phosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidate, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys).

[0163] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). Oxygen protecting groups include -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc )2, and -P(=O)(N(R bb )2)2, but are not limited to, R aa , R bb , and R cc is as defined herein. Oxygen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3 rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0164] Exemplary oxygen protecting groups include methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, and 2-methoxyethoxymethyl (MEM). , 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4- Methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl , 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4''-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4''-tris(levulinoyloxyphenyl)methyl, 4,4',4''-tris(benzoyloxyphenyl)methyl ) methyl, 3-(imidazol)-1-yl)bis(4',4''-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethyl Isopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate acetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyl dithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-Methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyldithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, Examples of the alkyl esters include, but are not limited to, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, 2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0165] The term "leaving group" is given its ordinary meaning in the art of synthetic organic chemistry and refers to an atom or group that can be displaced by a nucleophile. Examples of suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformate. In certain embodiments, the leaving group is halogen, alkanesulfonyloxy, arenesulfonyloxy, diazonium, alkyldiazene, aryldiazene, alkyltriazene, aryltriazene, nitro, alkylnitrate, arylnitrate, alkylphosphate, arylphosphate, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxyammonia, alkylamine, arylamine, hydroxyl group, alkyloxy group, or aryloxy. In some cases, the leaving group is a sulfonate ester, such as toluenesulfonate (tosylate, -OTs), methanesulfonate (mesylate, -OMs), p-bromobenzenesulfonyloxy (brosylate, -OBs), -OS(=O)2(CF2)3CF3 (nonaflate, -ONf), or trifluoromethanesulfonate (triflate, -OTf). In some cases, the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. In some cases, the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. In some embodiments, the leaving group is a sulfonate-containing group. In some embodiments, the leaving group is a tosylate group. The leaving group may also be a phosphine oxide (e.g., formed during the Mitsunobu reaction) or an internal leaving group, such as an epoxide or a cyclic sulfate. Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.

[0166] "Carboxy" refers to the radical -C(=O)OH.

[0167] "Cyano" refers to the radical -CN.

[0168] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, a halo group is either fluoro or chloro.

[0169] "Haloalkyl" refers to an alkyl radical in which the alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl (-CF), difluoromethyl (-CHF), fluoromethyl (-CHF), chloromethyl (-CHCl), dichloromethyl (-CHCl), tribromomethyl (-CHBr), and the like.

[0170] "Hydroxy" refers to the radical --OH.

[0171] "Nitro" refers to the radical -NO2.

[0172] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups defined herein are optionally substituted (e.g., a "substituted" or "unsubstituted" alkyl group, a "substituted" or "unsubstituted" alkenyl group, a "substituted" or "unsubstituted" alkynyl group, a "substituted" or "unsubstituted" carbocyclyl group, a "substituted" or "unsubstituted" heterocyclyl group, a "substituted" or "unsubstituted" aryl group, or a "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen present on the group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent that, upon substitution, gives rise to a stable compound, e.g., a compound that does not undergo spontaneous change, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents are either the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, i.e., any of the substituents described herein, that result in the formation of a stable compound. Any and all such combinations are contemplated in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents, as described herein, that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

[0173] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa、-CO2H、-CHO、-C(OR cc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-S(=O)(=NR bb )R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa, -P(=O)2R aa , -OP(=O)2R aa , -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 and 5- to 14-membered heteroaryl, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may have 0, 1, 2, 3, 4, or 5 R dd groups, or two geminal hydrogens on the carbon atom are independently substituted with groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc is replaced by Each R aa But C 1~10 Alkyl, C 1~10 Haloalkyl, C2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R aa groups join to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may be joined by 0, 1, 2, 3, 4, or 5 R dd independently substituted with groups, Each R bb But hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R bbgroups join to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may be joined by 0, 1, 2, 3, 4, or 5 R dd independently substituted with groups, Each R cc But hydrogen, C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R cc groups join to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may be joined by 0, 1, 2, 3, 4, or 5 R dd independently substituted with groups, Each R dd But halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) ORee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is selected from 0, 1, 2, 3, 4, or 5 R gg groups or two geminal R dd the substituents may combine to form =O or =S; Each R ee But C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is selected from 0, 1, 2, 3, 4, or 5 R gg independently substituted with groups, Each R ff But hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, or two R ff groups join to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may be joined by 0, 1, 2, 3, 4, or 5 R gg independently substituted with groups, Each R gg are independently halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 Alkyl)3 + X - , -NH(C 1~6 alkyl)2 + X - , -NH2(C 1~6 alkyl) + X - , -NH3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C 1~6 alkyl), -OC(=NH)OC 1~6 Alkyl, -C(=NH)N(C 1~6 alkyl)2, -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl)2, -OC(NH)NH(C 1~6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1~6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, -SO2C 1~6 Alkyl, -SO2OC 1~6 Alkyl, -OSO2C 1~6 Alkyl, -SOC 1~6 Alkyl, -Si(C 1~6 alkyl)3, -OSi(C 1~6 alkyl)3-C(=S)N(C 1~6 alkyl)2, C(=S)NH(C 1~6 alkyl), C(=S)NH2, -C(=O)S(C 1~6 alkyl), -C(=S)SC 1~6 Alkyl, -SC(=S)SC 1~6 Alkyl, -P(=O)2(C1~6 alkyl), -P(=O)(C 1~6 alkyl)2, -OP(=O)(C 1~6 alkyl)2, -OP(=O)(OC 1~6 Alkyl)2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or two geminal R gg The substituents may combine to form =O or =S, and X - is the counter ion.

[0174] A "counterion" or "anionic counterion" is a negatively charged group associated with a cationic quaternary amino group to maintain electrical neutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HSO4 - , SO4 -2 Examples of suitable cations include sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0175] Nitrogen atoms can be substituted or unsubstituted depending on valence, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)Raa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R cc groups join to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may be joined by 0, 1, 2, 3, 4, or 5 R dd groups, and R aa , R bb , R cc and R dd is as defined above.

[0176] "Boronic acid group" [ka] "Boronate ester group" refers to [ka] In the formula, R b1 and R b2 are each independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R b1 and R b2 are optionally joined together with their intervening atoms to form a substituted or unsubstituted ring.

[0177] As used herein, a "chiral auxiliary" refers to a substituent having one or more asymmetric atoms (e.g., asymmetric carbon atoms) that biases a chemical reaction to favor the selective formation of one isomer (e.g., stereoisomer) over another, and is covalently attached to a substrate. Examples of chiral auxiliary groups include, but are not limited to, chiral oxazolidones.

[0178] These and other exemplary substituents are described in further detail in the detailed description, examples, and claims. The invention is not intended to be limited in any way by the above exemplary list of substituents.

[0179] compound In some embodiments, N-(6-amino-5-methylpyridin-3-yl)-2-((2R,5S)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide, a PRMT5 inhibitor (e.g., an MTA-uncompetitive PRMT5 inhibitor) of formula (I): [ka] Provided herein are compounds of the formula:

[0180] In certain embodiments, the compound of formula (I) is a crystalline form of the compound of formula (I). The compound of formula (I) may also be referred to as "Compound I."

[0181] In certain embodiments, the crystalline form of compound (I) is crystalline form A. In certain embodiments, form A has an XRPD pattern with one or more (e.g., one, two, three, four, or five) characteristic peaks between (inclusive) the following 2θ values ​​(in degrees): 6.2 to 6.6 (e.g., 6.4±0.2), 8.7 to 9.1 (e.g., 8.9±0.2), 12.5 to 12.9 (e.g., 12.7±0.2), 13.8 to 14.2 (e.g., 14.0±0.2), 18.9 to 19.3 (e.g., 19.1±0.2), 19.7 to 20.1 (e.g., 19.9±0.2), and 22.4 to 22.8 (e.g., 22.6±0.2). In certain embodiments, Form A has an XRPD pattern with one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) characteristic peaks between (inclusive) the following 2θ values ​​(in degrees): 6.2 to 6.6 (e.g., 6.4±0.2), 8.7 to 9.1 (e.g., 8.9±0.2), 12.5 to 12.9 (e.g., 12.7±0.2), 13.6 to 14.0 (e.g., 13.8±0.2), 13.8 to 14.2 (e.g., 13.9±0.2), 14.0 to 15.0 (e.g., 14.9±0.2), 15.0 to 16.0 (e.g., 15.0±0.2), 16.0 to 17.0 (e.g., 16.1±0.2), 17.0 to 18.0 (e.g., 17.1±0.2), 18.0 to 19.0 (e.g., 18.1±0.2), 19.0 to 20.0 (e.g., 20.1±0.2), 20.0 to 21.0 (e.g., 20.1±0.2), 21.0 to 22.0 (e.g., 21.1±0.2), 22.0 to 23.0 (e.g., 22.1±0.2), 23.0 to 24.0 (e.g., 23.1±0.2), 24.0 to 25.0 (e.g., 24.1±0.2), 25.0 to 26.0 (e For example, 14.0±0.2), 18.1 to 18.5 (for example, 18.3±0.2), 18.9 to 19.3 (for example, 19.1±0.2), 19.7 to 20.1 (for example, 19.9±0.2), 22.4 to 22.8 (for example, 22.6±0.2), 24.1 to 24.5 (for example, 24.3±0.2), 26.0 to 26.4 (for example, 26.2±0.2), 26.5 to 26.9 (for example, 26.7±0.2), and 28.0 to 28.4 (for example, 28.2±0.2).

[0182] In certain embodiments, the powder X-ray diffraction pattern of Form A may include one or more (e.g., one, two, three, four, or five) characteristic peaks in 2θ selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 14.0±0.2, 19.1±0.2, 19.9±0.2, 22.6±0.2.

[0183] In certain embodiments, the X-ray powder diffraction pattern of Form A may include one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) characteristic peaks in degrees 2θ selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 13.8±0.2, 14.0±0.2, 18.3±0.2, 19.1±0.2, 19.9±0.2, 22.6±0.2, 24.3±0.2, 26.2±0.2, and 26.7±0.2, 28.2±0.2.

[0184] In certain embodiments, the powder X-ray diffraction pattern of Form A comprises at least one characteristic peak for 2θ selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 13.8±0.2, 14.0±0.2, 18.3±0.2, 19.1±0.2, 19.9±0.2, 22.6±0.2, 24.3±0.2, 26.2±0.2, and 26.7±0.2, 28.2±0.2. In certain embodiments, the powder X-ray diffraction pattern of Form A comprises at least two characteristic peaks in terms of 2θ selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 13.8±0.2, 14.0±0.2, 18.3±0.2, 19.1±0.2, 19.9±0.2, 22.6±0.2, 24.3±0.2, 26.2±0.2, and 26.7±0.2, 28.2±0.2. In certain embodiments, the powder X-ray diffraction pattern of Form A comprises at least three characteristic peaks in terms of 2θ selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 13.8±0.2, 14.0±0.2, 18.3±0.2, 19.1±0.2, 19.9±0.2, 22.6±0.2, 24.3±0.2, 26.2±0.2, and 26.7±0.2, 28.2±0.2. In certain embodiments, the powder X-ray diffraction pattern of Form A comprises at least four characteristic peaks in terms of 2θ selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 13.8±0.2, 14.0±0.2, 18.3±0.2, 19.1±0.2, 19.9±0.2, 22.6±0.2, 24.3±0.2, 26.2±0.2, and 26.7±0.2, 28.2±0.2. In certain embodiments, the powder X-ray diffraction pattern of Form A comprises at least five characteristic peaks in terms of 2θ selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 13.8±0.2, 14.0±0.2, 18.3±0.2, 19.1±0.2, 19.9±0.2, 22.6±0.2, 24.3±0.2, 26.2±0.2, and 26.7±0.2, 28.2±0.2.In certain embodiments, the powder X-ray diffraction pattern of Form A comprises at least six characteristic peaks in terms of 2θ selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 13.8±0.2, 14.0±0.2, 18.3±0.2, 19.1±0.2, 19.9±0.2, 22.6±0.2, 24.3±0.2, 26.2±0.2, and 26.7±0.2, 28.2±0.2. In certain embodiments, the powder X-ray diffraction pattern of Form A comprises at least seven characteristic peaks in terms of 2θ selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 13.8±0.2, 14.0±0.2, 18.3±0.2, 19.1±0.2, 19.9±0.2, 22.6±0.2, 24.3±0.2, 26.2±0.2, and 26.7±0.2, 28.2±0.2. In certain embodiments, the powder X-ray diffraction pattern of Form A comprises at least eight characteristic peaks in terms of 2θ selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 13.8±0.2, 14.0±0.2, 18.3±0.2, 19.1±0.2, 19.9±0.2, 22.6±0.2, 24.3±0.2, 26.2±0.2, and 26.7±0.2, 28.2±0.2. In certain embodiments, the X-ray powder diffraction pattern of Form A comprises at least 9 characteristic peaks in 2θ selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 13.8±0.2, 14.0±0.2, 18.3±0.2, 19.1±0.2, 19.9±0.2, 22.6±0.2, 24.3±0.2, 26.2±0.2, and 26.7±0.2, 28.2±0.2. In certain embodiments, the X-ray powder diffraction pattern of Form A comprises at least 10 characteristic peaks in 2θ selected from the peaks at 6.4±0.2, 8.9±0.2, 12.7±0.2, 14.0±0.2, 19.1±0.2, 19.9±0.2, and 22.6±0.2.

[0185] In certain embodiments, Form A has an XRPD pattern with characteristic peaks at the following 2θ values ​​(in degrees): 6.4±0.2, 8.9±0.2, 12.7±0.2, 14.0±0.2, 19.1±0.2, 19.9±0.2, 22.6±0.2.

[0186] In certain embodiments, Form A has an XRPD pattern with characteristic peaks at the following 2θ values ​​(in degrees): 6.4±0.2, 8.9±0.2, 12.7±0.2, 13.8±0.2, 14.0±0.2, 18.3±0.2, 19.1±0.2, 19.9±0.2, 22.6±0.2, 24.3±0.2, 26.2±0.2, 26.7±0.2, and 28.2±0.2.

[0187] In some embodiments, Form A has an XRPD pattern (obtained using Cu Ka radiation) with characteristic peaks including 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 characteristic peaks at 2θ degrees (±0.2 degrees) shown in Table 1. [Table 1-1] [Table 1-2]

[0188] In certain embodiments, Form A can be characterized by the thermogravimetric analysis (TGA) shown in Figure 2A, which shows two small mass losses below 250°C for a total water loss of about 0.5%, and decomposition at temperatures above 250°C.

[0189] In certain embodiments, Form A is substantially characterized by the differential scanning calorimetry profile (DSC) shown in Figure 2B. In some embodiments, Form A may be characterized by the differential scanning calorimetry profile (DSC) shown in Figure 2B, exhibiting a melting peak at about 168.7°C.

[0190] In certain embodiments, Form A is substantially characterized by the DVS profile shown in Figures 3A and 3B.

[0191] In certain embodiments, Form A has a unit cell as determined by crystallography with the following dimensions: a=5.0705(2) Å; b=13.9249(7) Å; c=13.9877(7) α=87.522(2)°; β=85.730(2)°, and γ=81.474(2)°. In some embodiments, Form A has a triclinic crystal system. In some embodiments, Form A has a P1 space group. In some ... 3 In some embodiments, Form A has a Z value of 2. In some embodiments, Form A has a volume of 1.397 Mg / m 3 In certain embodiments, the crystalline form of the compound of formula (I) comprises a mixture of two or more crystalline forms. In certain embodiments, the crystalline form of the compound of formula (I) is substantially pure crystalline form A.

[0192] Methods for preparing compounds In some embodiments, N-(6-amino-5-methylpyridin-3-yl)-2-((2R,5S)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound of formula (I)): [ka] or a salt thereof, the process comprising: Formula (II): [ka] by hydrogenating a compound of formula (III-a): [ka] and forming a compound of formula (I) In the formula, R 1 is a chiral auxiliary.

[0193] In some embodiments, the process involves protecting the nitrogen group of the compound of formula (III-a), thereby forming a compound of formula (III): [ka] and forming a compound of In the formula, R 2 is a nitrogen protecting group.

[0194] In some embodiments, the process comprises: Formula (III): [ka] with a compound of formula (IV): [ka] and cross-coupling with a compound of formula (V): [ka] and further comprising producing a compound of In the formula, R 2 is a nitrogen protecting group, R 3 is a boronic acid or boronic ester.

[0195] In some embodiments, the process involves removing a nitrogen protecting group from a compound of formula (V), thereby forming a compound of formula (Va): [ka] The method further comprises forming a compound of formula (I).

[0196] In some embodiments, the process comprises: Formula (Va): [ka] by reducing a compound of formula (VI): [ka] The method further comprises producing a compound of formula (I).

[0197] In some embodiments, the process comprises: Formula (VI): [ka] with a compound of formula (VII): [ka] whereby a compound of formula (Ia): [ka] and further comprising producing a compound of In the formula, R 6 , R 7 , R 8 , and R 9 are each independently H or a nitrogen protecting group.

[0198] In some embodiments, R 8 , R 9 , or R 8 and R 9 are nitrogen protecting groups, the process further comprises a deprotection step to remove the nitrogen protecting groups from the compound of formula (Ia), thereby producing a compound of formula (I) or a salt thereof.

[0199] In some embodiments, the process further comprises converting the salt of the compound of formula (I) to the free base of the compound of formula (I).

[0200] In some embodiments, the process further comprises a crystallization step to produce a crystalline form of the compound of formula (I) (eg, the free base of the compound of formula (I)).

[0201] In some embodiments, a process for producing a crystalline form of a compound of formula (I) is provided, the process comprising: [ka] The method includes crystallizing the compound of formula (I).

[0202] In some embodiments, N-(6-amino-5-methylpyridin-3-yl)-2-((2R,5S)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound of formula (I)): [ka] or a salt thereof, the process comprising: (a) Formula (II): [ka] by hydrogenating a compound of formula (III-a): [ka] and forming a compound of the formula: (b) protecting the nitrogen of the compound of formula (III-a) with a nitrogen-protecting group, thereby obtaining a compound of formula (III): [ka] and forming a compound of the formula: (c) Formula (III): [ka] with a compound of formula (IV): [ka] and cross-coupling with a compound of formula (V): [ka] and forming a compound of the formula: (d) removing the nitrogen protecting group from the compound of formula (V), thereby forming a compound of formula (Va): [ka] and forming a compound of the formula: (e) reducing the compound of formula (Va), thereby obtaining a compound of formula (VI): [ka] and forming a compound of the formula: (f) Formula (VI): [ka] with a compound of formula (VII): [ka] whereby a compound of formula (Ia): [ka] and forming a compound of the formula: (g) Optionally, R 8 , R 9 , or R 8 and R 9 are nitrogen protecting groups, deprotecting the compound of formula (Ia), thereby producing a compound of formula (I) or a salt thereof; Including, In the formula, R 1 is a chiral auxiliary, R 2 is a nitrogen protecting group, R 6 , R 7 , R 8 , and R 9 are each independently H or a nitrogen protecting group; R 3 is a boronic acid group or a boronic ester group.

[0203] In some embodiments, N-(6-amino-5-methylpyridin-3-yl)-2-((2R,5S)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound of formula (I)): [ka] or a salt thereof, the process comprising: Formula (VI): [ka] with a compound of formula (VII): [ka] whereby a compound of formula (Ia): [ka] to produce a compound of the formula In the formula, R 6 , R 7 , R 8 , and R 9 are each independently H or a nitrogen protecting group; and Optionally, R 8 , R 9 , or R 8 and R 9 are nitrogen protecting groups, deprotecting the compound of formula (Ia), thereby producing a compound of formula (I) or a salt thereof; Includes:

[0204] In some embodiments, the process comprises: Formula (Va): [ka] by reducing a compound of formula (VI): [ka] The method further comprises producing a compound of formula (I).

