Solid forms of macrocyclic farnesyltransferase inhibitors and formulations thereof, and methods of making and using macrocyclic compounds and solid forms thereof

Abstract

The present disclosure relates to solid forms of Compound 1, or pharmaceutically acceptable forms thereof, pharmaceutically acceptable salts of Compound 1, or pharmaceutically acceptable solvates thereof, pharmaceutical compositions comprising them, methods of making them, and methods of using them in the treatment of farnesylated protein dependent cancers.

Description

[0001] 1. Cross-referencing This application claims priority to International Patent Application No. PCT / CN2023 / 097389, filed on May 31, 2023, which is incorporated herein by reference in its entirety. 2. Technical Field This document provides a solid form of compound 1 or a pharmaceutically acceptable form thereof, a pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable solvate thereof, pharmaceutical compositions comprising them, methods for preparing them, and methods for using them to treat cancers dependent on farnesylated proteins. 3. Summary of the Invention In one aspect, it is in solid form, which comprises compound 1 or a pharmaceutically acceptable salt and / or solvate thereof: .

[0004] In another aspect, it is a pharmaceutically acceptable salt of compound 1 or an isotope thereof, or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt.

[0005] In another aspect, there is a pharmaceutical composition comprising: i) a solid form comprising, in an amount of about 0.1 mg to about 200 mg, a pharmaceutically acceptable salt and / or solvate thereof of compound 1, and ii) one or more pharmaceutically acceptable excipients.

[0006] In another aspect, there is a method for preparing a pharmaceutical composition as provided herein, the method comprising: i) optionally de-aggregating compound 1 or a pharmaceutically acceptable salt and / or solvate thereof in a solid form; ii) mixing compound 1 or a pharmaceutically acceptable salt and / or solvate thereof in a solid form with a first portion of a disintegrant, a gliding agent, and a filler to form a first blend; iii) de-aggregating the first blend to form a de-aggregated first blend; iv) de-aggregating a second portion of the filler; v) blending the de-aggregated first blend with the de-aggregated second portion of the filler to form a second blend; vi) blending the second blend with a lubricant to form a lubricated blend; and vii) optionally compressing the lubricated blend into tablets using a rotary press.

[0007] In another aspect, there is a method for preparing a pharmaceutical composition as provided herein, the method comprising: i) optionally de-agglomerating compound 1 or a pharmaceutically acceptable salt and / or solvate thereof in solid form; ii) mixing compound 1 or a pharmaceutically acceptable salt and / or solvate thereof in solid form with a first portion of a filler, a gliding agent, and a disintegrant to form a first blend; iii) de-agglomerating the first blend and then blending the first blend to form a second blend; iv) blending the second blend with a first portion of a lubricant to form a lubricated intragranular blend; v) forming granules from the intragranular blend, for example, using a roller compactor and a sieve; vi) blending the granules with a second portion of a disintegrant and a second portion of a lubricant to form a lubricated final blend; and vii) optionally compressing the lubricated final blend into tablets using a rotary press.

[0008] In another aspect, there is a method for preparing a pharmaceutical composition as provided herein, the method comprising: i) optionally deagglomerating compound 1 or a pharmaceutically acceptable salt and / or solvate thereof in a solid form; ii) granulating compound 1 or a pharmaceutically acceptable salt and / or solvate thereof, a filler, a flow aid and a disintegrant together with a binder and water to form wet granules; iii) drying the wet granules to form dry granules; iv) blending the granules with a lubricant to form a lubricated final blend; and v) optionally compressing the lubricated final blend into tablets using a rotary press.

[0009] In another aspect, it is a method for preparing the following: Compound 1: , Or in a pharmaceutically acceptable form, the method comprising: (a) To cause racemic compound 19: , Reaction with chiral acids in solvents to form diastereomeric salts of compound 1 and compound 2: , One of the two diastereomers is selectively precipitated from the solvent, and the other of the two diastereomers is selectively soluble in the solvent. (b) Separate the precipitate from the solvent; (c) Reacting the diastereomeric salt of compound 1 with a base to provide compound 1, and (d) Optionally, recrystallize compound 1 from ACN / water in a ratio of about 2:1 to about 1:5, or optionally about 1:1 to about 1:3.

[0010] In another aspect, it is a method for preparing the following: Compound 1: , Or a pharmaceutically acceptable form thereof, the method comprising making compound 18A: , The reaction with a cyanide equivalent and a palladium catalyst, optionally in the presence of a zinc source and / or a phosphine ligand, yields compound 19: , And by chiral separation and purification of racemic compound 19 to provide compound 1.

[0011] In another aspect, there is a method for preparing compound 9, which includes making compound 7: , Reacts with a demethylating agent to form compound 8: , Compound 8 was then reacted with TBSCl and a base to form compound 9.

[0012] In another aspect, there is a method for preparing compound 11: , The method includes making compound 23: , It reacts with TBSC1 in the presence of a base to form compound 11.

[0013] Another aspect is a method for preparing compound 19: , The method includes chlorinating compound 17 with a chlorinating agent: , To form compound 18: , Furthermore, compound 18 is reacted with an ammonia equivalent to form compound 19.

[0014] In another aspect, there is a method for preparing compound 14: , The method includes making compound 13: , Deprotection was carried out under deprotection conditions to form compound 14.

[0015] In another aspect, there is a method for preparing compound 12: , The method includes making compound 11: , With compound 9: , Condensation to form compound 12.

[0016] In another aspect, there is a method for preparing compound 13, which includes coupling compound 12 with 1-methylimidazole to form compound 13.

[0017] In another aspect, it is a compound selected from the following: And its salt.

[0018] In another aspect, it is a compound 1 or compound 2 ( R )-chlorocyclic phosphate, ( S ()-chlorocyclic phosphate, (+)-tartrate, (-)-tartrate, (+)-camphor sulfonate, (-)-camphor sulfonate, L-(-)-di-p-methoxybenzoyl tartrate, D-(+)-di-p-methoxybenzoyl tartrate, L-(-)-di-toluyl tartrate, D-(+)-di-toluyl tartrate, (R)-BINAP phosphate, ( S )-BINAP phosphate, benzoyl-1-tartrate or benzoyl-D-tartrate.

[0019] In another aspect, there is a method for inhibiting farnesyltransferase, the method comprising contacting the farnesyltransferase with an effective amount of a compound 1 as provided herein, a pharmaceutically acceptable salt of compound 1 as provided herein, or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt thereof in solid form, or with a pharmaceutical composition comprising a solid form as provided herein, optionally wherein the farnesyltransferase is present in cells, optionally wherein contact with the farnesyltransferase occurs in cells, optionally wherein the cells are in a subject, optionally wherein the cells are mammalian cells, optionally wherein the cells are human cells, and optionally wherein the subject has a cancer dependent on farnesylated proteins.

[0020] In another aspect, there is a method for treating a subject with farnesylation-dependent cancer, the method comprising administering to a subject suffering from farnesylation-dependent cancer a therapeutically effective amount of a solid form of compound 1 as provided herein, a pharmaceutically acceptable salt of compound 1 as provided herein or an isotope thereof, or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising a solid form as provided herein, optionally wherein the subject is a human. 4. Description of the attached drawings Figure 1 Provides representative X-ray powder diffraction (XRPD) patterns of the amorphous form of the free base of compound 1.

[0022] Figure 2 A representative Oak Ridge Thermal Ellipsoid (ORTEP) illustration is provided for single-crystal analysis of compound 1 in its free base hemihydrate form 1.

[0023] Figure 3 A representative XRPD spectrum of compound 1 in its free base hemihydrate form 1 is provided.

[0024] Figure 4 Representative DSC and TGA thermograms of the free base hemihydrate form 1 of compound 1 are provided.

[0025] Figure 5 Representative XRPD spectra of the benzoate form 2 of compound 1 are provided.

[0026] Figure 6 Representative DSC and TGA thermograms of the benzoate form 2 of compound 1 are provided.

[0027] Figure 7 A representative XRPD spectrum of form 3 of the benzenesulfonate (benzenesulfonic acid) of compound 1 is provided.

[0028] Figure 8 Representative DSC and TGA thermograms of form 3 of the benzenesulfonate (benzenesulfonic acid) of compound 1 are provided.

[0029] Figure 9 A representative XRPD spectrum of the chloride salt of compound 1 in form 4 is provided.

[0030] Figure 10 Representative DSC and TGA thermograms of form 4, the chloride salt of compound 1, are provided.

[0031] Figure 11 A representative XRPD spectrum of the chloride salt of compound 1 in form 5 is provided.

[0032] Figure 12Representative DSC and TGA thermograms of the chloride salt of compound 1 in form 5 are provided.

[0033] Figure 13 A representative XRPD spectrum of citrate form 6 of compound 1 is provided.

[0034] Figure 14 Representative DSC and TGA thermograms of citrate form 6 of compound 1 are provided.

[0035] Figure 15 A representative XRPD spectrum of citrate form 7 of compound 1 is provided.

[0036] Figure 16 Representative DSC and TGA thermograms of citrate form 7 of compound 1 are provided.

[0037] Figure 17 Representative XRPD spectra of the fumarate form 8 of compound 1 are provided.

[0038] Figure 18 Representative DSC and TGA thermograms of the fumarate form 8 of compound 1 are provided.

[0039] Figure 19 Representative XRPD spectra of gentianate form 9 of compound 1 are provided.

[0040] Figure 20 Representative DSC and TGA thermograms of the gentianate form 9 of compound 1 are provided.

[0041] Figure 21 Representative XRPD spectra of gentianate form 10 of compound 1 are provided.

[0042] Figure 22 Representative DSC and TGA thermograms of the gentianate form 10 of compound 1 are provided.

[0043] Figure 23 Representative XRPD spectra of the glycolate form 11 of compound 1 are provided.

[0044] Figure 24 Representative DSC and TGA thermograms of the glycolate form 11 of compound 1 are provided.

[0045] Figure 25 A representative XRPD spectrum of compound 1 in the form of 1-hydroxy-2-naphthoic acid salt 12 is provided.

[0046] Figure 26 Representative DSC and TGA thermograms of compound 1 in the form of 1-hydroxy-2-naphthoic acid salt 12 are provided.

[0047] Figure 27 A representative XRPD spectrum of compound 1 in the form of 1-hydroxy-2-naphthoic acid salt 13 is provided.

[0048] Figure 28 Representative DSC and TGA thermograms of compound 1 in its 1-hydroxy-2-naphthoic acid salt form 13 are provided.

[0049] Figure 29 Representative XRPD spectra of the malate form 14 of compound 1 are provided.

[0050] Figure 30 Representative DSC and TGA thermograms of the malate form 14 of compound 1 are provided.

[0051] Figure 31 Representative XRPD spectra of the malate form 15 of compound 1 are provided.

[0052] Figure 32 Representative DSC and TGA thermograms of the malate form 15 of compound 1 are provided.

[0053] Figure 33 Representative XRPD spectra of maleate form 16 of compound 1 are provided.

[0054] Figure 34 Representative DSC and TGA thermograms of maleate form 16 of compound 1 are provided.

[0055] Figure 35 Representative XRPD spectra of maleate form 17 of compound 1 are provided.

[0056] Figure 36 Representative DSC and TGA thermograms of maleate form 17 of compound 1 are provided.

[0057] Figure 37 Representative XRPD spectra of the methanesulfonate form 18 of compound 1 are provided.

[0058] Figure 38 Representative DSC and TGA thermograms of the methanesulfonate form 18 of compound 1 are provided.

[0059] Figure 39 Representative XRPD spectra of the oxalate form 19 of compound 1 are provided.

[0060] Figure 40 Representative DSC and TGA thermograms of the oxalate form 19 of compound 1 are provided.

[0061] Figure 41Representative XRPD spectra of phosphate form 20 of compound 1 are provided.

[0062] Figure 42 Representative DSC and TGA thermograms of the phosphate form 20 of compound 1 are provided.

[0063] Figure 43 Representative XRPD spectra of compound 1 in tartrate form 21 are provided.

[0064] Figure 44 Representative DSC and TGA thermograms of the tartrate form 21 of compound 1 are provided.

[0065] Figure 45 Representative XRPD spectra of compound 1 in tartrate form 22 are provided.

[0066] Figure 46 Representative DSC and TGA thermograms of the tartrate form 22 of compound 1 are provided.

[0067] Figure 47 Representative XRPD spectra of toluenesulfonate form 23 of compound 1 are provided.

[0068] Figure 48 Representative DSC and TGA thermograms of toluenesulfonate form 23 of compound 1 are provided.

[0069] Figure 49 Representative XRPD spectra of the free base anhydrous form 24 of compound 1 are provided.

[0070] Figure 50 Representative DSC and TGA thermograms of the free base anhydrous form 24 of compound 1 are provided.

[0071] Figure 51 Exemplary methods are illustrated for preparing tablets having strengths of 0.2 mg, 1 mg, 10 mg, and 50 mg of compound 1 or its pharmaceutically acceptable salts and / or solvates (free base equivalents). 5. Detailed Implementation 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. Where there are multiple definitions for terms herein, those definitions in this section shall prevail unless otherwise stated.

[0073] As used herein, in the specification and appended claims, unless the context clearly indicates otherwise, the indefinite articles “a” and “an” and the definite article “the” include both plural and singular references.

[0074] When the term "range" is used herein to refer to physical properties (such as molecular weight) or chemical properties (such as chemical formula), it is intended to include all combinations and sub-combinations of the range, including the endpoint figures at both limits of the range, and specific embodiments thereof. As used herein and unless otherwise stated, the terms "about" and "approximately" are used in conjunction with providing a specific temperature or temperature range for characterizing a particular solid form, such as, for example, describing a specific temperature, dehydration, desolvation, or glass transition temperature; mass variation, such as, for example, mass variation with temperature or humidity; solvent or water content, for example, by mass or percentage; or a range of values, such as, for example, the position of a peak in an analysis by IR or Raman spectroscopy or XRPD; indicating that the range of such values ​​may deviate to a degree that would be reasonable to a person skilled in the art, while still describing a particular solid form. For example, in certain embodiments, the terms “about” and “approximately” used in this context indicate that the numerical value or range of values ​​may vary within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the listed values ​​or ranges of values. For example, in some embodiments, the value for the XRPD peak position may vary by up to ±0.2 degrees 2θ while still describing a specific XRPD peak. For example, in some embodiments, the value for a DSC thermal event having an onset temperature or DSC peak temperature (each expressed in degrees Celsius (°C)) may vary by up to ±2°C while still describing a specific temperature. As used herein, a tilde (i.e., “~”) preceding a numerical value or range of values ​​indicates “about” or “approximately”.

[0075] The term "between" includes the endpoint numbers at the two boundaries of the range. For example, a range described by "between 3 and 5" includes the numbers "3" and "5".

[0076] As used herein, the term "API correction factor" should be understood as a correction factor calculation used to characterize a specific batch of active pharmaceutical ingredient (API), determined based on the purity of the API, the amount of any water present, the content of any residual solvents, and the residue on ignition (ROI): API correction factor = (API purity) * (1 - water content - residual solvents - ROI). This is achieved using methods known in the art, such as HPLC and / or 1The purity of the API is determined by ¹H NMR. The water content is determined using methods known in the art, such as Karl Fischer analysis. The ROI is determined using methods known in the art, for example, by igniting the sample and heating the residue at a high temperature, such as about 450°C to about 600°C, and weighing the remaining material. The API correction factor used is at least about 0.95, or at least about 0.96, or at least about 0.97, or at least about 0.98, or at least about 0.99. In some aspects, the API correction factor is at least 0.97, or from about 0.97 to about 0.98.

[0077] As used herein, the terms “administer,” “administering,” or “administration” refer to the act of delivering or having a compound or pharmaceutical composition delivered to a subject by methods described herein or otherwise known in the art. Administering a compound or pharmaceutical composition includes prescribing the compound or pharmaceutical composition to a patient. Exemplary forms of administration include oral dosage forms such as tablets, capsules, syrups, and suspensions; injectable dosage forms such as intravenous (IV), intramuscular (IM), or intraperitoneal (IP) dosage forms; transdermal dosage forms, including creams, gels, powders, or patches; buccal dosage forms; and inhaled powders, sprays, suspensions, and rectal suppositories. In some embodiments, the form of administration is an oral dosage form, such as a tablet.

[0078] As used herein, a “pharmaceutically acceptable form” of the compounds disclosed herein includes, but is not limited to, pharmaceutically acceptable salts, solvates, isomers, and isotopes (i.e., isotopically labeled derivatives) of the compounds disclosed herein, including combinations thereof (e.g., pharmaceutically acceptable salts of compounds or solvates of such compounds, salts or solvates of salts, or solvates of isomers and / or isotopes). In some embodiments, a “pharmaceutically acceptable form” includes, but is not limited to, pharmaceutically acceptable salts, solvates, isomers (e.g., tautomers or stereoisomers), and isotopes (i.e., isotopically labeled derivatives) of compound 1 disclosed herein, and combinations thereof.

[0079] In some implementations, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of a subject within a reasonable medical judgment without excessive toxicity, irritation, allergic reactions, etc., and that are proportionate to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail (see [link to relevant documentation]). J. Pharm.Sci(1977) 66: 1–19). Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable pharmaceutically acceptable inorganic and organic acids and bases, such as suitable inorganic and organic addition acids and bases. For example, pharmaceutically acceptable salts of the compounds provided herein are derived from suitable pharmaceutically acceptable inorganic or organic acids, such as suitable inorganic or organic addition acids, sometimes referred to as conjugate acids. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, benzoates, benzenesulfonates, chloride salts, citrates, fumarates, gentianates, glutarates, glycolates, hippurates, 1-hydroxy-2-naphthoate, malates, maleates, methanesulfonates, oxalates, phosphates, sulfates, tartrates, or toluenesulfonates. In some embodiments, compound 1 or a pharmaceutically acceptable solvate and / or isotopic salt thereof is or comprises compound 1 or a pharmaceutically acceptable solvate and / or isotopic form thereof and a conjugate acid (pharmacologically acceptable salt) in a molar ratio ranging from about 2:1 to about 1:2. In some embodiments, the solid form comprises compound 1 or a pharmaceutically acceptable solvate and / or isotopic form thereof and a conjugate acid (pharmacologically acceptable salt) in a molar ratio ranging from about 2:1 to about 1:2. In some embodiments, the molar ratio of compound 1 or a pharmaceutically acceptable solvate to the conjugate acid is in the range of about 2:1 to about 0.1:1. In some embodiments, the molar ratio of compound 1 or a pharmaceutically acceptable solvate to the conjugate acid is in the range of about 2:1 to about 1:1. In some embodiments, the molar ratio of compound 1 or a pharmaceutically acceptable solvate to the conjugate acid is in the range of about 0.1:1 to about 1:2. In some embodiments, the molar ratio of compound 1 or its pharmaceutically acceptable solvate to the conjugate acid is in the range of about 1:1 to about 1:2. In some embodiments, the molar ratio of compound 1 or its pharmaceutically acceptable solvate and / or isotopic form to the conjugate acid (pharmaceutically acceptable salt) is about 2:1, about 1.9:1, about 1.8:1, about 1.7:1, about 1.6:1, about 1.5:1, about 1.4:1, about 1.3:1, about 1.2:1, about 1.1:1, about 1:1, about 0.9:1, about 0.8:1, etc. The ratios are approximately 0.7:1, 0.6:1, 0.5:1, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, or 1:2, such as 2:1, 1:1, or 1:2. In some embodiments, the molar ratio of compound 1 or its pharmaceutically acceptable solvate to the conjugate acid is approximately 1:2.In some embodiments, the molar ratio of compound 1 or its pharmaceutically acceptable solvate to the conjugate acid is about 1:1. In some embodiments, the molar ratio of compound 1 or its pharmaceutically acceptable solvate to the conjugate acid is about 2:1.

[0080] In some embodiments, the pharmaceutically acceptable form of the compounds disclosed herein does not include the salt form of the compounds disclosed herein (i.e., not a salt), and is sometimes referred to as the free form or free base form. In some embodiments, the free base form of the compounds disclosed herein is a pharmaceutically acceptable solvate and / or isotopic form of the compounds. In some embodiments, the free base form of the compounds disclosed herein is a pharmaceutically acceptable solvate form of the compounds.

[0081] In some embodiments, the pharmaceutically acceptable form is a solvate (e.g., a hydrate). As used herein, the terms "solvate," "pharmaceutically acceptable solvate," or "pharmaceutically acceptable solvent" refer to a compound that also includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. In some embodiments, the solvate is a crystalline form of molecules, atoms, and / or ions, and also includes molecules of one or more solvents incorporated into the crystal lattice structure. Solvent molecules in the solvate may be present in a regular and / or disordered arrangement. In some embodiments, the solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. For example, a solvate having a non-stoichiometric amount of solvent molecules may arise due to partial loss of solvent from the solvate. The solvate may exist as a dimer or oligomer containing more than one molecule or compound ABC within the crystal lattice structure. The solvate may be a solvate of the disclosed compound or a pharmaceutically acceptable salt thereof. In the case where the solvent is water, the solvate is a "hydrate." In some embodiments, the solvate is a hydrate. Pharmaceutically acceptable solvates and hydrates are, for example, complexes comprising 0.1, 0.25, 0.50, 0.75, or 1 solvent molecule or water molecule, or 1 to about 100, 1 to about 10, 1 to about 2, about 3, or about 4 solvent molecules or water molecules. In some embodiments, a pharmaceutically acceptable solvate of compound 1 or its pharmaceutically acceptable salt and / or isotopic form is or comprises compound 1 or its pharmaceutically acceptable salt and / or isotopic form and a pharmaceutically acceptable solvent in a molar ratio ranging from about 2:1 to about 1:2. In some embodiments, the molar ratio of compound 1 to solvent is in the range of about 2:1 to about 0.1:1. In some embodiments, the molar ratio of compound 1 to solvent is in the range of about 2:1 to about 1:1. In some embodiments, the molar ratio of compound 1 to solvent is in the range of about 0.1:1 to about 1:2. In some embodiments, the molar ratio of compound 1 to solvent is in the range of about 1:1 to about 1:2. In some embodiments, the molar ratio of compound 1 to solvent is about 2:1, about 1.9:1, about 1.8:1, about 1.7:1, about 1.6:1, about 1.5:1, about 1.4:1, about 1.3:1, about 1.2:1, about 1.1:1, about 1:1, about 0.9:1, about 0.8:1, about 0.7:1, about 0.6:1, about 0.5:1, about 1:0.5, about 1:0.6, about 1:0.7, about 1:0.8, about 1:0.9, about 1:1.1, about 1:1.2, about 1:1.3, about 1:1.4, about 1:1.5, about 1:1.6, about 1:1.7, about 1:1.8, about 1:1.9, or about 1:2, such as about 2:1, about 1:1, or about 1:2. In some embodiments, the molar ratio of compound 1 to solvent is about 1:2 (i.e., a dual solvate).In some embodiments, the molar ratio of compound 1 to solvent is about 1:1 (i.e., a monosolvate). In some embodiments, the molar ratio of compound 1 to solvent is about 2:1 (i.e., a hemisolvate). In some embodiments, the pharmaceutically acceptable solvent (solvate) is or may comprise hydrates, hemihydrates, isobutyl acetate solvates, isopropyl acetate solvates, tetrahydrofuran solvates, acetone solvates, acetonitrile solvates, or combinations thereof. For example, in some embodiments, the pharmaceutically acceptable solvate is water, and the molar ratio of compound 1 to solvent is about 1:2 (also referred to as a hemihydrate). In some embodiments, the pharmaceutically acceptable solvate of compound 1 or its pharmaceutically acceptable salt and / or isotope form is in solid form.

[0082] In some embodiments, the term “pharmaceutically acceptable salt or solvation” of the compounds disclosed herein includes, but is not limited to, pharmaceutically acceptable salts and / or solvations of the compounds disclosed herein, including combinations thereof (e.g., solvations of pharmaceutically acceptable salts), and also includes isotopes of compounds or solvations of such compounds, salts or solvations of salts (i.e., isotopically labeled derivatives).

[0083] In some embodiments, the pharmaceutically acceptable form of the compounds disclosed herein does not include the solvate form of the compounds disclosed herein, sometimes referred to as the nonsolvent form. For example, the pharmaceutically acceptable form of the compounds disclosed herein may exclude water, sometimes referred to as the anhydrous form of the compounds disclosed herein. In some embodiments, the nonsolvent form of the compounds disclosed herein is a pharmaceutically acceptable salt and / or isotopic form of the compounds. In some embodiments, the nonsolvent form of the compounds disclosed herein is a pharmaceutically acceptable salt form of the compounds. Unless otherwise stated, it should be understood that the nonsolvent form of the compounds has a solvate residue of about 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less, about 0.5% or less, or about 0.25% or less. For example, the anhydrous form of the compounds has a residual water content of about 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less, about 0.5% or less, or about 0.25% or less.

[0084] In some embodiments, the pharmaceutically acceptable form is an isomer. An "isomer" is a different compound having the same molecular formula. In some embodiments, the isomer may be a stereoisomer. In some embodiments, the isomer may be a tautomer. In some embodiments, the isomer may be a geometric isomer. A "stereoisomer" is an isomer that differs only in the spatial arrangement of its atoms. Stereoisomers include, for example, enantiomers, diastereomers, and hindered isomers. A hindered isomer is a stereoisomer resulting from hindered rotation around a single bond, where an energy difference due to steric strain or other factors creates a rotational barrier sufficient to allow identification and potential separation of individual conformational isomers. As used herein, the term "isomer" includes any and all geometric and stereoisomers. For example, "isomers" include geometric double-bond cis-isomers and trans-isomers, also known as... E -Isomers and Z -Isomers; Restricted transisomers; R -enantiomers and S -Enantiomer; diastereomer, ( d –Isomers and ( l (Isomers, racemic mixtures thereof, and other mixtures thereof that fall within the scope of this disclosure.)

[0085] To further understand, based on the above discussion of enantiomeric enrichment and enantiomeric excess, a compound disclosed herein that refers to having one or more stereocenters without specifying a particular chirality (e.g., R-enantiomer or S-enantiomer) will be understood to refer to a compound as a racemic mixture (or a mixture of diastereomers), while including R-name or S-name will be understood to refer to the enantiomeric (or diastereomeric) form of the compound, such as an enantiomerically (or diastereomerically) enriched form of the compound, or an enantiomerically excess of the specified enantiomeric form of the compound. The symbol for a compound having R-name or S-name should be understood to include enantiomeric enrichment or enantiomerically excess of the specified enantiomer of the compound, and is not limited to 100% of a single specified enantiomer of the compound.

[0086] It should be noted that if there is a difference between the described structure and the name of the structure, the described structure will be given higher weight.

[0087] An enantiomer is a pair of stereoisomers that are non-overlapping mirror images of each other. A mixture of any proportion of a pair of enantiomers can be called a racemic mixture. Where appropriate, the terms "(±)" or "(rac)" are used to refer to racemic mixtures. A diastereomer is a stereoisomer having at least two asymmetric atoms, but which are not mirror images of each other. This can be determined according to the Cahn-Ingold-Prelog. RSThe system specifies absolute stereochemistry. When the compound is enantiomeric, the stereochemistry at each chiral carbon can be used... R or S Designation. Resolved compounds with unknown absolute configurations may be designated (+) or (-) based on the direction (right-handed or left-handed) of their rotational plane-polarized light at the wavelength of the sodium D line. Some compounds described herein contain one or more asymmetric centers and thus can produce enantiomers, diastereomers, and other stereoisomers that can be defined as (R)- or (S)- based on the absolute stereochemistry at each asymmetric atom. The chemical entities, pharmaceutical compositions, and methods of the present invention are intended to include all such possible isomers, including racemic mixtures, optically substantially pure forms, and intermediate mixtures.

[0088] Stereoisomers, such as optically active (+) and (-), or optically active ( R )-Isomers and ( S Stereoisomers can be synthesized or prepared asymmetrically, for example, using chiral synthons or chiral reagents, or separated using techniques such as chromatography on a chiral stationary phase. For example, stereoisomers can be separated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques, J... . et al. (Wiley-Interscience, New York, 1981); Wilen, SH et al. Tetrahedron 33: 2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (Edited by Ellieel, Univ. of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., Separation of Enantiomers : Synthetic Methods (Wiley-VCHVerlag gmbH&Co.KGaA, Weinheim, Germany, 2014); Toda, F., Enantiomer Separation: Fundamentals and Practical Methods (Springer Science &Business Media, 2007); Subramanian, G. Chiral Separation Techniques: A Practical Approach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0089] It should be understood that the chiral centers of the compounds provided herein can undergo epimerization in vivo. Therefore, those skilled in the art will recognize that, for compounds that undergo epimerization in vivo, administration of the (R) form is equivalent to administration of the (S) form.

[0090] In some implementations, the pharmaceutically acceptable form is a tautomer. As used herein, the term "tautomer" is a type of isomer that comprises two or more interconvertible compounds resulting from at least one form of hydrogen atom migration and at least one change in valence (e.g., single bond to double bond, triple bond to double bond, triple bond to single bond, or vice versa). "Tautomerism" includes proton shift or proton transfer tautomerism, which is considered a subfield of acid-base chemistry. "Proton shift tautomerism" or "proton transfer tautomerism" involves proton migration accompanied by a change in bond order. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Chemical equilibrium of tautomers can be reached where tautomerism is possible (e.g., in solution). Tautomerism (i.e., the reaction that provides tautomer pairs) can be catalyzed by acid or base, or can occur without the action or presence of external reagents. The concentration of the isomer form will depend on the environment in which the compound is present and can vary depending, for example, whether the compound is a solid or in an organic or aqueous solution. Exemplary tautomers include, but are not limited to, keto-enol; amide-imide; lactam-lactamimide; enamine-imide; and enamine-(different)enamine tautomers. For example, in aqueous solution, pyrazole can exhibit the following isomers, which are referred to as tautomers of each other: .

[0091] As will be readily understood by those skilled in the art, a variety of functional groups and other structures can exhibit tautomerism, and all tautomers of the compounds are within the scope of the compounds provided herein.

[0092] In some embodiments, the pharmaceutically acceptable form is an isotope. As used herein, the term "isotope" refers to an isotopically enriched compound that is the same as those described herein, but in fact has one or more atoms replaced by atoms with atomic masses or mass numbers different from those normally found in nature. Unless otherwise stated, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. Examples of isotopes that can be incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, respectively, such as...2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 35 Cl、 36 Cl and 37 Cl, these are also within the scope of this specification. For example, compounds having the structure of the present invention but in which hydrogen atoms at one or more atoms are replaced or enriched by deuterium or tritium are within the scope of this disclosure. In some embodiments, compounds are provided herein labeled with isotopes in which one or more hydrogen atoms are replaced or enriched by deuterium. In some embodiments, compounds are provided herein labeled with isotopes in which one or more hydrogen atoms are replaced or enriched by tritium. Further, compounds are labeled with heavier isotopes such as deuterium (i.e., 2 H) Substitution can provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life and reduced dose requirements). Disclosed isotopically labeled compounds can generally be prepared by replacing non-isotopically labeled reagents with isotopically labeled reagents. Isotopically enriched compounds, such as compound 1 or its pharmaceutically acceptable form, including solid forms of compound 1 or its pharmaceutically acceptable form, can generally be prepared using procedures known to those skilled in the art by replacing non-isotopically enriched reagents with suitable isotopically enriched reagents. Unless otherwise stated, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, a molecule having the structure of the invention but with hydrogen at one or more atoms replaced or enriched by deuterium or tritium, or carbon at one or more atoms replaced by deuterium or tritium. 13 C or 14 Compounds with C substitution or enrichment are within the scope of this disclosure. In some embodiments, compounds are provided that are isotopically labeled with one or more hydrogen atoms substituted or enriched by deuterium. In some embodiments, compounds are provided that are isotopically labeled with 1 to 3 hydrogen atoms substituted or enriched by deuterium. In some embodiments, compounds are provided that are isotopically labeled with one or more hydrogen atoms substituted or enriched by tritium. In some embodiments, compounds are provided that have one or more carbon atoms substituted or enriched by deuterium. 13 Compounds labeled with C-substituted or enriched isotopes. In some embodiments, this document provides compounds having one or more carbon atoms substituted or enriched. 14 Compounds labeled with isotopes that have been replaced or enriched with C.

[0093] When a compound is rich in deuterium, the ratio of deuterium to hydrogen on the deuterated atoms of the molecule is generally greater than the ratio of deuterium to hydrogen found in naturally occurring compounds.

[0094] As used herein and unless otherwise stated, the term "solid form" and related terms refer to a physical form that is not primarily liquid or gaseous. As used herein, the terms "one solid form" and "multiple solid forms" encompass semi-solids. Solid forms can be crystalline, amorphous, partially crystalline, partially amorphous, or mixtures of forms.

[0095] The solid forms described herein may have varying degrees of crystallinity or lattice order. The solid forms described herein are not limited to any particular degree of crystallinity or lattice order and may be 0-100% crystalline. Methods for determining crystallinity are known to those skilled in the art, such as those described in Suryanarayanan, R. X-Ray Power Diffractometry The methods described in Physical Characterization of Pharmaceutical Salts, edited by HGBrittain, Mercel Dekkter, Murray Hill, NJ, 1995, pp. 187–199, are incorporated herein by reference in their entirety. In some embodiments, the solid form provided herein is about 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% crystalline, such as about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% crystalline or higher.

[0096] As used herein and unless otherwise stated, the term "crystallization" and related terms, when used to describe a substance, component, product, or form, mean that the substance, component, product, or form is substantially crystalline, as determined, for example, by X-ray diffraction. See, for example, Remington : The Science and Practice of Pharmacy , 21st edition, Lippincott, Williams and Wilkins, Baltimore, MD (2005); The United States Pharmacopeia , 23rd edition, 1843-1844 (1995).

[0097] As used herein and unless otherwise stated, the term "crystalline form" and related terms refer to a crystalline solid form. Crystalline forms include monocomponent and multicomponent crystalline forms, including but not limited to polymorphs, solvates, hydrates, and other molecular complexes, as well as salts, solvates of salts, hydrates of salts, eutectic salts, other molecular complexes of salts, and their polymorphs. In some embodiments, the crystalline form of a substance may be substantially free of amorphous and / or other crystalline forms. In some embodiments, the crystalline form of a substance may contain less than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% by weight of one or more amorphous and / or other crystalline forms. In some embodiments, the crystalline form of a substance may be physically and / or chemically pure. In some embodiments, the crystalline form of a substance may be about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% physically and / or chemically pure.

[0098] A "single-component" solid form containing a compound consists essentially of that compound. A "multi-component" solid form containing a compound contains significant amounts of one or more additional substances, such as ions and / or molecules, within the solid form. For example, in some embodiments, a crystalline multi-component solid form containing a compound also contains one or more substances non-covalently bonded at regular positions in a crystal lattice. As another example, in some embodiments, an amorphous multi-component solid form containing a compound also contains one or more polymers, and the compound is dispersed in a solid matrix containing the polymer.

[0099] The crystalline form of a substance can be obtained by a number of methods. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, recrystallization in confined spaces (such as in nanopores or capillaries), recrystallization on surfaces or templates (such as on polymers), recrystallization in the presence of additives (such as eutectic antimolecules), desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, grinding, and solvent drop grinding.

[0100] Unless otherwise stated, the terms “a polymorph,” “a polymorphic form,” “multiple polymorphs,” “multiple polymorphic forms,” and related terms herein refer to two or more crystalline forms composed of essentially the same molecule, multiple molecules, or ions. Like different crystalline forms, different polymorphs can have different physical properties, such as, for example, melting temperature, heat of fusion, solubility, dissolution rate, and / or vibrational spectrum, as a result of different arrangements or conformations of molecules or ions in the crystal lattice. Differences in the physical properties exhibited by polymorphs can affect drug parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rate (an important factor in bioavailability). Stability differences can be caused by changes in chemical reactivity (e.g., differential oxidation, causing dosage forms to discolor more rapidly when composed of one polymorph than another) or mechanical changes (e.g., tablets crumbling during storage as a kinetically favorable polymorph transforms into a thermodynamically more stable one) or both (e.g., tablets of one polymorph are more prone to decomposition at high humidity). Due to differences in solubility / dissolution, some polymorphic transformations can lead to inefficiency in extreme cases, or toxicity in other extreme cases. Furthermore, the physical properties of the crystals can be important during processing (e.g., one polymorph may be more likely to form solvates or may be difficult to filter and wash away impurities, and particle shape and size distributions may differ between polymorphs).

[0101] As used herein and unless otherwise stated, the terms “amorphous,” “amorphous form,” and related terms mean that the substance, component, or product under discussion is not substantially crystalline as determined by X-ray diffraction. Specifically, the term “amorphous form” describes a disordered solid form, i.e., a solid form lacking long-range crystalline order. In some embodiments, the amorphous form of a substance may be substantially free of other amorphous and / or crystalline forms. In other embodiments, the amorphous form of a substance may contain less than about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% by weight of one or more other amorphous and / or crystalline forms. In some embodiments, the amorphous form of a substance may be physically and / or chemically pure. In some embodiments, the amorphous form of a substance may be about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% physically and / or chemically pure. In some embodiments, the amorphous form of the substance may contain additional components or ingredients (e.g., additives, polymers, or excipients that may be used to further stabilize the amorphous form). In some embodiments, the amorphous form may be a solid solution.

[0102] The amorphous form of a substance can be obtained by a variety of methods. These methods include, but are not limited to, heating, melting and cooling, rapid melting and cooling, solvent evaporation, rapid solvent evaporation, desolvation, sublimation, grinding, ball milling, cryogenic grinding, spray drying, and freeze drying.

[0103] Techniques used to characterize crystalline and amorphous forms include, but are not limited to, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), single-crystal X-ray diffraction, vibrational spectroscopy (e.g., infrared (IR) and Raman spectroscopy), solid-state and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hot-stage microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility measurements, dissolution measurements, elemental analysis, and Karl Fischer analysis. Characteristic unit cell parameters can be determined using one or more techniques, such as, but not limited to, X-ray diffraction and neutron diffraction, including single-crystal diffraction and powder diffraction. Techniques that can be used to analyze powder diffraction data include profile refinement, such as Rietwald refinement, which can be used, for example, to analyze diffraction peaks associated with a single phase in samples containing more than one solid phase. Other methods that can be used to analyze powder diffraction data include cell indexing, which allows those skilled in the art to determine unit cell parameters from samples containing crystalline powder. In some embodiments, Cu Kα radiation is used to obtain XRPD spectra. In some embodiments, the peaks listed for the XRPD spectra have relative intensities greater than about 5%, greater than about 10%, greater than about 15%, or greater than about 20%. In some embodiments, the heating rate (ratio) for DSC is about 10 °C / min. In some embodiments, a slower heating rate (such as 0.5 °C–2.0 °C / min) can be used for more accurate DSC testing. Sample disks used for DSC testing include, for example, aluminum disks, platinum disks, and stainless steel disks. The disks can have different constructions, such as open disks, pinhole disks, or hermetically sealed disks. In some embodiments, the heating rate for TGA is about 10 °C / min.

[0104] Unless otherwise stated, the terms “X-ray powder diffraction”, “powder X-ray diffraction”, “PXRD” and “XRPD” are used interchangeably in this application.

[0105] Solid forms can exhibit unique physical characterization data that are specific to a particular solid form, such as the crystalline forms provided herein. This characterization data can be obtained using various techniques known to those skilled in the art, including, for example, X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis, and nuclear magnetic resonance spectroscopy. Data provided by these techniques can be used to identify a specific solid form. Those skilled in the art can determine whether a solid form is one of the forms provided herein by performing one of these characterization techniques and determining whether the resulting data “matches” or “substantially matches” the characteristics identified as a specific solid form. Those skilled in the art understand that those characterization data that “match” or “substantially match” a reference solid form correspond to the same solid form as the reference solid form. In analyzing whether data “matches” or “substantially matches,” those skilled in the art understand that specific characterization data points can vary to a reasonable degree due to, for example, experimental errors and routine inter-sample analytical variability, while still describing a given solid form. For example, an XRPD pattern, DSC thermogram, or TGA thermogram that “matches” or “substantially matches” one or more of the XRPD patterns, DSC thermograms, or TGA thermograms shown herein is an XRPD pattern, DSC thermogram, or TGA thermogram that a person skilled in the art would consider to represent the same compound sample in single-crystal form as the one or more patterns provided herein. Therefore, a matching or substantially consistent XRPD pattern, DSC thermogram, or TGA thermogram may be identical to one of the patterns in the figures, or more likely, may be slightly different from one or more of the patterns in the figures. For example, an XRPD pattern that is slightly different from one or more of the patterns in the figures may not necessarily show every line of the diffraction pattern presented herein and / or may show slight variations in the appearance or intensity of the lines or shifts in the position of the lines. These differences are generally caused by differences in the conditions involved in obtaining the data or differences in the purity of the sample used to obtain the data. Those skilled in the art can determine whether a sample of crystalline compound is in the same or different form as disclosed herein by comparing the XRPD spectrum, DSC thermogram, or TGA thermal curve of the sample with the corresponding XRPD spectrum, DSC thermogram, or TGA thermal curve disclosed herein.

[0106] When used without further limitations, "substantially pure" means that the compound has a purity of more than about 90% by weight, for example, more than about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% by weight, and also includes a purity of about 100% by weight. The remaining material may contain other forms of the compound and / or reaction impurities and / or processing impurities arising from its preparation. If the compound is "substantially pure" with respect to the presence of other remaining materials, it may be described as "substantially physically pure." When limited, "substantially pure" means that the indicated compound contains less than about 10% by weight, less than about 5% by weight, less than about 4% by weight, less than about 3% by weight, less than about 2% by weight, less than about 1% by weight, less than about 0.5% by weight, or less than about 0.1% by weight of the indicated impurities. In some embodiments, the solid form (e.g., crystalline or amorphous form) provided herein is substantially pure, i.e., substantially free of other solid forms and / or other chemical compounds, containing less than about 25 wt%, 20 wt%, 15 wt%, 10 wt%, 9 wt%, 8 wt%, 7 wt%, 6 wt%, 5 wt%, 4 wt%, 3 wt%, 2 wt%, 1 wt%, 0.75 wt%, 0.5 wt%, 0.25 wt%, or 0.1 wt% of one or more other solid forms and / or chemical compounds. For example, in some embodiments, the solid form of compound 1 is substantially pure (e.g., having a purity of at least about 90 wt%, at least about 95 wt%, at least about 96 wt%, at least about 97 wt%, at least about 98 wt%, or at least about 99 wt%). Purity can be assessed using techniques known in the art, such as HPLC determination.

[0107] The term "substantially pure" can also be limited. If a compound is "substantially pure" with respect to chemical impurities (e.g., the presence of reaction impurities and / or processing impurities arising from its preparation), it may be referred to as "substantially chemically pure." If a compound is "substantially pure" with respect to the presence of another stereoisomer, such as other enantiomers, it may be referred to as "substantially stereoisomerically pure," such as "substantially enantiomerically pure." As used herein and unless otherwise indicated, the term stereoisomerically pure means that one stereoisomer of a compound is substantially free of other stereoisomers of the compound.

[0108] As used herein, and unless otherwise indicated, "substantially free of" another chemical compound, solid form, or composition means, in some embodiments, that the compound, solid form, or composition contains less than about 50 wt%, 45 wt%, 40 wt%, 35 wt%, 30 wt%, 25 wt%, 20 wt%, 15 wt%, 10 wt%, 9 wt%, 8 wt%, 7 wt%, 6 wt%, 5 wt%, 4 wt%, 3 wt%, 2 wt%, 1 wt%, 0.5 wt%, 0.4 wt%, 0.3 wt%, 0.2 wt%, 0.1 wt%, 0.05 wt%, or 0.01 wt% of another compound, solid form, or composition.

[0109] As used herein, and unless otherwise stated, the "substantially physically pure" solid form is substantially free of other solid forms. In some embodiments, the substantially physically pure crystalline form contains less than about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.01% by weight of one or more other solid forms. The detection of other solid forms can be performed by any method readily apparent to those skilled in the art, including but not limited to diffraction analysis, thermal analysis, elemental combustion analysis, and / or spectroscopic analysis.

[0110] As used herein, and unless otherwise stated, the "substantially chemically pure" solid form is substantially free of other compounds (i.e., chemical impurities). In some embodiments, the substantially chemically pure solid form contains less than about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.01% by weight of one or more other chemical compounds. The detection of other chemical compounds can be performed by any method readily apparent to those skilled in the art, including but not limited to chemical analysis methods such as, for example, mass spectrometry, spectral analysis, thermal analysis, elemental combustion analysis, and / or chromatographic analysis.

[0111] For example, in some embodiments, the enantiomer may be substantially free of the corresponding enantiomer and may also be referred to as "optically enriched," "enantiomer-enriched," "enantiomer-pure," and "non-racemic," as used interchangeably herein, wherein the amount of one enantiomer is greater than the amount of that enantiomer in a control mixture of the racemic composition (e.g., greater than 1:1 by weight). A typical enantiomer-pure compound contains greater than about 80% by weight of one enantiomer of the compound and less than about 20% by weight of another enantiomer of the compound, greater than about 90% by weight of one enantiomer of the compound and less than about 10% by weight of another enantiomer of the compound, greater than about 95% by weight of one enantiomer of the compound and less than about 5% by weight of another enantiomer of the compound, or greater than about 97% by weight of one enantiomer of the compound and less than about 3% by weight of another enantiomer of the compound.

[0112] For example, an enantiomer enrichment formulation of S enantiomers means relative to the total weight of the formulation (e.g., S Isomers and R The total weight of the isomers) contains a compound formulation having more than about 50% by weight, such as more than about 60% by weight, more than about 70% by weight, or more than about 80% by weight of the S enantiomer. In some embodiments, enrichment can be much greater than about 80% by weight, providing a formulation that is “substantially enantiomerically enriched,” “substantially enantiomerically pure,” or “substantially non-racemic”, meaning a composition formulation of an enantiomer having more than about 85% by weight relative to the total weight of the formulation, such as more than about 90% by weight, more than about 95% by weight, more than about 96% by weight, more than about 97% by weight, more than about 98% by weight, more than about 98.5% by weight, more than about 99% by weight, or more than about 99.5% by weight. In some embodiments, compound 1 (i.e., ( S )-3-amino-3-(1-methyl-1 H -imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-dibenzocyclohexane-2 2 , 4 4 The solid form of (-dicarboxynitrile) is enantiomerically pure (i.e., substantially free of compound 2 (i.e., (R)-3-amino-3-(1-methyl-1-dicarboxynitrile)). H -imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-dibenzocyclohexane-2 2 , 4 4(-dicarboxynitrile). In some embodiments, the solid form of compound 1 is substantially enantiomerically pure, wherein less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, or less than about 0.1% by weight of another enantiomer (e.g., compound 2, R enantiomer). In some embodiments, the solid form of compound 1 is substantially enantiomerically pure (e.g., having an enantiomeric purity of at least about 98.0% by weight, at least about 98.5% by weight, at least about 99.0% by weight, at least about 99.5% by weight, or at least about 99.9% by weight).