[0205] In some embodiments, the process is represented by formula (V): [ka] by removing the nitrogen protecting group from a compound of formula (Va): [ka] and further comprising producing a compound of In the formula, R 2 is a nitrogen protecting group.

[0206] In some embodiments, the process comprises: Formula (III): [ka] with a compound of formula (IV): [ka] and cross-coupling with a compound of formula (V): [ka] and further comprising producing a compound of In the formula, R 2 is a nitrogen protecting group, R 3 is a boronic acid group or a boronic ester group.

[0207] In some embodiments, the process further comprises protecting the nitrogen group of the compound of formula (III-a) with a nitrogen protecting group, thereby producing a compound of formula (III). 2 is a nitrogen protecting group. In some embodiments, R 2 is a carbamate group. In some embodiments, R 2 teeth, [ka] is.

[0208] In some embodiments, protecting the nitrogen group of Formula (III-a) is performed in a sixth solvent. In some embodiments, the sixth solvent is an aprotic solvent. In some embodiments, the sixth solvent is acetonitrile. In some embodiments, protecting the nitrogen group of Formula (III-a) is performed in the presence of a fourth base. In some embodiments, the fourth base is a pyridine base. In some embodiments, the fourth base is dimethylaminopyridine (DMAP).

[0209] In some embodiments, the process comprises: Formula (II): [ka] by hydrogenating a compound of formula (III-a): [ka] and further comprising producing a compound of In the formula, R 1 is a chiral auxiliary.

[0210] In some embodiments, the chiral auxiliary is an optionally substituted oxazolidinone.

[0211] In some embodiments, the chiral auxiliary is [ka] where R 10 is C 1~6 alkyl, benzyl (Bn), or phenyl (Ph). In some embodiments, R 10 is C 1~6 In some embodiments, R 10 is benzyl (Bn). In some embodiments, R 10 is phenyl (Ph).

[0212] In some embodiments, the chiral auxiliary is [ka] is.

[0213] In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with a first catalyst.

[0214] In some embodiments, hydrogenating the compound of Formula (II) reduces the compound of Formula (II) to less than about 10 mol% (e.g., less than about 9 mol%, less than about 8 mol%, less than about 7 mol%, less than about 6 mol%, less than about 5 mol%, less than about 4 mol%, less than about 3 mol%, less than about 2.75 mol%, less than about 2.5 mol%, less than about 2.25 mol%, less than about 2 mol%, less than about 1.95 mol%, less than about 1.85 mol%, less than about 1.75 mol%, less than about 1.65 mol%). In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 10 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 9 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 8 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 7 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 6 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 5 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 4 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 3 mol% of the first catalyst.In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 2.75 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 2.5 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 2.25 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 2 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 1.95 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 1.85 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 1.75 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 1.65 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 1.55 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 1.45 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 1.35 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 1.25 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 1.15 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 1.05 mol% of the first catalyst.In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 1 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 0.9 mol%, or less than about 0.8 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 0.7 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 0.6 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 0.5 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 0.4 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 0.3 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 0.2 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with less than about 0.1 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with from about 0.1 mol% to about 10 mol% (e.g., from about 0.5 mol% to about 1 mol%, from about 1 mol% to about 1.5 mol%, from about 1 mol% to about 2 mol%, from about 1.5 mol% to about 2 mol%, or from about 1.5 mol% to about 2.5 mol%) of the first catalyst.

[0215] In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with about 0.1 mol% to about 10 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with about 0.5 mol% to about 1 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with about 1 mol% to about 1.5 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with about 1 mol% to about 2 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with about 1.5 mol% to about 2 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with about 1.5 mol % to about 2.5 mol % of a first catalyst.

[0216] In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with about 1.0 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with about 1.2 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with about 1.4 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with about 1.6 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with about 1.7 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with about 1.8 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with about 2.0 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with about 2.2 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with about 2.5 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with about 3.0 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with about 4.0 mol% of the first catalyst. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with about 5.0 mol% of the first catalyst.

[0217] In some embodiments, the first catalyst is a palladium catalyst. In some embodiments, the first catalyst is a palladium(0) catalyst. In some embodiments, the first catalyst is palladium on carbon. In some embodiments, the first catalyst is about 5 wt% palladium on carbon. In some embodiments, the first catalyst is about 10 wt% palladium on carbon.

[0218] In some embodiments, hydrogenating the compound of Formula (II) is carried out in the presence of a third acid. In some embodiments, the third acid is an inorganic acid. In some embodiments, the third acid is hydrochloric acid. In some embodiments, hydrogenating the compound of Formula (II) is carried out in a fifth solvent. In some embodiments, the fifth solvent is a mixture of solvents. In some embodiments, the fifth solvent is a mixture of tetrahydrofuran and water.

[0219] In some embodiments, hydrogenating the compound of Formula (II) is carried out at a temperature of about 20°C to about 100°C (e.g., about 30°C to about 90°C, about 40°C to about 80°C, about 50°C to about 70°C, about 60°C to about 70°C). In some embodiments, hydrogenating the compound of Formula (II) is carried out at a temperature of about 60°C to about 70°C.

[0220] In some embodiments, hydrogenating the compound of Formula (II) comprises using a flow system. In some embodiments, hydrogenating the compound of Formula (II) comprises using a continuous flow system. In some embodiments, hydrogenating the compound of Formula (II) comprises using a micro-packed bed reactor. In some embodiments, hydrogenating the compound of Formula (II) is carried out under flow hydrogenation conditions. In some embodiments, hydrogenating the compound of Formula (II) is carried out under continuous flow hydrogenation conditions.

[0221] In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with hydrogen gas. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with hydrogen gas under a pressure of at least about 1.0 megapascal (MPa) (e.g., at least about 2.0 megapascal (MPa), at least about 3.0 megapascal (MPa), or at least about 4.0 megapascal (MPa), or at least about 5.0 megapascal (MPa)). In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with hydrogen gas under a pressure of about 1.0 MPa to about 5.0 MPa. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with hydrogen gas under a pressure of about 2.0 MPa to about 4.0 MPa. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with hydrogen gas under a pressure of about 1.0 MPa. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with hydrogen gas at a pressure of about 2.0 MPa. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with hydrogen gas at a pressure of about 3.0 MPa. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with hydrogen gas at a pressure of about 4.0 MPa. In some embodiments, hydrogenating the compound of Formula (II) comprises contacting the compound of Formula (II) with hydrogen gas at a pressure of about 5.0 MPa.

[0222] In some embodiments, R 3 is a boronic acid group. In some embodiments, R 3 is a boronic ester group. In some embodiments, R 3 teeth, [ka] where R 3a and R 3bare each independently H or C 1~6 alkyl, and R 3a and R 3b is optionally bonded together with their intervening atoms to form 0, 1, 2, 3, 4, 5, or 6 occurrences of R 3c and each R forms a 5- to 10-membered ring optionally substituted by 3c independently, C 1~6 It is alkyl.

[0223] In some embodiments, R 3a and R 3b are each independently, C 1~6 alkyl, and R 3a and R 3b can be zero, one, two, three, four, five, or six R's bonded together with their intervening atoms. 3c and each R forms a 5- to 10-membered ring optionally substituted by 3c independently, C 1~6 In some embodiments, R 3a and R 3b are each independently, C 1~6 alkyl, and R 3a and R 3b can be zero, one, two, three, four, five, or six R's bonded together with their intervening atoms. 3c and each R 3c is -Me. In some embodiments, R 3 teeth, [ka] is.

[0224] In some embodiments, cross-coupling a compound of Formula (III) with a compound of Formula (IV) comprises: (a) Formula (III): [ka] by contacting a compound of formula (III) with a sulfonylation / dehydration agent to convert the compound of formula (III-b): [ka] to a compound of formula (III-b), In the formula, R 2 is a nitrogen protecting group as defined herein, and R 4 is an alkyl, haloalkyl, or aryl sulfonate (e.g., methanesulfonate (-OS(=O)2CH3), trifluoromethanesulfonate (-OS(=O)2CF3), phenylsulfonate (-OS(=O)2Ph), toluenesulfonate (-OS(=O)2C6H4-CH3)); (b) reacting a compound of formula (III-b) with a compound of formula (IV): [ka] whereby a compound of formula (V): [ka] and forming a compound of the formula: Includes:

[0225] In some embodiments, R 4 is trifluoromethanesulfonate, and the compound of formula (III-b) is [ka] In some embodiments, cross-coupling a compound of Formula (III) with a compound of Formula (IV) comprises contacting a compound of Formula (III) with a sulfonylating / dehydrating agent in the presence of a first base (e.g., thereby converting the compound of Formula (III) to a compound of Formula (III-b)). In some embodiments, the dehydrating agent is a sulfonimide. In some embodiments, the sulfonylation / dehydrating agent is 1,1,1-trifluoro-N-phenyl-N-(trifluoromethanesulfonyl)methanesulfonamide (PHNTf2).

[0226] In some embodiments, the first base is an inorganic base. In some embodiments, the first base is an organic base.

[0227] In some embodiments, the first base is a lithium base. In some embodiments, the first base is an amine base. In some embodiments, the first base is lithium bis(trimethylsilyl)amide (LiHMDS).

[0228] In some embodiments, contacting the compound of Formula (III) with the sulfonylating / dehydrating agent to produce the compound of Formula (III-b) is carried out in a fourth solvent. In some embodiments, the fourth solvent is an aprotic solvent. In some embodiments (e.g., an ethereal solvent). In some embodiments, the solvent is tetrahydrofuran.

[0229] In some embodiments, contacting a compound of Formula (III) with a sulfonylation / dehydration agent to form a compound of Formula (III-b) is carried out at a temperature below about 0°C (e.g., below about -10°C, below about -20°C, below about -30°C, below about -40°C, below about -60°C, below about -70°C, below about -80°C). In some embodiments, contacting a compound of Formula (III) with a sulfonylation / dehydration agent to form a compound of Formula (III-b) is carried out at a temperature below about -60°C. In some embodiments, contacting a compound of Formula (III) with a sulfonylation / dehydration agent to form a compound of Formula (III-b) is carried out at a temperature of about -50°C to -80°C. In some embodiments, contacting a compound of Formula (III) with a sulfonylation / dehydration agent to form a compound of Formula (III-b) is carried out at a temperature of about -70°C.

[0230] In some embodiments, cross-coupling a compound of Formula (III) with a compound of Formula (IV) comprises contacting a compound of Formula (III-b) with a compound of Formula (IV) in the presence of a second catalyst.

[0231] In some embodiments, cross-coupling of a compound of Formula (III) with a compound of Formula (IV) is performed at a concentration of less than about 10 mol% (e.g., less than about 9 mol%, less than about 8 mol%, less than about 7 mol%, less than about 6 mol%, less than about 5 mol%, less than about 4 mol%, less than about 3 mol%, less than about 2.75 mol%, less than about 2.5 mol%, less than about 2.25 mol%, less than about 2 mol%, less than about 1.95 mol%, less than about 1.85 mol%, less than about 1.75 mol%, less than about 1.65 mol%, less than about 1.55 mol%). the method comprises contacting a compound of Formula (III-b) with a compound of Formula (IV) in the presence of a second catalyst (less than about 1.45 mol%, less than about 1.35 mol%, less than about 1.25 mol%, less than about 1.15 mol%, less than about 1.05 mol%, less than about 1 mol%, less than about 0.9 mol%, less than about 0.8 mol%, less than about 0.7 mol%, less than about 0.6 mol%, less than about 0.5 mol%, less than about 0.4 mol%, less than about 0.3 mol%, less than about 0.2 mol%, or less than about 0.1 mol%). In some embodiments, cross-coupling a compound of Formula (III) with a compound of Formula (IV) comprises contacting a compound of Formula (III-b) with a compound of Formula (IV) in the presence of about 0.1 mol % to about 10 mol % (e.g., about 0.5 mol % to about 7 mol %, about 1 mol % to about 5 mol %, about 1 mol % to about 4 mol %, about 2 mol % to about 5 mol %, or about 2 mol % to about 4 mol %) of a second catalyst.

[0232] In some embodiments, cross-coupling a compound of Formula (III) with a compound of Formula (IV) comprises contacting a compound of Formula (III-b) with a compound of Formula (IV) in the presence of about 0.1 mol% to about 10 mol% of a second catalyst. In some embodiments, cross-coupling a compound of Formula (III) with a compound of Formula (IV) comprises contacting a compound of Formula (III-b) with a compound of Formula (IV) in the presence of about 0.5 mol% to about 7 mol% of a second catalyst. In some embodiments, cross-coupling a compound of Formula (III) with a compound of Formula (IV) comprises contacting a compound of Formula (III-b) with a compound of Formula (IV) in the presence of about 1 mol% to about 5 mol% of a second catalyst. In some embodiments, cross-coupling a compound of Formula (III) with a compound of Formula (IV) comprises contacting a compound of Formula (III-b) with a compound of Formula (IV) in the presence of about 1 mol% to about 4 mol% of a second catalyst. In some embodiments, cross-coupling a compound of Formula (III) with a compound of Formula (IV) comprises contacting a compound of Formula (III-b) with a compound of Formula (IV) in the presence of about 2 mol% to about 5 mol% of a second catalyst. In some embodiments, cross-coupling a compound of Formula (III) with a compound of Formula (IV) comprises contacting a compound of Formula (III-b) with a compound of Formula (IV) in the presence of about 2 mol% to about 4 mol% of a second catalyst.

[0233] In some embodiments, cross-coupling a compound of Formula (III) with a compound of Formula (IV) comprises contacting a compound of Formula (III-b) with a compound of Formula (IV) in the presence of about 1 mol% of a second catalyst. In some embodiments, cross-coupling a compound of Formula (III) with a compound of Formula (IV) comprises contacting a compound of Formula (III-b) with a compound of Formula (IV) in the presence of about 2 mol% of a second catalyst. In some embodiments, cross-coupling a compound of Formula (III) with a compound of Formula (IV) comprises contacting a compound of Formula (III-b) with a compound of Formula (IV) in the presence of about 3 mol% of a second catalyst. In some embodiments, cross-coupling a compound of Formula (III) with a compound of Formula (IV) comprises contacting a compound of Formula (III-b) with a compound of Formula (IV) in the presence of about 4 mol% of a second catalyst. In some embodiments, cross-coupling a compound of Formula (III) with a compound of Formula (IV) comprises contacting a compound of Formula (III-b) with a compound of Formula (IV) in the presence of about 5 mol % of a second catalyst.

[0234] In some embodiments, the second catalyst is a palladium catalyst. In some embodiments, the second catalyst is a palladium(II) catalyst. In some embodiments, the second catalyst is bis(triphenylphosphine)palladium(II) dichloride.

[0235] In some embodiments, cross-coupling a compound of Formula (III) with a compound of Formula (IV) comprises contacting a compound of Formula (III-b) with a compound of Formula (IV) in the presence of a second base.

[0236] In some embodiments, the second base is an inorganic base. In some embodiments, the second base is a carbonate base. In some embodiments, the second base is potassium phosphate tripotassium (K3PO4).

[0237] In some embodiments, contacting the compound of Formula (III-b) with the compound of Formula (IV) occurs in a seventh solvent. In some embodiments, the seventh solvent is a mixture of solvents. In some embodiments, the seventh solvent is a mixture of tetrahydrofuran and water.

[0238] In some embodiments, contacting the compound of Formula (III-b) with the compound of Formula (IV) is carried out at a temperature of about 20°C to about 120°C (e.g., about 30°C to about 110°C, about 40°C to about 100°C, about 50°C to about 90°C, or about 60°C to about 80°C). In some embodiments, hydrogenating the compound of Formula (II) is carried out at a temperature of about 60°C to about 80°C.

[0239] In some embodiments, the process further comprises removing a nitrogen protecting group of the compound of Formula (V) to produce a compound of Formula (Va). In some embodiments, removing the nitrogen protecting group of the compound of Formula (V) comprises contacting the compound of Formula (V) with a first acid.

[0240] In some embodiments, the first acid is an inorganic acid. In some embodiments, the first acid is hydrochloric acid (HCl) or phosphoric acid (H3PO4). In some embodiments, the first acid is hydrochloric acid (HCl).

[0241] In some embodiments, the first acid is an organic acid, hi some embodiments, the first acid is trifluoromethanesulfonic acid (TfOH), trifluoroacetic acid (TFA), or p-toluenesulfonic acid (PTSA).

[0242] In some embodiments, removing the nitrogen protecting group of the compound of Formula (V) is performed in an eighth solvent. In some embodiments, the eighth solvent is a protic solvent. In some embodiments, the eighth solvent is methanol.

[0243] In some embodiments, reducing the compound of Formula (Va) comprises contacting the compound of Formula (Va) with a reducing agent. In some embodiments, the reducing agent is a hydride reducing agent. In some embodiments, the reducing agent is a borohydride reducing agent. In some embodiments, the reducing agent is sodium borohydride (NaBH4).

[0244] In some embodiments, reducing the compound of Formula (Va) comprises contacting the compound of Formula (Va) with the first solvent at a temperature below about 0° C. (e.g., below about −1° C., below about −2° C., below about −3° C., below about −4° C., below about −5° C., below about −6° C., below about −7° C., below about −8° C., or below about −10° C.). In some embodiments, reducing the compound of Formula (Va) comprises contacting the compound of Formula (Va) with the first solvent at a temperature of about −20° C. to 20° C. In some embodiments, reducing the compound of Formula (Va) comprises contacting the compound of Formula (Va) with the first solvent at a temperature of about −15° C. to 10° C. In some embodiments, reducing the compound of Formula (Va) comprises contacting the compound of Formula (Va) with the first solvent at a temperature of about −10° C. to 0° C. In some embodiments, reducing the compound of Formula (Va) comprises contacting the compound of Formula (Va) with the first solvent at a temperature of about −15° C. to −5° C. In some embodiments, reducing the compound of Formula (Va) comprises contacting the compound of Formula (Va) with the first solvent at a temperature of about −20° C. In some embodiments, reducing the compound of Formula (Va) comprises contacting the compound of Formula (Va) with the first solvent at a temperature of about −10° C. In some embodiments, reducing the compound of Formula (Va) comprises contacting the compound of Formula (Va) with the first solvent at a temperature of about −0° C. In some embodiments, reducing the compound of Formula (Va) comprises contacting the compound of Formula (Va) with the first solvent at a temperature of about 10° C. In some embodiments, reducing the compound of Formula (Va) comprises contacting the compound of Formula (Va) with the first solvent at a temperature of about 20° C.

[0245] In some embodiments, the first solvent is a protic solvent, hi some embodiments, the first solvent is methanol.

[0246] In some embodiments, R 6 is a nitrogen protecting group, and R 7 is a nitrogen protecting group. In some embodiments, R 6 is a nitrogen protecting group, and R 7 is H. In some embodiments, R 6 is a carbamate group, and R 7 is a carbamate group. In some embodiments, R 6 is a carbamate group, and R 7 is H. In some embodiments, R 6 teeth, [ka] and R 7 teeth, [ka] In some embodiments, R 6 teeth, [ka] and R 7is H. In some embodiments, coupling a compound of Formula (VI) with a compound of Formula (VII) comprises contacting a compound of Formula (VI) with a compound of Formula (VII) in a molar ratio of about 1.5:1 to about 1:1.5. In some embodiments, coupling a compound of Formula (VI) with a compound of Formula (VII) comprises contacting a compound of Formula (VI) with a compound of Formula (VII) in a molar ratio of about 1:1 to about 1:1.4. In some embodiments, coupling a compound of Formula (VI) with a compound of Formula (VII) comprises contacting a compound of Formula (VI) with a compound of Formula (VII) in a molar ratio of about 1:1.1 to about 1:1.4. In some embodiments, coupling a compound of Formula (VI) with a compound of Formula (VII) comprises contacting a compound of Formula (VI) with a compound of Formula (VII) in a molar ratio of about 1:1.1 to about 1:1.4. In some embodiments, coupling a compound of Formula (VI) with a compound of Formula (VII) comprises contacting a compound of Formula (VI) with a compound of Formula (VII) in a molar ratio of about 1:1.3. In some embodiments, coupling the compound of Formula (VIa) with the compound of Formula (VII) comprises contacting the compound of Formula (VI) with the compound of Formula (VII) in the presence of a coupling reagent.