[0113] The embodiments provided herein cover the use of the stereoisomeric pure forms of such compounds as well as the use of mixtures of those forms. For example, mixtures containing equal or unequal amounts of enantiomers of a particular compound can be used in the methods and compositions provided herein.

[0114] The “enantiomer excess” or “% enantiomer excess” of a composition (e.g., a composition comprising a mixture of enantiomers of a compound) can be calculated using the equation shown below. In the example shown below, a composition containing 90% of one enantiomer (e.g., S (enantiomer) and 10% of another enantiomer (e.g., R A mixture of enantiomers is called having an 80% enantiomer excess. For example, in some embodiments, the compounds described herein are mixtures of enantiomers of a compound (racemic) and contain an enantiomer in excess of one enantiomer at a rate greater than about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5%, such as an S enantiomer in excess of the R enantiomer. For example, the compounds provided herein may have a single enantiomer with an ee greater than about 95%, such as about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5%. In some embodiments, the mixture of enantiomers of the compound (racemic) has an enantiomer in excess of one enantiomer at about 55% to about 99.5%, about 60% to about 99.5%, about 65% to about 99.5%, about 70% to about 99.5%, about 75% to about 99.5%, about 80% to about 99.5%, about 85% to about 99.5%, about 90% to about 99.5%, about 95% to about 99.5%, about 96% to about 99.5%, about 97% to about 99.5%, about 98% to about 99.5%, or about 99% to about 99.5%, or greater than about 99.5%, such as relative to one enantiomer. R Enantiomer excess S Enantiomer.

[0115] As used herein, the term "pharmaceuticalally acceptable excipient" should be understood to mean a carrier, excipient, or diluent approved by a federal or state regulatory agency or listed in the United States Pharmacopeia or other recognized pharmacopoeia for use in animals, and more particularly in humans. The term "carrier" refers to a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or medium administered in conjunction with a therapeutic agent. Such drug carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is a specific carrier for drug compositions intended for intravenous administration. Saline solutions and aqueous solutions of dextran and glycerol can also be used as liquid carriers, particularly for injectable solutions. For example, the term pharmaceutically acceptable carrier, excipient, or diluent includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delay agents. The use of such media and reagents for pharmaceutically active substances is well known in the art. Unless any conventional media or reagent is incompatible with the active ingredient, its use in therapeutic compositions should be considered. Additional active ingredients may also be incorporated into pharmaceutical compositions. Typical compositions and dosage forms contain one or more excipients. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the manner in which the dosage form is administered to a patient and the specific active ingredient in the dosage form. Examples of excipients that may be used in oral dosage forms provided herein include, but are not limited to, fillers, flow aids, disintegrants, lubricants, or binders, or combinations thereof.

[0116] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS edition, Handbook of Chemistry and Physics, 75th edition, inner cover, and specific functional groups are generally defined as described herein. Furthermore, general principles of organic chemistry, as well as specific functional groups and reactivity, are described in the following literature: Organic Chemistry , Thomas Sorrell, UniversityScience Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry , 5th edition, John Wiley &Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations , VCHPublishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0117] The term "protecting group" has its commonly associated meaning in organic synthesis, such as a group that selectively blocks one or more reaction sites in a polyfunctional compound, allowing the chemical reaction to proceed selectively at another unprotected reaction site, and enabling the group to be readily removed after the selective reaction is complete. Various protecting groups are disclosed, for example, in THGreene and PGMUTS. Protective Groups in Organic Synthesis The fourth edition of John Wiley & Sons, New York (2006), is incorporated herein by reference in its entirety. For example, hydroxyl protection is the presence of at least one hydroxyl group in a compound that is protected by a hydroxyl protecting group. Similarly, amines and other reactive groups can be similarly protected.

[0118] As used herein and unless otherwise indicated, the term "method" as provided herein refers to a method provided herein for preparing compounds as described herein or their solid forms (e.g., crystalline, partially crystalline, or amorphous forms). Modifications to the methods provided herein (e.g., starting materials, reagents, protecting groups, solvents, temperatures, reaction times, purification) are also provided herein. In general, the technical teachings of one embodiment provided herein can be combined with the technical teachings disclosed in any other embodiment provided herein.

[0119] As used herein, and unless otherwise indicated, the terms “addition,” “reaction,” “treatment,” etc., in the context of methods (such as reaction methods or crystallization methods) mean contacting one reactant, reagent, solvent, catalyst, reactive group, etc., with another reactant, reagent, solvent, catalyst, reactive group, etc. Reactants, reagents, solvents, catalysts, reactive groups, etc., may be added individually, simultaneously, or separately, and may be added in any order. Reactants, reagents, solvents, catalysts, reactive groups, etc., may be added individually at once (either delivered all at once or delivered over a period of time), or added in discrete portions (also delivered all at once or delivered over a period of time). They may be added with or without heating, and may optionally be added under an inert atmosphere. “Reaction” can refer to in-situ formation or intramolecular reaction, wherein the reactive groups are located within the same molecule.

[0120] As used herein, the term "combination" refers to the association of one or more chemical entities with one or more other chemical entities. Combination includes the process of adding one or more compounds to a solid, liquid, or gaseous mixture, or a liquid solution or multiphase liquid mixture of one or more compounds (identical or other chemical entities). The behavior of combination includes one or more processes in which one or more compounds react with one or more compounds (identical or other chemical entities) (e.g., bond formation or cleavage; salt formation, solvate formation, chelation, or other non-bond-changing association). The behavior of combination may include alterations to one or more compounds, such as by isomerization (e.g., tautomerization, separation of one isomer with another, or racemization).

[0121] As used herein, and unless otherwise indicated, the term “transformation” refers to subjecting a compound at hand to reaction conditions suitable for the formation of the desired compound.

[0122] As used herein, the term "recovery" includes, but is not limited to, the action of obtaining one or more compounds by collection during and / or after the method steps disclosed herein, and the action of obtaining one or more compounds by separating one or more compounds from one or more other chemical entities during and / or after the method steps disclosed herein. The term "collection" refers to any action known in the art for this purpose, including but not limited to filtration, decanting mother liquor from a solid to obtain one or more compounds, and evaporating a liquid medium in a solution or other mixture to obtain a solid, oil, or other residue comprising one or more compounds. Solids may be crystalline, amorphous, partially crystalline, or amorphous, powder, granules, having different particle sizes, uniform particle sizes, and other characteristics known in the art. Oils may vary in color and viscosity and include one or more solid forms as a non-homogeneous mixture, and other characteristics known in the art. The term "separation" refers to any action known in the art for this purpose, including but not limited to separating one or more compounds from a solution or mixture using, for example, seedless crystallization or other precipitation techniques (e.g., adding an antisolvent to a solution to induce compound precipitation; heating a solution and then cooling it to induce compound precipitation; scraping the surface of a solution with a tool to induce compound precipitation) and distillation techniques. Recovery of one or more compounds may include preparing salts, solvates, hydrates, chelates or other complexes of the compounds, which are then collected or separated as described above.

[0123] As used herein, the term "catalyst precursor" refers to a chemical composition in which one or more components of an active catalyst (e.g., a metal center and a supporting ligand) are added to a reaction mixture to cause the formation of an active catalyst in situ. Those skilled in the art will recognize that even when the metal source and supporting ligand are added to the reaction mixture in the form of a single chemical entity (e.g., Pd(dppf)Cl2), further in-situ activation and / or reaction may be required to produce an active catalyst. Nevertheless, as used herein, the term "catalyst" includes, but is not limited to, chemical compositions in which more than one component of an active catalyst (e.g., a metal center and a supporting ligand) is added to the reaction mixture in the form of a single chemical entity (e.g., Pd(dppf)Cl2), even if further in-situ activation and / or reaction is required to produce an active catalyst.

[0124] As used herein, and unless otherwise stated, the terms “solvent,” “organic solvent,” or “inert solvent” as used in the context of methods (such as reaction methods or crystallization methods) each mean a solvent that is inert under the described reaction conditions. Unless otherwise stated, 1 cc (or mL) of solvent constitutes a volume equivalent (or “vol.”) for every gram of limiting reagent.

[0125] As used herein, the term "selective precipitation" refers to a precipitate formed when a mixture of compounds 1 and 2 (such as compound 19) reacts with a chiral acid in a solvent to form a pair of diastereomeric salts, wherein the precipitate is enantiomerically enriched in either compound 1 or compound 2, for example, having an increased %ee relative to the starting mixture. As used herein, the term "selectively soluble" refers to a mother liquor formed when a mixture of compounds 1 and 2 (such as compound 19) reacts with a chiral acid in a solvent to form a pair of diastereomeric salts, wherein the mother liquor is enantiomerically enriched in either compound 1 or compound 2, for example, having an increased %ee relative to the starting mixture.

[0126] As used in this article, the term "HNSCC" refers to head and neck squamous cell carcinoma (HNSCC). Head and neck squamous cell carcinoma (HNSCC) is the seventh most common invasive cancer worldwide, with approximately 830,000 new cases diagnosed and 200,000 deaths annually worldwide, including approximately 54,000 new cases in the United States each year. It is also the most common cancer in Central Asia. HNSCC has two distinct causes and corresponding tumor types. The first subtype is associated with smoking and alcohol consumption and is not related to human papillomavirus (HPV- or HPV-negative). The second subtype is associated with high-risk HPV infection (HPV+ or HPV-positive). The second subtype is primarily limited to oropharyngeal cancer. HPV+ tumors are a distinct entity with a better prognosis and may require different treatments. A large proportion of HNSCC, especially oropharyngeal cancer, is caused by HPV infection. High-risk HPV subtype 16 accounts for 85% of all HPV+ tumors in HNSCC. P16 can be used as an alternative biomarker for HPV infection in HNSCC, particularly in the oropharynx. More accurate HPV tests are available and are based on E6 / E7 testing (Liang C et al. Cancer Res. 2012; 72: 5004-5013).

[0127] As used in this article, the terms "HRAS mutation" or "H-Ras mutation" refer to... HRAS Activating mutations in genes or H-Ras proteins. H-Ras mutations can refer to... HRAS Genetic alterations in the DNA sequence of a gene that lead to oncogenic activation of the corresponding H-Ras protein, or alterations in the amino acid sequence of the H-Ras protein that lead to its oncogenic activation. Therefore, the terms "HRAS mutation" or "H-Ras mutation" as used herein do not refer to... HRAS The mutations do not result in oncogenic activation of the H-Ras protein in the gene itself, nor in the H-Ras protein sequence; however, such mutations can still be present in samples or subjects. Therefore, samples or subjects without any of the “H-Ras mutations” used herein may still be eligible for oncogenic activation. HRAS Mutations in the gene that do not affect H-Ras protein activity or mutations that impair H-Ras protein activity, or mutations in the H-Ras protein that do not affect its activity or mutations that impair its activity. Samples or subjects may have... HRAS Multiple copies of the gene. Samples or subjects may also possess both wild-type and mutant H-Ras proteins. As used herein, samples or subjects with H-Ras mutations may also possess wild-type H-Ras proteins. HRAS A copy of the gene and / or wild-type H-Ras protein. As used herein, identifying a sample or subject as "having wild-type H-Ras" means having only wild-type H-Ras. HRASSamples or subjects containing the H-Ras gene and wild-type H-Ras protein without the H-Ras mutation. In some implementations, the mutation... HRAS The gene encodes a mutant H-Ras protein, in which HRAS The gene mutation in the corresponding mutant H-Ras protein is or contains a modification in the codon encoding an amino acid substitution at a specific position selected from G12, G13, Q61, Q22, K117, A146, and any combination thereof. In some embodiments, HRAS The gene mutation is a mutation at the codon encoding the G12 position of the mutant H-Ras protein, where an amino acid is substituted. In some embodiments, the HRAS gene mutation is at the codon encoding the G12R substitution in the mutant H-Ras protein. HRAS The gene mutation can be a mutation at the codon where G12C, G12D, G12A, G12V, G12S, G12F, G12R, or G12N is substituted in the protein encoding the mutant H-Ras. In some embodiments, HRAS The gene mutation is a mutation at the codon where the G12V is substituted in the protein encoding the mutant H-Ras. In some implementations, HRAS Gene mutations are mutations at the codons where an amino acid is substituted at the G13 position in the protein encoding the mutant H-Ras. HRAS The gene mutation can be a mutation at the codon where G13A, G13C, G13V, G13D, G13R, G13S, G13N, or G13V is substituted in the protein encoding the mutant H-Ras. In some embodiments, HRAS The gene mutation is a mutation at the codon where G13C is substituted in the protein encoding the mutant H-Ras. In some implementations, HRAS The gene mutation is a mutation at the codon where the G13R is substituted in the protein encoding the mutant H-Ras. In some implementations, HRAS Gene mutations are mutations at the codons where an amino acid is substituted at position Q61 in the protein encoding the mutant H-Ras. HRAS The gene mutation can be a mutation at the codon where Q61E, Q61K, Q61H, Q61L, Q61P, or Q61R is substituted in the mutated H-Ras protein. In some implementations, HRAS The gene mutation is a mutation at the codon where Q61L is substituted in the protein encoding the mutant H-Ras. In some implementations, HRAS The gene mutation is a mutation at the codon where the Q61R is substituted in the protein encoding the mutant H-Ras. In some implementations, HRAS The gene mutation is a mutation at the codon where an amino acid is substituted at position Q22 in the protein encoding the mutant H-Ras. In some implementations, HRASThe gene mutation is a mutation at the codon where Q22K or Q22T is substituted in the protein encoding the mutant H-Ras. In some implementations, HRAS The gene mutation is a mutation at the codon where an amino acid is substituted at the K117 position in the protein encoding the mutant H-Ras. In some implementations, HRAS The gene mutation is a mutation at the codon where K117N or K117L is substituted in the protein encoding the mutant H-Ras. In some implementations, HRAS Gene mutations are mutations at the codon where an amino acid is substituted at position A146 in the protein encoding the mutant H-Ras. HRAS The gene mutation can be a mutation at the codon where A146V, A146T, or A146P is substituted in the protein encoding the mutant H-Ras. In some implementations, HRAS The gene mutation is a mutation at the codon where A146P is substituted in the mutated H-Ras protein. In some embodiments, the mutation may be a mutation at another codon that leads to the activation of the H-Ras protein.

[0128] As used herein and unless otherwise indicated, the term "subject" as intended may refer to animals, including, but not limited to, humans (e.g., males or females of any age group, such as adult subjects or adolescent subjects); primates (e.g., cynomolgus monkeys, rhesus monkeys) and / or other mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, dogs, rabbits, rodents, and / or birds (e.g., commercially relevant birds such as chickens, ducks, geese, quails, and / or turkeys). In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is an adolescent. In some embodiments, the subject is an adult. In some embodiments, the subject is a patient, such as a human patient. In some embodiments, the subject may be a patient, such as a patient with a farnesylation-dependent cancer.

[0129] As used herein, the terms “prevention” and “preventing” are used to refer to methods for obtaining a beneficial or desired outcome, including but not limited to methods for preventing benefits. For the purpose of preventing benefits, the compounds and pharmaceutical compositions disclosed herein may be administered to patients at risk of developing a particular disease, or to patients who report one or more physiological symptoms of a disease or condition, even if such a diagnosis may not have been made.

[0130] When used herein, the term “therapeutic effect” encompasses therapeutic and / or preventive benefits as described herein. Preventive effects include delaying or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping, or reversing the progression of a disease or condition, or any combination thereof.

[0131] As used herein, the terms “treat,” “treating,” “treatment,” and “improvement” are used interchangeably. These terms refer to methods used to achieve a beneficial or desired outcome, including but not limited to therapeutic benefits. A therapeutic benefit means the eradication or improvement of an underlying condition that is being treated. Similarly, a therapeutic benefit is achieved by eradicating or improving one or more physiological symptoms associated with an underlying condition, resulting in an improvement observed in the patient, although the patient may still have the underlying disease or condition. For example, when used in relation to patients with farnesylation-dependent cancers, it refers to an effect that reduces the severity of the cancer or inhibits or slows its progression, including (a) inhibiting cancer growth or preventing cancer development, and (b) causing cancer regression, or delaying or minimizing one or more symptoms associated with the presence of cancer.

[0132] This disclosure can be more fully understood by referring to the following detailed description and illustrative examples, which are intended to illustrate non-limiting embodiments.

[0133] 5.1 Compounds In some embodiments, compound 1 is provided herein, which may be named ( S )-3-amino-3-(1-methyl-1 H -imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-dibenzocyclohexane-2 2 , 4 4 -Dicarbonyl nitrile, and has the following structure: .

[0134] In some embodiments, compound 2 is provided herein, which may be named ( R )-3-amino-3-(1-methyl-1 H -imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-dibenzocyclohexane-2 2 , 4 4 -Dicarbonyl nitrile, and has the following structure: .

[0135] In some embodiments, compound 19 is provided herein, which may be named (3-amino-3-(1-methyl-1 ... H -imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-dibenzocyclohexane-2 2 , 4 4 -Dicarbonyl nitrile, and has the following structure: .

[0136] As used herein, compound 19 describes a racemic mixture of compound 1 and compound 2, but as described herein, unequal mixtures of compound 1 and compound 2 are also considered.

[0137] The useful compounds described herein include compounds 1, 2 and 19 and their pharmaceutically acceptable forms, such as compound 1 and its pharmaceutically acceptable forms.

[0138] As used herein, the compounds disclosed herein include, but are not limited to, their free base form or pharmaceutically acceptable salts, their solvates or hydrates, and isotopes of such compounds. In some embodiments, the free base or pharmaceutically acceptable salt of compound 1, or its hydrates or solvates and / or isotopes, are contemplated. Throughout this application, disclosure relating to compound 1, compound 2, compound 19, or any intermediate compound as disclosed herein in their synthesis should be understood to also include the isotopes of said compounds as provided herein.

[0139] The synthesis and certain uses, inhibitory activities, and metabolic stability of compounds 1, 2, and 19, and their pharmaceutically acceptable forms, as described herein, are described in International Patent Application PCT / US2022 / 80565, which is incorporated herein by reference in its entirety. This application provides improved methods for preparing compounds 1, 2, and 19, and their pharmaceutically acceptable forms. In some embodiments, the compound used in the therapeutic or inhibitory methods provided herein is compound 1 or a pharmaceutically acceptable form thereof. In some embodiments, the compound used in the therapeutic or inhibitory methods provided herein is a pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable solvate and / or isotope thereof. In some embodiments, the compound or solid form used in the therapeutic or inhibitory methods provided herein is a solid form of compound 1 or a pharmaceutically acceptable form thereof. In some embodiments, the compound used in the therapeutic or inhibitory methods provided herein is a crystalline solid form of compound 1 or a pharmaceutically acceptable form thereof. Throughout this application, disclosures relating to the use of compound 1 or its pharmaceutically acceptable form are equally applicable to compound 2 or its pharmaceutically acceptable form, or compound 19 or its pharmaceutically acceptable form.

[0140] In some embodiments, this document provides compounds as intermediate compounds disclosed in the synthesis of compound 1 or its pharmaceutically acceptable form as provided herein.

[0141] 5.2 Solid form Potential drug solids include crystalline solids and amorphous solids. Amorphous solids are characterized by a lack of long-range structural order, while crystalline solids are characterized by periodic structures. The desired class of drug solids depends on the specific application; amorphous solids are sometimes selected based on, for example, enhanced dissolution profiles, while crystalline solids may be desired due to properties such as, for example, physical or chemical stability (see, for example, SR Vippagunta et al.). Adv. Drug. Deliv. Rev., (2001) 48: 3-26; L. Yu, Adv. Drug. Deliv. Rev., (2001) 48: 27-42). Changes in solid form can affect a variety of physical and chemical properties, which may provide benefits or disadvantages in terms of processing, formulation, stability, bioavailability, and other important drug characteristics.

[0142] Whether crystalline or amorphous, the potential solid forms of drug compounds can include both single-component and multi-component solids. Single-component solids consist primarily of the drug compound, with no other compounds present. The diversity among single-component crystalline materials can potentially arise from polymorphism, where multiple three-dimensional arrangements exist for a particular drug compound (see, for example, SR Byrn et al.). Solid State Chemistry of Drugs , (1999) SSCI, WestLafayette).

[0143] Further diversity among the potential solid forms of drug compounds can arise from the possibility of multi-component solids. Crystalline solids containing two or more ionic substances are called salts (see, for example...). Handbook of Pharmaceutical Salts: Properties, Selection and Use, PHStahl and CG Wermuth (eds., 2002, Wiley, Weinheim). Other types of multicomponent solids that may potentially provide additional property enhancements to drug compounds or their salts include, for example, hydrates, solvates, cocrystals, and cage-like inclusion compounds (see, for example, SR Byrn et al.). Solid State Chemistry of Drugs, (1999) SSCI, West Lafayette). Multicomponent crystalline forms may be potentially susceptible to polymorphism, where a given multicomponent composition can exist in more than one three-dimensional crystalline arrangement. The discovery of solid forms is crucial in the development of safe, effective, stable, and marketable pharmaceutical compounds.

[0144] It is important to note that the existence of a crystalline form of a compound cannot be predicted a priori, nor can it be predicted whether such a form possesses properties suitable for drug development (physical properties, stability, dissolution, purity, etc.) or how to successfully prepare them (see, for example, Braga and Grepioni, 2005, “Making crystals from crystals: a greenroute to crystal engineering and polymorphism”). Chem.Commun .: 3635-3645 (Regarding crystal engineering, if the instructions are not very precise and / or if other external factors affect the process, the results may be unpredictable); Jones et al., 2006, Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement, MRS Bulletin 31: 875-879 (Currently, it is generally impossible to calculate and predict the number of observable polymorphs even for the simplest molecules); Price, 2004, “The computational prediction of pharmaceutical crystal structures and polymorphism,” Advanced Drug Delivery Reviews 56: 301-319 (“Price”); and Bernstein, 2004, “CrystalStructure Prediction and Polymorphism, ” ACA Transactions 39: 14-23 (There is much to learn and do before we can confidently assert that we can predict crystal structures (let alone polymorphic forms)).

[0145] For a given drug compound, the diversity of its solid forms can lead to a potential diversity in its physical and chemical properties. The discovery and selection of solid forms is crucial in the development of effective, stable, and marketable drug products.

[0146] The solid forms provided herein can be used as active pharmaceutical ingredients in the preparation of formulations for use in animals or humans. Therefore, the embodiments herein cover the use of these solid forms as final pharmaceutical products. Some embodiments provide solid forms that can be used to prepare final dosage forms with improved properties, such as powder flowability, compaction properties, tableting properties, stability properties, and excipient compatibility properties, which are necessary for the manufacture, processing, formulation, and / or storage of the final pharmaceutical product. Some embodiments herein provide pharmaceutical compositions comprising single-component crystalline forms and / or multi-component crystalline forms, said crystalline forms comprising compound 1 and pharmaceutically acceptable excipients.

[0147] Solid form and related terms refer to a physical form that is not primarily liquid or gaseous. A solid form can be crystalline or a mixture of crystalline and amorphous forms. A “single-component” solid form containing a specific compound consists essentially of that compound. A “multi-component” solid form containing a specific compound contains that compound and significant amounts of one or more other substances, such as ions and / or molecules within the solid form, for example, solvent molecules. The solid forms described herein can be crystalline or intermediate forms (e.g., mixtures of crystalline and amorphous forms). Therefore, the crystalline forms described herein can have varying degrees of crystallinity or lattice order. The solid forms described herein are not limited to any particular degree of crystallinity or lattice order and can be 0-100% crystalline. Methods for determining crystallinity are known to those skilled in the art, such as those described in the following literature: Suryanarayanan, R., X-Ray Powder Diffractometry Physical Characterization of Pharmaceutical Solids, edited by HGBrittain, Marcel Dekker, Murray Hill, NJ, 1995, pp. 187-199, which is incorporated herein by reference in its entirety. In some embodiments, the solid form described herein is about 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% crystalline.

[0148] Solid forms can exhibit unique physical characterization data that are specific to a particular solid form (such as the crystalline forms described herein). This characterization data can be obtained using various techniques known to those skilled in the art, including, for example, XRPD, DSC, TGA, and NMR spectroscopy. Data provided by these techniques can be used to identify a particular solid form. Those skilled in the art can determine whether a solid form is one of the forms described herein by performing one of these characterization techniques and determining whether the resulting data is “substantially similar” to reference data provided herein that characterizes the solid form as a particular solid form. Those skilled in the art understand that characterization data “substantially similar” to a reference solid form corresponds to the same solid form as the reference solid form. In analyzing whether data are “substantially similar,” those skilled in the art understand that specific characterization data points can vary to a reasonable degree due to, for example, experimental errors and routine inter-sample analysis, while still describing a given solid form.

[0149] In some embodiments, this document provides a solid form comprising compound 1 or a pharmaceutically acceptable salt or solvate thereof: .

[0150] In some embodiments, the solid form comprising Compound 1 or a pharmaceutically acceptable salt or solvate thereof may be a crystalline form, a substantially crystalline form, a partially crystalline form, or a mixture of crystalline and amorphous forms. In some embodiments, the solid form is crystalline. In some embodiments, the solid form is amorphous. In some embodiments, the solid form does not include an amorphous form. In some embodiments, the solid form is a pharmaceutically acceptable salt of Compound 1, a pharmaceutically acceptable solvate of Compound 1, or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the solid form comprises a free base of Compound 1. In some embodiments, the solid form is a free base of Compound 1. In some embodiments, the solid form is a pharmaceutically acceptable salt of Compound 1. In some embodiments, the solid form is a pharmaceutically acceptable solvate of Compound 1. In some embodiments, the solid form is a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the solid form is a nonsolvent of Compound 1 or a pharmaceutically acceptable salt of Compound 1. In some embodiments, the solid form is an anhydrous form of Compound 1 or a pharmaceutically acceptable salt of Compound 1. In some embodiments, the solid form is a crystalline free base hemihydrate of compound 1. In some embodiments, the solid form is substantially pure. In some embodiments, the solid form is substantially chemically pure. In some embodiments, the solid form is substantially physically pure. In some embodiments, the solid form is substantially enantiomeric pure. In some embodiments, the solid form of compound 1 or its pharmaceutically acceptable salts and / or solvates has an enantiomeric purity of at least about 98% (e.g., about 98.5%, about 99%, or about 99.5%).

[0151] In some embodiments, the pharmaceutically acceptable solvant in solid form is selected from the group consisting of: hydrates, hemihydrates, isobutyl acetate solvates, isopropyl acetate solvates, tetrahydrofuran solvates, acetone solvates, acetonitrile solvates, or combinations thereof. In some embodiments, the pharmaceutically acceptable solvant in solid form is a hydrate. In some embodiments, the solid form is a hydrate of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable solvent are present in a molar ratio ranging from 2:1 to 1:2. In some embodiments, the molar ratio of compound 1 or a pharmaceutically acceptable salt thereof to a solvent in solid form is in the range of about 2:1 to about 1:1. In some embodiments, the molar ratio of compound 1 or a pharmaceutically acceptable salt thereof to a solvent in solid form is in the range of about 1:1 to about 1:2. In some embodiments, the molar ratio of compound 1 or a pharmaceutically acceptable salt thereof to a solvent in solid form is about 1:2 (i.e., a dual solvate). In some embodiments, the molar ratio of compound 1 or a pharmaceutically acceptable salt thereof to the solvent in the solid form is about 1:1 (i.e., a monosolvate). In some embodiments, the molar ratio of compound 1 or a pharmaceutically acceptable salt thereof to the solvent in the solid form is about 2:1 (i.e., a hemisolvate). In some embodiments, the solvent is water, and compound 1 or a pharmaceutically acceptable salt thereof and water are present in the solid form in a molar ratio of about 2:1 (a hemihydrate). In some embodiments, the solid form is a hemihydrate of compound 1 or a pharmaceutically acceptable salt thereof.

[0152] In some embodiments, the pharmaceutically acceptable salt in solid form is selected from the group consisting of benzoates, benzenesulfonates, chloride salts, citrates, fumarates, gentianates, glycolates, 1-hydroxy-2-naphthylcarboxylate, malates, maleates, methanesulfonates, oxalates, phosphates, tartrates, and toluenesulfonates. In some embodiments, the pharmaceutically acceptable salt in solid form is a benzoate. In some embodiments, the pharmaceutically acceptable salt in solid form is a fumarate. In some embodiments, the pharmaceutically acceptable salt in solid form is a 1-hydroxy-2-naphthylcarboxylate. In some embodiments, compound 1 in solid form or its pharmaceutically acceptable solvate and its pharmaceutically acceptable salt (conjugate acid) are present in a molar ratio ranging from 2:1 to 1:2. In some embodiments, the molar ratio of compound 1 in solid form or its pharmaceutically acceptable solvate to the conjugate acid is in the range of about 2:1 to about 1:1. In some embodiments, the molar ratio of compound 1 or its pharmaceutically acceptable solvate to the conjugate acid in solid form is in the range of about 1:1 to about 1:2. In some embodiments, the molar ratio of compound 1 or its pharmaceutically acceptable solvate to the conjugate acid in solid form is about 1:1.

[0153] 5.2.1 Form 1 of Compound 1 In some embodiments, compound 1 is provided herein in form 1. In some embodiments, form 1 of compound 1 is a crystalline free base, hemihydrate of compound 1. In some embodiments, form 1 of compound 1 is substantially free of amorphous compound 1. In some embodiments, form 1 of compound 1 is substantially free of other crystalline forms of compound 1 (i.e., polymorphs). In some embodiments, form 1 of compound 1 is substantially free of salt forms of compound 1. In some embodiments, form 1 of compound 1 is provided as substantially pure form 1 of compound 1.

[0154] Figure 3 The paper provides a representative XRPD spectrum of compound 1 in form 1.

[0155] In some embodiments, form 1 has an enantiomeric purity of about 98%, about 98.5%, about 99%, or about 99.5% or higher. In some embodiments, form 1 is crystalline. In some embodiments, form 1 is substantially crystalline. In some embodiments, form 1 is about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% crystalline or higher.

[0156] In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form 1 contains peaks at approximately 9.0°, 12.8°, 16.6°, and 18.4° 2θ. In some embodiments, the XRPD pattern also contains peaks at approximately 8.6°, 12.0°, 18.1°, and 23.2° 2θ. In some embodiments, the XRPD pattern also contains peaks at approximately 16.1°, 17.1°, 24.1°, and 25.6° 2θ. In some embodiments, the XRPD pattern contains peaks at approximately 8.6°, 9.0°, 12.0°, 12.8°, 16.1°, 16.6°, 17.1°, 18.1°, 18.4°, 23.2°, 24.1°, and 25.6° 2θ.

[0157] In some embodiments, this document provides a solid form comprising a free base, hemihydrate of compound 1, characterized in that, when measured using Cu Kα radiation, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all XRPD peaks are approximately located (e.g., 2θ ± 0.2 degrees) at the following positions: 8.6°, 9.0°, 12.0°, 12.8°, 16.1°, 16.6°, 17.1°, 18.1°, 18.4°, 23.2°, 24.1°, and 25.6° 2θ. In some embodiments, this solid form is characterized by at least 3 peaks. In some embodiments, this solid form is characterized by at least 5 peaks. In some embodiments, this solid form is characterized by at least 7 peaks. In some embodiments, this solid form is characterized by at least 9 peaks. In some embodiments, this solid form is characterized by at least 11 peaks. In some embodiments, this solid form is characterized by all peaks.

[0158] In some implementations, form 1 has the same Figure 3 The XRPD map presented in the image is basically a match for the XRPD map.

[0159] In some implementations, form 1 has the following approximate unit cell size: α = 90°, β = 107.8°, and γ = 90°. In some embodiments, form 1 has a unit cell with space group P21. In some embodiments, the volume of form 1 is approximately... Unit cell. In some embodiments, the Z-value of form 1 is 2. In some embodiments, the density of form 1 is approximately 1.325 g / cm³. 3 .

[0160] Figure 4 Representative overlay plots of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of compound 1 in form 1 are provided.

[0161] In some embodiments, Form 1 exhibits thermal (endothermic) events with an onset temperature of about 83°C and thermal (endothermic) events with an onset temperature of about 212°C and / or endothermic peaks at about 137°C and about 221°C, as characterized by DSC at a temperature gradient of about 10°C / min. In some embodiments, Form 1 is characterized in that the DSC thermogram is substantially as follows: Figure 4 The DSC thermogram is shown in the image.

[0162] In some embodiments, form 1 does not exhibit weight loss when heated below about 75°C, as characterized by TGA. In some embodiments, form 1 exhibits about 1.8% weight loss when heated from about 75°C to about 170°C, as characterized by TGA. In some embodiments, form 1 is characterized in that its TGA thermogram is substantially as shown in the figure. Figure 4 The TGA thermal spectrum is shown in the image.

[0163] In some implementations, Form 1 has a purity of at least 98%, 98.5%, 99%, or 99.5%.

[0164] In some embodiments, Form 1 has solubility in SGF medium of approximately 4.69 mg / mL, 5.04 mg / mL, and 3.67 mg / mL at 0.5 h, 2 h, and 24 h, respectively. In some embodiments, Form 1 has solubility in FeSSIF medium of approximately 0.29 mg / mL, 0.31 mg / mL, and 0.33 mg / mL at 0.5 h, 2 h, and 24 h, respectively.

[0165] In some implementations, Form 1 is prepared according to the procedure of Example 1.

[0166] This application covers all combinations of the above-described embodiments.

[0167] 5.2.2 Form 2 of Compound 1 In some embodiments, form 2 of compound 1 is provided herein. In some embodiments, form 2 of compound 1 is a crystalline benzoate of compound 1. In some embodiments, form 2 has a molar ratio of compound 1 to benzoic acid of about 1:1. In some embodiments, form 2 of compound 1 is substantially free of amorphous compound 1. In some embodiments, form 2 of compound 1 is substantially free of other crystalline forms of compound 1 (i.e., polymorphs). In some embodiments, form 2 of compound 1 is provided as a substantially pure form 2 of compound 1.

[0168] Figure 5 The paper provides a representative XRPD spectrum of compound 1 in form 2.

[0169] In some embodiments, form 2 has an enantiomeric purity of about 98%, about 98.5%, about 99%, or about 99.5% or higher. In some embodiments, form 2 is crystalline. In some embodiments, form 2 is substantially crystalline. In some embodiments, form 2 is partially crystalline. In some embodiments, form 2 is about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% crystalline or higher.

[0170] In some embodiments, the X-ray powder diffraction (XRPD) pattern of form 2 includes peaks at approximately 4.7°, 17.0°, and 19.4° 2θ. In some embodiments, the XRPD pattern also includes peaks at approximately 12.7°, 16.6°, 17.8°, 18.9°, and 21.4° 2θ. In some embodiments, the XRPD pattern also includes peaks at approximately 13.5°, 13.7°, 14.3°, 23.0°, 23.9°, and 24.6° 2θ. In some embodiments, the XRPD pattern includes peaks at approximately 4.7°, 12.7°, 13.5°, 13.7°, 14.3°, 16.6°, 17.0°, 17.8°, 18.9°, 19.4°, 21.4°, 23.0°, 23.9°, and 24.6° 2θ.

[0171] In some embodiments, this document provides a solid form comprising a benzoate of compound 1, characterized in that, when measured using Cu Kα radiation, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all XRPD peaks are approximately located (e.g., 2θ ± 0.2 degrees) at the following positions: 4.7°, 12.7°, 13.5°, 13.7°, 14.3°, 16.6°, 17.0°, 17.8°, 18.9°, 19.4°, 21.4°, 23.0°, 23.9°, and 24.6° 2θ. In some embodiments, the solid form is characterized by at least 3 peaks. In some embodiments, the solid form is characterized by at least 5 peaks. In some embodiments, the solid form is characterized by at least 7 peaks. In some embodiments, the solid form is characterized by at least 9 peaks. In some embodiments, the solid form is characterized by at least 11 peaks. In some embodiments, the solid form is characterized by at least 13 peaks. In some implementations, the solid form is characterized by all peaks.

[0172] In some implementations, form 2 has the same Figure 5 The XRPD map presented in the image is basically a match for the XRPD map.

[0173] Figure 6Representative overlay plots of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of compound 1 in form 2 are provided.

[0174] In some embodiments, Form 2 exhibits a thermal (endothermic) event with an onset temperature of approximately 209°C and / or an endothermic peak at approximately 216°C, as characterized by a temperature gradient of approximately 10°C / min using DSC. In some embodiments, Form 2 is characterized in that the DSC thermogram is substantially as follows: Figure 6 The DSC thermogram is shown in the image.

[0175] In some embodiments, Form 2 does not exhibit weight loss when heated below approximately 180°C, as characterized by TGA. In some embodiments, Form 2 is characterized in that its TGA thermogram is substantially as shown in... Figure 6 The TGA thermal spectrum is shown in the image.

[0176] In some embodiments, Form 2 has (a) a purity of at least 98%, 98.5%, 99%, or 99.5%; (b) solubility in SGF medium of about 4.17 mg / mL, 4.47 mg / mL, and 4.49 mg / mL at 0.5 h, 2 h, and 24 h, respectively; (c) solubility in FeSSIF medium of about 0.72 mg / mL, 0.68 mg / mL, and 0.54 mg / mL at 0.5 h, 2 h, and 24 h, respectively; or (d) a combination of any one of (a)-(c).

[0177] In some implementations, Form 2 is prepared according to the procedure of Example 2.

[0178] This application covers all combinations of the above-described embodiments.

[0179] 5.2.3 Form 3 of Compound 1 In some embodiments, form 3 of compound 1 is provided herein. In some embodiments, form 3 of compound 1 is a crystalline benzenesulfonate of compound 1. In some embodiments, form 3 has a molar ratio of compound 1 to benzenesulfonate of about 1:0.9. In some embodiments, form 3 of compound 1 is substantially free of amorphous compound 1. In some embodiments, form 3 of compound 1 is substantially free of other crystalline forms of compound 1 (i.e., polymorphs). In some embodiments, form 3 of compound 1 is provided as substantially pure form 3 of compound 1.

[0180] Figure 7 The paper provides a representative XRPD spectrum of compound 1 in form 3.

[0181] In some embodiments, form 3 has an enantiomeric purity of about 98%, about 98.5%, about 99%, or about 99.5% or higher. In some embodiments, form 3 is crystalline. In some embodiments, form 3 is substantially crystalline. In some embodiments, form 3 is moderately crystalline. In some embodiments, form 3 is partially crystalline. In some embodiments, form 3 is about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% crystalline or higher.

[0182] In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form 3 contains peaks at approximately 7.6°, 8.9°, and 14.3° 2θ. In some embodiments, the XRPD pattern also contains peaks at approximately 17.9° and 19.7° 2θ. In some embodiments, the XRPD pattern also contains peaks at approximately 21.0° and 24.8° 2θ. In some embodiments, the XRPD pattern contains peaks at approximately 7.6°, 8.9°, 14.3°, 17.9°, 19.7°, 21.0°, and 24.8° 2θ.

[0183] In some embodiments, this document provides a solid form comprising a benzenesulfonate of compound 1, characterized in that, when measured using Cu Kα radiation, 1, 2, 3, 4, 5, 6, or all of the XRPD peaks are approximately located (e.g., 2θ ± 0.2 degrees) at the following positions: 7.6°, 8.9°, 14.3°, 17.9°, 19.7°, 21.0°, and 24.8° 2θ. In some embodiments, the solid form is characterized by at least 3 peaks. In some embodiments, the solid form is characterized by at least 5 peaks. In some embodiments, the solid form is characterized by all peaks.

[0184] In some implementations, form 3 has the same characteristics as... Figure 7 The XRPD map presented in the image is basically a match for the XRPD map.

[0185] Figure 8 Representative overlay plots of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of compound 1 in form 3 are provided.

[0186] In some embodiments, Form 3 exhibits a thermal (endothermic) event with an onset temperature of approximately 186°C and / or an endothermic peak at approximately 206°C, as characterized by a temperature gradient of approximately 10°C / min via DSC. In some embodiments, Form 3 is characterized in that the DSC thermogram is substantially as follows: Figure 8 The DSC thermogram is shown in the image.

[0187] In some embodiments, form 3 exhibits a weight loss of approximately 5.7% when heated in the range of approximately 95°C to approximately 230°C, as characterized by TGA. In some embodiments, form 3 is characterized in that its TGA thermogram is substantially as shown in... Figure 8 The TGA thermal spectrum is shown in the image.

[0188] In some implementations, Form 3 is prepared according to the procedure of Example 3.

[0189] This application covers all combinations of the above-described embodiments.

[0190] 5.2.4 Form 4 of Compound 1 In some embodiments, form 4 of compound 1 is provided herein. In some embodiments, form 4 of compound 1 is a crystalline hydrochloride salt of compound 1. In some embodiments, form 4 has a molar ratio of compound 1 to hydrochloric acid of about 1:1, optionally wherein the solid form is a hydrate. In some embodiments, form 4 of compound 1 is substantially free of amorphous compound 1. In some embodiments, form 4 of compound 1 is substantially free of other crystalline forms of compound 1 (i.e., polymorphs). In some embodiments, form 4 of compound 1 is provided as a substantially pure form 4 of compound 1.

[0191] Figure 9 The paper provides a representative XRPD spectrum of compound 1 in form 4.

[0192] In some embodiments, form 4 has an enantiomeric purity of about 98%, about 98.5%, about 99%, or about 99.5% or higher. In some embodiments, form 4 is crystalline. In some embodiments, form 4 is substantially crystalline. In some embodiments, form 4 is moderately crystalline. In some embodiments, form 4 is partially crystalline. In some embodiments, form 4 is about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% crystalline or higher.

[0193] In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form 4 contains peaks at approximately 5.3°, 16.7°, 19.1°, and 26.0° 2θ. In some embodiments, the XRPD pattern also contains peaks at approximately 5.3°, 16.7°, 19.1°, and 26.0° 2θ. In some embodiments, the XRPD pattern also contains peaks at approximately 5.3°, 16.7°, 19.1°, and 26.0° 2θ. In some embodiments, the XRPD pattern contains peaks at approximately 5.3°, 8.6°, 11.2°, 12.6°, 15.3°, 15.9°, 16.7°, 17.8°, 19.1°, 24.3°, 26.0°, and 28.2° 2θ.

[0194] In some embodiments, this document provides a solid form comprising the hydrochloride salt of compound 1, characterized in that, when measured using Cu Kα radiation, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all XRPD peaks are approximately located (e.g., 2θ ± 0.2 degrees) at the following positions: 5.3°, 8.6°, 11.2°, 12.6°, 15.3°, 15.9°, 16.7°, 17.8°, 19.1°, 24.3°, 26.0°, and 28.2° 2θ. In some embodiments, the solid form is characterized by at least 3 peaks. In some embodiments, the solid form is characterized by at least 5 peaks. In some embodiments, the solid form is characterized by at least 7 peaks. In some embodiments, the solid form is characterized by at least 9 peaks. In some embodiments, the solid form is characterized by at least 11 peaks. In some embodiments, the solid form is characterized by all peaks.

[0195] In some implementations, form 4 has the same characteristics as... Figure 9 The XRPD map presented in the image is basically a match for the XRPD map.

[0196] Figure 10 Representative overlay plots of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of compound 1 in form 4 are provided.

[0197] In some embodiments, Form 4 exhibits thermal (endothermic) events with onset temperatures of approximately 28°C, approximately 98°C, and approximately 242°C, and / or endothermic peak temperatures at approximately 64°C, approximately 116°C, and approximately 258°C (two overlapping peaks), as characterized by a temperature gradient of approximately 10°C / min using DSC. In some embodiments, Form 4 is characterized in that the DSC thermogram is substantially as follows: Figure 10 The DSC thermogram is shown in the image.

[0198] In some embodiments, Form 4 exhibits approximately 3.2% weight loss when heated from room temperature to approximately 90°C and approximately 2.7% weight loss when heated from approximately 90°C to 140°C, as characterized by TGA. In some embodiments, Form 4 is characterized in that its TGA thermogram is substantially as shown in... Figure 10 The TGA thermal spectrum is shown in the image.

[0199] In some implementations, Form 4 is prepared according to the procedure of Example 4.

[0200] This application covers all combinations of the above-described embodiments.

[0201] 5.2.5 Form of Compound 1 In some embodiments, form 5 of compound 1 is provided herein. In some embodiments, form 5 of compound 1 is a crystalline hydrochloride salt of compound 1. In some embodiments, form 4 has a molar ratio of compound 1 to hydrochloric acid of about 1:1, optionally wherein the solid form is a hydrate. In some embodiments, form 5 of compound 1 is substantially free of amorphous compound 1. In some embodiments, form 5 of compound 1 is substantially free of other crystalline forms of compound 1 (i.e., polymorphs). In some embodiments, form 5 of compound 1 is provided as a substantially pure form 5 of compound 1.

[0202] Figure 11 The paper provides a representative XRPD spectrum of compound 1 in form 5.

[0203] In some embodiments, form 5 has an enantiomeric purity of about 98%, about 98.5%, about 99%, or about 99.5% or higher. In some embodiments, form 5 is crystalline. In some embodiments, form 5 is substantially crystalline. In some embodiments, form 5 is moderately crystalline. In some embodiments, form 5 is partially crystalline. In some embodiments, form 5 is about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% crystalline or higher.

[0204] In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form 5 contains peaks at approximately 6.3°, 8.4°, 15.1°, and 23.5° 2θ. In some embodiments, the XRPD pattern also contains peaks at approximately 10.7° and 17.9° 2θ. In some embodiments, the XRPD pattern also contains peaks at approximately 20.8° and 21.6° 2θ. In some embodiments, the XRPD pattern contains peaks at approximately 6.3°, 8.4°, 10.7°, 15.1°, 17.9°, 20.8°, 21.6°, and 23.5° 2θ.

[0205] In some embodiments, this document provides a solid form comprising the hydrochloride salt of compound 1, characterized in that, when measured using Cu Kα radiation, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all of the XRPD peaks are approximately located (e.g., 2θ ± 0.2 degrees) at the following positions: 6.3°, 8.4°, 10.7°, 15.1°, 17.9°, 20.8°, 21.6°, and 23.5° 2θ. In some embodiments, the solid form is characterized by at least 3 peaks. In some embodiments, the solid form is characterized by at least 5 peaks. In some embodiments, the solid form is characterized by at least 7 peaks. In some embodiments, the solid form is characterized by all peaks.

[0206] In some implementations, form 5 has the same characteristics as... Figure 11 The XRPD map presented in the image is basically a match for the XRPD map.

[0207] Figure 12 Representative overlay plots of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of compound 1 in form 5 are provided.

[0208] In some embodiments, Form 5 exhibits a thermal (endothermic) event with an onset temperature of about 244°C and / or an endothermic peak temperature of about 247°C, as characterized by a temperature gradient of about 10°C / min via DSC. In some embodiments, Form 5 is characterized in that the DSC thermogram is substantially as follows: Figure 12 The DSC thermogram is shown in the image.

[0209] In some embodiments, Form 5 exhibits approximately 5.3% weight loss up to approximately 130°C and approximately 12% weight loss in the range of approximately 175°C to approximately 300°C, as characterized by TGA. In some embodiments, Form 5 is characterized in that its TGA thermogram is substantially as shown in... Figure 12 The TGA thermal spectrum is shown in the image.