[0247] In some embodiments, the coupling reagent is an anhydride coupling reagent, a triazole-based coupling reagent, a carbodiimide coupling reagent, an imidazolium coupling reagent, a phosphonium salt coupling reagent, or a pyridinium salt coupling reagent.

[0248] In some embodiments, the coupling reagent is an anhydride coupling reagent. Examples of an anhydride coupling reagent include, but are not limited to, propylphosphonic anhydride (T3P®).

[0249] In some embodiments, the coupling reagent is a triazole-based coupling reagent. Examples of triazole-based coupling reagents include, but are not limited to, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU). In some embodiments, the coupling reagent is 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) or 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU). In some embodiments, the coupling reagent is 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), or 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU). In some embodiments, the coupling reagent is 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) or 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU).In some embodiments, the coupling reagent is 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU).

[0250] In some embodiments, the coupling reagent is a carbodiimide coupling reagent. Examples of carbodiimide coupling reagents include, but are not limited to, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), and ethyl-(N',N'-dimethylamino)propylcarbodiimide hydrochloride (EDC).

[0251] In some embodiments, the coupling reagent is an imidazolium coupling reagent. Examples of imidazolium coupling reagents include, but are not limited to, carbonyldiimidazole (CDI), chloro-1,3-dimethylimidazolidinium hexafluorophosphate, 2-chloro-1,3-dimethylimidazolinium chloride, and 1,1′-oxalyl imidazole.

[0252] In some embodiments, the coupling reagent is a phosphonium salt coupling reagent. Examples of phosphonium salt coupling reagents include, but are not limited to, benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP), benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazol-1-yloxy)trispyrrolidinophosphonium hexafluorophosphate (PyAOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl).

[0253] In some embodiments, the coupling reagent is a pyridinium salt coupling reagent. Examples of pyridinium salt coupling reagents include, but are not limited to, 2-chloro-1-methylpyridinium iodide (Mukaiyama's reagent).

[0254] In some embodiments, the compound of Formula (VI) and the coupling reagent have a molar ratio of about 1.5:1 to about 1:1.5. In some embodiments, the compound of Formula (VI) and the coupling reagent have a molar ratio of about 1:1 to about 1:1.5. In some embodiments, the coupling reagent has a molar ratio of about 1:1.1 to about 1:1.4.

[0255] In some embodiments, the compound of Formula (VI) and the coupling reagent have a molar ratio of about 1:1.2 to about 1:1.4. In some embodiments, the compound of Formula (VI) and the coupling reagent have a molar ratio of about 1:1.3.

[0256] In some embodiments, coupling the compound of Formula (VI) with the compound of Formula (VII) comprises contacting the compound of Formula (VI) with the compound of Formula (VII) in the presence of a third base.

[0257] In some embodiments, the third base is an organic base. In some embodiments, the third base is an amine base. In some embodiments, the third base is triethylamine (TEA), N,N-diisopropylethylamine (DIPEA), or pyridine.

[0258] In some embodiments, the third base is triethylamine (TEA) or N,N-diisopropylethylamine (DIPEA).

[0259] In some embodiments, coupling the compound of Formula (VI) with the compound of Formula (VII) comprises contacting the compound of Formula (VI) with the compound of Formula (VII) in a ninth solvent. In some embodiments, the ninth solvent is an aprotic solvent. In some embodiments, the ninth solvent is tetrahydrofuran.

[0260] In some embodiments, R 8 is a nitrogen protecting group, and R 9 is a nitrogen protecting group. In some embodiments, R 8 is a nitrogen protecting group, and R 9 is H. In some embodiments, R 8 is a carbamate group, and R 9 is a carbamate group. In some embodiments, R 8 is a carbamate group, and R 9 is H. In some embodiments, R 8 teeth, [ka] and R 9 teeth, [ka] In some embodiments, R 8 teeth, [ka] and R 9 is H.

[0261] In some embodiments, the process further comprises removing each nitrogen protecting group from the compound of Formula (Ia).

[0262] In some embodiments, removing each nitrogen protecting group from the compound of Formula (Ia) comprises contacting the compound of Formula (Ia) with a second acid.

[0263] In some embodiments, removing each nitrogen protecting group from the compound of Formula (Ia) comprises contacting the compound of Formula (Ia) with a second acid at a temperature of about 0°C to about 100°C (e.g., about 15°C to about 65°C, about 20°C to about 50°C, about 25°C to about 45°C, or about 35°C to about 55°C). In some embodiments, removing each nitrogen protecting group from the compound of Formula (Ia) comprises contacting the compound of Formula (Ia) with a second acid at a temperature of about 15°C to about 65°C. In some embodiments, removing each nitrogen protecting group from the compound of Formula (Ia) comprises contacting the compound of Formula (Ia) with a second acid at a temperature of about 20°C to about 50°C. In some embodiments, removing each nitrogen protecting group from the compound of Formula (Ia) comprises contacting the compound of Formula (Ia) with a second acid at a temperature of about 25°C to about 45°C. In some embodiments, removing each nitrogen protecting group from the compound of Formula (Ia) comprises contacting the compound of Formula (Ia) with a second acid at a temperature of about 35° C. to about 55° C. In some embodiments, removing each nitrogen protecting group from the compound of Formula (Ia) comprises contacting the compound of Formula (Ia) with a second acid at a temperature of about 70° C. In some embodiments, removing each nitrogen protecting group from the compound of Formula (Ia) comprises contacting the compound of Formula (Ia) with a second acid at a temperature of about 60° C. In some embodiments, removing each nitrogen protecting group from the compound of Formula (Ia) comprises contacting the compound of Formula (Ia) with a second acid at a temperature of about 50° C. In some embodiments, removing each nitrogen protecting group from the compound of Formula (Ia) comprises contacting the compound of Formula (Ia) with a second acid at a temperature of about 45° C. In some embodiments, removing each nitrogen protecting group from the compound of Formula (Ia) comprises contacting the compound of Formula (Ia) with a second acid at a temperature of about 40° C. In some embodiments, removing each nitrogen protecting group from the compound of Formula (Ia) comprises contacting the compound of Formula (Ia) with a second acid at a temperature of about 30° C. In some embodiments, removing each nitrogen protecting group from the compound of Formula (Ia) comprises contacting the compound of Formula (Ia) with a second acid at a temperature of about 20° C.

[0264] In some embodiments, the compound of Formula (Ia) and the second acid have a molar ratio of about 1:1 to about 1:10. In some embodiments, the compound of Formula (Ia) and the second acid have a molar ratio of about 1:2 to about 1:7. In some embodiments, the compound of Formula (Ia) and the second acid have a molar ratio of about 1:3 to about 1:6. In some embodiments, the compound of Formula (Ia) and the second acid have a molar ratio of about 1:3 to about 1:5. In some embodiments, the compound of Formula (Ia) and the second acid have a molar ratio of about 1:4.

[0265] In some embodiments, the second acid is an inorganic acid. In some embodiments, the second acid is hydrochloric acid (HCl) or phosphoric acid (H3PO4).

[0266] In some embodiments, the second acid is an organic acid. In some embodiments, the second acid is trifluoromethanesulfonic acid (TfOH), trifluoroacetic acid (TFA), or p-toluenesulfonic acid (PTSA). In some embodiments, the second acid is trifluoromethanesulfonic acid (TfOH).

[0267] In some embodiments, removal of each nitrogen protecting group from a compound of Formula (Ia) provides a salt of a compound of Formula (I). In some embodiments, the salt of a compound of Formula (I) is a hydrochloride salt. In some embodiments, the salt of a compound of Formula (I) is a trifluoroacetate salt. In some embodiments, the salt of a compound of Formula (I) is a trifluoromethanesulfonate salt. In some embodiments, the salt of a compound of Formula (I) is a paratoluenesulfonate salt.

[0268] In some embodiments, the compound of formula (I) is not purified by chromatography. In some embodiments, the entire process for preparing the compound of formula (I) does not include purification by chromatography.

[0269] In some embodiments, the process further comprises converting the salt of the compound of Formula (I) to a free base of the compound of Formula (I). In some embodiments, converting the salt of the compound of Formula (I) to a free base of the compound of Formula (I) comprises contacting the salt of the compound of Formula (I) with a fifth base in a tenth solvent. In some embodiments, the fifth base is an inorganic base. In some embodiments, the fifth base is a carbonate base. In some embodiments, the fifth base is sodium carbonate. In some embodiments, the tenth solvent is a mixture of water and an organic solvent. In some embodiments, the tenth solvent is a mixture of water, ethanol, and tetrahydrofuran.

[0270] In some embodiments, the process further comprises producing a crystalline form of the compound of formula (I) (eg, the free base of the compound of formula (I)).

[0271] In some embodiments, producing a crystalline form of the compound of Formula (I) comprises subjecting a solution of the compound of Formula (I) to conditions that cause crystallization of the compound of Formula (I).

[0272] In some embodiments, producing a crystalline form of the compound of Formula (I) comprises dissolving the compound of Formula (I) in a first solvent and partially evaporating the first solvent. In some embodiments, the process further comprises seeding the solution obtained by dissolving the compound of Formula (I) in the first solvent with a small amount (e.g., less than about 5% of the amount of the compound of Formula (I) present in the solution) of crystals of the compound of Formula (I).

[0273] In some embodiments, the first solvent is a protic solvent. In some embodiments, the first solvent is a polar solvent.

[0274] In some embodiments, the first solvent is MeCN, methanol, ethanol, isopropyl alcohol, n-propanol, n-BuOH, water, or a mixture thereof. In some embodiments, the first solvent is MeCN, ethanol, methanol, water, or a mixture thereof. In some embodiments, the first solvent is a mixture of water and methanol (e.g., a 9:1 v / v mixture). In some embodiments, the process further comprises adding water to the mixture obtained after partially evaporating the first solvent. In some embodiments, the process further comprises stirring the suspension obtained from the previous step for at least 1 hour (e.g., about 1-10 hours, about 2-8 hours, about 3-6 hours, about 5 hours). In some embodiments, producing a crystalline form of the compound of Formula (I) further comprises a filtration step to collect the crude crystalline form of the compound of Formula (I).

[0275] In some embodiments, producing the crystalline form of the compound of Formula (I) further comprises slurrying the crude crystalline form of the compound of Formula (I) in a second solvent and filtering by centrifugation.

[0276] In some embodiments, the second solvent is a protic solvent. In some embodiments, the second solvent is a polar solvent. In some embodiments, the second solvent is MeCN, methanol, ethanol, isopropyl alcohol, n-propanol, n-BuOH, water, or a mixture thereof.

[0277] In some embodiments, the second solvent is MeCN, ethanol, methanol, water, or a mixture thereof, hi some embodiments, the second solvent is a mixture of methanol and water.

[0278] Pharmaceutical Composition In some embodiments, Formula (I) [ka] or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0279] In some embodiments, the compound of formula (I) as a free base [ka] and at least one pharmaceutically acceptable excipient.

[0280] In some embodiments, the pharmaceutically active ingredient is a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0281] In some embodiments, the pharmaceutically active ingredient is the free base of the compound of formula (I).

[0282] 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.

[0283] The amounts and ranges set forth below for the "compound of Formula (I)" may refer to the compound of Formula (I) generally, to a crystalline form of the compound of Formula (I), or to crystalline Form A of the compound of Formula (I) described herein. For compositions and dosage forms that include a pharmaceutically acceptable salt of the compound of Formula (I), the amounts and ranges set forth below for the "compound of Formula (I)" refer to the dose equivalent to the free base of the compound included in the composition or dosage form.

[0284] In some embodiments, the pharmaceutical composition comprises about 5% (w / w) to about 50% (w / w) of a compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 10% (w / w) to about 45% (w / w) of a compound of Formula (I).

[0285] In some embodiments, the pharmaceutical composition comprises about 8% (w / w) to about 17% (w / w), about 25% (w / w) to about 35% (w / w), or about 35% (w / w) to about 45% (w / w) of a compound of Formula (I).

[0286] In some embodiments, the pharmaceutical composition comprises about 8% (w / w) to about 17% (w / w) of a compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 10% (w / w) to about 15% (w / w) of a compound of Formula (I).

[0287] In some embodiments, the pharmaceutical composition comprises about 12% (w / w) to about 13% (w / w) of a compound of formula (I).

[0288] In some embodiments, the pharmaceutical composition comprises about 12.5% ​​(w / w) of a compound of formula (I).

[0289] In some embodiments, the pharmaceutical composition comprises about 25% (w / w) to about 35% (w / w) of a compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 27% (w / w) to about 33% (w / w) of a compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 29% (w / w) to about 31% (w / w) of a compound of Formula (I).

[0290] In some embodiments, the pharmaceutical composition comprises about 29.2% (w / w) to about 29.7% (w / w) of the compound of formula (I).

[0291] In some embodiments, the pharmaceutical composition comprises about 29.4% (w / w) of the compound of formula (I).

[0292] In some embodiments, the pharmaceutical composition comprises about 35% (w / w) to about 45% (w / w) of a compound of Formula (I). In some embodiments, the pharmaceutical composition comprises about 37% (w / w) to about 43% (w / w) of a compound of Formula (I).

[0293] In some embodiments, the pharmaceutical composition comprises about 39% (w / w) to about 31% (w / w) of a compound of formula (I).

[0294] In some embodiments, the pharmaceutical composition comprises about 40% (w / w) of a compound of formula (I).

[0295] In certain embodiments, the pharmaceutical composition comprises about 12.5% ​​(w / w), about 29.4% (w / w), or about 40% (w / w) of a compound of formula (I).

[0296] In some embodiments, the pharmaceutical composition comprises a bulking agent, hi certain embodiments, the bulking agent is selected from the group consisting of sugars, inorganic substances, microcrystalline cellulose, starches, polysaccharides, cellulose, polyvinylpyrrolidone, polyvinylacrylate, and combinations thereof.

[0297] In certain embodiments, the bulking agent 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 dibasic calcium phosphate, hydroxyapatite, sodium carbonate, sodium bicarbonate, calcium carbonate, bentonite, kaolin, and combinations thereof.

[0298] In certain embodiments, the bulking agent 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.

[0299] In some embodiments, the bulking agent is microcrystalline cellulose (e.g., Avicel®). Microcrystalline cellulose bulking agents can be of different grades. In some embodiments, the bulking agent is microcrystalline cellulose PH102, PH200, or a mixture thereof. In some embodiments, the bulking agent is microcrystalline cellulose PH102 (e.g., Avicel® PH102). In some embodiments, the bulking agent is microcrystalline cellulose PH200 (e.g., Avicel® PH200). In some embodiments, the bulking agent is a mixture of microcrystalline cellulose PH102 (e.g., Avicel® PH102) and microcrystalline cellulose PH200 (e.g., Avicel® PH200). In another embodiment, the bulking agent comprises equal amounts of two grades of microcrystalline cellulose.

[0300] In certain embodiments, the pharmaceutical composition comprises about 50% (w / w) to about 90% (w / w) of a bulking agent. In certain embodiments, the pharmaceutical composition comprises about 50% (w / w) to about 60% (w / w) of a bulking agent. In certain embodiments, the pharmaceutical composition comprises about 52% (w / w) to about 58% (w / w) of a bulking agent. In certain embodiments, the pharmaceutical composition comprises about 52% (w / w) to about 56% (w / w) of a bulking agent.

[0301] In certain embodiments, the pharmaceutical composition comprises about 50% (w / w), about 51% (w / w), about 52% (w / w), about 53% (w / w), about 54% (w / w), about 55% (w / w), about 56% (w / w), about 57% (w / w), or about 58% (w / w) of bulking agent.

[0302] In certain embodiments, the pharmaceutical composition comprises about 54% (w / w) bulking agent.

[0303] In certain embodiments, the pharmaceutical composition comprises about 61% (w / w) to about 70% (w / w) of a bulking agent. In certain embodiments, the pharmaceutical composition comprises about 63% (w / w) to about 68% (w / w) of a bulking agent. In certain embodiments, the pharmaceutical composition comprises about 65% (w / w) to about 66% (w / w) of a bulking agent.

[0304] In certain embodiments, the pharmaceutical composition comprises about 61% (w / w), about 62% (w / w), about 63% (w / w), about 64% (w / w), about 65% (w / w), about 65.4% (w / w), about 66% (w / w), about 67% (w / w), about 68% (w / w), about 69% (w / w), or about 70% (w / w) of bulking agent. In certain embodiments, the pharmaceutical composition comprises about 64% (w / w), about 65% (w / w), about 65.4% (w / w), about 66% (w / w), or about 67% (w / w) of bulking agent.

[0305] In certain embodiments, the pharmaceutical composition comprises about 65.4% (w / w) bulking agent.

[0306] In certain embodiments, the pharmaceutical composition comprises about 75% (w / w) to about 85% (w / w) of a bulking agent. In certain embodiments, the pharmaceutical composition comprises about 77% (w / w) to about 83% (w / w) of a bulking agent. In certain embodiments, the pharmaceutical composition comprises about 79% (w / w) to about 82% (w / w) of a bulking agent. In certain embodiments, the pharmaceutical composition comprises about 80% (w / w) to about 82% (w / w) of a bulking agent.

[0307] In certain embodiments, the pharmaceutical composition comprises about 75% (w / w), about 76% (w / w), about 77% (w / w), about 78% (w / w), about 79% (w / w), about 80% (w / w), about 81% (w / w), about 81.5% (w / w), about 82% (w / w), about 83% (w / w), about 84% (w / w), or about 85% (w / w) of bulking agent. In certain embodiments, the pharmaceutical composition comprises about 80% (w / w), about 81% (w / w), about 81.5% (w / w), about 82% (w / w), or about 83% (w / w) of bulking agent.

[0308] In certain embodiments, the pharmaceutical composition comprises about 81.5% (w / w) bulking agent.

[0309] In some embodiments, the pharmaceutical composition comprises a glidant, hi certain embodiments, the glidant is selected from the group consisting of colloidal silicon dioxide, talc, kaolin, bentonite, or a combination thereof.

[0310] In another embodiment, the glidant is colloidal silicon dioxide. In some embodiments, the colloidal silicon dioxide is prepared via a process involving the flame hydrolysis of silicon tetrachloride in an oxygen-hydrogen flame and is referred to as "fumed silica" or "untreated fumed silica" (e.g., Aerosil® 200, CAB-O-SIL® M-5P).

[0311] In certain embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 1.5% (w / w) of a glidant. In certain embodiments, the pharmaceutical composition comprises about 0.75% (w / w) to about 1.25% (w / w) of a glidant. In certain embodiments, the pharmaceutical composition comprises about 0.8% (w / w) to about 1% (w / w) of a glidant. In certain embodiments, the pharmaceutical composition comprises about 0.75% (w / w) to about 0.95% (w / w) of a glidant. In certain embodiments, the pharmaceutical composition comprises about 0.85% (w / w) to about 0.9% (w / w) of a glidant. In certain embodiments, the pharmaceutical composition comprises about 0.9% (w / w) to about 1.1% (w / w) of a glidant. In certain embodiments, the pharmaceutical composition comprises about 0.95% (w / w) to about 1.05% (w / w) of a glidant.