[0210] In some implementations, Form 5 is prepared according to the procedure of Example 5.

[0211] This application covers all combinations of the above-described embodiments.

[0212] 5.2.6 Form of Compound 1 In some embodiments, form 6 of compound 1 is provided herein. In some embodiments, form 6 of compound 1 is a crystalline citrate of compound 1. In some embodiments, form 6 has a molar ratio of compound 1 to citrate of about 1:0.8, optionally wherein the solid form is a solvate. In some embodiments, form 6 of compound 1 is substantially free of amorphous compound 1. In some embodiments, form 6 of compound 1 is substantially free of other crystalline forms of compound 1 (i.e., polymorphs). In some embodiments, form 6 of compound 1 is provided as substantially pure form 6 of compound 1.

[0213] Figure 13 The paper provides a representative XRPD spectrum of compound 1 in form 6.

[0214] In some embodiments, form 6 has an enantiomeric purity of about 98%, about 98.5%, about 99%, or about 99.5% or higher. In some embodiments, form 6 is crystalline. In some embodiments, form 6 is substantially crystalline. In some embodiments, form 6 is moderately crystalline. In some embodiments, form 6 is partially crystalline. In some embodiments, form 6 is about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% crystalline or higher.

[0215] In some embodiments, the X-ray powder diffraction (XRPD) pattern of form 6 contains peaks at approximately 12.0°, 16.6°, and 18.1° 2θ. In some embodiments, the XRPD pattern also contains peaks at approximately 12.9°, 19.5°, and 23.3° 2θ. In some embodiments, the XRPD pattern also contains peaks at approximately 24.2°, 25.6°, and 26.1° 2θ. In some embodiments, the XRPD pattern contains peaks at approximately 12.0°, 12.9°, 16.6°, 18.1°, 19.5°, 23.3°, 24.2°, 25.6°, and 26.1° 2θ.

[0216] In some embodiments, this document provides a solid form comprising a citrate of compound 1, characterized in that, when measured using Cu Kα radiation, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all XRPD peaks are approximately located (e.g., 2θ ± 0.2 degrees) at the following positions: 12.0°, 12.9°, 16.6°, 18.1°, 19.5°, 23.3°, 24.2°, 25.6°, and 26.1° 2θ. In some embodiments, the solid form is characterized by at least 3 peaks. In some embodiments, the solid form is characterized by at least 5 peaks. In some embodiments, the solid form is characterized by at least 7 peaks. In some embodiments, the solid form is characterized by all peaks.

[0217] In some implementations, form 6 has the same characteristics as... Figure 13 The XRPD map presented in the image is basically a match for the XRPD map.

[0218] Figure 14 Representative overlay plots of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of compound 1 in form 6 are provided.

[0219] In some embodiments, Form 6 exhibits thermal (endothermic) events with onset temperatures of approximately 92°C and 144°C and / or endothermic peak temperatures of approximately 102°C and 177°C, respectively, as characterized by a temperature gradient of approximately 10°C / min using DSC. In some embodiments, Form 6 is characterized in that the DSC thermogram is substantially as follows: Figure 14 The DSC thermogram is shown in the image.

[0220] In some embodiments, form 6 exhibits a weight loss of approximately 5.1% when heated from approximately 26°C to approximately 150°C, as characterized by TGA. In some embodiments, form 6 is characterized in that its TGA thermogram is substantially as shown in... Figure 14 The TGA thermal spectrum is shown in the image.

[0221] In some implementations, Form 6 is prepared according to the procedure of Example 6.

[0222] This application covers all combinations of the above-described embodiments.

[0223] 5.2.7 Form 7 of Compound 1 In some embodiments, form 7 of compound 1 is provided herein. In some embodiments, form 7 of compound 1 is a crystalline citrate of compound 1. In some embodiments, form 7 has a molar ratio of compound 1 to citrate of about 1:1, optionally wherein the solid form is a hydrate. In some embodiments, form 7 of compound 1 is substantially free of amorphous compound 1. In some embodiments, form 7 of compound 1 is substantially free of other crystalline forms of compound 1 (i.e., polymorphs). In some embodiments, form 7 of compound 1 is provided as substantially pure form 7 of compound 1.

[0224] Figure 15 The paper provides a representative XRPD spectrum of compound 1 in form 7.

[0225] In some embodiments, form 7 has an enantiomeric purity of about 98%, about 98.5%, about 99%, or about 99.5% or higher. In some embodiments, form 7 is crystalline. In some embodiments, form 7 is substantially crystalline. In some embodiments, form 7 is moderately crystalline. In some embodiments, form 7 is partially crystalline. In some embodiments, form 7 is about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% crystalline or higher.

[0226] In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form 7 includes peaks at approximately 11.0°, 15.0°, 19.0°, 22.1°, 27.7°, and 29.8° 2θ. In some embodiments, the XRPD pattern also includes peaks at approximately 22.1°, 24.2°, 24.6°, 25.2°, 25.8°, and 26.5° 2θ. In some embodiments, the XRPD pattern includes peaks at approximately 8.5°, 8.8°, 12.7°, 13.3°, 13.8°, 16.7°, 17.1°, 17.5°, and 17.9° 2θ. In some implementations, the XRPD spectrum includes peaks at approximately 8.5°, 8.8°, 11.0°, 12.7°, 13.3°, 13.8°, 15.0°, 16.7°, 17.1°, 17.5°, 17.9°, 19.0°, 21.1°, 22.1°, 24.2°, 24.6°, 25.2°, 25.8°, 26.5°, 27.7°, and 29.8° 2θ.

[0227] In some embodiments, this document provides a solid form comprising a citrate of compound 1, characterized in that, when measured using Cu Kα radiation, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all of the XRPD peaks are approximately located (e.g., 2θ ± 0.2 degrees) at the following positions: 8.5°, 8.8°, 11.0°, 12.7°, 13.3°, 13.8°, 15.0°, 16.7°, 17.1°, 17.5°, 17.9°, 19.0°, 21.1°, 22.1°, 24.2°, 24.6°, 25.2°, 25.8°, 26.5°, 27.7°, and 29.8° 2θ. In some embodiments, this solid form is characterized by at least 3 peaks. In some embodiments, this solid form is characterized by at least 5 peaks. In some embodiments, this solid form is characterized by at least 7 peaks. In some embodiments, the solid form is characterized by at least 9 peaks. In some embodiments, the solid form is characterized by at least 11 peaks. In some embodiments, the solid form is characterized by at least 13 peaks. In some embodiments, the solid form is characterized by all peaks.

[0228] In some implementations, form 7 has the same characteristics as... Figure 15 The XRPD map presented in the image is basically a match for the XRPD map.

[0229] Figure 16 Representative overlay plots of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of compound 1 in form 7 are provided.

[0230] In some embodiments, Form 7 exhibits thermal (endothermic) events with onset temperatures of approximately 41°C, approximately 135°C, and approximately 169°C, and / or endothermic peak temperatures of approximately 58°C, approximately 139°C, and approximately 188°C, as characterized by DSC at a temperature gradient of approximately 10°C / min. In some embodiments, Form 7 is characterized in that the DSC thermogram is substantially as follows: Figure 16 The DSC thermogram is shown in the image.

[0231] In some embodiments, form 7 exhibits a weight loss of approximately 2.8% when heated from approximately 25°C to approximately 100°C, as characterized by TGA. In some embodiments, form 7 is characterized in that its TGA thermogram is substantially as shown in... Figure 16 The TGA thermal spectrum is shown in the image.

[0232] In some implementations, Form 7 is prepared according to the procedure of Example 7.

[0233] This application covers all combinations of the above-described embodiments.

[0234] 5.2.8 Form of Compound 1 In some embodiments, form 8 of compound 1 is provided herein. In some embodiments, form 8 of compound 1 is a crystalline fumarate of compound 1. In some embodiments, form 8 has a molar ratio of about 1:1 of compound 1 to fumarate, optionally wherein the solid form is a solvate, optionally wherein the solvate is a hydrate. In some embodiments, form 8 of compound 1 is substantially free of amorphous compound 1. In some embodiments, form 8 of compound 1 is substantially free of other crystalline forms of compound 1 (i.e., polymorphs). In some embodiments, form 8 of compound 1 is provided as a substantially pure form 8 of compound 1.

[0235] Figure 17 The paper provides a representative XRPD spectrum of compound 1 in form 8.

[0236] In some embodiments, form 8 has an enantiomeric purity of about 98%, about 98.5%, about 99%, or about 99.5% or higher. In some embodiments, form 8 is crystalline. In some embodiments, form 8 is substantially crystalline. In some embodiments, form 8 is about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% crystalline or higher.

[0237] In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form 8 contains peaks at approximately 8.6°, 10.9°, 16.7°, and 23.3° 2θ. In some embodiments, the XRPD pattern also contains peaks at approximately 4.9°, 11.4°, and 17.6° 2θ. In some embodiments, the XRPD pattern also contains peaks at approximately 12.7°, 14.6°, and 26.0° 2θ. In some embodiments, the XRPD pattern contains peaks at approximately 4.9°, 8.6°, 10.9°, 11.4°, 12.7°, 14.6°, 16.7°, 17.6°, 23.3°, and 26.0° 2θ.

[0238] In some embodiments, this document provides a solid form comprising a fumarate of compound 1, characterized in that, when measured using Cu Kα radiation, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all of the XRPD peaks are approximately located (e.g., 2θ ± 0.2 degrees) at the following positions: 4.9°, 8.6°, 10.9°, 11.4°, 12.7°, 14.6°, 16.7°, 17.6°, 23.3°, and 26.0° 2θ. In some embodiments, the solid form is characterized by at least 3 peaks. In some embodiments, the solid form is characterized by at least 5 peaks. In some embodiments, the solid form is characterized by at least 7 peaks. In some embodiments, the solid form is characterized by at least 9 peaks. In some embodiments, the solid form is characterized by all peaks.

[0239] In some implementations, form 8 has the same characteristics as... Figure 17 The XRPD map presented in the image is basically a match for the XRPD map.

[0240] Figure 18 Representative overlay plots of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of compound 1 in form 8 are provided.

[0241] In some embodiments, Form 8 exhibits thermal (endothermic) events with an onset temperature of about 28°C and / or an endothermic peak at about 100°C, and thermal (endothermic decomposition) events with an onset temperature of about 206°C and / or a peak temperature of about 214°C, as characterized by DSC at a temperature gradient of about 10°C / min. In some embodiments, Form 8 is characterized in that the DSC thermogram is substantially as follows: Figure 18 The DSC thermogram is shown in the image.

[0242] In some embodiments, form 8 exhibits a weight loss of approximately 2.0% when heated from approximately 24.5°C to approximately 150°C, as characterized by TGA. In some embodiments, form 8 is characterized in that its TGA thermogram is substantially as shown in [the original text]. Figure 18 The TGA thermal spectrum is shown in the image.

[0243] In some implementations, Form 8 has a purity of at least 98%, 98.5%, 99%, or 99.5%.

[0244] In some embodiments, form 8 has solubility in SGF medium of about ≥5 mg / mL, ≥5 mg / mL, and ≥5 mg / mL at 0.5 h, 2 h, and 24 h, respectively. In some embodiments, form 8 has solubility in FeSSIF medium of about 1.27 mg / mL, 1.26 mg / mL, and 1.15 mg / mL at 0.5 h, 2 h, and 24 h, respectively.

[0245] In some implementations, Form 8 is prepared according to the procedure of Example 8.

[0246] This application covers all combinations of the above-described embodiments.

[0247] 5.2.9 Form 9 of Compound 1 In some embodiments, form 9 of compound 1 is provided herein. In some embodiments, form 9 of compound 1 is a crystalline gentianate salt of compound 1. In some embodiments, form 9 has a molar ratio of compound 1 to gentianate of about 1:1, optionally wherein the solid form is a solvate. In some embodiments, form 9 of compound 1 is substantially free of amorphous compound 1. In some embodiments, form 9 of compound 1 is substantially free of other crystalline forms of compound 1 (i.e., polymorphs). In some embodiments, form 9 of compound 1 is provided as substantially pure form 9 of compound 1.

[0248] Figure 19 The paper provides a representative XRPD spectrum of compound 1 in form 9.

[0249] In some embodiments, form 9 has an enantiomeric purity of about 98%, about 98.5%, about 99%, or about 99.5% or higher. In some embodiments, form 9 is crystalline. In some embodiments, form 9 is substantially crystalline. In some embodiments, form 9 is partially crystalline. In some embodiments, form 9 is about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% crystalline or higher.

[0250] In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form 9 includes peaks at approximately 8.0°, 9.6°, 16.5°, 17.6°, 18.7°, and 24.6° 2θ. In some embodiments, the XRPD pattern also includes peaks at approximately 11.7°, 12.2°, 19.9°, and 26.5° 2θ. In some embodiments, the XRPD pattern also includes peaks at approximately 13.8°, 15.4°, 16.1°, 20.8°, and 21.7° 2θ. In some implementations, the XRPD spectrum includes peaks at approximately 8.0°, 9.6°, 11.7°, 12.2°, 13.8°, 15.4°, 16.1°, 16.5°, 17.6°, 18.7°, 19.9°, 20.8°, 21.7°, 24.6°, and 26.5° 2θ.

[0251] In some embodiments, this document provides a solid form comprising a gentianate of compound 1, characterized in that, when measured using Cu Kα radiation, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all of the XRPD peaks are approximately located (e.g., 2θ ± 0.2 degrees) at the following positions: 8.0°, 9.6°, 11.7°, 12.2°, 13.8°, 15.4°, 16.1°, 16.5°, 17.6°, 18.7°, 19.9°, 20.8°, 21.7°, 24.6°, and 26.5° 2θ. In some embodiments, this solid form is characterized by at least 3 peaks. In some embodiments, this solid form is characterized by at least 5 peaks. In some embodiments, this solid form is characterized by at least 7 peaks. In some embodiments, this solid form is characterized by at least 9 peaks. In some embodiments, this solid form is characterized by at least 11 peaks. In some embodiments, the solid form is characterized by at least 13 peaks. In some embodiments, the solid form is characterized by all peaks.

[0252] In some implementations, form 9 has the same characteristics as... Figure 19 The XRPD map presented in the image is basically a match for the XRPD map.

[0253] Figure 20 Representative overlay plots of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of compound 1 in form 9 are provided.

[0254] In some embodiments, Form 9 exhibits thermal (endothermic) events with onset temperatures of approximately 56°C and 256°C and / or endothermic peak temperatures of approximately 81°C and 263°C, respectively, as characterized by a temperature gradient of approximately 10°C / min using DSC. In some embodiments, Form 9 is characterized in that the DSC thermogram is substantially as follows: Figure 20 The DSC thermogram is shown in the image.

[0255] In some embodiments, Form 9 exhibits a weight loss of approximately 2.2% when heated from approximately 26.5°C to approximately 100°C, as characterized by TGA. In some embodiments, Form 9 is characterized in that its TGA thermogram is substantially as shown in... Figure 20 The TGA thermal spectrum is shown in the image.

[0256] In some implementations, Form 9 is prepared according to the procedure of Example 9.

[0257] This application covers all combinations of the above-described embodiments.

[0258] 5.2.10 Form 10 of Compound 1 In some embodiments, form 10 of compound 1 is provided herein. In some embodiments, form 10 of compound 1 is a crystalline gentianate salt of compound 1. In some embodiments, form 10 has a molar ratio of compound 1 to gentianate of about 1:1, and wherein the solid form is anhydrous. In some embodiments, form 10 of compound 1 is substantially free of amorphous compound 1. In some embodiments, form 10 of compound 1 is substantially free of other crystalline forms of compound 1 (i.e., polymorphs). In some embodiments, form 10 of compound 1 is provided as substantially pure form 10 of compound 1.

[0259] Figure 21 The representative XRPD spectrum of compound 1 in form 10 is provided.

[0260] In some embodiments, form 10 has an enantiomeric purity of about 98%, about 98.5%, about 99%, or about 99.5% or higher. In some embodiments, form 10 is crystalline. In some embodiments, form 10 is substantially crystalline. In some embodiments, form 10 is moderately crystalline. In some embodiments, form 10 is partially crystalline. In some embodiments, form 10 is about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% crystalline or higher.

[0261] In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form 10 contains peaks at approximately 4.7°, 13.2°, and 16.9° 2θ. In some embodiments, the XRPD pattern also contains peaks at approximately 8.39°, 17.5°, 18.6°, 21.8°, and 25.3° 2θ. In some embodiments, the XRPD pattern also contains peaks at approximately 11.8°, 12.6°, 19.0°, 19.4°, and 23.8° 2θ. In some embodiments, the XRPD pattern contains peaks at approximately 4.7°, 8.39°, 11.8°, 12.6°, 13.2°, 16.9°, 17.5°, 18.6°, 19.0°, 19.4°, 21.8°, 23.8°, and 25.3° 2θ.

[0262] In some embodiments, this document provides a solid form comprising a gentianate of compound 1, characterized in that, when measured using Cu Kα radiation, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all XRPD peaks are approximately located (e.g., 2θ ± 0.2 degrees) at the following positions: 4.7°, 8.39°, 11.8°, 12.6°, 13.2°, 16.9°, 17.5°, 18.6°, 19.0°, 19.4°, 21.8°, 23.8°, and 25.3° 2θ. In some embodiments, this solid form is characterized by at least 3 peaks. In some embodiments, this solid form is characterized by at least 5 peaks. In some embodiments, this solid form is characterized by at least 7 peaks. In some embodiments, this solid form is characterized by at least 9 peaks. In some embodiments, this solid form is characterized by at least 11 peaks. In some embodiments, this solid form is characterized by all peaks.

[0263] In some implementations, form 10 has the same Figure 21 The XRPD map presented in the image is basically a match for the XRPD map.

[0264] Figure 22 Representative overlay plots of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of compound 1 in form 10 are provided.

[0265] In some embodiments, Form 10 exhibits a thermal (endothermic) event with an onset temperature of about 240°C and / or an endothermic peak temperature of about 245°C, as characterized by a temperature gradient of about 10°C / min using DSC. In some embodiments, Form 10 is characterized in that the DSC thermogram is substantially as follows: Figure 22 The DSC thermogram is shown in the image.

[0266] In some embodiments, form 10 exhibits a weight loss of approximately 0.4% when heated from approximately 120°C to approximately 200°C, as characterized by TGA. In some embodiments, form 10 is characterized in that its TGA thermogram is substantially as shown in... Figure 22 The TGA thermal spectrum is shown in the image.

[0267] In some implementations, Form 10 is prepared according to the procedure of Example 10.

[0268] This application covers all combinations of the above-described embodiments.

[0269] 5.2.11 Form 11 of Compound 1 In some embodiments, form 11 of compound 1 is provided herein. In some embodiments, form 11 of compound 1 is a crystalline glycolate of compound 1. In some embodiments, form 11 has a molar ratio of compound 1 to glycolic acid of about 1:1, optionally wherein the solid form is a hydrate. In some embodiments, form 11 of compound 1 is substantially free of amorphous compound 1. In some embodiments, form 11 of compound 1 is substantially free of other crystalline forms of compound 1 (i.e., polymorphs). In some embodiments, form 11 of compound 1 is provided as a substantially pure form 11 of compound 1.

[0270] Figure 23 The paper provides a representative XRPD spectrum of compound 1 in form 11.

[0271] In some embodiments, form 11 has an enantiomeric purity of about 98%, about 98.5%, about 99%, or about 99.5% or higher. In some embodiments, form 11 is crystalline. In some embodiments, form 11 is substantially crystalline. In some embodiments, form 11 is moderately crystalline. In some embodiments, form 11 is partially crystalline. In some embodiments, form 11 is about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% crystalline or higher.

[0272] In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form 11 contains peaks at approximately 7.4°, 12.6°, 16.7°, and 23.8° 2θ. In some embodiments, the XRPD pattern also contains peaks at approximately 16.2°, 23.4°, 25.7°, and 28.9° 2θ. In some embodiments, the XRPD pattern also contains peaks at approximately 19.0°, 20.3°, and 26.1° 2θ. In some embodiments, the XRPD pattern contains peaks at approximately 7.4°, 12.6°, 16.2°, 16.7°, 19.0°, 20.3°, 23.4°, 23.8°, 25.7°, 26.1°, and 28.9° 2θ.

[0273] In some embodiments, this document provides a solid form comprising the glycolate of compound 1, characterized in that, when measured using Cu Kα radiation, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all XRPD peaks are approximately located (e.g., 2θ ± 0.2 degrees) at the following positions: 7.4°, 12.6°, 16.2°, 16.7°, 19.0°, 20.3°, 23.4°, 23.8°, 25.7°, 26.1°, and 28.9° 2θ. In some embodiments, the solid form is characterized by at least 3 peaks. In some embodiments, the solid form is characterized by at least 5 peaks. In some embodiments, the solid form is characterized by at least 7 peaks. In some embodiments, the solid form is characterized by at least 9 peaks. In some embodiments, the solid form is characterized by all peaks.

[0274] In some implementations, form 11 has the same Figure 23 The XRPD map presented in the image is basically a match for the XRPD map.

[0275] Figure 24 Representative overlay plots of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of compound 1 in form 11 are provided.

[0276] In some embodiments, Form 11 exhibits thermal (endothermic) events with onset temperatures of about 35°C, about 116°C, and 152°C and / or endothermic peak temperatures of about 59°C, about 94°C, and about 170°C, as characterized by DSC at a temperature gradient of about 10°C / min. In some embodiments, Form 11 is characterized in that the DSC thermogram is substantially as follows: Figure 24 The DSC thermogram is shown in the image.

[0277] In some embodiments, Form 11 exhibits approximately 1.7% weight loss when heated from about 27°C to about 80°C and approximately 3.2% weight loss when heated from about 110°C to about 200°C, as characterized by TGA. In some embodiments, Form 11 is characterized in that its TGA thermogram is substantially as shown in... Figure 24 The TGA thermal spectrum is shown in the image.

[0278] In some implementations, Form 11 is prepared according to the procedure of Example 11.

[0279] This application covers all combinations of the above-described embodiments.

[0280] 5.2.12 Form 12 of Compound 1 In some embodiments, form 12 of compound 1 is provided herein. In some embodiments, form 12 of compound 1 is a crystalline 1-hydroxy-2-naphthoic acid salt of compound 1. In some embodiments, form 12 has a molar ratio of compound 1 to 1-hydroxy-2-naphthoic acid of about 1:1, optionally wherein the solid form is a solvate. In some embodiments, form 12 of compound 1 is substantially free of amorphous compound 1. In some embodiments, form 12 of compound 1 is substantially free of other crystalline forms of compound 1 (i.e., polymorphs). In some embodiments, form 12 of compound 1 is provided as a substantially pure form 12 of compound 1.

[0281] Figure 25 The paper provides a representative XRPD spectrum of compound 1 in form 12.

[0282] In some embodiments, form 12 has an enantiomeric purity of about 98%, about 98.5%, about 99%, or about 99.5% or higher. In some embodiments, form 12 is crystalline. In some embodiments, form 12 is substantially crystalline. In some embodiments, form 12 is moderately crystalline. In some embodiments, form 12 is partially crystalline. In some embodiments, form 12 is about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% crystalline or higher.

[0283] In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form 12 contains peaks at approximately 6.2°, 11.2°, 14.4°, and 22.3° 2θ. In some embodiments, the XRPD pattern also contains peaks at approximately 5.1°, 14.9°, and 18.3° 2θ. In some embodiments, the XRPD pattern also contains peaks at approximately 5.6° and 25.3° 2θ. In some embodiments, the XRPD pattern contains peaks at approximately 5.1°, 5.6°, 6.2°, 11.2°, 14.4°, 14.9°, 18.3°, 22.3°, and 25.3° 2θ.

[0284] In some embodiments, this document provides a solid form comprising compound 1, a 1-hydroxy-2-naphthylcarboxylate, characterized in that, when measured using Cu Kα radiation, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all XRPD peaks are approximately located (e.g., 2θ ± 0.2 degrees) at the following positions: 5.1°, 5.6°, 6.2°, 11.2°, 14.4°, 14.9°, 18.3°, 22.3°, and 25.3° 2θ. In some embodiments, the solid form is characterized by at least 3 peaks. In some embodiments, the solid form is characterized by at least 5 peaks. In some embodiments, the solid form is characterized by at least 7 peaks. In some embodiments, the solid form is characterized by at least 8 peaks. In some embodiments, the solid form is characterized by all peaks.

[0285] In some implementations, form 12 has the same Figure 25 The XRPD map presented in the image is basically a match for the XRPD map.

[0286] Figure 26 Representative overlay plots of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of compound 1 in form 12 are provided.

[0287] In some embodiments, Form 12 exhibits thermal (endothermic) events with onset temperatures of about 25°C and 178°C and / or endothermic peak temperatures of about 32°C and about 186°C, respectively, as characterized by a temperature gradient of about 10°C / min using DSC. In some embodiments, Form 12 is characterized in that the DSC thermogram is substantially as follows: Figure 26 The DSC thermogram is shown in the image.

[0288] In some embodiments, form 12 exhibits a weight loss of about 0.5% when heated from about 25°C to about 80°C and a weight loss of about 7.4% when heated from about 100°C to about 190°C, as characterized by TGA. In some embodiments, form 12 is characterized in that its TGA thermogram is substantially as shown in the figure. Figure 26 The TGA thermal spectrum is shown in the image.

[0289] In some implementations, Form 12 is prepared according to the procedure of Example 12.

[0290] This application covers all combinations of the above-described embodiments.

[0291] 5.2.13 Form 13 of Compound 1 In some embodiments, form 13 of compound 1 is provided herein. In some embodiments, form 13 of compound 1 is a crystalline 1-hydroxy-2-naphthoic acid salt of compound 1. In some embodiments, form 13 has a molar ratio of compound 1 to 1-hydroxy-2-naphthoic acid of about 1:1, wherein the solid form is anhydrous. In some embodiments, form 13 of compound 1 is substantially free of amorphous compound 1. In some embodiments, form 13 of compound 1 is substantially free of other crystalline forms of compound 1 (i.e., polymorphs). In some embodiments, form 13 of compound 1 is provided as a substantially pure form 13 of compound 1.

[0292] Figure 27 The paper provides a representative XRPD spectrum of compound 1 in form 13.

[0293] In some embodiments, form 13 has an enantiomeric purity of about 98%, about 98.5%, about 99%, or about 99.5% or higher. In some embodiments, form 13 is crystalline. In some embodiments, form 13 is substantially crystalline. In some embodiments, form 13 is about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% crystalline or higher.

[0294] In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form 13 includes peaks at approximately 16.6°, 18.1°, 19.1°, and 24.7° 2θ. In some embodiments, the XRPD pattern also includes peaks at approximately 8.9°, 12.5°, 14.7°, 19.7°, 21.6°, and 29.7° 2θ. In some embodiments, the XRPD pattern also includes peaks at approximately 11.8°, 12.0°, 15.4°, 23.3°, 25.8°, and 27.9° 2θ. In some implementations, the XRPD spectrum includes peaks at approximately 8.9°, 11.8°, 12.0°, 12.5°, 14.7°, 15.4°, 16.6°, 18.1°, 19.1°, 19.7°, 21.6°, 23.3°, 24.7°, 25.8°, 27.9°, and 29.7° 2θ.

[0295] In some embodiments, this document provides a solid form comprising compound 1, a 1-hydroxy-2-naphthoate, characterized in that, when measured using Cu Kα radiation, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all of the XRPD peaks are approximately located (e.g., 2θ ± 0.2 degrees) at the following positions: 8.9°, 11.8°, 12.0°, 12.5°, 14.7°, 15.4°, 16.6°, 18.1°, 19.1°, 19.7°, 21.6°, 23.3°, 24.7°, 25.8°, 27.9°, and 29.7° 2θ. In some embodiments, the solid form is characterized by at least 3 peaks. In some embodiments, the solid form is characterized by at least 5 peaks. In some embodiments, the solid form is characterized by at least 7 peaks. In some embodiments, the solid form is characterized by at least 9 peaks. In some embodiments, the solid form is characterized by at least 11 peaks. In some embodiments, the solid form is characterized by at least 13 peaks. In some embodiments, the solid form is characterized by at least 15 peaks. In some embodiments, the solid form is characterized by all peaks.

[0296] In some implementations, form 13 has the same Figure 27 The XRPD map presented in the image is basically a match for the XRPD map.

[0297] Figure 28 Representative overlay plots of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of compound 1 in form 13 are provided.

[0298] In some embodiments, Form 13 exhibits a thermal (endothermic, melting / decomposition) event with an onset temperature of about 187°C and / or an endothermic peak at about 194°C, as characterized by a temperature gradient of about 10°C / min via DSC. In some embodiments, Form 13 is characterized in that the DSC thermogram is substantially as follows: Figure 28 The DSC thermogram is shown in the image.

[0299] In some embodiments, form 13 does not exhibit weight loss below approximately 160°C, as characterized by TGA. In some embodiments, form 13 is characterized by a TGA thermogram that is substantially as shown in the image. Figure 28 The TGA thermal spectrum is shown in the image.

[0300] In some implementations, form 13 has a purity of at least 98%, 98.5%, 99%, or 99.5%.

[0301] In some embodiments, form 13 has solubility in SGF medium of about 3.86, 4.05, and 4.12 at 0.5 h, 2 h, and 24 h, respectively. In some embodiments, form 13 has solubility in FeSSIF medium of about 0.74 mg / mL, 0.82 mg / mL, and 0.78 mg / mL at 0.5 h, 2 h, and 24 h, respectively.

[0302] In some implementations, Form 13 is prepared according to the procedure of Example 13.

[0303] This application covers all combinations of the above-described embodiments.

[0304] 5.2.14 Form 14 of Compound 1 In some embodiments, form 14 of compound 1 is provided herein. In some embodiments, form 14 of compound 1 is a crystalline malate of compound 1. In some embodiments, form 14 has a molar ratio of compound 1 to malate of about 1:1, optionally wherein the solid form is a hydrate. In some embodiments, form 14 of compound 1 is substantially free of amorphous compound 1. In some embodiments, form 14 of compound 1 is substantially free of other crystalline forms of compound 1 (i.e., polymorphs). In some embodiments, form 14 of compound 1 is provided as substantially pure form 14 of compound 1.

[0305] Figure 29 The representative XRPD spectrum of compound 1 in form 14 is provided.

[0306] In some embodiments, form 14 has an enantiomeric purity of about 98%, about 98.5%, about 99%, or about 99.5% or higher. In some embodiments, form 14 is crystalline. In some embodiments, form 14 is substantially crystalline. In some embodiments, form 14 is about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% crystalline or higher.

[0307] In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form 14 includes peaks at approximately 4.7°, 16.9°, 17.3°, 20.8°, and 22.7° 2θ. In some embodiments, the XRPD pattern includes peaks at approximately 8.3°, 12.5°, 13.0°, 14.5°, 16.3°, 19.1°, 23.5°, 24.6°, 25.5°, and 28.2° 2θ. In some embodiments, the XRPD pattern also includes peaks at approximately 10.9°, 14.1°, 18.4°, 24.9°, 26.1°, 26.7°, and 27.1° 2θ. In some implementations, the XRPD spectrum includes peaks at approximately 4.7°, 8.3°, 10.9°, 12.5°, 13.0°, 14.1°, 14.5°, 16.3°, 16.9°, 17.3°, 18.4°, 19.1°, 20.8°, 22.7°, 23.5°, 24.6°, 24.9°, 25.5°, 26.1°, 26.7°, 27.1°, and 28.2° 2θ.

[0308] In some embodiments, this document provides a solid form comprising a malate of compound 1, characterized in that, when measured using Cu Kα radiation, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all of the XRPD peaks are approximately located (e.g., 2θ ± 0.2 degrees) at the following positions: 4.7°, 8.3°, 10.9°, 12.5°, 13.0°, 14.1°, 14.5°, 16.3°, 16.9°, 17.3°, 18.4°, 19.1°, 20.8°, 22.7°, 23.5°, 24.6°, 24.9°, 25.5°, 26.1°, 26.7°, 27.1°, and 28.2° 2θ. In some embodiments, this solid form is characterized by at least 3 peaks. In some embodiments, this solid form is characterized by at least 5 peaks. In some embodiments, this solid form is characterized by at least 7 peaks. In some embodiments, the solid form is characterized by at least 9 peaks. In some embodiments, the solid form is characterized by at least 11 peaks. In some embodiments, the solid form is characterized by at least 13 peaks. In some embodiments, the solid form is characterized by at least 15 peaks. In some embodiments, the solid form is characterized by at least 17 peaks. In some embodiments, the solid form is characterized by at least 19 peaks. In some embodiments, the solid form is characterized by all peaks.

[0309] In some implementations, form 14 has the same Figure 29 The XRPD map presented in the image is basically a match for the XRPD map.

[0310] Figure 30 Representative overlay plots of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of compound 1 in form 14 are provided.

[0311] In some embodiments, Form 14 exhibits thermal (endothermic) events with onset temperatures of approximately 28°C and 178°C and / or endothermic peak temperatures of approximately 69°C and 216°C, respectively, as characterized by a temperature gradient of approximately 10°C / min using DSC. In some embodiments, Form 14 is characterized in that the DSC thermogram is substantially as follows: Figure 30 The DSC thermogram is shown in the image.

[0312] In some embodiments, form 14 exhibits a weight loss of approximately 3.6% when heated from approximately 30°C to approximately 120°C, as characterized by TGA. In some embodiments, form 14 is characterized in that its TGA thermogram is substantially as shown in... Figure 30 The TGA thermal spectrum is shown in the image.

[0313] In some implementations, Form 14 is prepared according to the procedure of Example 14.

[0314] This application covers all combinations of the above-described embodiments.

[0315] 5.2.15 Form 15 of Compound 1 In some embodiments, form 15 of compound 1 is provided herein. In some embodiments, form 15 of compound 1 is a crystalline malate of compound 1. In some embodiments, form 15 has a molar ratio of compound 1 to malate of about 1:1, and wherein the solid form is a solvate. In some embodiments, form 15 of compound 1 is substantially free of amorphous compound 1. In some embodiments, form 15 of compound 1 is substantially free of other crystalline forms of compound 1 (i.e., polymorphs). In some embodiments, form 15 of compound 1 is provided as substantially pure form 15 of compound 1.

[0316] Figure 31 The paper provides a representative XRPD spectrum of compound 1 in form 15.

[0317] In some embodiments, form 15 has an enantiomeric purity of about 98%, about 98.5%, about 99%, or about 99.5% or higher. In some embodiments, form 15 is crystalline. In some embodiments, form 15 is substantially crystalline. In some embodiments, form 15 is moderately crystalline. In some embodiments, form 15 is about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% crystalline or higher.

[0318] In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form 15 contains peaks at approximately 11.1°, 12.5°, 16.6°, and 17.8° 2θ. In some embodiments, the XRPD pattern also contains peaks at approximately 8.39°, 22.0°, 23.3°, and 25.5° 2θ. In some embodiments, the XRPD pattern also contains peaks at approximately 13.9°, 14.7°, and 24.1° 2θ. In some embodiments, the XRPD pattern contains peaks at approximately 8.39°, 11.1°, 12.5°, 13.9°, 14.7°, 16.6°, 17.8°, 22.0°, 23.3°, 24.1°, and 25.5° 2θ.

[0319] In some embodiments, this document provides a solid form comprising a malate of compound 1, characterized in that, when measured using Cu Kα radiation, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all XRPD peaks are approximately located (e.g., 2θ ± 0.2 degrees) at the following positions: 8.39°, 11.1°, 12.5°, 13.9°, 14.7°, 16.6°, 17.8°, 22.0°, 23.3°, 24.1°, and 25.5° 2θ. In some embodiments, the solid form is characterized by at least 3 peaks. In some embodiments, the solid form is characterized by at least 5 peaks. In some embodiments, the solid form is characterized by at least 7 peaks. In some embodiments, the solid form is characterized by at least 9 peaks. In some embodiments, the solid form is characterized by all peaks.

[0320] In some implementations, form 15 has the same Figure 31 The XRPD map presented in the image is basically a match for the XRPD map.

[0321] Figure 32 Representative overlay plots of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of compound 1 in form 15 are provided.

[0322] In some embodiments, Form 15 exhibits thermal (endothermic) events with onset temperatures of approximately 127°C and 159°C and / or endothermic peak temperatures of approximately 145°C and 182°C, respectively, as characterized by a temperature gradient of approximately 10°C / min using DSC. In some embodiments, Form 15 is characterized in that the DSC thermogram is substantially as follows: Figure 32 The DSC thermogram is shown in the image.

[0323] In some embodiments, Form 15 exhibits a weight loss of approximately 3.1% when heated from approximately 90°C to approximately 160°C, and a weight loss of approximately 3.6% when heated from approximately 160°C to approximately 190°C, as characterized by TGA. In some embodiments, Form 15 is characterized in that its TGA thermogram is substantially as shown in... Figure 32 The TGA thermal spectrum is shown in the image.

[0324] In some implementations, Form 15 is prepared according to the procedure of Example 15.

[0325] This application covers all combinations of the above-described embodiments.

[0326] 5.2.16 Form 16 of Compound 1 In some embodiments, form 16 of compound 1 is provided herein. In some embodiments, form 16 of compound 1 is a crystalline maleate salt of compound 1. In some embodiments, form 16 has a molar ratio of compound 1 to maleic acid of about 1:1, optionally wherein the solid form is a hydrate. In some embodiments, form 16 of compound 1 is substantially free of amorphous compound 1. In some embodiments, form 16 of compound 1 is substantially free of other crystalline forms of compound 1 (i.e., polymorphs). In some embodiments, form 16 of compound 1 is provided as substantially pure form 16 of compound 1.

[0327] Figure 33 The paper provides a representative XRPD spectrum of compound 1 in form 16.

[0328] In some embodiments, form 16 has an enantiomeric purity of about 98%, about 98.5%, about 99%, or about 99.5% or higher. In some embodiments, form 16 is crystalline. In some embodiments, form 16 is substantially crystalline. In some embodiments, form 16 is moderately crystalline. In some embodiments, form 16 is about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% crystalline or higher.

[0329] In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form 16 includes peaks at approximately 12.2°, 12.6°, 26.1°, and 29.2° 2θ. In some embodiments, the XRPD pattern also includes peaks at approximately 4.8°, 16.7°, 24.7°, and 25.2° 2θ. In some embodiments, the XRPD pattern also includes peaks at approximately 14.5°, 17.3°, and 24.3° 2θ. In some embodiments, the XRPD pattern includes peaks at approximately 4.8°, 12.2°, 12.6°, 14.5°, 16.7°, 17.3°, 24.3°, 24.7°, 25.2°, 26.1°, and 29.2° 2θ.

[0330] In some embodiments, this document provides a solid form comprising the maleate of compound 1, characterized in that, when measured using Cu Kα radiation, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all XRPD peaks are approximately located (e.g., 2θ ± 0.2 degrees) at the following positions: 4.8°, 12.2°, 12.6°, 14.5°, 16.7°, 17.3°, 24.3°, 24.7°, 25.2°, 26.1°, and 29.2° 2θ. In some embodiments, the solid form is characterized by at least 3 peaks. In some embodiments, the solid form is characterized by at least 5 peaks. In some embodiments, the solid form is characterized by at least 7 peaks. In some embodiments, the solid form is characterized by at least 9 peaks. In some embodiments, the solid form is characterized by all peaks.

[0331] In some implementations, form 16 has the same Figure 33 The XRPD map presented in the image is basically a match for the XRPD map.

[0332] Figure 34 Representative overlay plots of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of compound 1 in form 16 are provided.

[0333] In some embodiments, Form 16 exhibits thermal (endothermic) events with onset temperatures of approximately 26°C and 198°C and / or endothermic peak temperatures of approximately 53°C and 206°C, respectively, as characterized by a temperature gradient of approximately 10°C / min using DSC. In some embodiments, Form 16 is characterized in that the DSC thermogram is substantially as follows: Figure 34 The DSC thermogram is shown in the image.

[0334] In some embodiments, form 16 exhibits a weight loss of approximately 1.8% when heated from approximately 24°C to approximately 100°C, as characterized by TGA. In some embodiments, form 16 is characterized in that its TGA thermogram is substantially as shown in... Figure 34 The TGA thermal spectrum is shown in the image.

[0335] In some implementations, Form 16 is prepared according to the procedure of Example 16.

[0336] This application covers all combinations of the above-described embodiments.

[0337] 5.2.17 Form 17 of Compound 1 In some embodiments, form 17 of compound 1 is provided herein. In some embodiments, form 17 of compound 1 is a crystalline maleate salt of compound 1. In some embodiments, form 17 has a molar ratio of compound 1 to maleic acid of about 1:1, optionally wherein the solid form is a hydrate. In some embodiments, form 17 of compound 1 is substantially free of amorphous compound 1. In some embodiments, form 17 of compound 1 is substantially free of other crystalline forms of compound 1 (i.e., polymorphs). In some embodiments, form 17 of compound 1 is provided as substantially pure form 17 of compound 1.

[0338] Figure 35 The paper provides a representative XRPD spectrum of compound 1 in form 17.

[0339] In some embodiments, form 17 has an enantiomeric purity of about 98%, about 98.5%, about 99%, or about 99.5% or higher. In some embodiments, form 17 is crystalline. In some embodiments, form 17 is substantially crystalline. In some embodiments, form 17 is moderately crystalline. In some embodiments, form 17 is about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% crystalline or higher.

[0340] In some embodiments, the X-ray powder diffraction (XRPD) pattern of form 17 includes peaks at approximately 9.5°, 15.2°, and 18.6° 2θ. In some embodiments, the XRPD pattern also includes peaks at approximately 4.8°, 8.2°, 16.6°, 17.3°, 20.9°, 27.0°, and 29.1° 2θ. In some embodiments, the XRPD pattern also includes peaks at approximately 12.8°, 14.4°, 24.0°, 25.2°, and 25.7° 2θ. In some implementations, the XRPD spectrum includes peaks at approximately 4.8°, 8.2°, 9.5°, 12.8°, 14.4°, 15.2°, 16.6°, 17.3°, 18.6°, 20.9°, 24.0°, 25.2°, 25.7°, 27.0°, and 29.1°2θ.

[0341] In some embodiments, this document provides a solid form comprising the maleate of compound 1, characterized in that, when measured using Cu Kα radiation, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all of the XRPD peaks are approximately located (e.g., 2θ ± 0.2 degrees) at the following positions: 4.8°, 8.2°, 9.5°, 12.8°, 14.4°, 15.2°, 16.6°, 17.3°, 18.6°, 20.9°, 24.0°, 25.2°, 25.7°, 27.0°, and 29.1° 2θ. In some embodiments, the solid form is characterized by at least 3 peaks. In some embodiments, the solid form is characterized by at least 5 peaks. In some embodiments, the solid form is characterized by at least 7 peaks. In some embodiments, the solid form is characterized by at least 9 peaks. In some embodiments, the solid form is characterized by at least 11 peaks. In some embodiments, the solid form is characterized by at least 13 peaks. In some embodiments, the solid form is characterized by all peaks.

[0342] In some implementations, form 17 has the same Figure 35 The XRPD map presented in the image is basically a match for the XRPD map.

[0343] Figure 36 Representative overlay plots of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of compound 1 in form 17 are provided.

[0344] In some embodiments, Form 17 exhibits thermal (endothermic) events with onset temperatures of about 27°C and 195°C and / or endothermic peak temperatures of about 60°C and about 205°C, respectively, as characterized by a temperature gradient of about 10°C / min using DSC. In some embodiments, Form 17 is characterized in that the DSC thermogram is substantially as follows: Figure 36The DSC thermogram is shown in the image.

[0345] In some embodiments, form 17 exhibits a weight loss of approximately 1.2% when heated from approximately 26°C to approximately 100°C, as characterized by TGA. In some embodiments, form 17 is characterized in that its TGA thermogram is substantially as shown in... Figure 36 The TGA thermal spectrum is shown in the image.

[0346] In some implementations, Form 17 is prepared according to the procedure of Example 17.

[0347] This application covers all combinations of the above-described embodiments.

[0348] 5.2.18 Form 18 of Compound 1 In some embodiments, form 18 of compound 1 is provided herein. In some embodiments, form 18 of compound 1 is a crystalline methanesulfonate of compound 1. In some embodiments, form 18 has a molar ratio of compound 1 to methanesulfonate of about 1:0.8, optionally wherein the solid form is a solvate. In some embodiments, form 18 of compound 1 is substantially free of amorphous compound 1. In some embodiments, form 18 of compound 1 is substantially free of other crystalline forms of compound 1 (i.e., polymorphs). In some embodiments, form 18 of compound 1 is provided as substantially pure form 18 of compound 1.

[0349] Figure 37 The paper provides a representative XRPD spectrum of compound 1 in form 18.

[0350] In some embodiments, form 18 has an enantiomeric purity of about 98%, about 98.5%, about 99%, or about 99.5% or higher. In some embodiments, form 18 is crystalline. In some embodiments, form 18 is substantially crystalline. In some embodiments, form 18 is moderately crystalline. In some embodiments, form 18 is partially crystalline. In some embodiments, form 18 is about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% crystalline or higher.

[0351] In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form 18 contains peaks at approximately 9.0°, 9.2°, 18.6°, and 19.2° 2θ. In some embodiments, the XRPD pattern also contains peaks at approximately 17.5°, 18.1°, and 23.1° 2θ. In some embodiments, the XRPD pattern also contains peaks at approximately 20.4°, 21.0°, and 21.2° 2θ. In some embodiments, the XRPD pattern contains peaks at approximately 9.0°, 9.2°, 17.5°, 18.1°, 18.6°, 19.2°, 20.4°, 21.0°, 21.2°, and 23.1° 2θ.

[0352] In some embodiments, this document provides a solid form comprising a methanesulfonate of compound 1, characterized in that, when measured using Cu Kα radiation, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all XRPD peaks are approximately located (e.g., 2θ ± 0.2 degrees) at the following positions: 9.0°, 9.2°, 17.5°, 18.1°, 18.6°, 19.2°, 20.4°, 21.0°, 21.2°, and 23.1° 2θ. In some embodiments, the solid form is characterized by at least 3 peaks. In some embodiments, the solid form is characterized by at least 5 peaks. In some embodiments, the solid form is characterized by at least 7 peaks. In some embodiments, the solid form is characterized by at least 9 peaks. In some embodiments, the solid form is characterized by all peaks.

[0353] In some implementations, form 18 has the same Figure 37 The XRPD map presented in the image is basically a match for the XRPD map.

[0354] Figure 38 Representative overlay plots of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of compound 1 in form 18 are provided.

[0355] In some embodiments, Form 18 exhibits a thermal (endothermic) event with an onset temperature of about 142°C and / or an endothermic peak temperature of about 146°C, as characterized by a temperature gradient of about 10°C / min via DSC. In some embodiments, Form 18 is characterized in that the DSC thermogram is substantially as follows: Figure 38 The DSC thermogram is shown in the image.

[0356] In some embodiments, form 18 exhibits a weight loss of about 5.6% when heated from about room temperature to about 145°C and a weight loss of about 9.5% when heated from about 145°C to about 200°C, as characterized by TGA. In some embodiments, form 18 is characterized in that its TGA thermogram is substantially as shown in... Figure 38 The TGA thermal spectrum is shown in the image.