[0312] In certain embodiments, the pharmaceutical composition comprises about 0.8% (w / w), about 0.82% (w / w), about 0.84% ​​(w / w), about 0.86% (w / w), about 0.87% (w / w), about 0.88% (w / w), 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 glidant. In certain embodiments, the pharmaceutical composition comprises about 0.86% (w / w), about 0.87% (w / w), about 0.88% (w / w), about 0.98% (w / w), about 1.00% (w / w), or about 1.02% (w / w) of a glidant.

[0313] In certain embodiments, the pharmaceutical composition comprises about 0.87% (w / w) of a glidant.

[0314] In certain embodiments, the pharmaceutical composition comprises about 1% (w / w) of a glidant.

[0315] In some embodiments, the pharmaceutical composition comprises a disintegrant. In certain embodiments, the disintegrant is selected from the group consisting of sodium starch glycolate, crospovidone, croscarmellose sodium, and combinations thereof. In other embodiments, the disintegrant is croscarmellose sodium (e.g., Ac-Di-Sol®).

[0316] In certain embodiments, the pharmaceutical composition comprises about 2% (w / w) to about 6% (w / w) of disintegrant. In certain embodiments, the pharmaceutical composition comprises about 3% (w / w) to about 5% (w / w) of disintegrant. In certain embodiments, the pharmaceutical composition comprises about 3.2% (w / w) to about 4% (w / w) of disintegrant. In certain embodiments, the pharmaceutical composition comprises about 3% (w / w) to about 3.8% (w / w) of disintegrant. In certain embodiments, the pharmaceutical composition comprises about 3.4% (w / w) to about 3.6% (w / w) of disintegrant. In certain embodiments, the pharmaceutical composition comprises about 3.6% (w / w) to about 4.4% (w / w) of disintegrant. In certain embodiments, the pharmaceutical composition comprises about 3.8% (w / w) to about 4.2% (w / w) of disintegrant.

[0317] In certain embodiments, the pharmaceutical composition comprises about 3.2% (w / w), about 3.28% (w / w), about 3.36% (w / w), about 3.44% (w / w), about 3.47% (w / w), about 3.52% (w / w), about 3.6% (w / w), about 3.68% (w / w), about 3.76% (w / w), 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), or about 4.4% (w / w) of disintegrant. In certain embodiments, the pharmaceutical composition comprises about 3.44% (w / w), about 3.47% (w / w), about 3.52% (w / w), about 3.92% (w / w), about 4.00% (w / w), or about 4.08% (w / w) of disintegrant.

[0318] In certain embodiments, the pharmaceutical composition comprises about 3.47% (w / w) of disintegrant.

[0319] In certain embodiments, the pharmaceutical composition comprises about 4% (w / w) of disintegrant.

[0320] In some embodiments, the pharmaceutical composition comprises a lubricant, hi certain embodiments, the lubricant is selected from the group consisting of sodium stearyl fumarate, magnesium stearate, stearic acid, glyceryl behenate, and combinations thereof.

[0321] In another embodiment, the lubricant is magnesium stearate.

[0322] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 1.5% (w / w) of a lubricant. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) to about 1.25% (w / w) of a lubricant. In some embodiments, the pharmaceutical composition comprises about 0.8% (w / w) to about 1% (w / w) of a lubricant. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) to about 0.95% (w / w) of a lubricant.

[0323] In some embodiments, the pharmaceutical composition comprises about 0.85% (w / w) to about 0.9% (w / w) of a lubricant. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) to about 1.1% (w / w) of a lubricant. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) to about 1.05% (w / w) of a lubricant.

[0324] In some embodiments, the pharmaceutical composition comprises about 0.8% (w / w), about 0.82% (w / w), about 0.84% ​​(w / w), about 0.86% (w / w), about 0.87% (w / w), about 0.88% (w / w), 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 comprises about 0.86% (w / w), about 0.87% (w / w), about 0.88% (w / w), about 0.98% (w / w), about 1.00% (w / w), or about 1.02% (w / w) of a lubricant.

[0325] In some embodiments, the pharmaceutical composition comprises about 0.87% (w / w) of a lubricant.

[0326] In some embodiments, the pharmaceutical composition comprises about 1% (w / w) of a lubricant.

[0327] In certain embodiments, (a) Formula (I) [ka] and a compound of (b) a bulking agent (e.g., microcrystalline cellulose); (c) a glidant (e.g., colloidal silicon dioxide); and (d) a disintegrant (e.g., croscarmellose sodium); and (e) a lubricant (e.g., magnesium stearate); A pharmaceutical composition comprising:

[0328] In some embodiments, the composition comprises a crystalline form (eg, Form A) of the compound of Formula (I) described herein.

[0329] In some embodiments, the composition comprises: (a) about 5% (w / w) to about 50% (w / w) of a compound of formula (I); (b) about 50% (w / w) to about 90% (w / w) of a bulking agent (e.g., crystalline cellulose); (c) about 0.5% (w / w) to about 1.5% (w / w) of a glidant (e.g., colloidal silicon dioxide); and (d) about 2% (w / w) to about 6% (w / w) of a disintegrant (e.g., croscarmellose sodium); and (e) about 0.5% (w / w) to about 1.5% (w / w) of a lubricant (e.g., magnesium stearate); whereby the total composition makes up 100% (w / w).

[0330] In some embodiments, the composition comprises: (a) about 10% (w / w) to about 45% (w / w) of a compound of formula (I); (b) about 50% (w / w) to about 90% (w / w) of a bulking agent (e.g., crystalline cellulose); (c) about 0.8% (w / w) to about 1% (w / w) of a glidant (e.g., colloidal silicon dioxide); and (d) about 3.2% (w / w) to about 4% (w / w) of a disintegrant (e.g., croscarmellose sodium); and (e) about 0.8% (w / w) to about 1% (w / w) of a lubricant (e.g., magnesium stearate); whereby the total composition makes up 100% (w / w).

[0331] In some embodiments, the composition comprises: (a) about 10% (w / w) to about 15% (w / w) of a compound of formula (I); (b) about 77% (w / w) to about 83% (w / w) of a bulking agent (e.g., crystalline cellulose); (c) about 0.95% (w / w) to about 1.05% (w / w) of a glidant (e.g., colloidal silicon dioxide); and (d) about 3.8% (w / w) to about 4.2% (w / w) of a disintegrant (e.g., croscarmellose sodium); and (e) about 0.95% (w / w) to about 1.05% (w / w) of a lubricant (e.g., magnesium stearate); whereby the total composition makes up 100% (w / w).

[0332] In some embodiments, the composition comprises: (a) about 12.5% ​​(w / w) of a compound of formula (I); (b) about 81.5% (w / w) of a bulking agent (e.g., microcrystalline cellulose); (c) about 1% (w / w) of a glidant (e.g., colloidal silicon dioxide); and (d) about 4% (w / w) of a disintegrant (e.g., croscarmellose sodium); and (e) about 1% (w / w) of a lubricant (e.g., magnesium stearate); whereby the total composition makes up 100% (w / w).

[0333] In some embodiments, the composition comprises: (a) about 27% (w / w) to about 33% (w / w) of a compound of formula (I); (b) about 63% (w / w) to about 68% (w / w) of a bulking agent (e.g., crystalline cellulose); (c) about 0.85% (w / w) to about 0.9% (w / w) of a glidant (e.g., colloidal silicon dioxide); and (d) about 3.4% (w / w) to about 3.6% (w / w) of a disintegrant (e.g., croscarmellose sodium); and (e) about 0.85% (w / w) to about 0.9% (w / w) of a lubricant (e.g., magnesium stearate); whereby the total composition makes up 100% (w / w).

[0334] In some embodiments, the composition comprises: (a) about 29.4% (w / w) of a compound of formula (I); (b) about 65.4% (w / w) of a bulking agent (e.g., microcrystalline cellulose); (c) about 0.87% (w / w) of a glidant (e.g., colloidal silicon dioxide); and (d) about 3.47% (w / w) of a disintegrant (e.g., croscarmellose sodium); and (e) about 0.87% (w / w) of a lubricant (e.g., magnesium stearate); whereby the total composition makes up 100% (w / w).

[0335] In some embodiments, the composition comprises: (a) about 37% (w / w) to about 43% (w / w) of a compound of formula (I); (b) about 52% (w / w) to about 58% (w / w) of a bulking agent (e.g., crystalline cellulose); (c) about 0.95% (w / w) to about 1.05% (w / w) of a glidant (e.g., colloidal silicon dioxide); and (d) about 3.8% (w / w) to about 4.2% (w / w) of a disintegrant (e.g., croscarmellose sodium); and (e) about 0.95% (w / w) to about 1.05% (w / w) of a lubricant (e.g., magnesium stearate); whereby the total composition makes up 100% (w / w).

[0336] In some embodiments, the composition comprises: (a) about 40% (w / w) of a compound of formula (I); (b) about 54% (w / w) of a bulking agent (e.g., microcrystalline cellulose); (c) about 1% (w / w) of a glidant (e.g., colloidal silicon dioxide); and (d) about 4% (w / w) of a disintegrant (e.g., croscarmellose sodium); and (e) about 1% (w / w) of a lubricant (e.g., magnesium stearate); whereby the total composition makes up 100% (w / w).

[0337] Pharmaceutically acceptable excipients can be present in either the intragranular or extragranular portions of the pharmaceutical composition, hi some embodiments, one or more pharmaceutically acceptable excipients are present in both the intragranular and extragranular portions.

[0338] In some embodiments, the pharmaceutical composition comprises an intragranular filler selected from the fillers described herein. In certain embodiments, the intragranular filler is microcrystalline cellulose (e.g., Avicel®). In other embodiments, the intragranular filler is microcrystalline cellulose PH102 (e.g., Avicel® PH102).

[0339] In certain embodiments, the pharmaceutical composition comprises about 30% (w / w) to about 70% (w / w) of intragranular bulking agent, hi certain embodiments, the pharmaceutical composition comprises about 35% (w / w) to about 60% (w / w) of intragranular bulking agent.

[0340] In certain embodiments, the pharmaceutical composition comprises about 50% (w / w) to about 60% (w / w) intragranular bulking agent. In certain embodiments, the pharmaceutical composition comprises about 52% (w / w) to about 58% (w / w) intragranular bulking agent. In certain embodiments, the pharmaceutical composition comprises about 54% (w / w) to about 57% (w / w) intragranular bulking agent.

[0341] In certain embodiments, the pharmaceutical composition comprises about 50% (w / w), about 51% (w / w), about 52% (w / w), about 53% (w / w), about 54% (w / w), about 55% (w / w), about 56% (w / w), about 56.5% (w / w), about 57% (w / w), about 58% (w / w), about 59% (w / w), or about 60% (w / w) of intragranular bulking agent. In some embodiments, the pharmaceutical composition comprises about 53% (w / w), about 54% (w / w), about 55% (w / w), about 56% (w / w), about 56.5% (w / w), about 57% (w / w), or about 58% (w / w) of intragranular bulking agent.

[0342] In some embodiments, the pharmaceutical composition comprises about 54% (w / w) intragranular bulking agent.

[0343] In some embodiments, the pharmaceutical composition comprises about 56.5% (w / w) intragranular bulking agent.

[0344] In some embodiments, the pharmaceutical composition comprises about 35% (w / w) to about 45% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 37% (w / w) to about 43% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 37% (w / w) to about 41% (w / w) intragranular filler.

[0345] In some embodiments, the pharmaceutical composition comprises about 35% (w / w), about 36% (w / w), about 37% (w / w), about 38% (w / w), about 39% (w / w), about 39.7% (w / w), about 40% (w / w), about 41% (w / w), about 42% (w / w), or about 43% (w / w) of intragranular bulking agent. In some embodiments, the pharmaceutical composition comprises about 38% (w / w), about 39% (w / w), about 39.7% (w / w), about 40% (w / w), or about 41% (w / w) of intragranular bulking agent.

[0346] In some embodiments, the pharmaceutical composition comprises about 39.7% (w / w) intragranular bulking agent.

[0347] In some embodiments, the pharmaceutical composition comprises an extragranular bulking agent selected from the bulking agents described herein. In certain embodiments, the extragranular bulking agent is microcrystalline cellulose (e.g., Avicel®). In some embodiments, the extragranular bulking agent is selected from microcrystalline cellulose PH102 (e.g., Avicel® PH102), PH200 (e.g., Avicel® PH200), or a mixture thereof. In some embodiments, the extragranular bulking agent is a single grade of microcrystalline cellulose. In other embodiments, the intragranular bulking agent is microcrystalline cellulose PH200 (e.g., Avicel® PH200). In some embodiments, the extragranular bulking agent is a mixture of grades of microcrystalline cellulose. In some embodiments, the extragranular bulking agent is a mixture of microcrystalline cellulose PH200 (e.g., Avicel® PH200) and PH102 (e.g., Avicel® PH102). In some embodiments, the mixture comprises equal weight percentages of microcrystalline cellulose PH200 and PH102 (e.g., "25.68% w / w bulking agent" may comprise 12.84% w / w PH200 and 12.84% w / w PH102).

[0348] In some embodiments, the pharmaceutical composition comprises from about 0% (w / w) to about 40% (w / w) extragranular bulking agent. In some embodiments, the pharmaceutical composition comprises from about 0% (w / w) to about 30% (w / w) extragranular bulking agent. In some embodiments, the pharmaceutical composition comprises from about 0% (w / w) to about 25% (w / w) extragranular bulking agent.

[0349] In some embodiments, the pharmaceutical composition comprises 0% (w / w) extragranular bulking agent.

[0350] In some embodiments, the pharmaceutical composition comprises about 15% (w / w) to about 35% (w / w) of an extragranular bulking agent. In some embodiments, the pharmaceutical composition comprises about 20% (w / w) to about 30% (w / w) of an extragranular bulking agent. In some embodiments, the pharmaceutical composition comprises about 22% (w / w) to about 27% (w / w) of an extragranular bulking agent. In some embodiments, the pharmaceutical composition comprises about 15% (w / w) to about 35% (w / w) of an extragranular bulking agent, wherein the extragranular bulking agent is microcrystalline cellulose PH200 (e.g., Avicel® PH200). In some embodiments, the pharmaceutical composition comprises about 20% (w / w) to about 30% (w / w) of an extragranular bulking agent, wherein the extragranular bulking agent is microcrystalline cellulose PH200 (e.g., Avicel® PH200). In some embodiments, the pharmaceutical composition comprises about 22% (w / w) to about 27% (w / w) of an extragranular bulking agent, and the extragranular bulking agent is microcrystalline cellulose PH200 (e.g., Avicel® PH200).

[0351] In some embodiments, the pharmaceutical composition comprises about 20% (w / w), about 21% (w / w), about 22% (w / w), about 23% (w / w), about 24% (w / w), about 25% (w / w), about 25.7% (w / w), about 26% (w / w), about 27% (w / w), about 28% (w / w), about 29% (w / w), or about 30% (w / w) of extragranular bulking agent. In some embodiments, the pharmaceutical composition comprises about 20% (w / w), about 21% (w / w), about 22% (w / w), about 23% (w / w), about 24% (w / w), about 25% (w / w), about 25.7% (w / w), about 26% (w / w), about 27% (w / w), about 28% (w / w), about 29% (w / w), or about 30% (w / w) of an extragranular bulking agent, wherein the extragranular bulking agent is microcrystalline cellulose PH200 (e.g., Avicel® PH200).

[0352] In some embodiments, the pharmaceutical composition comprises about 25% (w / w) extragranular bulking agent. In some embodiments, the pharmaceutical composition comprises about 25% (w / w) extragranular bulking agent, wherein the extragranular bulking agent is microcrystalline cellulose PH200 (e.g., Avicel® PH200). In some embodiments, the pharmaceutical composition comprises about 25% (w / w) extragranular bulking agent comprising about 12.5% ​​w / w extragranular crystalline cellulose PH200 and about 12.5% ​​w / w extragranular crystalline cellulose PH102.

[0353] In some embodiments, the pharmaceutical composition comprises about 25.7% (w / w) extragranular bulking agent comprising about 12.85% w / w extragranular crystalline cellulose PH200 and about 12.85% w / w extragranular crystalline cellulose PH102.

[0354] In some embodiments, the pharmaceutical composition comprises an intragranular glidant selected from the glidants described herein, hi some embodiments, the intragranular glidant is colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P).

[0355] In some embodiments, the pharmaceutical composition comprises from about 0.25% (w / w) to about 0.75% (w / w) of an intragranular flow enhancer. In some embodiments, the pharmaceutical composition comprises from about 0.3% (w / w) to about 0.6% (w / w) of an intragranular flow enhancer. In some embodiments, the pharmaceutical composition comprises from about 0.35% (w / w) to about 0.55% (w / w) of an intragranular flow enhancer. In some embodiments, the pharmaceutical composition comprises from about 0.3% (w / w) to about 0.45% (w / w) of an intragranular flow enhancer. In some embodiments, the pharmaceutical composition comprises from about 0.35% (w / w) to about 0.4% (w / w) of an intragranular flow enhancer. In some embodiments, the pharmaceutical composition comprises from about 0.45% (w / w) to about 0.55% (w / w) of an intragranular flow enhancer. In some embodiments, the pharmaceutical composition comprises about 0.48% (w / w) to about 0.52% (w / w) of an intragranular flow enhancer.

[0356] In some embodiments, the pharmaceutical composition comprises about 0.30% (w / w), about 0.31% (w / w), about 0.32% (w / w), about 0.33% (w / w), about 0.34% (w / w), about 0.35% (w / w), about 0.36% (w / w), about 0.37% (w / w), about 0.38% (w / w), about 0.39% (w / w), about 0.4% (w / w), about 0.41% (w / w), about 0.42% (w / w). about 0.43% (w / w), about 0.44% (w / w), 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 flow promoter. In some embodiments, the pharmaceutical composition comprises about 0.35% (w / w), about 0.36% (w / w), about 0.37% (w / w), about 0.38% (w / w), about 0.39% (w / w), 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 flow enhancer.

[0357] In some embodiments, the pharmaceutical composition comprises about 0.37% (w / w) of an intragranular flow enhancer.

[0358] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) of an intragranular glidant.

[0359] In some embodiments, the pharmaceutical composition comprises an extragranular glidant selected from the glidants described herein, hi some embodiments, the extragranular glidant is colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P).

[0360] In some embodiments, the pharmaceutical composition comprises about 0.25% (w / w) to about 0.75% (w / w) of an extragranular flow enhancer. In some embodiments, the pharmaceutical composition comprises about 0.3% (w / w) to about 0.7% (w / w) of an extragranular flow enhancer. In some embodiments, the pharmaceutical composition comprises about 0.4% (w / w) to about 0.6% (w / w) of an extragranular flow enhancer. In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w) to about 0.55% (w / w) of an extragranular flow enhancer.

[0361] In some embodiments, the pharmaceutical composition comprises 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 flow enhancer. In some embodiments, the pharmaceutical composition comprises 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 flow enhancer.

[0362] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) of an extragranular glidant.

[0363] In some embodiments, the pharmaceutical composition comprises an intragranular disintegrant selected from the disintegrants described herein, hi certain embodiments, the intragranular disintegrant is croscarmellose sodium.

[0364] In some embodiments, the pharmaceutical composition comprises about 1% (w / w) to about 3% (w / w) of an intragranular disintegrant, hi some embodiments, the pharmaceutical composition comprises about 1.2% (w / w) to about 2.4% (w / w) of an intragranular disintegrant.