[0357] In some implementations, Form 18 is prepared according to the procedure of Example 18.

[0358] This application covers all combinations of the above-described embodiments.

[0359] 5.2.19 Form of Compound 1 In some embodiments, form 19 of compound 1 is provided herein. In some embodiments, form 19 of compound 1 is a crystalline oxalate of compound 1. In some embodiments, form 19 has a molar ratio of compound 1 to oxalate of about 1:1, optionally wherein the solid form is a solvate. In some embodiments, form 19 of compound 1 is substantially free of amorphous compound 1. In some embodiments, form 19 of compound 1 is substantially free of other crystalline forms of compound 1 (i.e., polymorphs). In some embodiments, form 19 of compound 1 is provided as substantially pure form 19 of compound 1.

[0360] Figure 39 The paper provides a representative XRPD spectrum of compound 1 in form 19.

[0361] In some embodiments, form 19 has an enantiomeric purity of about 98%, about 98.5%, about 99%, or about 99.5% or higher. In some embodiments, form 19 is crystalline. In some embodiments, form 19 is substantially crystalline. In some embodiments, form 19 is moderately crystalline. In some embodiments, form 19 is about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% crystalline or higher.

[0362] In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form 19 contains peaks at approximately 4.7°, 13.2°, 19.8°, and 25.0° 2θ. In some embodiments, the XRPD pattern also contains peaks at approximately 8.5°, 11.4°, 14.2°, 15.7°, and 17.1° 2θ. In some embodiments, the XRPD pattern also contains peaks at approximately 8.8°, 9.7°, 20.5°, and 25.9° 2θ. In some embodiments, the XRPD pattern contains peaks at approximately 4.7°, 8.5°, 8.8°, 9.7°, 11.4°, 13.2°, 14.2°, 15.7°, 17.1°, 19.8°, 20.5°, 25.0°, and 25.9° 2θ.

[0363] In some embodiments, this document provides a solid form comprising an oxalate of compound 1, characterized in that, when measured using Cu Kα radiation, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all XRPD peaks are approximately located (e.g., 2θ ± 0.2 degrees) at the following positions: 4.7°, 8.5°, 8.8°, 9.7°, 11.4°, 13.2°, 14.2°, 15.7°, 17.1°, 19.8°, 20.5°, 25.0°, and 25.9° 2θ. In some embodiments, this solid form is characterized by at least 3 peaks. In some embodiments, this solid form is characterized by at least 5 peaks. In some embodiments, this solid form is characterized by at least 7 peaks. In some embodiments, this solid form is characterized by at least 9 peaks. In some embodiments, this solid form is characterized by at least 11 peaks. In some embodiments, this solid form is characterized by all peaks.

[0364] In some implementations, form 19 has the same Figure 39 The XRPD map presented in the image is basically a match for the XRPD map.

[0365] Figure 40 Representative overlay plots of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of compound 1 in form 19 are provided.

[0366] In some embodiments, Form 19 exhibits thermal (endothermic) events with onset temperatures of approximately 92°C, approximately 137°C, and 194°C and / or endothermic peak temperatures of approximately 137°C, approximately 190°C, and approximately 194°C, as characterized by DSC at a temperature gradient of approximately 10°C / min. In some embodiments, Form 19 is characterized in that the DSC thermogram is substantially as follows: Figure 40 The DSC thermogram is shown in the image.

[0367] In some embodiments, Form 19 exhibits a weight loss of approximately 7.4% when heated from approximately 90°C to approximately 190°C and a weight loss of approximately 19.0% when heated from approximately 190°C to approximately 240°C, as characterized by TGA. In some embodiments, Form 19 is characterized in that its TGA thermogram is substantially as shown in... Figure 40 The TGA thermal spectrum is shown in the image.

[0368] In some implementations, Form 19 is prepared according to the procedure of Example 19.

[0369] This application covers all combinations of the above-described embodiments.

[0370] 5.2.20 Form of Compound 1 20 In some embodiments, form 20 of compound 1 is provided herein. In some embodiments, form 20 of compound 1 is a crystalline phosphate of compound 1. In some embodiments, form 20 is a monophosphate of compound 1, optionally wherein the solid form is a hydrate. In some embodiments, form 20 of compound 1 is substantially free of amorphous compound 1. In some embodiments, form 20 of compound 1 is substantially free of other crystalline forms of compound 1 (i.e., polymorphs). In some embodiments, form 20 of compound 1 is provided as substantially pure form 20 of compound 1.

[0371] Figure 41 The paper provides a representative XRPD spectrum of compound 1 in form 20.

[0372] In some embodiments, form 20 has an enantiomeric purity of about 98%, about 98.5%, about 99%, or about 99.5% or higher. In some embodiments, form 20 is crystalline. In some embodiments, form 20 is substantially crystalline. In some embodiments, form 20 is moderately crystalline. In some embodiments, form 20 is about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% crystalline or higher.

[0373] In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form 20 includes peaks at approximately 9.4°, 15.1°, 16.6°, and 18.2° 2θ. In some embodiments, the XRPD pattern also includes peaks at approximately 8.5°, 10.6°, 12.3°, 14.1°, 17.5°, 20.1°, 22.5°, and 23.6° 2θ. In some embodiments, the XRPD pattern also includes peaks at approximately 11.1°, 12.8°, 22.0°, 24.4°, 25.3°, 26.9°, and 31.7° 2θ. In some implementations, the XRPD spectrum contains peaks at approximately 8.5°, 9.4°, 10.6°, 11.1°, 12.3°, 12.8°, 14.1°, 15.1°, 16.6°, 17.5°, 18.2°, 20.1°, 22.0°, 22.5°, 23.6°, 24.4°, 25.3°, 26.9°, and 31.7° 2θ.

[0374] In some embodiments, this document provides a solid form comprising a phosphate of compound 1, characterized in that, when measured using Cu Kα radiation, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all of the XRPD peaks are approximately located (e.g., 2θ ± 0.2 degrees) at the following positions: 8.5°, 9.4°, 10.6°, 11.1°, 12.3°, 12.8°, 14.1°, 15.1°, 16.6°, 17.5°, 18.2°, 20.1°, 22.0°, 22.5°, 23.6°, 24.4°, 25.3°, 26.9°, and 31.7° 2θ. In some embodiments, this solid form is characterized by at least 3 peaks. In some embodiments, this solid form is characterized by at least 5 peaks. In some embodiments, this solid form is characterized by at least 7 peaks. In some embodiments, this solid form is characterized by at least 9 peaks. In some embodiments, the solid form is characterized by at least 11 peaks. In some embodiments, the solid form is characterized by at least 13 peaks. In some embodiments, the solid form is characterized by at least 15 peaks. In some embodiments, the solid form is characterized by at least 17 peaks. In some embodiments, the solid form is characterized by all peaks.

[0375] In some implementations, form 20 has the same Figure 41 The XRPD map presented in the image is basically a match for the XRPD map.

[0376] Figure 42 Representative overlay plots of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of compound 1 in form 20 are provided.

[0377] In some embodiments, Form 20 exhibits a thermal (endothermic) event with an onset temperature of about 34°C and / or an endothermic peak temperature of about 74°C, as characterized by a temperature gradient of about 10°C / min using DSC. In some embodiments, Form 20 is characterized in that the DSC thermogram is substantially as follows: Figure 42 The DSC thermogram is shown in the image.

[0378] In some embodiments, form 20 exhibits a weight loss of approximately 4.5% when heated from approximately 25°C to approximately 110°C, as characterized by TGA. In some embodiments, form 20 is characterized in that its TGA thermogram is substantially as shown in... Figure 42 The TGA thermal spectrum is shown in the image.

[0379] In some implementations, form 20 is prepared according to the procedure of example 20.

[0380] This application covers all combinations of the above-described embodiments.

[0381] 5.2.21 Form 21 of Compound 1 In some embodiments, form 21 of compound 1 is provided herein. In some embodiments, form 21 of compound 1 is a crystalline tartrate salt of compound 1. In some embodiments, form 21 has a molar ratio of compound 1 to tartrate of about 1:1, optionally wherein the solid form is a hydrate. In some embodiments, form 21 of compound 1 is substantially free of amorphous compound 1. In some embodiments, form 21 of compound 1 is substantially free of other crystalline forms of compound 1 (i.e., polymorphs). In some embodiments, form 21 of compound 1 is provided as a substantially pure form 21 of compound 1.

[0382] Figure 43 The paper provides a representative XRPD spectrum of compound 1 in form 21.

[0383] In some embodiments, form 21 has an enantiomeric purity of about 98%, about 98.5%, about 99%, or about 99.5% or higher. In some embodiments, form 21 is crystalline. In some embodiments, form 21 is substantially crystalline. In some embodiments, form 21 is moderately crystalline. In some embodiments, form 21 is about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% crystalline or higher.

[0384] In some embodiments, the X-ray powder diffraction (XRPD) pattern of form 21 contains peaks at approximately 13.2°, 16.9°, 17.2°, 17.7°, 18.4°, and 25.3° 2θ. In some embodiments, the XRPD pattern also contains peaks at approximately 8.3°, 12.3°, 20.9°, and 24.0° 2θ. In some embodiments, the XRPD pattern also contains peaks at approximately 14.5°, 19.9°, and 22.4° 2θ. In some embodiments, the XRPD pattern contains peaks at approximately 8.3°, 12.3°, 13.2°, 14.5°, 16.9°, 17.2°, 17.7°, 18.4°, 19.9°, 20.9°, 22.4°, 24.0°, and 25.3° 2θ.

[0385] In some embodiments, this document provides a solid form comprising a tartrate of compound 1, characterized in that, when measured using Cu Kα radiation, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all XRPD peaks are approximately located (e.g., 2θ ± 0.2 degrees) at the following positions: 8.3°, 12.3°, 13.2°, 14.5°, 16.9°, 17.2°, 17.7°, 18.4°, 19.9°, 20.9°, 22.4°, 24.0°, and 25.3° 2θ. In some embodiments, this solid form is characterized by at least 3 peaks. In some embodiments, this solid form is characterized by at least 5 peaks. In some embodiments, this solid form is characterized by at least 7 peaks. In some embodiments, this solid form is characterized by at least 9 peaks. In some embodiments, this solid form is characterized by at least 11 peaks. In some embodiments, this solid form is characterized by all peaks.

[0386] In some implementations, form 21 has the same Figure 43 The XRPD map presented in the image is basically a match for the XRPD map.

[0387] Figure 44 Representative overlay plots of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of compound 1 in form 21 are provided.

[0388] In some embodiments, form 21 exhibits thermal (endothermic) events with onset temperatures of about 29°C and 201°C and / or endothermic peak temperatures of about 70°C and about 204°C, as characterized by a temperature gradient of about 10°C / min using DSC. In some embodiments, form 21 is characterized in that the DSC thermogram is substantially as follows: Figure 44 The DSC thermogram is shown in the image.

[0389] In some embodiments, form 21 exhibits a weight loss of approximately 6.8% when heated from approximately 30°C to approximately 140°C, as characterized by TGA. In some embodiments, form 21 is characterized in that its TGA thermogram is substantially as shown in... Figure 44 The TGA thermal spectrum is shown in the image.

[0390] In some implementations, form 21 is prepared according to the procedure of example 21.

[0391] This application covers all combinations of the above-described embodiments.

[0392] 5.2.22 Form of Compound 1 In some embodiments, form 22 of compound 1 is provided herein. In some embodiments, form 22 of compound 1 is a crystalline tartrate salt of compound 1. In some embodiments, form 22 has a molar ratio of compound 1 to tartrate of about 1:1, and optionally the solid form is a solvate. In some embodiments, form 22 of compound 1 is substantially free of amorphous compound 1. In some embodiments, form 22 of compound 1 is substantially free of other crystalline forms of compound 1 (i.e., polymorphs). In some embodiments, form 22 of compound 1 is provided as a substantially pure form 22 of compound 1.

[0393] Figure 45 The paper provides a representative XRPD spectrum of compound 1 in form 22.

[0394] In some embodiments, form 22 has an enantiomeric purity of about 98%, about 98.5%, about 99%, or about 99.5% or higher. In some embodiments, form 22 is crystalline. In some embodiments, form 22 is substantially crystalline. In some embodiments, form 22 is moderately crystalline. In some embodiments, form 22 is about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% crystalline or higher.

[0395] In some embodiments, the X-ray powder diffraction (XRPD) pattern of form 22 includes peaks at approximately 10.6°, 11.2°, 16.6°, 17.6°, 18.1°, and 22.5° 2θ. In some embodiments, the XRPD pattern also includes peaks at approximately 8.5°, 14.6°, 22.0°, 25.2°, 25.6°, and 29.9° 2θ. In some embodiments, the XRPD pattern also includes peaks at approximately 12.3°, 14.2°, 23.7°, 23.9°, and 27.4° 2θ. In some implementations, the XRPD spectrum contains peaks at approximately 8.5°, 10.6°, 11.2°, 12.3°, 14.2°, 14.6°, 16.6°, 17.6°, 18.1°, 22.0°, 22.5°, 23.7°, 23.9°, 25.2°, 25.6°, 27.4°, and 29.9° 2θ.

[0396] In some embodiments, this document provides a solid form comprising a tartrate of compound 1, characterized in that, when measured using Cu Kα radiation, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all of the XRPD peaks are approximately located (e.g., 2θ ± 0.2 degrees) at the following positions: 8.5°, 10.6°, 11.2°, 12.3°, 14.2°, 14.6°, 16.6°, 17.6°, 18.1°, 22.0°, 22.5°, 23.7°, 23.9°, 25.2°, 25.6°, 27.4°, and 29.9° 2θ. In some embodiments, this solid form is characterized by at least 3 peaks. In some embodiments, this solid form is characterized by at least 5 peaks. In some embodiments, this solid form is characterized by at least 7 peaks. In some embodiments, this solid form is characterized by at least 9 peaks. In some embodiments, the solid form is characterized by at least 11 peaks. In some embodiments, the solid form is characterized by at least 13 peaks. In some embodiments, the solid form is characterized by at least 15 peaks. In some embodiments, the solid form is characterized by all peaks.

[0397] In some implementations, form 22 has the same Figure 45 The XRPD map presented in the image is basically a match for the XRPD map.

[0398] Figure 46 Representative overlay plots of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of compound 1 in form 22 are provided.

[0399] In some embodiments, form 22 exhibits thermal (endothermic) events with onset temperatures of about 27°C, about 106°C, and 209°C and / or endothermic peak temperatures of about 51°C, about 141°C, and about 222°C, as characterized by a temperature gradient of about 10°C / min using DSC. In some embodiments, form 22 is characterized in that the DSC thermogram is substantially as follows: Figure 46 The DSC thermogram is shown in the image.

[0400] In some embodiments, form 22 exhibits a weight loss of approximately 2.8% when heated from approximately 80°C to approximately 170°C, as characterized by TGA. In some embodiments, form 22 is characterized in that its TGA thermogram is substantially as shown in... Figure 46 The TGA thermal spectrum is shown in the image.

[0401] In some implementations, form 22 is prepared according to the procedure of example 22.

[0402] This application covers all combinations of the above-described embodiments.

[0403] 5.2.23 Form of Compound 1 In some embodiments, form 23 of compound 1 is provided herein. In some embodiments, form 23 of compound 1 is a crystalline toluenesulfonate of compound 1. In some embodiments, form 23 has a molar ratio of compound 1 to p-toluenesulfonate of about 1:0.8, optionally wherein the solid form is a solvate. In some embodiments, form 23 of compound 1 is substantially free of amorphous compound 1. In some embodiments, form 23 of compound 1 is substantially free of other crystalline forms of compound 1 (i.e., polymorphs). In some embodiments, form 23 of compound 1 is provided as a substantially pure form 23 of compound 1.

[0404] Figure 47 The paper provides a representative XRPD spectrum of compound 1 in form 23.

[0405] In some embodiments, form 23 has an enantiomeric purity of about 98%, about 98.5%, about 99%, or about 99.5% or higher. In some embodiments, form 23 is crystalline. In some embodiments, form 23 is substantially crystalline. In some embodiments, form 23 is moderately crystalline. In some embodiments, form 23 is partially crystalline. In some embodiments, form 23 is about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% crystalline or higher.

[0406] In some embodiments, the X-ray powder diffraction (XRPD) pattern of form 23 contains peaks at approximately 8.5°, 14.6°, 18.1°, and 21.7° 2θ. In some embodiments, the XRPD pattern also contains peaks at approximately 6.8°, 17.7°, and 23.8° 2θ. In some embodiments, the XRPD pattern also contains peaks at approximately 18.8° and 22.9° 2θ. In some embodiments, the XRPD pattern contains peaks at approximately 6.8°, 8.5°, 14.6°, 17.7°, 18.1°, 18.8°, 21.7°, 22.9°, and 23.8° 2θ.

[0407] In some embodiments, this document provides a solid form comprising a toluenesulfonate of compound 1, characterized in that, when measured using Cu Kα radiation, 1, 2, 3, 4, 5, 6, 7, 8, or all of the XRPD peaks are approximately located (e.g., 2θ ± 0.2 degrees) at the following positions: 6.8°, 8.5°, 14.6°, 17.7°, 18.1°, 18.8°, 21.7°, 22.9°, and 23.8° 2θ. In some embodiments, the solid form is characterized by at least 3 peaks. In some embodiments, the solid form is characterized by at least 5 peaks. In some embodiments, the solid form is characterized by at least 7 peaks. In some embodiments, the solid form is characterized by at least 8 peaks. In some embodiments, the solid form is characterized by all peaks.

[0408] In some implementations, form 23 has the same Figure 47 The XRPD map presented in the image is basically a match for the XRPD map.

[0409] Figure 48 Representative overlay plots of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of compound 1 in form 23 are provided.

[0410] In some embodiments, form 23 exhibits thermal (endothermic) events with onset temperatures of approximately 83°C and 186°C and / or endothermic peak temperatures of approximately 120°C and 202°C, respectively, as characterized by a temperature gradient of approximately 10°C / min using DSC. In some embodiments, form 23 is characterized in that the DSC thermogram is substantially as follows: Figure 48 The DSC thermogram is shown in the image.

[0411] In some embodiments, form 23 exhibits a weight loss of about 1.8% when heated from about room temperature to about 100°C and a weight loss of about 5.6% when heated from about 100°C to about 180°C, as characterized by TGA. In some embodiments, form 23 is characterized in that its TGA thermogram is substantially as shown in... Figure 48 The TGA thermal spectrum is shown in the image.

[0412] In some implementations, form 23 is prepared according to the procedure of example 23.

[0413] This application covers all combinations of the above-described embodiments.

[0414] 5.2.24 Form 24 of Compound 1 In some embodiments, form 24 of compound 1 is provided herein. In some embodiments, form 24 of compound 1 is a crystalline anhydrous form of compound 1. In some embodiments, form 24 of compound 1 is substantially free of amorphous compound 1. In some embodiments, form 24 of compound 1 is substantially free of other crystalline forms of compound 1 (i.e., polymorphs). In some embodiments, form 24 of compound 1 is substantially free of salt forms of compound 1. In some embodiments, form 24 of compound 1 is provided as a substantially pure form 24 of compound 1.

[0415] Figure 49 The paper provides a representative XRPD spectrum of compound 1 in form 24.

[0416] In some embodiments, form 24 has an enantiomeric purity of about 98%, about 98.5%, about 99%, or about 99.5% or higher. In some embodiments, form 24 is crystalline. In some embodiments, form 24 is substantially crystalline. In some embodiments, form 24 is about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% crystalline or higher.

[0417] In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form 24 contains peaks at approximately 9.5°, 11.8°, 14.6°, and 20.9° 2θ. In some embodiments, the XRPD pattern also contains peaks at approximately 14.8°, 16.4°, 22.3°, and 23.8° 2θ. In some embodiments, the XRPD pattern also contains peaks at approximately 16.6°, 17.1°, 24.2°, and 25.1° 2θ. In some embodiments, the XRPD pattern contains peaks at approximately 9.5°, 11.8°, 14.6°, 14.8°, 16.4°, 16.6°, 17.1°, 20.9°, 22.3°, 23.8°, 24.2°, and 25.1° 2θ.

[0418] In some embodiments, this document provides a solid form comprising anhydrous compound 1, characterized in that, when measured using Cu Kα radiation, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all XRPD peaks are approximately located (e.g., 2θ ± 0.2 degrees) at the following positions: 9.5°, 11.8°, 14.6°, 14.8°, 16.4°, 16.6°, 17.1°, 20.9°, 22.3°, 23.8°, 24.2°, and 25.1° 2θ. In some embodiments, this solid form is characterized by at least 3 peaks. In some embodiments, this solid form is characterized by at least 5 peaks. In some embodiments, this solid form is characterized by at least 7 peaks. In some embodiments, this solid form is characterized by at least 9 peaks. In some embodiments, this solid form is characterized by at least 11 peaks. In some embodiments, this solid form is characterized by all peaks.

[0419] In some implementations, form 24 has the same Figure 49 The XRPD map presented in the image is basically a match for the XRPD map.

[0420] Figure 50 Representative overlay plots of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of compound 1 in form 24 are provided.

[0421] In some embodiments, form 24 exhibits a thermal (endothermic) event with an onset temperature of about 240°C and / or an endothermic peak at about 246°C, as characterized by a temperature gradient of about 10°C / min via DSC. In some embodiments, form 24 is characterized in that the DSC thermogram is substantially as follows: Figure 50 The DSC thermogram is shown in the image.

[0422] In some embodiments, form 24 does not exhibit weight loss when heated to approximately 200°C, as characterized by TGA. In some embodiments, form 24 is characterized by a TGA thermogram that is substantially as shown in the image. Figure 50 The TGA thermal spectrum is shown in the image.

[0423] In some implementations, form 24 is prepared according to the procedure of example 14.

[0424] This application covers all combinations of the above-described embodiments.

[0425] 5.3 Pharmaceutically acceptable salts of compound 1 In some implementations, this document provides pharmaceutically acceptable salts of compound 1: , Or its isotopes, or pharmaceutically acceptable solvates of pharmaceutically acceptable salts. In some embodiments, the pharmaceutically acceptable salt is a benzoate, benzenesulfonate, chloride salt, citrate, fumarate, gentianate, glutarate, glycolate, hippurate, 1-hydroxy-2-naphthylcarboxate, malate, maleate, methanesulfonate, oxalate, phosphate, sulfate, tartrate, or toluenesulfonate. In some embodiments, the pharmaceutically acceptable salt of compound 1 or its pharmaceutically acceptable solvate is substantially pure. In some embodiments, the pharmaceutically acceptable salt of compound 1 or its pharmaceutically acceptable solvate is substantially chemically pure. In some embodiments, the pharmaceutically acceptable salt of compound 1 or its pharmaceutically acceptable solvate is substantially physically pure. In some embodiments, the pharmaceutically acceptable salt of compound 1 or its pharmaceutically acceptable solvate is substantially enantiomeric pure. In some embodiments, the pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable solvate thereof has an enantiomeric purity of at least about 98% (e.g., about 98.5%, about 99%, or about 99.5%). In some embodiments, the pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable solvate thereof has a compound 1 / conjugate acid molar ratio in the range of about 2:1 to about 1:2. In some embodiments, the pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable solvate thereof has a compound 1 / conjugate acid molar ratio in the range of about 2:1 to about 1:1. In some embodiments, the pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable solvate thereof has a compound 1 / conjugate acid molar ratio in the range of about 1:1 to about 1:2. In some embodiments, the pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable solvate thereof has a compound 1 / conjugate acid molar ratio of about 1:1. In some embodiments, the pharmaceutically acceptable salt of compound 1 is a nonsolvent of the pharmaceutically acceptable salt of compound 1. In some embodiments, a pharmaceutically acceptable salt of compound 1 is an anhydrous form of a pharmaceutically acceptable salt of compound 1. In some embodiments, a pharmaceutically acceptable salt of compound 1 is a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of compound 1. In some embodiments, a pharmaceutically acceptable salt of compound 1 is a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of compound 1, wherein the pharmaceutically acceptable solvate is a hydrate, a hemihydrate, isobutyl acetate, isopropyl acetate, tetrahydrofuran solvate, acetone solvate, acetonitrile solvate, or a combination thereof. In some embodiments, the pharmaceutically acceptable solvate is a hydrate. In some embodiments, the pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of compound 1 has a compound 1 / solvent molar ratio in the range of about 2:1 to about 1:2.In some embodiments, the pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of compound 1 has a compound 1 / solvent molar ratio in the range of about 2:1 to about 1:1. In some embodiments, the pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of compound 1 has a compound 1 / solvent molar ratio in the range of about 1:1 to about 1:2. In some embodiments, the pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of compound 1 has a compound 1 / solvent molar ratio of about 1:1.