[0365] In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) to about 2.2% (w / w) of an intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.2% (w / w) to about 1.8% (w / w) of an intragranular disintegrant.

[0366] In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) to about 1.6% (w / w) of an intragranular disintegrant, hi some embodiments, the pharmaceutical composition comprises about 1.8% (w / w) to about 2.2% (w / w) of an intragranular disintegrant.

[0367] In some embodiments, the pharmaceutical composition comprises about 1.92% (w / w) to about 2.08% (w / w) of intragranular disintegrant.

[0368] In some embodiments, the pharmaceutical composition comprises about 1.2% (w / w), about 1.24% (w / w), about 1.28% (w / w), about 1.32% (w / w), about 1.36% (w / w), about 1.4% (w / w), about 1.44% (w / w), about 1.47% (w / w), about 1.52% (w / w), about 1.56% (w / w), about 1.6% (w / w), about 1.64% (w / w), about 1.68% (w / w), about 1.69% (w / w), about 1.70% (w / w), about 1.71% (w / w), about 1.72% (w / w), about 1.73% (w / w), about 1.74% (w / w), about 1.75% (w / w), about 1.76% (w / w), about 1.77% (w / w), about 1.78% (w / w), about 1.79% (w / w), about 1.80% (w / w), about 1.81% (w / w), about 1.82% (w / w), about 1.83% (w / w), about 1.84% (w / w), about 1.85% (w / w), about 1.86% (w / w), about 1.87% (w / w), about 1.88% (w / w), about 1.89% (w / w), about 1.90% (w / w), about 1.91% (w / w), 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 about 1.72% (w / w), about 1.76% (w / w), about 1.8% (w / w), about 1.84% (w / w), 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 intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w), about 1.44% (w / w), about 1.47% (w / w), about 1.52% (w / w), about 1.56% (w / w), about 1.92% (w / w), about 1.96% (w / w), about 2% (w / w), about 2.04% (w / w), or about 2.08% (w / w) of intragranular disintegrant.

[0369] In some embodiments, the pharmaceutical composition comprises about 1.47% (w / w) intragranular disintegrant.

[0370] In some embodiments, the pharmaceutical composition comprises about 2% (w / w) intragranular disintegrant.

[0371] 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.

[0372] In some embodiments, the pharmaceutical composition comprises about 2% (w / w) to about 3% (w / w) of an extragranular disintegrant, hi some embodiments, the pharmaceutical composition comprises about 1.2% (w / w) to about 2.8% (w / w) of an extragranular disintegrant.

[0373] In some embodiments, the pharmaceutical composition comprises about 1.6% (w / w) to about 2.4% (w / w) of an extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.8% (w / w) to about 2.2% (w / w) of an extragranular disintegrant.

[0374] In some embodiments, the pharmaceutical composition comprises about 1.8% (w / w), about 1.84% (w / w), 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 comprises about 1.92% (w / w), about 1.96% (w / w), about 2% (w / w), about 2.04% (w / w), or about 2.08% (w / w) of an extragranular disintegrant.

[0375] In some embodiments, the pharmaceutical composition comprises about 2% (w / w) extragranular disintegrant.

[0376] 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.

[0377] In some embodiments, the pharmaceutical composition comprises about 0.25% (w / w) to about 0.75% (w / w) of intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.3% (w / w) to about 0.6% (w / w) of intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.35% (w / w) to about 0.55% (w / w) of intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.3% (w / w) to about 0.45% (w / w) of intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.35% (w / w) to about 0.4% (w / w) of intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w) to about 0.55% (w / w) of intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.48% (w / w) to about 0.52% (w / w) of an intragranular lubricant.

[0378] In some embodiments, the pharmaceutical composition comprises about 0.30% (w / w), about 0.31% (w / w), about 0.32% (w / w), about 0.33% (w / w), about 0.34% (w / w), about 0.35% (w / w), about 0.36% (w / w), about 0.37% (w / w), about 0.38% (w / w), about 0.39% (w / w), about 0.4% (w / w), about 0.41% (w / w), about 0.42% (w / w), or about 0.43% (w / w). / w), about 0.43% (w / w), about 0.44% (w / w), 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 intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.35% (w / w), about 0.36% (w / w), about 0.37% (w / w), about 0.38% (w / w), about 0.39% (w / w), 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 intragranular lubricant.

[0379] In some embodiments, the pharmaceutical composition comprises about 0.37% (w / w) of an intragranular lubricant.

[0380] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) of an intragranular lubricant.

[0381] 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.

[0382] In some embodiments, the pharmaceutical composition comprises from about 0.25% (w / w) to about 0.75% (w / w) of an extragranular lubricant, hi some embodiments, the pharmaceutical composition comprises from about 0.3% (w / w) to about 0.7% (w / w) of an extragranular lubricant.

[0383] In some embodiments, the pharmaceutical composition comprises about 0.4% (w / w) to about 0.6% (w / w) of an extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w) to about 0.55% (w / w) of an extragranular lubricant.

[0384] In some embodiments, the pharmaceutical composition comprises 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 extragranular lubricant. In some embodiments, the pharmaceutical composition comprises 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 extragranular lubricant.

[0385] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) extragranular lubricant.

[0386] In some embodiments, (a) Formula (I) [ka] and a compound of (b) an intragranular bulking agent (e.g., microcrystalline cellulose); (c) an intragranular flow promoter (e.g., colloidal silicon dioxide); and (d) an intragranular disintegrant (e.g., croscarmellose sodium); and (e) an extragranular lubricant (e.g., magnesium stearate); and (f) an extragranular bulking agent (e.g., microcrystalline cellulose); (g) an extragranular flow promoter (e.g., colloidal silicon dioxide); and (h) an extragranular disintegrant (e.g., croscarmellose sodium); and (i) an extragranular lubricant (e.g., magnesium stearate); A pharmaceutical composition comprising:

[0387] In some embodiments, (a) Formula (I) [ka] (e.g., crystalline form A described herein) of the compound of (b) an intragranular bulking agent (e.g., microcrystalline cellulose); (c) an intragranular flow promoter (e.g., colloidal silicon dioxide); and (d) an intragranular disintegrant (e.g., croscarmellose sodium); and (e) an extragranular lubricant (e.g., magnesium stearate); and (f) an extragranular bulking agent (e.g., microcrystalline cellulose); (g) an extragranular flow promoter (e.g., colloidal silicon dioxide); and (h) an extragranular disintegrant (e.g., croscarmellose sodium); and (i) an extragranular lubricant (e.g., magnesium stearate); A pharmaceutical composition comprising:

[0388] In some embodiments, the pharmaceutical composition comprises: (a) about 5% (w / w) to about 50% (w / w) of a compound of formula (I) (e.g., crystalline form A); (b) about 30% (w / w) to about 70% (w / w) of an intragranular bulking agent (e.g., microcrystalline cellulose); (c) about 0.25% (w / w) to about 0.75% (w / w) of an intragranular flow enhancer (e.g., colloidal silicon dioxide); and (d) about 1% (w / w) to about 3% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium); and (e) about 0.25% (w / w) to about 0.75% (w / w) of an intragranular lubricant (e.g., magnesium stearate); (f) about 0% (w / w) to about 40% (w / w) of an extragranular bulking agent (e.g., microcrystalline cellulose); (g) about 0.25% (w / w) to about 0.75% (w / w) of an extragranular flow promoter (e.g., colloidal silicon dioxide); (h) about 1% (w / w) to about 3% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium); (i) about 0.25% (w / w) to about 0.75% (w / w) of an extragranular lubricant (e.g., magnesium stearate); whereby the total composition makes up 100% (w / w).

[0389] In some embodiments, the pharmaceutical composition comprises: (a) about 10% (w / w) to about 45% (w / w) of a compound of formula (I) (e.g., crystalline form A); (b) about 35% (w / w) to about 60% (w / w) of an intragranular bulking agent (e.g., microcrystalline cellulose); (c) about 0.35% (w / w) to about 0.55% (w / w) of an intragranular flow promoter (e.g., colloidal silicon dioxide); and (d) about 1.4% (w / w) to about 2.2% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium); and (e) about 0.35% (w / w) to about 0.55% (w / w) of an intragranular lubricant (e.g., magnesium stearate); (f) about 0% (w / w) to about 30% (w / w) of an extragranular bulking agent (e.g., microcrystalline cellulose); (g) about 0.35% (w / w) to about 0.55% (w / w) of an extragranular flow promoter (e.g., colloidal silicon dioxide); (h) about 1.8% (w / w) to about 2.2% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium); (i) about 0.35% (w / w) to about 0.55% (w / w) of an extragranular lubricant (e.g., magnesium stearate); whereby the total composition makes up 100% (w / w).

[0390] In some embodiments, the pharmaceutical composition comprises: (a) about 10% (w / w) to about 15% (w / w) of a compound of formula (I) (e.g., crystalline form A); (b) about 52% (w / w) to about 58% (w / w) of an intragranular bulking agent (e.g., microcrystalline cellulose); (c) about 0.95% (w / w) to about 1.05% (w / w) of an intragranular flow enhancer (e.g., colloidal silicon dioxide); and (d) about 1.92% (w / w) to about 2.08% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium); and (e) about 0.95% (w / w) to about 1.05% (w / w) of an intragranular lubricant (e.g., magnesium stearate); (f) about 22% (w / w) to about 27% (w / w) of an extragranular bulking agent (e.g., microcrystalline cellulose); (g) about 0.45% (w / w) to about 0.55% (w / w) of an extragranular flow promoter (e.g., colloidal silicon dioxide); (h) about 1.8% (w / w) to about 2.2% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium); (i) about 0.45% (w / w) to about 0.55% (w / w) of an extragranular lubricant (e.g., magnesium stearate); whereby the total composition makes up 100% (w / w).

[0391] In some embodiments, the pharmaceutical composition comprises: (a) about 12.5% ​​(w / w) of a compound of formula (I) (e.g., crystalline form A); (b) about 56.5% (w / w) of an intragranular bulking agent (e.g., microcrystalline cellulose); (c) about 0.5% (w / w) of an intragranular flow promoter (e.g., colloidal silicon dioxide); and (d) about 2% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium); and (e) about 0.5% (w / w) of an intragranular lubricant (e.g., magnesium stearate); (f) about 25% (w / w) of an extragranular bulking agent (e.g., microcrystalline cellulose); (g) about 0.5% (w / w) of an extragranular flow promoter (e.g., colloidal silicon dioxide); and (h) about 2% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium); (i) about 0.5% (w / w) of an extragranular lubricant (e.g., magnesium stearate); whereby the total composition makes up 100% (w / w).

[0392] In some embodiments, the pharmaceutical composition comprises: (a) about 27% (w / w) to about 33% (w / w) of a compound of formula (I) (e.g., crystalline form A); (b) about 37% (w / w) to about 43% (w / w) of an intragranular bulking agent (e.g., microcrystalline cellulose); (c) about 0.85% (w / w) to about 0.9% (w / w) of an intragranular flow enhancer (e.g., colloidal silicon dioxide); and (d) about 1.4% (w / w) to about 1.6% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium); and (e) about 0.85% (w / w) to about 0.9% (w / w) of an intragranular lubricant (e.g., magnesium stearate); (f) about 0% (w / w) to about 30% (w / w) of an extragranular bulking agent (e.g., microcrystalline cellulose); (g) about 0.45% (w / w) to about 0.55% (w / w) of an extragranular flow promoter (e.g., colloidal silicon dioxide); (h) about 1.8% (w / w) to about 2.2% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium); (i) about 0.45% (w / w) to about 0.55% (w / w) of an extragranular lubricant (e.g., magnesium stearate); whereby the total composition makes up 100% (w / w).

[0393] In some embodiments, the pharmaceutical composition comprises: (a) about 29.4% (w / w) of a compound of formula (I) (e.g., crystalline form A); (b) about 39.7% (w / w) of an intragranular bulking agent (e.g., microcrystalline cellulose); (c) about 0.37% (w / w) of an intragranular flow promoter (e.g., colloidal silicon dioxide); and (d) about 1.47% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium); and (e) about 0.37% (w / w) of an intragranular lubricant (e.g., magnesium stearate); (f) about 25.7% (w / w) of an extragranular bulking agent (e.g., microcrystalline cellulose); (g) about 0.5% (w / w) of an extragranular flow promoter (e.g., colloidal silicon dioxide); and (h) about 2% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium); (i) about 0.5% (w / w) of an extragranular lubricant (e.g., magnesium stearate); whereby the total composition makes up 100% (w / w).

[0394] In some embodiments, the pharmaceutical composition comprises: (a) about 37% (w / w) to about 43% (w / w) of a compound of formula (I) (e.g., crystalline form A); (b) about 52% (w / w) to about 58% (w / w) of an intragranular bulking agent (e.g., microcrystalline cellulose); (c) about 0.95% (w / w) to about 1.05% (w / w) of an intragranular flow enhancer (e.g., colloidal silicon dioxide); and (d) about 1.92% (w / w) to about 2.08% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium); and (e) about 0.95% (w / w) to about 1.05% (w / w) of an intragranular lubricant (e.g., magnesium stearate); (f) about 0% (w / w) to about 30% (w / w) of an extragranular bulking agent (e.g., microcrystalline cellulose); (g) about 0.45% (w / w) to about 0.55% (w / w) of an extragranular flow promoter (e.g., colloidal silicon dioxide); (h) about 1.8% (w / w) to about 2.2% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium); (i) about 0.45% (w / w) to about 0.55% (w / w) of an extragranular lubricant (e.g., magnesium stearate); whereby the total composition makes up 100% (w / w).

[0395] In some embodiments, the pharmaceutical composition comprises: (a) about 40% (w / w) of a compound of formula (I) (e.g., crystalline form A); (b) about 54% (w / w) of an intragranular bulking agent (e.g., microcrystalline cellulose); (c) about 0.5% (w / w) of an intragranular flow promoter (e.g., colloidal silicon dioxide); and (d) about 2% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium); and (e) about 0.5% (w / w) of an intragranular lubricant (e.g., magnesium stearate); (f) about 0% (w / w) of an extragranular bulking agent (e.g., microcrystalline cellulose); (g) about 0.5% (w / w) of an extragranular flow promoter (e.g., colloidal silicon dioxide); and (h) about 2% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium); (i) about 0.5% (w / w) of an extragranular lubricant (e.g., magnesium stearate); whereby the total composition makes up 100% (w / w).

[0396] In some embodiments, the pharmaceutical composition comprises: (a) about 5% (w / w) to about 50% (w / w) of a compound of formula (I) (e.g., crystalline form A); (b) about 30% (w / w) to about 70% (w / w) of intragranular crystalline cellulose (e.g., crystalline cellulose PH102, e.g., Avicel® PH102), (c) about 0.25% (w / w) to about 0.75% (w / w) of intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P); (d) about 1% (w / w) to about 3% (w / w) of intragranular croscarmellose sodium (Ac-Di-Sol®); and (e) about 0.25% (w / w) to about 0.75% (w / w) intragranular magnesium stearate; (f) about 0% (w / w) to about 40% (w / w) of extragranular crystalline cellulose; (g) about 0.25% (w / w) to about 0.75% (w / w) of extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P); (h) about 1% (w / w) to about 3% (w / w) extragranular croscarmellose sodium (Ac-Di-Sol®); (i) about 0.25% (w / w) to about 0.75% (w / w) extragranular magnesium stearate; whereby the total composition makes up 100% (w / w).

[0397] In some embodiments, the pharmaceutical composition comprises: (a) about 10% (w / w) to about 45% (w / w) of a compound of formula (I) (e.g., crystalline form A); (b) about 35% (w / w) to about 60% (w / w) of intragranular crystalline cellulose (e.g., crystalline cellulose PH102, e.g., Avicel® PH102), (c) about 0.35% (w / w) to about 0.55% (w / w) of intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P); (d) about 1.4% (w / w) to about 2.2% (w / w) intragranular croscarmellose sodium (Ac-Di-Sol®); and (e) about 0.35% (w / w) to about 0.55% (w / w) intragranular magnesium stearate; (f) about 0% (w / w) to about 30% (w / w) of extragranular crystalline cellulose; (g) about 0.35% (w / w) to about 0.55% (w / w) of extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P); (h) about 1.8% (w / w) to about 2.2% (w / w) extragranular croscarmellose sodium (Ac-Di-Sol®); and (i) about 0.35% (w / w) to about 0.55% (w / w) extragranular magnesium stearate; whereby the total composition makes up 100% (w / w).

[0398] In some embodiments, the pharmaceutical composition comprises: (a) about 10% (w / w) to about 15% (w / w) of a compound of formula (I) (e.g., crystalline form A); (b) about 52% (w / w) to about 58% (w / w) of intragranular crystalline cellulose (e.g., crystalline cellulose PH102, e.g., Avicel® PH102); (c) about 0.95% (w / w) to about 1.05% (w / w) of intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P); (d) about 1.92% (w / w) to about 2.08% (w / w) intragranular croscarmellose sodium (Ac-Di-Sol®); and (e) about 0.95% (w / w) to about 1.05% (w / w) intragranular magnesium stearate; (f) about 22% (w / w) to about 27% (w / w) extragranular crystalline cellulose (e.g., crystalline cellulose PH200, e.g., Avicel® PH200); (g) about 0.45% (w / w) to about 0.55% (w / w) of extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P); (h) about 1.8% (w / w) to about 2.2% (w / w) extragranular croscarmellose sodium (Ac-Di-Sol®); and (i) about 0.45% (w / w) to about 0.55% (w / w) extragranular magnesium stearate; whereby the total composition makes up 100% (w / w).

[0399] In some embodiments, the pharmaceutical composition comprises: (a) about 12.5% ​​(w / w) of a compound of formula (I) (e.g., crystalline form A); (b) about 56.5% (w / w) intragranular crystalline cellulose (e.g., crystalline cellulose PH102, e.g., Avicel® PH102); and (c) about 0.5% (w / w) intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P); and (d) about 2% (w / w) intragranular croscarmellose sodium (Ac-Di-Sol®); and (e) about 0.5% (w / w) intragranular magnesium stearate; (f) about 25% (w / w) extragranular crystalline cellulose (e.g., crystalline cellulose PH200, e.g., Avicel® PH200); (g) about 0.5% (w / w) extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P); (h) about 2% (w / w) extragranular croscarmellose sodium (Ac-Di-Sol®); and (i) about 0.5% (w / w) extragranular magnesium stearate; whereby the total composition makes up 100% (w / w).

[0400] In some embodiments, the pharmaceutical composition comprises: (a) about 27% (w / w) to about 33% (w / w) of a compound of formula (I) (e.g., crystalline form A); (b) about 37% (w / w) to about 43% (w / w) of intragranular crystalline cellulose (e.g., crystalline cellulose PH102, e.g., Avicel® PH102); (c) about 0.85% (w / w) to about 0.9% (w / w) of intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P); (d) about 1.4% (w / w) to about 1.6% (w / w) intragranular croscarmellose sodium (Ac-Di-Sol®); and (e) about 0.85% (w / w) to about 0.9% (w / w) intragranular magnesium stearate; (f) about 0% (w / w) to about 30% (w / w) of extragranular crystalline cellulose (e.g., a 1:1 ratio of crystalline cellulose PH200 (e.g., Avicel® PH200 and crystalline cellulose PH102 (e.g., Avicel® PH102)); (g) about 0.45% (w / w) to about 0.55% (w / w) of extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P); (h) about 1.8% (w / w) to about 2.2% (w / w) extragranular croscarmellose sodium (Ac-Di-Sol®); and (i) about 0.45% (w / w) to about 0.55% (w / w) extragranular magnesium stearate; whereby the total composition makes up 100% (w / w).

[0401] In some embodiments, the pharmaceutical composition comprises: (a) about 29.4% (w / w) of a compound of formula (I) (e.g., crystalline form A); (b) about 39.7% (w / w) intragranular crystalline cellulose (e.g., crystalline cellulose PH102, e.g., Avicel® PH102); and (c) about 0.37% (w / w) intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P); and (d) about 1.47% (w / w) intragranular croscarmellose sodium (Ac-Di-Sol®); and (e) about 0.37% (w / w) intragranular magnesium stearate; (f) about 25.7% (w / w) extragranular crystalline cellulose (e.g., a 1:1 ratio of crystalline cellulose PH200 (e.g., Avicel® PH200) (about 12.85% w / w) and crystalline cellulose PH102 (e.g., Avicel® PH102) (about 12.85% w / w)); (g) about 0.5% (w / w) extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P); (h) about 2% (w / w) extragranular croscarmellose sodium (Ac-Di-Sol®); and (i) about 0.5% (w / w) extragranular magnesium stearate; whereby the total composition makes up 100% (w / w).

[0402] In some embodiments, the pharmaceutical composition comprises: (a) about 37% (w / w) to about 43% (w / w) of a compound of formula (I) (e.g., crystalline form A); (b) about 52% (w / w) to about 58% (w / w) of intragranular crystalline cellulose (e.g., crystalline cellulose PH102, e.g., Avicel® PH102); (c) about 0.95% (w / w) to about 1.05% (w / w) of intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P); (d) about 1.92% (w / w) to about 2.08% (w / w) intragranular croscarmellose sodium (Ac-Di-Sol®); and (e) about 0.95% (w / w) to about 1.05% (w / w) intragranular magnesium stearate; (f) about 0% (w / w) to about 30% (w / w) of extragranular crystalline cellulose; (g) about 0.45% (w / w) to about 0.55% (w / w) of extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P); (h) about 1.8% (w / w) to about 2.2% (w / w) extragranular croscarmellose sodium (Ac-Di-Sol®); and (i) about 0.45% (w / w) to about 0.55% (w / w) extragranular magnesium stearate; whereby the total composition makes up 100% (w / w).

[0403] In some embodiments, the pharmaceutical composition comprises: (a) about 40% (w / w) of a compound of formula (I) (e.g., crystalline form A); (b) about 54% (w / w) intragranular crystalline cellulose (e.g., crystalline cellulose PH102, e.g., Avicel® PH102); and (c) about 0.5% (w / w) intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P); and (d) about 2% (w / w) intragranular croscarmellose sodium (Ac-Di-Sol®); and (e) about 0.5% (w / w) intragranular magnesium stearate; (f) about 0% (w / w) extragranular crystalline cellulose; (g) about 0.5% (w / w) extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P); (h) about 2% (w / w) extragranular croscarmellose sodium (Ac-Di-Sol®); and (i) about 0.5% (w / w) extragranular magnesium stearate; whereby the total composition makes up 100% (w / w).

[0404] Dosage form In some embodiments, a dosage form is provided comprising the pharmaceutical composition described herein.

[0405] In some embodiments, a dosage form intended for oral administration is provided that comprises a pharmaceutical composition described herein.

[0406] In certain embodiments, the dosage form is selected from the group consisting of a powder, a sachet, a stick pack, a capsule, a minitab, and a tablet.

[0407] In certain embodiments, the dosage form is a tablet.

[0408] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 50 mg to 1000 mg.

[0409] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 100 mg to 750 mg.

[0410] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 50 mg to 150 mg.

[0411] 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.

[0412] 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.

[0413] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 100 mg.

[0414] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 300 mg to 500 mg.

[0415] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, 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, or about 500 mg.

[0416] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 320 mg, about 330 mg, about 340 mg, about 350 mg, or about 360 mg.

[0417] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 340 mg.

[0418] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 380 mg, about 390 mg, about 400 mg, about 410 mg, or about 420 mg.

[0419] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 400 mg.

[0420] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 600 mg to 900 mg.

[0421] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, or about 900 mg.

[0422] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, or about 800 mg.

[0423] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 750 mg.

[0424] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 100 mg, about 340 mg, about 400 mg, or about 750 mg.

[0425] In some embodiments, the composition comprises from about 5 mg to about 400 mg of a compound of Formula (I). In some embodiments, the dosage form comprises from about 10 mg to about 350 mg of a compound of Formula (I).

[0426] In some embodiments, the dosage form contains about 8 mg to about 17 mg, about 40 mg to about 60 mg, about 80 mg to about 120 mg, or about 250 to about 350 mg of the compound of Formula (I). In some embodiments, the dosage form contains about 8 mg to about 17 mg of the compound of Formula (I). In some embodiments, the dosage form contains about 10 mg to about 15 mg of the compound of Formula (I). In some embodiments, the dosage form contains about 12 mg to about 13 mg of the compound of Formula (I).

[0427] In some embodiments, the dosage form comprises about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 12.5 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, or about 17 mg of the compound of formula (I).

[0428] In some embodiments, the dosage form comprises about 12.5 mg of the compound of formula (I).

[0429] In some embodiments, the dosage form contains about 40 mg to about 60 mg of the compound of Formula (I). In some embodiments, the dosage form contains about 45 mg to about 55 mg of the compound of Formula (I). In some embodiments, the dosage form contains about 47 mg to about 53 mg of the compound of Formula (I).

[0430] 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).

[0431] In some embodiments, the dosage form comprises about 50 mg of the compound of formula (I).

[0432] In some embodiments, the dosage form contains about 80 mg to about 120 mg of the compound of Formula (I). In some embodiments, the dosage form contains about 90 mg to about 110 mg of the compound of Formula (I). In some embodiments, the dosage form contains about 95 mg to about 105 mg of the compound of Formula (I). In some embodiments, the dosage form contains about 98 mg to about 102 mg of the compound of Formula (I).

[0433] In some embodiments, the dosage form comprises about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 101 mg, about 102 mg, about 103 mg, about 104 mg, about 105 mg, about 106 mg, about 107 mg, about 108 mg, about 109 mg, or about 110 mg of the compound of formula (I).

[0434] In some embodiments, the dosage form comprises about 100 mg of the compound of formula (I).

[0435] In some embodiments, the dosage form contains about 250 to about 350 mg of the compound of Formula (I). In some embodiments, the dosage form contains about 260 to about 340 mg of the compound of Formula (I). In some embodiments, the dosage form contains about 270 to about 330 mg of the compound of Formula (I). In some embodiments, the dosage form contains about 280 to about 320 mg of the compound of Formula (I). In some embodiments, the dosage form contains about 290 to about 310 mg of the compound of Formula (I). In some embodiments, the dosage form contains about 295 to about 305 mg of the compound of Formula (I).

[0436] In some embodiments, the dosage form comprises about 290 mg, about 291 mg, about 292 mg, about 293 mg, about 294 mg, about 295 mg, about 296 mg, about 297 mg, about 298 mg, about 299 mg, about 300 mg, about 301 mg, about 302 mg, about 303 mg, about 304 mg, about 305 mg, about 306 mg, about 307 mg, about 308 mg, about 309 mg, or about 310 mg of the compound of formula (I).

[0437] In certain embodiments, the dosage form comprises about 300 mg of the compound of formula (I).

[0438] In some embodiments, the dosage form contains about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 12.5 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 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, about 55 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 101 mg, about Contains 102 mg, about 103 mg, about 104 mg, about 105 mg, about 106 mg, about 107 mg, about 108 mg, about 109 mg, about 110 mg, about 290 mg, about 291 mg, about 292 mg, about 293 mg, about 294 mg, about 295 mg, about 296 mg, about 297 mg, about 298 mg, about 299 mg, about 300 mg, about 301 mg, about 302 mg, about 303 mg, about 304 mg, about 305 mg, about 306 mg, about 307 mg, about 308 mg, about 309 mg, or about 310 mg of the compound of formula (I).

[0439] In some embodiments, the dosage form comprises about 10 mg, about 11 mg, about 12 mg, about 12.5 mg, about 13 mg, about 14 mg, about 15 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 101 mg, about 102 mg, about 103 mg, about 104 mg, about 295 mg, about 296 mg, about 297 mg, about 298 mg, about 299 mg, about 300 mg, about 301 mg, about 302 mg, about 303 mg, about 304 mg, or about 305 mg of the compound of Formula (I).

[0440] In certain embodiments, the dosage form comprises about 12.5 mg, about 50 mg, about 100 mg, or about 300 mg of the compound of formula (I).

[0441] In some embodiments, the dosage form comprises 12.5 mg of the compound of formula (I), 56.5 mg of intragranular crystalline cellulose, 0.5 mg of intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 2 mg of intragranular croscarmellose sodium (Ac-Di-Sol®), 0.5 mg of intragranular magnesium stearate, 25 mg of extragranular crystalline cellulose, 0.5 mg of extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 2 mg of extragranular croscarmellose sodium (Ac-Di-Sol®), and 0.5 mg of extragranular magnesium stearate.

[0442] In some embodiments, the dosage form comprises 50 mg of the compound of formula (I), 226 mg of intragranular crystalline cellulose, 2 mg of intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 8 mg of intragranular croscarmellose sodium (Ac-Di-Sol®), 2 mg of intragranular magnesium stearate, 100 mg of extragranular crystalline cellulose, 2 mg of extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 8 mg of extragranular croscarmellose sodium (Ac-Di-Sol®), and 2 mg of extragranular magnesium stearate.

[0443] In some embodiments, the dosage form contains 100 mg of the compound of formula (I), 135 mg of intragranular crystalline cellulose, 1.25 mg of intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 5 mg of intragranular croscarmellose sodium (Ac-Di-Sol®), 1.25 mg of intragranular magnesium stearate, 87.3 mg of extragranular crystalline cellulose (e.g., 43.65 mg of PH200 and 43.65 mg of PH102), 1.7 mg of extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 6.8 mg of extragranular croscarmellose sodium (Ac-Di-Sol®), and 1.7 mg of extragranular magnesium stearate.

[0444] In some embodiments, the dosage form comprises 300 mg of the compound of formula (I), 405 mg of intragranular crystalline cellulose, 3.75 mg of intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 15 mg of intragranular croscarmellose sodium (Ac-Di-Sol®), 3.75 mg of intragranular magnesium stearate, 3.75 mg of extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 15 mg of extragranular croscarmellose sodium (Ac-Di-Sol®), and 3.75 mg of extragranular magnesium stearate.

[0445] In certain embodiments, the tablet further comprises a coating. In certain embodiments, the coating is selected from the group consisting of a film-forming polymer, a plasticizer, and combinations thereof. In certain embodiments, the film-forming polymer is selected from the group consisting of hypromellose, ethyl cellulose, 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 comprises polyvinyl alcohol.

[0446] In certain embodiments, the coating comprises 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.

[0447] Preparation method In some embodiments, there is provided a process for preparing a pharmaceutical composition described herein, the process comprising, for example, (a) mixing a compound of formula (I) with one or more pharmaceutically acceptable excipients to obtain a mixture; (b) granulating the mixture to obtain granules; (c) milling the granules to obtain an intragranular phase; (d) mixing the intragranular phase with one or more extragranular excipients to obtain a pharmaceutical composition; Includes:

[0448] In another aspect, there is provided a process for preparing the dosage forms described herein, the process comprising, for example, (e) mixing a compound of formula (I) with one or more pharmaceutically acceptable excipients to obtain a mixture; (f) granulating the mixture to obtain granules; (g) milling the granules to obtain an intragranular phase; (h) mixing the intragranular phase with one or more extragranular excipients to obtain a pharmaceutical composition (pharmaceutical mixture); (i) compressing the pharmaceutical mixture into tablets; Includes:

[0449] 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, glidants, and combinations thereof.

[0450] In certain embodiments, in step (a), the compound of formula (I) is mixed with a filler, a disintegrant, a lubricant, and a glidant.

[0451] In certain embodiments, in step (a), the bulking agent is microcrystalline cellulose.

[0452] In some embodiments, in step (a), the disintegrant is croscarmellose sodium.

[0453] In certain embodiments, in step (a), the glidant is colloidal silicon dioxide.

[0454] In certain embodiments, in step (a), the lubricant is magnesium stearate.

[0455] In certain embodiments, in step (d), the one or more extragranular excipients are selected from the group consisting of fillers, disintegrants, lubricants, glidants, and combinations thereof.

[0456] In some embodiments, in step (d), the intragranular phase is mixed with a filler, a disintegrant, a lubricant, and a glidant.

[0457] In certain embodiments, in step (d), the disintegrant is croscarmellose sodium.

[0458] In some embodiments, in step (d), the glidant is colloidal silicon dioxide.

[0459] In certain embodiments, in step (d), the lubricant is magnesium stearate.

[0460] In certain embodiments, granulating the mixture to obtain granules comprises a dry granulation process step. In certain embodiments, granulating the mixture to obtain granules comprises a wet granulation process step.

[0461] In certain embodiments, the tablet comprises a coating. In certain embodiments, the coating comprises one or more film-forming polymers selected from the group consisting of hypromellose, ethylcellulose, polyvinylpyrrolidone, polyacrylates, plasticizers, and combinations thereof. In other embodiments, the coating comprises polyvinyl alcohol.

[0462] In certain embodiments, the coating comprises 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.

[0463] In some embodiments, there is provided a pharmaceutical composition as described herein, prepared by a process as described herein.

[0464] Methods of Use and Treatment Treatment of MTAP-deficient and / or MTA-accumulating proliferative disorders 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 deletion in a subset of human cancers has been 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, more than 50% of malignant peripheral nerve sheath tumors (MPNSTs) have deletions in MTAP (Lee et al., Nat. Gen. (2014)). Other cancers in which MTAP deletion is common include glioblastoma (GBM), mesothelioma, bladder cancer, pancreatic cancer, esophageal cancer, squamous cell lung cancer, melanoma, diffuse large B-cell lymphoma (DLBCL), head and neck cancer, cholangiocarcinoma, lung adenoma, sarcoma, gastric cancer, glioma, adrenal carcinoma, thymoma, breast cancer, liver cancer, ovarian cancer, papillary renal cell carcinoma, uterine cancer, prostate cancer, and clear cell renal cell carcinoma. Loss of MTAP in cancer cells is one of the mechanisms that leads to MTAP deficiency in cancer cells, increasing intracellular MTA accumulation and increasing dependency on protein arginine methyltransferase 5 (PRMT5). Other mechanisms that lead to MTAP deficiency include, among others, MTAP translocations and MTAP epigenetic silencing, which may also lead to MTAP-null and / or MTAP-deficient tumors. Because PRMT5 mediates the formation of symmetric dimethylarginine (SDMA), PRMT5 activity can be assessed by measuring SDMA levels using antibodies against SDMA or SDMA-modified polypeptides.

[0465] In some embodiments, methods are provided for treating a human or animal subject having or diagnosed as having an MTAP deficiency-associated and / or MTA accumulation proliferative disorder (e.g., cancer), the methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure (e.g., a crystalline form of the compound of Formula (I), crystalline Form A of the 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.

[0466] In some embodiments, provided are compounds of the present disclosure (e.g., crystalline forms of the compound of Formula (I), crystalline Form A of the compound of Formula (I)) or pharmaceutical compositions comprising compounds of Formula (I) of the present disclosure for use in methods of treating a human or animal subject having or diagnosed with an MTAP deficiency-associated and / or MTA accumulation proliferative disorder (e.g., cancer). In some embodiments, the compound or composition is provided in a therapeutically effective amount.

[0467] In some embodiments, provided are compounds of the present disclosure (e.g., crystalline forms of the compound of Formula (I), crystalline Form A of the compound of Formula (I)) or pharmaceutical compositions comprising compounds of Formula (I) of the present disclosure for use in the manufacture of a medicament for treating a human or animal subject having or diagnosed with an MTAP deficiency-associated and / or MTA accumulation proliferative disorder (e.g., cancer). In some embodiments, the compound or composition is provided in a therapeutically effective amount.

[0468] In some embodiments, there is provided a use of a compound of the present disclosure (e.g., a crystalline form of the compound of Formula (I), crystalline Form A of the compound of Formula (I)) or a pharmaceutical composition comprising a compound of Formula (I) of the present disclosure in a method of treating a human or animal subject having or diagnosed with an MTAP deficiency-associated and / or MTA accumulation proliferative disorder (e.g., cancer). In some embodiments, the use is of a therapeutically effective amount of the compound or composition.

[0469] In some embodiments, there is provided a use of a compound of the present disclosure (e.g., a crystalline form of the compound of Formula (I), crystalline Form A of the compound of Formula (I)) or a pharmaceutical composition comprising a compound of Formula (I) of the present disclosure in the manufacture of a medicament for treating a human or animal subject having or diagnosed with an MTAP deficiency-associated and / or MTA accumulation proliferative disorder (e.g., cancer). In some embodiments, the use is of a therapeutically effective amount of the compound or composition.

[0470] In some embodiments, a method is provided for treating an MTAP deficiency-associated and / or MTA accumulation proliferative disorder (e.g., cancer) in a subject in need of such treatment, the method comprising administering to the subject an effective amount (e.g., a therapeutically effective amount) of a compound of the present disclosure (e.g., a crystalline form of the compound of Formula (I), crystalline Form A of the 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.

[0471] In some embodiments, methods are provided for treating a human or animal subject having or diagnosed as having an MTAP deficiency-associated and / or MTA accumulation proliferative disorder (e.g., cancer), the methods comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of the present disclosure. In some embodiments, the method comprises administering to the subject a dosage form of the present disclosure. In one embodiment, the compound or composition is administered in combination with a second therapeutic agent.

[0472] In some embodiments, methods are provided for treating an MTAP deficiency-associated and / or MTA accumulation proliferative disorder (e.g., cancer) in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of the present disclosure. In certain embodiments, the methods comprise administering to the subject a dosage form of the present disclosure. In one embodiment, the compound or composition is administered in combination with a second therapeutic agent.

[0473] In some embodiments, the subject is a human.

[0474] In certain embodiments, the disease is an MTAP-deficient and / or MTA-accumulating cancer.

[0475] In some embodiments, the cancer is a glioma, glioblastoma, malignant peripheral nerve sheath tumor (MPNST, e.g., intracranial 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), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous cell or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, biliary sarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon, or a sarcoma.

[0476] In some embodiments, the cancer is MTAP-deficient and / or MTA-accumulating glioma, glioblastoma, malignant peripheral nerve sheath tumor (MPNST, e.g., intracranial 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), 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, biliary sarcoma, brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon cancer, sarcoma, or CNS metastasis from a solid tumor.

[0477] In some embodiments, the cancer is a central nervous system (CNS) malignancy. In some embodiments, the CNS malignancy is selected from a glioma (e.g., a low-grade glioma, an intermediate-grade glioma), an intracranial MPNST tumor, a glioblastoma, a glioblastoma multiforme, or a CNS metastasis derived from a solid tumor. In some embodiments, the CNS malignancy is a glioma. In some embodiments, the CNS malignancy is a low-grade glioma. In some embodiments, the CNS malignancy is an intermediate-grade glioma. In some embodiments, the CNS malignancy is a glioblastoma or a glioblastoma multiforme. In some embodiments, the CNS malignancy is a glioblastoma. In some embodiments, the CNS malignancy is a glioblastoma multiforme. In some embodiments, the CNS malignancy is an MTAP-deficient glioblastoma. In some embodiments, the CNS malignancy is an intracranial MPNST tumor. In some embodiments, the CNS malignancy is a CNS metastasis derived from a solid tumor.

[0478] In some embodiments, the cancer is a cancer selected from the group consisting of cholangiocarcinoma, NSCLC (adenocarcinoma), NSCLC (squamous cell carcinoma), bladder cancer, and DLBCL. In some embodiments, the cancer is a cancer selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma), mesothelioma, cholangiocarcinoma, urothelial carcinoma, and malignant peripheral nerve sheath tumor. In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (adenocarcinoma). In some embodiments, the cancer is NSCLC (squamous cell carcinoma). In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is DLBCL.

[0479] In some embodiments, the cancer is a cancer selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma), mesothelioma, cholangiocarcinoma, urothelial carcinoma, and malignant peripheral nerve sheath tumor.

[0480] In some embodiments, the compound of Formula (I), its crystalline form (e.g., crystalline Form A), pharmaceutical composition (e.g., comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof), and dosage form described herein can be used in a method of inhibiting the proliferation of MTAP-deficient cells in a subject in need thereof, the method comprising administering to the subject a compound of Formula (I), its crystalline form (e.g., crystalline Form A), pharmaceutical composition (e.g., comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof), or dosage form described herein in an amount effective to inhibit the proliferation of MTAP-deficient cells. In one embodiment, the subject in need thereof is suffering from a cancer selected from the group consisting of glioma, glioblastoma, malignant peripheral nerve sheath tumor (MPNST, e.g., intracranial 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), 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, biliary sarcoma, brain, stomach, kidney, breast, endometrial, urinary tract, liver, soft tissue, pleural, and colon cancer, sarcoma, or CNS metastases from solid tumors.

[0481] In some embodiments, the cancer is a central nervous system (CNS) malignancy. In some embodiments, the CNS malignancy is selected from a glioma (e.g., a low-grade glioma, an intermediate-grade glioma), an intracranial MPNST tumor, a glioblastoma, a glioblastoma multiforme, or a CNS metastasis derived from a solid tumor. In some embodiments, the CNS malignancy is a glioma. In some embodiments, the CNS malignancy is a low-grade glioma. In some embodiments, the CNS malignancy is an intermediate-grade glioma. In some embodiments, the CNS malignancy is a glioblastoma or a glioblastoma multiforme. In some embodiments, the CNS malignancy is a glioblastoma. In some embodiments, the CNS malignancy is a glioblastoma multiforme. In some embodiments, the CNS malignancy is an MTAP-deficient glioblastoma. In some embodiments, the CNS malignancy is an intracranial MPNST tumor. In some embodiments, the CNS malignancy is a CNS metastasis derived from a solid tumor.

[0482] In some embodiments, the cancer is a cancer selected from the group consisting of cholangiocarcinoma, NSCLC (adenocarcinoma), NSCLC (squamous cell carcinoma), bladder cancer, and DLBCL. In some embodiments, the cancer is a cancer selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma), mesothelioma, cholangiocarcinoma, urothelial carcinoma, and malignant peripheral nerve sheath tumor. In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (adenocarcinoma). In some embodiments, the cancer is NSCLC (squamous cell carcinoma). In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is DLBCL.

[0483] In some embodiments, the cancer is a cancer selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma), mesothelioma, cholangiocarcinoma, urothelial carcinoma, and malignant peripheral nerve sheath tumor.

[0484] In some embodiments, a compound of Formula (I) described herein, a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form described herein can be used in a method of inhibiting the proliferation of MTA-accumulating cells in a subject in need thereof, the method comprising administering to the subject a compound of Formula (I) described herein, a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form described herein in an amount effective to inhibit the proliferation of MTA-accumulating cells. In one embodiment, the subject in need thereof is suffering from a cancer selected from the group consisting of glioma, glioblastoma, malignant peripheral nerve sheath tumor (MPNST, e.g., intracranial 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), 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, biliary sarcoma, brain, stomach, kidney, breast, endometrial, urinary tract, liver, soft tissue, pleural, and colon cancer, sarcoma, or CNS metastases from solid tumors.

[0485] In some embodiments, the cancer is a CNS malignancy. In some embodiments, the CNS malignancy is selected from a glioma (e.g., a low-grade glioma, an intermediate-grade glioma), an intracranial MPNST tumor, a glioblastoma, a glioblastoma multiforme, or a CNS metastasis derived from a solid tumor. In some embodiments, the CNS malignancy is a glioma. In some embodiments, the CNS malignancy is a low-grade glioma. In some embodiments, the CNS malignancy is an intermediate-grade glioma. In some embodiments, the CNS malignancy is a glioblastoma or a glioblastoma multiforme. In some embodiments, the CNS malignancy is a glioblastoma. In some embodiments, the CNS malignancy is a glioblastoma multiforme. In some embodiments, the CNS malignancy is an MTAP-deficient glioblastoma. In some embodiments, the CNS malignancy is an intracranial MPNST tumor. In some embodiments, the CNS malignancy is a CNS metastasis derived from a solid tumor.

[0486] In some embodiments, the cancer is a cancer selected from the group consisting of cholangiocarcinoma, NSCLC (adenocarcinoma), NSCLC (squamous cell carcinoma), bladder cancer, and DLBCL. In some embodiments, the cancer is a cancer selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma), mesothelioma, cholangiocarcinoma, urothelial carcinoma, and malignant peripheral nerve sheath tumor. In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (adenocarcinoma). In some embodiments, the cancer is NSCLC (squamous cell carcinoma). In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is DLBCL.

[0487] In some embodiments, the cancer is a cancer selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma), mesothelioma, cholangiocarcinoma, urothelial carcinoma, and malignant peripheral nerve sheath tumor.

[0488] In some embodiments, the compound of Formula (I) described herein, a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form described herein can be used in a method of suppressing the proliferation of MTAP-deficient and / or MTA-accumulating cells in a subject in need thereof, the method comprising administering to the subject a compound of Formula (I) described herein, a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form described herein in an amount effective to inhibit the proliferation of MTAP-deficient and / or MTA-accumulating cells. In one embodiment, the subject in need thereof is suffering from a cancer selected from the group consisting of glioma, glioblastoma, malignant peripheral nerve sheath tumor (MPNST, e.g., intracranial 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), 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, biliary sarcoma, brain, stomach, kidney, breast, endometrial, urinary tract, liver, soft tissue, pleural, and colon cancer, sarcoma, or CNS metastases from solid tumors.

[0489] In some embodiments, the cancer is a CNS malignancy. In some embodiments, the CNS malignancy is selected from a glioma (e.g., a low-grade glioma, an intermediate-grade glioma), an intracranial MPNST tumor, a glioblastoma, a glioblastoma multiforme, or a CNS metastasis derived from a solid tumor. In some embodiments, the CNS malignancy is a glioma. In some embodiments, the CNS malignancy is a low-grade glioma. In some embodiments, the CNS malignancy is an intermediate-grade glioma. In some embodiments, the CNS malignancy is a glioblastoma or a glioblastoma multiforme. In some embodiments, the CNS malignancy is a glioblastoma. In some embodiments, the CNS malignancy is a glioblastoma multiforme. In some embodiments, the CNS malignancy is an MTAP-deficient glioblastoma. In some embodiments, the CNS malignancy is an intracranial MPNST tumor. In some embodiments, the CNS malignancy is a CNS metastasis derived from a solid tumor.

[0490] In some embodiments, the cancer is a cancer selected from the group consisting of cholangiocarcinoma, NSCLC (adenocarcinoma), NSCLC (squamous cell carcinoma), bladder cancer, and DLBCL. In some embodiments, the cancer is a cancer selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma), mesothelioma, cholangiocarcinoma, urothelial carcinoma, and malignant peripheral nerve sheath tumor. In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (adenocarcinoma). In some embodiments, the cancer is NSCLC (squamous cell carcinoma). In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is DLBCL.

[0491] In some embodiments, the cancer is a cancer selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma), mesothelioma, cholangiocarcinoma, urothelial carcinoma, and malignant peripheral nerve sheath tumor.

[0492] Combination therapy In some embodiments, methods are provided for treating MTAP-deficient and / or MTA-accumulating proliferative disorders (e.g., cancer) using a compound of Formula (I), a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., one comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form described herein in combination with one or more therapeutic agents.

[0493] In some embodiments, methods are provided for treating MTAP-deficient and / or MTA-accumulating proliferative disorders (e.g., cancer) using a compound of Formula (I), a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form described herein in combination with a second therapeutic agent. In some embodiments, methods are provided for treating MTAP-deficient and / or MTA-accumulating proliferative disorders (e.g., cancer) using a compound of Formula (I), a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form described herein in combination with a second therapeutic agent and a third therapeutic agent. In some embodiments, methods are provided for treating MTAP-deficient and / or MTA-accumulating proliferative disorders (e.g., cancer) using a compound of Formula (I), a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form described herein in combination with a second therapeutic agent, a third therapeutic agent, and a fourth therapeutic agent.

[0494] The term "combination" refers to either a fixed combination in one unit dosage form, or a combined administration in which the compound of Formula (I) described herein, a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., one comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form and a combination partner (e.g., another drug (also referred to as a "therapeutic agent" or "co-drug") as described below) may be administered simultaneously or separately within a time interval, particularly where such time interval allows the combination partners to exhibit a cooperative effect (e.g., synergistic effect). Such single components may be packaged in a kit or individually packaged. One or both of the components (e.g., powder or liquid) may be reconstituted or diluted to the desired dose before administration. Terms such as "co-administration" or "co-administration," as used herein, are meant to encompass the administration of selected combination partners to a single subject (e.g., patient) in need thereof, and are intended to include therapeutic regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term "pharmaceutical combination," as used herein, refers to a product resulting from the mixing or combining of two or more therapeutic agents, and includes both fixed and non-fixed combinations of therapeutic agents. The term "fixed combination" means that both therapeutic agents, e.g., the compound of Formula (I) described herein, its crystalline form (e.g., crystalline Form A), pharmaceutical compositions (e.g., those containing the compound of Formula (I) or a pharmaceutically acceptable salt thereof), or dosage forms, and combination partners, are administered to a patient simultaneously in the form of a single entity or dosage form. The term "non-fixed combination" means that both therapeutic agents, e.g., the compound of Formula (I) described herein, its crystalline form (e.g., crystalline Form A), pharmaceutical compositions (e.g., those containing the compound of Formula (I) or a pharmaceutically acceptable salt thereof), or dosage forms, and combination partners, are administered to a patient simultaneously, concurrently, or sequentially as separate entities without specific time restrictions, such administration providing therapeutically effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, e.g., the administration of three or more therapeutic agents.

[0495] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in this disclosure. Such administration encompasses co-administration of such therapeutic agents in a substantially simultaneous manner (such as a single capsule with a fixed ratio of active ingredients). Alternatively, such administration encompasses co-administration in multiple containers for each active ingredient, or in separate containers (e.g., tablets, capsules, powders, and liquids). The powders and / or liquids may be reconstituted or diluted to the desired dose prior to administration. Furthermore, such administration encompasses the use of various therapeutic agents in a sequential manner, either at about the same time or at different times.

[0496] In certain embodiments, the compound of Formula (I), a crystalline form thereof (e.g., crystalline Form A), pharmaceutical composition (e.g., one comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof), or dosage form described herein is combined with other therapeutic agents, including, but not limited to, other anti-cancer agents, anti-allergic agents, anti-emetic agents (or anti-emetic drugs), analgesics, cytoprotective agents, and combinations thereof.

[0497] In some embodiments, a compound of Formula (I) described herein, a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form may be combined with an agonist, such as anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), injectable busulfan (Busulfex®), capecitabine (Xeloda®), N4-pen (Penoxacin®), or benzodiazepine (Benoxacin®). Benzyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), injectable cytarabine liposome (DepoCyt®), ), dacarbazine (DTIC-Dome®), dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), injectable daunorubicin citrate liposome (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil Uracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, gemcitabine (difluorodeoxycytidine), hydroxyurea (Hydrea®), idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®),6-mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), Mylotarg, paclitaxel (Taxol®), nab-paclitaxel (Abraxane®), Phoenix (Yttrium 90 / MX-DTPA), pentostatin, carmustine-containing polifeprosan 20 implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide Methods for treating a disease or disorder (e.g., cancer) are provided, comprising administering or co-administering, in any order, a common chemotherapeutic agent selected from the group consisting of benzodiazepine (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), injectable topotecan hydrochloride (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®) to a patient in need of such treatment.

[0498] In some embodiments, provided are methods of treating a disease or disorder (e.g., cancer) comprising administering or co-administering, in any order, a compound of Formula (I), a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form described herein and an EGFR inhibitor (e.g., cetuximab, panitumimab, erlotinib, gefitinib, and EGFRiNOS) to a patient in need of such treatment. In some embodiments, there is provided a method of treating a disease or disorder (e.g., cancer) comprising administering or co-administering, in any order, a compound of Formula (I), a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form described herein and a MAPK pathway inhibitor (e.g., BRAFi, pan-RAFi, MEKi, ERKi; a PI3K-mTOR pathway inhibitor (such as an alpha-specific PI3Ki, a pan-class I PI3Ki, and an mTOR / PI3Ki, specifically everolimus and its analogs)) to a patient in need of such treatment.

[0499] Deletion of MTAP can occur simultaneously with a mutation in the KRAS gene (e.g., KRASG12C). In some embodiments, provided are methods of treating a disease or disorder (e.g., cancer) comprising administering or co-administering, in any order, a compound of Formula (I), a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form described herein and a KRAS inhibitor (e.g., a pan-KRAS or specific G12C, G12D, G13C inhibitor, e.g., adagrasib, sotorasib, LY3537982, RMC-6236, RMC-6291, RMC-9805, RMC-8839) to a patient in need of such treatment.

[0500] In some embodiments, provided are methods of treating a disease or disorder (e.g., cancer) comprising administering or co-administering, in any order, a compound of Formula (I), a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form described herein and a spliceosome inhibitor (e.g., an SF3b1 inhibitor; e.g., E7107) to a patient in need of such treatment.

[0501] In some embodiments, provided are methods for treating a disease or disorder (e.g., cancer) comprising administering or co-administering, in any order, a compound of Formula (I), a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., one comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form described herein and an HDAC inhibitor or a DNA methyltransferase inhibitor to a patient in need of such treatment. In some embodiments, the HDAC inhibitor is trichostatin A. In some embodiments, the DNA methyltransferase inhibitor is 5-azacytidine.

[0502] In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or co-administering, in any order, a compound of Formula (I), a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form described herein and a MAT2A inhibitor (e.g., AG-270, IDE397, S95035) to a patient in need of treatment for the disease or disorder.

[0503] In some embodiments, provided are methods of treating a disease or disorder (e.g., cancer) comprising administering or co-administering, in any order, a compound of Formula (I), a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form described herein and an inhibitor of a protein that interacts with or requires PRMT5 function, including, but not limited to, pICIN, WDR77, or RIOK1, to a patient in need of treatment for the disease or disorder.

[0504] In some embodiments, provided are methods of treating a disease or disorder (e.g., cancer) comprising administering or co-administering, in any order, a compound of Formula (I), a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form described herein, and an HDM2 inhibitor and / or 5-FU or other purine analog (e.g., 6-thioguanine, 6-mercaptopurine) to a patient in need of such treatment.

[0505] In some embodiments, provided are methods of treating a disease or disorder (e.g., cancer) comprising administering or co-administering, in any order, a compound of Formula (I), a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form described herein and a CDK4 inhibitor, including but not limited to, LEE011 or a CDK4 / 6 inhibitor (e.g., palbociclib (Ibrance®), ribociclib (Kisqali®), and abemaciclib (Verzenio®)), to a patient in need of such treatment.

[0506] In some embodiments, provided are methods of treating a disease or disorder (e.g., cancer) comprising administering or co-administering, in any order, a compound of Formula (I), a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form described herein and a targeted therapy (including but not limited to, inhibitors of HDM2i, PI3K / mTOR-I, MAPKi, RTKi (EGFRi, FGFRi, METi, IGFiRi, JAKi, and WNTi) that utilizes the dependency of individual target tumors on relevant pathways as determined by appropriate predictive markers to a patient in need of such treatment.

[0507] In some embodiments, methods are provided for treating a disease or disorder (e.g., cancer) comprising administering or co-administering, in any order, a compound of Formula (I), a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form described herein and immunotherapy to a patient in need of such treatment.

[0508] In some embodiments, methods of treating a disease or disorder are provided, e.g., to treat a subject (e.g., a human subject) having a disease or disorder described herein (e.g., a cancer described herein), comprising administering or co-administering, in any order, a cancer immunotherapy (e.g., a checkpoint blockade antibody) to a patient in need of treatment for the disease or disorder (e.g., cancer).

[0509] In some embodiments, the immunotherapeutic agent is an anti-CTLA-4 antibody (eg, ipilimumab, tremelimumab).

[0510] In some embodiments, the immunotherapeutic agent is an anti-PD-1 antibody (e.g., anti-PD-1 or anti-PD-L1). In some embodiments, the immunotherapeutic agent is an anti-PD-1 agent (e.g., an anti-PD-1 antibody, e.g., nivolumab (i.e., MDX-1106, BMS-936558, ONO-4538), CT-011, AMP-224, pembrolizumab (MK-3475), pidilizumab, cemiplimab, dostallimab, prolgolimab, spartalizumab, camrelizumab, sasanlimab, sintilimab, tislelizumab, toripalimab, retifanlimab, MEDI0680, budigalimab, geptanolimab). In some embodiments, the immunotherapeutic agent is an anti-PD-L1 agent (e.g., an anti-PD-L1 antibody, e.g., BMS936559 (i.e., MDX-1105), durvalumab (MEDI4736), avelumab (MSB0010718C), embafolimab, cosibelimab, sugemalimab, AUNP-12, or atezolizumab (MPDL-3280A), or an anti-PD-L1 small molecule (e.g., CA-170)).

[0511] In some embodiments, the immunotherapeutic agent is a checkpoint blockade antibody (e.g., anti-TIM3, anti-LAG3, anti-TIGIT, including IMP321 and MGA271).

[0512] In some embodiments, the immunotherapeutic agent is a cell-based therapy. In some embodiments, the cell-based therapy is a CAR-T therapy.

[0513] In some embodiments, the immunotherapeutic agent is a costimulatory antibody (eg, anti-4-1BB, anti-OX40, anti-GITR, anti-CD27, anti-CD40).

[0514] In some embodiments, the immunotherapeutic agent is a cancer vaccine, such as a neoantigen. Such vaccines can be developed using peptides or RNA.

[0515] In some embodiments, the immunotherapeutic agent is an oncolytic virus.

[0516] In some embodiments, the immunotherapeutic agent is a STING pathway agonist. Exemplary STING agonists include MK-1454 and ADU-S100.

[0517] In some embodiments, methods are provided for treating a disease or disorder (e.g., cancer) comprising administering or co-administering, in any order, a compound of Formula (I), a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., one comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form described herein and a disease-specific huMAB (e.g., an anti-HER3 huMAB) to a patient in need of treatment for the disease or disorder.

[0518] In some embodiments, methods are provided for treating a disease or disorder (e.g., cancer) comprising administering or co-administering, in any order, a compound of Formula (I), a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., one comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form described herein and an ADC / ADCC that exploits the expression of relevant surface targets on a target tumor of interest to a patient in need of such treatment.

[0519] In some embodiments, methods are provided for treating a disease or disorder (e.g., cancer) comprising administering or co-administering, in any order, a compound of Formula (I), a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form described herein and one or more DNA damage pathway inhibitors to a patient in need of such treatment. In some embodiments, the DNA damage pathway inhibitor is selected from the group consisting of bleomycin, an ATM inhibitor (e.g., AZD1390), a USP1 inhibitor, a WEE1 inhibitor (e.g., AZD1775), and a Chk1 inhibitor (e.g., AZD7762). In some embodiments, the DNA damage pathway inhibitor is a DNA alkylating agent.

[0520] In some embodiments, provided are methods of treating a disease or disorder (e.g., cancer) comprising administering or co-administering, in any order, a compound of Formula (I), a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., one comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form described herein and a PARP inhibitor to a patient in need of such treatment. In some embodiments, the PARP inhibitor is selected from the group consisting of olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib, CEP9722, E7016, iniparib, and 3-aminobenzamide.

[0521] Some patients may experience allergic reactions to the PRMT5 inhibitors and / or other anti-cancer agent(s) described herein during or after administration, and therefore, anti-allergy agents are often administered to minimize the risk of allergic reactions.In some embodiments, a compound of Formula (I) described herein, a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form may be combined with an anti-allergy agent (e.g., a corticosteroid, e.g., dexamethasone (e.g., Decadron®), beclomethasone (e.g., Beclovent®), hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, sold under the trade names Ala-Cort®, Solu-Cortef®, Hydrocort Acetate®, and Lanacort®), prednisolone (sold under the trade names Delta-Cortel®, Orapred®, Pediapred®, and Prelone®), prednisone (Deltasone®, Liquid and Orasone®), methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, sold under the trade names Duralone®, Medralone®, Medrol®, M-Prednisol®, and Solu-Medrol®), antihistamines such as diphenhydramine (e.g., Benadryl®), hydroxyzine, and cyproheptadine, and bronchodilators such as beta-adrenergic receptor agonists, albuterol (e.g., Proventil®), and terbutaline (Brethine®), in any order to a patient in need of such treatment.

[0522] Some patients may experience nausea during and after administration of the PRMT5 inhibitors and / or other anti-cancer agent(s) described herein, and therefore antiemetics are used to prevent nausea (upper stomach) and vomiting. In some embodiments, provided are methods of treating a disease or disorder (e.g., cancer) comprising administering or co-administering, in any order, a compound of Formula (I), a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form described herein and an antiemetic drug (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 of such treatment.

[0523] Medications to alleviate pain experienced during treatment are often prescribed to make patients more comfortable. In some embodiments, methods are provided for treating a disease or disorder (e.g., cancer) comprising administering or co-administering, in any order, a compound of Formula (I), a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form described herein with an analgesic (e.g., an over-the-counter 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®), and fentanyl (e.g., Duragesic®)) to a patient in need of such treatment.

[0524] To protect normal cells from treatment toxicity and limit organ toxicity, cytoprotective agents (neuroprotectants, free radical scavengers, cardioprotectants, anthracycline extravasation neutralizers, nutrients, etc.) may be used as adjunctive therapy. In some embodiments, provided are methods of treating a disease or disorder (e.g., cancer) comprising administering or co-administering, in any order, a compound of Formula (I), a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form described herein, and a cytoprotective agent (e.g., amifostine (Ethyol®), glutamine, dimesna (Tavocept®), mesna (Mesnex®), dexrazoxane (Zinecard® or Totect®), xaliproden (Xaprila®), and leucovorin (also known as leucovorin calcium, citrovorum factor, and folinic acid)) to a patient in need of such treatment.

[0525] The structures of the active compounds identified by code numbers, generic names or trade names can be obtained from the actual edition of the standard catalogue "The Merck Index" or from databases such as Patents International (e.g. IMS World Publications).

[0526] The above-described compounds can be used in combination with the PRMT5 inhibitors described herein, and such compounds can be prepared and administered as described in the art, including but not limited to, the documents cited above.

[0527] In one embodiment, a pharmaceutical composition is provided 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), alone or in combination with other anti-cancer agents, together with a pharmaceutically acceptable carrier suitable for administration to a human or animal subject.

[0528] In particular, the compositions will either be formulated together as a combination therapy or will be administered separately.

[0529] In combination therapy, the PRMT5 inhibitors described herein and the other anti-cancer agent(s) may be administered simultaneously, concurrently, or sequentially without any specific time restriction, and such administration provides therapeutically effective levels of the two compounds in the patient's body.

[0530] In a preferred embodiment, the compound of the present disclosure (the compound of Formula (I) described herein, its crystalline form (e.g., crystalline Form A), pharmaceutical composition (e.g., comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof), or dosage form) and other anticancer agent(s) are generally administered sequentially in any order by infusion or orally. The dosing regimen may vary depending on the stage of the disease, the patient's physical condition, the safety profile of the individual drugs, and the tolerance of the individual drugs, as well as other criteria known to the attending physician and the physician(s) administering the combination. The PRMT5 inhibitors described herein and other anticancer agent(s) may be administered within minutes of each other or may be administered several hours, days, or even weeks apart, depending on the particular cycle being used in the treatment. Furthermore, the cycle may involve administering one drug more frequently than the other during the treatment cycle and at different doses each time the drugs are administered.

[0531] In another aspect, a kit is provided that includes one or more PRMT5 inhibitor(s) described herein (a compound of Formula (I) described herein, a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form) and a second therapeutic agent disclosed herein. Exemplary kits include (a) a PRMT5 inhibitor described herein (a compound of Formula (I) described herein, a crystalline form thereof (e.g., crystalline Form A), a pharmaceutical composition (e.g., c...

Claims

1. N-(6-amino-5-methylpyridin-3-yl)-2-((2R,5S)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound of formula (I)) 【Chemistry 201】 A crystalline form of The crystalline form, wherein the X-ray powder diffraction (XRPD) pattern of the crystalline form comprises one or more peaks at 2θ angles selected from 6.4±0.2, 8.9±0.2, 12.7±0.2, 14.0±0.2, 19.1±0.2, 19.9±0.2, 22.6±0.2 degrees.

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

3. 3. The pharmaceutical composition of claim 2, wherein the compound of formula (I) is in the crystalline form of claim 1.

4. The pharmaceutical composition according to claim 2 or 3, wherein the composition comprises from about 5% (w / w) to about 50% (w / w) of the compound of formula (I).

5. (a) a compound represented by formula (I) 【Chemistry 202】 or a pharma- ceutically acceptable salt thereof; (b) a bulking agent (e.g., microcrystalline cellulose); (c) a glidant (e.g., colloidal silicon dioxide); and (d) a disintegrant (e.g., croscarmellose sodium); and (e) a lubricant (e.g., magnesium stearate); and 23. A pharmaceutical composition comprising:

6. 6. The pharmaceutical composition of claim 5, wherein the composition comprises a crystalline form of the compound of formula (I) of claim 1.

7. The composition, (a) about 5% (w / w) to about 50% (w / w) of a compound of formula (I) as described above; (b) about 50% (w / w) to about 90% (w / w) of a bulking agent (e.g., microcrystalline cellulose); (c) about 0.5% (w / w) to about 1.5% (w / w) of a glidant (e.g., colloidal silicon dioxide); (d) about 2% (w / w) to about 6% (w / w) of a disintegrant (e.g., croscarmellose sodium); (e) about 0.5% (w / w) to about 1.5% (w / w) of a lubricant (e.g., magnesium stearate); 7. The pharmaceutical composition of claim 5 or 6, wherein the total composition percentage of the composition is 100% (w / w).

8. (a) a compound represented by formula (I) 【Chemistry 203】 and (b) an intragranular bulking agent (e.g., microcrystalline cellulose); (c) an intragranular flow promoter (e.g., colloidal silicon dioxide, (d) an intragranular disintegrant (e.g., croscarmellose sodium); and (e) an extragranular lubricant (e.g., magnesium stearate); (f) an extragranular bulking agent (e.g., microcrystalline cellulose); (g) an extragranular flow promoter (e.g., colloidal silicon dioxide); and (h) an extragranular disintegrant (e.g., croscarmellose sodium); and (i) an extragranular lubricant (e.g., magnesium stearate); 23. A pharmaceutical composition comprising:

9. The pharmaceutical composition according to claim 8, wherein said composition comprises a crystalline form of the compound of formula (I) according to any one of claims 1 to 4.

10. The composition, (a) about 5% (w / w) to about 50% (w / w) of a compound of formula (I) as described above; (b) about 30% (w / w) to about 70% (w / w) of an intragranular bulking agent (e.g., microcrystalline cellulose); (c) about 0.25% (w / w) to about 0.75% (w / w) of an intragranular flow enhancer (e.g., colloidal silicon dioxide); (d) about 1% (w / w) to about 3% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium); (e) about 0.25% (w / w) to about 0.75% (w / w) of an intragranular lubricant (e.g., magnesium stearate); (f) from about 0% (w / w) to about 40% (w / w) of an extragranular bulking agent (e.g., microcrystalline cellulose); (g) about 0.25% (w / w) to about 0.75% (w / w) of an extragranular flow enhancer (e.g., colloidal silicon dioxide); (h) about 1% (w / w) to about 3% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium); (i) about 0.25% (w / w) to about 0.75% (w / w) of an extragranular lubricant (e.g., magnesium stearate); 10. The pharmaceutical composition of claim 8 or 9, wherein the total composition percentage of the composition is 100% (w / w).

11. The composition, (a) about 12.5% ​​(w / w) of the compound of formula (I); (b) about 56.5% (w / w) of an intragranular bulking agent (e.g., microcrystalline cellulose); (c) about 0.5% (w / w) of an intragranular flow promoter (e.g., colloidal silicon dioxide); (d) about 2% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium); and (e) about 0.5% (w / w) of an intragranular lubricant (e.g., magnesium stearate); (f) about 25% (w / w) of an extragranular bulking agent (e.g., microcrystalline cellulose); (g) about 0.5% (w / w) of an extragranular flow enhancer (e.g., colloidal silicon dioxide); (h) about 2% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium); (i) about 0.5% (w / w) of an extragranular lubricant (e.g., magnesium stearate); 10. The pharmaceutical composition of claim 8 or 9, wherein the total composition percentage of the composition is 100% (w / w).

12. The composition, (a) about 29.4% (w / w) of the compound of formula (I); (b) about 39.7% (w / w) of an intragranular bulking agent (e.g., microcrystalline cellulose); (c) about 0.37% (w / w) of an intragranular flow promoter (e.g., colloidal silicon dioxide); (d) about 1.47% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium); and (e) about 0.37% (w / w) of an intragranular lubricant (e.g., magnesium stearate); (f) about 25.7% (w / w) of an extragranular bulking agent (e.g., microcrystalline cellulose); (g) about 0.5% (w / w) of an extragranular flow enhancer (e.g., colloidal silicon dioxide); (h) about 2% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium); (i) about 0.5% (w / w) of an extragranular lubricant (e.g., magnesium stearate); 10. The pharmaceutical composition of claim 8 or 9, wherein the total composition percentage of the composition is 100% (w / w).

13. The composition, (a) about 40% (w / w) of the compound of formula (I); (b) about 54% (w / w) of an intragranular bulking agent (e.g., microcrystalline cellulose); (c) about 0.5% (w / w) of an intragranular flow promoter (e.g., colloidal silicon dioxide); (d) about 2% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium); and (e) about 0.5% (w / w) of an intragranular lubricant (e.g., magnesium stearate); (f) about 0% (w / w) of an extragranular bulking agent (e.g., microcrystalline cellulose); (g) about 0.5% (w / w) of an extragranular flow enhancer (e.g., colloidal silicon dioxide); (h) about 2% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium); (i) about 0.5% (w / w) of an extragranular lubricant (e.g., magnesium stearate); 10. The pharmaceutical composition of claim 8 or 9, wherein the total composition percentage of the composition is 100% (w / w).

14. A dosage form comprising the pharmaceutical composition according to any one of claims 2 to 13.

15. 15. The dosage form of claim 14, wherein the total weight of the pharmaceutical composition in the dosage form is from about 50 mg to 1000 mg.

16. The dosage form of claim 14 or 15, wherein the composition comprises from about 5 mg to about 400 mg of the compound of formula (I).

17. The dosage form of any one of claims 14 to 16, wherein the composition comprises about 12.5 mg, about 50 mg, about 100 mg, or about 300 mg of the compound of formula (I).

18. A method for treating an MTAP deficiency and / or an MTA accumulation disease in a subject in need of such treatment, comprising administering to the subject a pharmaceutical composition according to any one of claims 2 to 13 comprising a therapeutically effective amount of the compound of formula (I).

19. 19. The method of claim 18, wherein the disease is an MTAP-deficient and / or MTA-accumulating cancer.

20. 1. A method of treating cancer in a subject in need thereof, comprising: a) assessing the level of MTAP and / or MTA in a test sample obtained from the subject, wherein the MTA level can be assessed 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 to a reference, wherein MTAP deficiency and / or MTA accumulation in the test sample compared to the reference indicates whether the cancer in the subject will respond to therapeutic treatment with a PRMT5 inhibitor; c) administering to the subject identified in step b) a pharmaceutical composition according to any one of claims 2 to 13 comprising an effective amount (e.g. a therapeutically effective amount) of the compound of formula (I); The method comprising:

21. 21. The method of claim 19 or 20, wherein the cancer is a glioma, a glioblastoma, a malignant peripheral nerve sheath tumor (MPNST, e.g., intracranial MPNST), an esophageal cancer (e.g., an esophageal squamous cell carcinoma or an esophageal adenocarcinoma), a bladder cancer (e.g., a bladder urothelial carcinoma), a pancreatic cancer (e.g., a pancreatic adenocarcinoma), a mesothelioma, a melanoma, a non-small cell lung cancer (NSCLC; e.g., a lung squamous cell carcinoma or a lung adenocarcinoma), an astrocytoma, an undifferentiated pleomorphic sarcoma, a diffuse large B-cell lymphoma (DLBCL), a leukemia, a head and neck cancer, a gastric adenocarcinoma, a myxofibrosarcoma, a bile duct sarcoma, a brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colon cancer, a sarcoma, or a CNS metastasis from a solid tumor.

22. 21. The method of claim 19 or 20, wherein the cancer is a central nervous system (CNS) malignancy.

23. 23. The method of claim 22, wherein the CNS malignancy is selected from a glioma (e.g., low-grade glioma, intermediate-grade glioma), an intracranial MPNST tumor, a glioblastoma, a glioblastoma multiforme, or a CNS metastasis from a solid tumor.

24. 21. The method of claim 19 or 20, wherein the cancer is glioblastoma.

25. The method of any one of claims 19 to 24, wherein the method further comprises administration of a second therapeutic agent.

26. N-(6-amino-5-methylpyridin-3-yl)-2-((2R,5S)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound of formula (I)): 【Chemistry 204】 or a salt thereof, comprising: Formula (II): 【Chemistry 205】 by hydrogenating a compound of formula (III-a): 【Chemistry 206】 forming a compound of In the formula, R １ is a chiral auxiliary.

27. The process comprising: The formula (III-a): 【Chemistry 207】 by protecting the nitrogen group of a compound of formula (III): 【Chemistry 208】 27. The process of claim 26, further comprising producing a compound of formula:

28. The process comprising: Formula (III): 【Chemistry 209】 with a compound of formula (IV): 【Chemistry 210】 thereby cross-coupling a compound of formula (V): 【Chemistry 211】 and further comprising producing a compound of In the formula, R ２ is a nitrogen protecting group, R ３ 28. The process of claim 26 or 27, wherein is a boronic acid or a boronic ester.

29. The process comprises reacting a compound represented by formula (V): 【Chemistry 212】 by removing said nitrogen protecting group from a compound of formula (V-a): 【Chemistry 213】 The process of any one of claims 26 to 28, further comprising producing a compound of formula:

30. The process comprising: The formula (V-a): 【Chemistry 214】 by reducing a compound of formula (VI): 【Chemistry 215】 30. The process of any one of claims 26 to 29, further comprising producing a compound of formula:

31. The process comprising: The compound of formula (VI): 【Chemistry 216】 With a compound of formula (VII): 【Chemistry 217】 to a compound of formula (I-a): 【Chemistry 218】 and further comprising producing a compound of In the formula, R ６ , R ７ , R ８ , and R ９ The process of any one of claims 26 to 30, wherein each is independently H or a nitrogen protecting group.

32. The process comprises reacting a compound represented by formula (I-a): 【Chemical 219】 removing said nitrogen protecting group from a compound of formula (I): 【Chemistry 220】 or a salt thereof.

33. N-(6-amino-5-methylpyridin-3-yl)-2-((2R,5S)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound of formula (I)): 【Chemistry 221】 or a salt thereof, comprising: (a) Formula (II): 【Chemical 222】 by hydrogenating a compound of formula (III-a): 【Chemical 223】 and forming a compound of the formula: (b) The compound represented by formula (III-a): 【Chemical 224】 by protecting the nitrogen group of a compound of formula (III): 【Chemistry 225】 and forming a compound of the formula: (c) the compound represented by formula (III): 【Chemical 226】 With a compound of formula (IV) 【Chemical 227】 thereby cross-coupling a compound of formula (V): 【Chemical 228】 and forming a compound of the formula: (d) a compound represented by the formula (V): 【Chemical 229】 by removing said nitrogen protecting group from a compound of formula (V-a): 【Chemistry 230】 and forming a compound of the formula: (e) reducing the compound of formula (Va) to thereby form a compound of formula (VI): 【Chemistry 231】 and forming a compound of the formula: (f) the compound of formula (VI): 【Chemistry 232】 With a compound of formula (VII): 【Chemistry 233】 to a compound of formula (I-a): 【Chemical 234】 and producing a compound of the formula: In the formula, R １ is a chiral auxiliary, R ２ is a nitrogen protecting group, R ６ , R ７ , R ８ , and R ９ are each independently H or a nitrogen protecting group; R ３ is a boronic acid group or a boronic ester group.

34. R ８ , R ９ or both are nitrogen protecting groups, and the process comprises reacting a compound represented by formula (I-a): 【Chemistry 235】 removing said nitrogen protecting group from a compound of formula (I): 【Chemistry 236】 or a salt thereof.

35. N-(6-amino-5-methylpyridin-3-yl)-2-((2R,5S)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)-2-oxoacetamide (compound of formula (I)): 【Chemistry 237】 or a salt thereof, comprising: Formula (VI): 【Chemical 238】 With a compound of formula (VII): 【Chemical 239】 to a compound of formula (I-a): 【Chemistry 240】 forming a compound of In the formula, R ６ , R ７ , R ８ , and R ９ is each independently H or a nitrogen protecting group; Optionally, R ８ , R ９ or when both are nitrogen protecting groups, removing said nitrogen protecting groups from said compound of formula (I-a), thereby producing said compound of formula (I) or a salt thereof; The process comprising:

36. The process comprising: Formula (V-a): 【Chemical 241】 by reducing a compound of formula (VI): 【Chemical formula 242】 36. The process of claim 35, further comprising producing a compound of formula:

37. The process comprises reacting a compound of formula (V): 【Chemical 243】 by removing the nitrogen protecting group from the compound of formula (V-a): 【Chemical 244】 37. The process of claim 35 or 36, further comprising producing a compound of formula:

38. The process comprising: Formula (III): 【Chemistry 245】 with a compound of formula (IV): 【Chemical 246】 thereby cross-coupling a compound of formula (V): 【Chemical 247】 and further comprising producing a compound of In the formula, R ２ is a nitrogen protecting group, R ３ The process of any one of claims 35 to 37, wherein is a boronic acid group or a boronic ester group.

39. The process comprising: Formula (III-a): 【Chemical formula 248】 by protecting the nitrogen group of the compound of formula (III): 【Chemical 249】 The process of any one of claims 35 to 38, further comprising producing a compound of formula:

40. The process comprising: Formula (II): 【Chemistry 250】 by hydrogenating a compound of formula (III-a): 【Chemistry 251】 and further comprising producing a compound of In the formula, R １ The process of any one of claims 35 to 39, wherein is a chiral auxiliary.

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