[0426] In some implementation schemes, a pharmaceutically acceptable salt of compound 1 is ( S )-3-amino-3-(1-methyl-1 H -imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-dibenzocyclohexane-2 2 , 4 4 - Dicarboxynitrile benzoate or a pharmaceutically acceptable solvate thereof. In some embodiments, the benzoate of compound 1 has a compound 1 / benzoic acid molar ratio in the range of about 2:1 to about 1:2, such as about 2:1 to about 1:1 or about 1:1 to about 1:2. In some embodiments, the benzoate of compound 1 has a compound 1 / benzoic acid molar ratio of about 1:1.

[0427] In some implementation schemes, a pharmaceutically acceptable salt of compound 1 is ( S )-3-amino-3-(1-methyl-1 H -imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-dibenzocyclohexane-2 2 , 4 4 - Dimethylnitrile benzenesulfonate or its pharmaceutically acceptable solvate.

[0428] In some implementation schemes, a pharmaceutically acceptable salt of compound 1 is ( S )-3-amino-3-(1-methyl-1 H -imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-dibenzocyclohexane-2 2 , 4 4 - Dichloronitrile chloride salts or pharmaceutically acceptable solvates thereof.

[0429] In some implementation schemes, a pharmaceutically acceptable salt of compound 1 is ( S )-3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-dibenzocyclohexane-2 2 , 4 4- Dicarboxynitrile citrate or its pharmaceutically acceptable solvates.

[0430] In some implementation schemes, a pharmaceutically acceptable salt of compound 1 is ( S )-3-amino-3-(1-methyl-1 H -imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-dibenzocyclohexane-2 2 , 4 4 - Dicarboxynitrile fumarate or a pharmaceutically acceptable solvate thereof. In some embodiments, the fumarate of compound 1 has a compound 1 / fumarate molar ratio in the range of about 2:1 to about 1:2, such as about 2:1 to about 1:1 or about 1:1 to about 1:2. In some embodiments, the fumarate of compound 1 has a compound 1 / fumarate molar ratio of about 1:1.

[0431] In some implementation schemes, a pharmaceutically acceptable salt of compound 1 is ( S )-3-amino-3-(1-methyl-1 H -imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-dibenzocyclohexane-2 2 , 4 4 - Dicarboxylic acid gentioate or its pharmaceutically acceptable solvate.

[0432] In some implementation schemes, a pharmaceutically acceptable salt of compound 1 is ( S )-3-amino-3-(1-methyl-1 H -imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-dibenzocyclohexane-2 2 , 4 4 - Dicarboxynitrile glutarate or its pharmaceutically acceptable solvates.

[0433] In some implementation schemes, a pharmaceutically acceptable salt of compound 1 is ( S )-3-amino-3-(1-methyl-1 H -imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-dibenzocyclohexane-2 2 , 4 4 - Dicarboxylate or its pharmaceutically acceptable solvate.

[0434] In some implementation schemes, a pharmaceutically acceptable salt of compound 1 is ( S )-3-amino-3-(1-methyl-1 H-imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-dibenzocyclohexane-2 2 , 4 4 - Dicarboxynitrile hippurate or its pharmaceutically acceptable solvates.

[0435] In some implementation schemes, a pharmaceutically acceptable salt of compound 1 is ( S )-3-amino-3-(1-methyl-1 H -imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-dibenzocyclohexane-2 2 , 4 4 -Dicarboxynitrile 1-hydroxy-2-naphthoic acid salt or a pharmaceutically acceptable solvate thereof.

[0436] In some embodiments, the 1-hydroxy-2-naphthoic acid salt of compound 1 has a compound 1 / 1-hydroxy-2-naphthoic acid molar ratio in the range of about 2:1 to about 1:2, such as about 2:1 to about 1:1 or about 1:1 to about 1:2. In some embodiments, the 1-hydroxy-2-naphthoic acid salt of compound 1 has a compound 1 / 1-hydroxy-2-naphthoic acid molar ratio of about 1:1.

[0437] In some implementation schemes, a pharmaceutically acceptable salt of compound 1 is ( S )-3-amino-3-(1-methyl-1 H -imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-dibenzocyclohexane-2 2 , 4 4 - Dicarboxynitrile malate or its pharmaceutically acceptable solvate.

[0438] In some implementation schemes, a pharmaceutically acceptable salt of compound 1 is ( S )-3-amino-3-(1-methyl-1 H -imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-dibenzocyclohexane-2 2 , 4 4 - Dicarboxylic acid maleate or its pharmaceutically acceptable solvate.

[0439] In some implementation schemes, a pharmaceutically acceptable salt of compound 1 is ( S )-3-amino-3-(1-methyl-1 H -imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-dibenzocyclohexane-2 2 , 4 4- Dimethylnitrile methanesulfonate or its pharmaceutically acceptable solvates.

[0440] In some implementation schemes, a pharmaceutically acceptable salt of compound 1 is ( S )-3-amino-3-(1-methyl-1 H -imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-dibenzocyclohexane-2 2 , 4 4 - Dicarboxylic acid oxalate or its pharmaceutically acceptable solvate.

[0441] In some implementation schemes, a pharmaceutically acceptable salt of compound 1 is ( S )-3-amino-3-(1-methyl-1 H -imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-dibenzocyclohexane-2 2 , 4 4 - Dicarboxynitrile phosphate or its pharmaceutically acceptable solvates.

[0442] In some implementation schemes, a pharmaceutically acceptable salt of compound 1 is ( S )-3-amino-3-(1-methyl-1 H -imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-dibenzocyclohexane-2 2 , 4 4 - Dichloronitrile sulfate or its pharmaceutically acceptable solvates.

[0443] In some implementation schemes, a pharmaceutically acceptable salt of compound 1 is ( S )-3-amino-3-(1-methyl-1 H -imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-dibenzocyclohexane-2 2 , 4 4 - Dicarboxynitrile tartrate or its pharmaceutically acceptable solvates.

[0444] In some implementation schemes, a pharmaceutically acceptable salt of compound 1 is ( S )-3-amino-3-(1-methyl-1 H -imidazol-5-yl)-6-oxa-2(4,6)-quinoline-1,4(1,3)-dibenzocyclohexane-2 2 , 4 4 - Dimethyl nitrile toluenesulfonate or its pharmaceutically acceptable solvates.

[0445] 5.4 Pharmaceutical Compositions and Preparation Methods In some embodiments, this document provides a pharmaceutical composition comprising: i) a solid form comprising compound 1 or a pharmaceutically acceptable salt and / or solvate thereof: , The amount is from about 0.1 mg to about 200 mg, and ii) one or more pharmaceutically acceptable excipients. In some embodiments, the solid form contained in the pharmaceutical composition is crystalline. In some embodiments, the amount of compound 1 contained in the pharmaceutical composition is about 0.2 mg free base equivalent. In some embodiments, the amount of compound 1 contained in the pharmaceutical composition is about 1.0 mg free base equivalent. In some embodiments, the amount of compound 1 contained in the pharmaceutical composition is about 10 mg free base equivalent. In some embodiments, the amount of compound 1 contained in the pharmaceutical composition is about 50 mg free base equivalent. In some embodiments, the pharmaceutical composition comprises the solid form of compound 1 as disclosed herein. In some embodiments, the pharmaceutical composition comprises any one of forms 1 to 24 of compound 1 as disclosed herein. In some embodiments, the pharmaceutical composition comprises the solid form of crystalline free base hemihydrate of compound 1 as disclosed herein. In some embodiments, the pharmaceutical composition comprises form 1 of compound 1 as disclosed herein. In some embodiments, the pharmaceutical composition is formulated as an immediate-release oral dosage form. In some embodiments, the pharmaceutical composition is a tablet. In some embodiments, the tablet is a coated tablet. In some embodiments, the tablet coating is a spray-dry film coating. In some embodiments, the tablet coating comprises a polymer, a plasticizer, and a pigment. In some embodiments, the tablet coating comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc. In some embodiments, the one or more pharmaceutically acceptable excipients comprise a filler, a flow aid, a disintegrant, a lubricant, or a binder, or a combination thereof.

[0446] In some embodiments, the pharmaceutical composition includes a filler. In some embodiments, the filler is present at about 40% w / w to about 95% w / w (or by weight); % refers to the weight of a specific component per total weight of the composition; typically, for tablet compositions, this is relative to the weight of the uncoated core tablet). In some embodiments, the filler is silanized microcrystalline cellulose, microcrystalline cellulose, D-mannitol, or a combination thereof. In some embodiments, the filler is silanized microcrystalline cellulose.

[0447] In some embodiments, the pharmaceutical composition comprises a flow aid. In some embodiments, the amount of the flow aid is colloidal silica. In some embodiments, the colloidal silica is present in an amount of about 0.5% w / w to about 5% w / w, or about 0.5% w / w, about 1.0% w / w, or about 1.5% w / w, or about 1.0% w / w.

[0448] In some embodiments, the pharmaceutical composition comprises a disintegrant. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the disintegrant is present in an amount of about 1% w / w to about 6% w / w, or about 2.0% w / w, about 2.5% w / w, about 3.0% w / w, about 3.5% w / w, or about 4.0% w / w, or about 3.0% w / w. In some embodiments, the pharmaceutical composition comprises a lubricant.

[0449] In some embodiments, the lubricant is magnesium stearate. In some embodiments, the lubricant is present in an amount of about 0.5% w / w to about 2.5% w / w, or about 0.5% w / w, about 1.0% w / w, about 1.5% w / w, or about 2.0% w / w, or about 1.0% w / w, or about 1.5% w / w.

[0450] In some embodiments, the pharmaceutical composition comprises a binder. In some embodiments, the binder is povidone. In some embodiments, the binder is present in an amount of about 3% w / w to about 10% w / w and about 3 mg to about 15 mg.

[0451] In some embodiments, this document provides a pharmaceutical composition wherein (a) a solid form is present in an amount of about 0.1 mg to about 25 mg of free base equivalent, and silanized microcrystalline cellulose is present in an amount of about 70% w / w to about 97% w / w, or (b) a solid form is present in an amount of about 25 mg to about 200 mg of free base equivalent, and silanized microcrystalline cellulose is present in an amount of about 40% w / w to about 70% w / w. In some embodiments, a solid form is present in an amount of about 0.2 mg of free base equivalent, and silanized microcrystalline cellulose is present in an amount of about 75% w / w to about 95% w / w and about 73 mg to about 75.4 mg. In some embodiments, the solid form is present in an amount of about 1.0 mg of free base equivalent, and the silanized microcrystalline cellulose is present in an amount of about 75% w / w to about 95% w / w and (a) about 80 mg to about 380 mg, or (b) about 80 mg to about 90 mg, or (c) about 370 mg to about 378 mg. In some embodiments, the solid form is present in an amount of about 10 mg of free base equivalent, and the silanized microcrystalline cellulose is present in an amount of about 75% w / w to about 95% w / w and about 75 mg to about 85 mg. In some embodiments, the solid form is present in an amount of about 50 mg of free base equivalent, and the silanized microcrystalline cellulose is present in an amount of about 40% w / w to about 50% w / w and about 40 mg to about 50 mg, or the silanized microcrystalline cellulose is present in an amount of about 60% w / w to about 70% w / w and about 60 mg to about 70 mg.

[0452] In some embodiments, the pharmaceutical composition comprises: (a) a core tablet comprising about 0.21 mg of compound 1 (form 1), about 75.4 mg of silanized microcrystalline cellulose, about 0.8 mg of colloidal silica, about 2.4 mg of croscarmellose sodium, and about 1.2 mg of magnesium stearate; and (b) a tablet coating. In some embodiments, the pharmaceutical composition is a 0.2 mg compound 1 (free base equivalent) strength composition.

[0453] In some embodiments, the pharmaceutical composition comprises: (a) a core tablet comprising about 1.03 mg of compound 1 (form 1), about 377 mg of silanized microcrystalline cellulose, about 4.0 mg of colloidal silica, about 12.0 mg of croscarmellose sodium, and about 6.0 mg of magnesium stearate; and (b) a tablet coating. In some embodiments, the pharmaceutical composition is a 1 mg compound 1 (free base equivalent) strength composition.

[0454] In some embodiments, the pharmaceutical composition comprises: (a) a core tablet comprising about 10.3 mg of compound 1 (form 1), about 84.2 mg of silanized microcrystalline cellulose, about 1.0 mg of colloidal silica, about 3.0 mg of croscarmellose sodium, and about 1.5 mg of magnesium stearate; and (b) a tablet coating. In some embodiments, the pharmaceutical composition is a 10 mg compound 1 (free base equivalent) strength composition.

[0455] In some embodiments, the pharmaceutical composition comprises: (a) a core tablet comprising about 51.5 mg of Compound 1 (Form 1), about 43.0 mg of silanized microcrystalline cellulose, about 1.0 mg of colloidal silica, about 3.0 mg of croscarmellose sodium, and about 1.5 mg of magnesium stearate; and (b) a tablet coating. In some embodiments, the core tablet comprises: (a) an inner portion comprising 51.5 mg of Compound 1 (Form 1), about 43.0 mg of silanized microcrystalline cellulose, about 1.0 mg of colloidal silica, about 2.0 mg of croscarmellose sodium, and about 1.0 mg of magnesium stearate; and (b) an outer portion comprising about 1.0 mg of croscarmellose sodium and about 0.5 mg of magnesium stearate. In some embodiments, these pharmaceutical compositions are 50 mg Compound 1 (free base equivalent) strength compositions.

[0456] In some embodiments, the pharmaceutical composition comprises: (a) a core tablet comprising about 51.4 mg of Compound 1 (Form 1), about 43.1 mg of silanized microcrystalline cellulose, about 1.0 mg of colloidal silica, about 3.0 mg of croscarmellose sodium, and about 1.5 mg of magnesium stearate; and (b) a tablet coating. In some embodiments, the core tablet comprises: (a) an inner portion comprising 51.4 mg of Compound 1 (Form 1), about 43.1 mg of silanized microcrystalline cellulose, about 1.0 mg of colloidal silica, about 2.0 mg of croscarmellose sodium, and about 1.0 mg of magnesium stearate; and (b) an outer portion comprising about 1.0 mg of croscarmellose sodium and about 0.5 mg of magnesium stearate. In some embodiments, these pharmaceutical compositions are 50 mg Compound 1 (free base equivalent) strength compositions.

[0457] In some embodiments, the pharmaceutical composition comprises: (a) a core tablet comprising about 1.0 mg of compound 1 (form 1), about 5.0 mg of povidone, about 89 mg of silanized microcrystalline cellulose, about 1.0 mg of colloidal silica, about 3.0 mg of croscarmellose sodium, and about 1.0 mg of magnesium stearate; and (b) a tablet coating. In some embodiments, the pharmaceutical composition is a 1 mg compound 1 (free base equivalent) strength composition.

[0458] In some embodiments, the pharmaceutical composition comprises: (a) a core tablet comprising about 10 mg of compound 1 (form 1), about 5.0 mg of povidone, about 80 mg of silanized microcrystalline cellulose, about 1.0 mg of colloidal silica, about 3.0 mg of croscarmellose sodium, and about 1.0 mg of magnesium stearate; and (b) a tablet coating. In some embodiments, the composition is a 10 mg compound 1 (free base equivalent) strength composition.

[0459] In some embodiments, the pharmaceutical composition comprises: (a) a core tablet comprising about 52 mg of compound 1 (form 1), about 10.0 mg of povidone, about 128 mg of silanized microcrystalline cellulose, about 2.0 mg of colloidal silica, about 6.0 mg of croscarmellose sodium, and about 2.0 mg of magnesium stearate; and (b) a tablet coating. In some embodiments, the pharmaceutical composition comprises: (a) a core tablet comprising about 51.5 mg of compound 1 (form 1), about 10.0 mg of povidone, about 128.5 mg of silanized microcrystalline cellulose, about 2.0 mg of colloidal silica, about 6.0 mg of croscarmellose sodium, and about 2.0 mg of magnesium stearate; and (b) a tablet coating. In some embodiments, the core tablet comprises: (a) an inner portion comprising compound 1 (form 1), silicified microcrystalline cellulose, colloidal silica, croscarmellose sodium, and povidone; and (b) an outer portion comprising magnesium stearate. In some embodiments, the composition is a 50 mg compound 1 (free base equivalent) strength composition.

[0460] In some embodiments, this document provides a method for preparing a pharmaceutical composition as disclosed herein, the method comprising: i) optionally de-agglomerating compound 1 or a pharmaceutically acceptable salt and / or solvate thereof in a solid form; ii) mixing compound 1 or a pharmaceutically acceptable salt and / or solvate thereof in a solid form with a first portion of a disintegrant, a gliding agent, and a filler to form a first blend; iii) de-agglomerating the first blend to form a de-agglomerated first blend; iv) de-agglomerating a second portion of the filler; v) blending the de-agglomerated first blend with the de-agglomerated second portion of the filler to form a second blend; vi) blending the second blend with a lubricant to form a lubricated blend; and vii) optionally compressing the lubricated blend into tablets using a rotary press. In some embodiments, the method includes de-agglomerating compound 1 or a pharmaceutically acceptable salt and / or solvate thereof in a solid form. In some embodiments, the method further includes viii) coating the compressed tablets. In some embodiments, the coating is a spray dry film coating. In some embodiments, the method further includes (ix) packaging the film-coated tablets into a container. In some embodiments, the amount of compound 1 present in the pharmaceutical composition or its pharmaceutically acceptable salts and / or solvates in solid form is about 0.2 mg, about 1 mg, or about 10 mg of free base equivalent.

[0461] In some embodiments, this document provides a method for preparing a pharmaceutical composition as disclosed herein, the method comprising: i) optionally de-agglomerating compound 1 or a pharmaceutically acceptable salt and / or solvate thereof in a solid form; ii) mixing compound 1 or a pharmaceutically acceptable salt and / or solvate thereof in a solid form with a first portion of a filler, a gliding agent, and a disintegrant to form a first blend; iii) de-agglomerating the first blend and then blending the first blend to form a second blend; iv) blending the second blend with a first portion of a lubricant to form a lubricated intragranular blend; v) forming granules from the intragranular blend, for example, using a roller compactor and a sieve; vi) blending the granules with a second portion of a disintegrant and a second portion of a lubricant to form a lubricated final blend; and vii) optionally compressing the lubricated final blend into tablets using a rotary press. In some embodiments, the method includes de-agglomerating compound 1 or a pharmaceutically acceptable salt and / or solvate thereof in a solid form. In some embodiments, the method further includes viii) coating the compressed tablets. In some embodiments, the coating is a spray-dry film coating. In some embodiments, the method further includes ix) packaging the film-coated tablets into a container. In some embodiments, the amount of compound 1 or its pharmaceutically acceptable salts and / or solvates present in the film-coated tablets in solid form is 50 mg of free base equivalent.

[0462] In some embodiments, this document provides a method for preparing a pharmaceutical composition as disclosed herein, the method comprising: i) optionally deagglomerating compound 1 or a pharmaceutically acceptable salt and / or solvate thereof in a solid form; ii) granulating compound 1 or a pharmaceutically acceptable salt and / or solvate thereof in a solid form, a filler, a flow aid, and a disintegrant together with a binder and water to form wet granules; iii) drying the wet granules to form dry granules; iv) blending the granules with a lubricant to form a lubricated final blend; and v) optionally compressing the lubricated final blend into tablets using a rotary press. In some embodiments, the method comprises deagglomerating compound 1 or a pharmaceutically acceptable salt and / or solvate thereof in a solid form. In some embodiments, the method further comprises vii) coating the compressed tablets. In some embodiments, the coating is a spray-dry film coating. In some embodiments, the method further comprises viii) packaging the film-coated tablets into containers. In some embodiments, the amount of compound 1 or its pharmaceutically acceptable salts and / or solvates present in the film-coated tablets in solid form is 1 mg, 10 mg, or 50 mg of free base equivalent. In some embodiments, dry particles are milled to form a lubricating final blend prior to blending with a lubricant. In some embodiments, particles are milled using a sieve with a mesh size of about 0.5 mm to about 2 mm or about 1 mm. In some embodiments, wet particles are milled using, for example, a 3 / 8-inch sieve prior to drying.

[0463] 5.5 Synthesis In some embodiments, this document provides a method for preparing compound 1: , Or in a pharmaceutically acceptable form, the method comprises one or more of the steps shown in scheme AF: Option A. Option B . Option C . Option D . Option E . Option F . In some embodiments, this document provides a method for preparing compound 1 or a pharmaceutically acceptable form thereof, the method comprising: (a) To cause racemic compound 19: , Reaction with chiral acids in solvents to form diastereomeric salts of compound 1 and compound 2: , One of the two diastereomers is selectively precipitated from the solvent, and the other of the two diastereomers is selectively soluble in the solvent. (b) Separate the precipitate from the solvent; (c) Reacting the diastereomeric salt of compound 1 with a base to provide compound 1, and (d) Optionally, recrystallize compound 1 from ACN / water in a ratio of about 2:1 to about 1:5, or optionally about 1:1 to about 1:3.

[0464] In some embodiments, the chiral acid is (R)-chlorocyclic phosphoric acid, (S)-chlorocyclic phosphoric acid, (+)-tartaric acid, (-)-tartaric acid, (+)-camphorsulfonic acid, (-)-camphorsulfonic acid, L-(-)-di-p-methoxybenzoyl tartaric acid, D-(+)-di-p-methoxybenzoyl tartaric acid, L-(-)-di-toluyl tartaric acid, D-(+)-di-toluyl tartaric acid, ( R )-BINAP phosphate, ( S The chiral acid is (R)-BINAP phosphoric acid, benzoyl-L-tartaric acid, or benzoyl-D-tartaric acid. In some embodiments, the chiral acid is benzoyl-D-tartaric acid or benzoyl-L-tartaric acid, and the solvent is acetone or DCM. In some embodiments, the chiral acid is (R)-BINAP phosphoric acid or ( S) The compound is 1-BINAP phosphoric acid, and the solvent is dioxane, acetone, ACN, IPAc, MEK, THF, 2-MeTHF, dioxolane, or ethylene glycol dimethyl ether. For example, in some embodiments, the solvent is THF or dioxolane. In some embodiments, the chiral acid is benzoyl-D-tartaric acid, and the diastereomeric salt of compound 1 is a diastereomeric salt selectively soluble in the solvent. In some embodiments, the chiral acid is benzoyl-L-tartaric acid, and the diastereomeric salt of compound 1 is a diastereomeric salt selectively precipitated from the solvent. In some embodiments, the base is Na₂CO₃, K₂CO₃, NaOH, or KOH, or wherein the base is Na₂CO₃. In some embodiments, the solvent is DCM.

[0465] In some embodiments, the methods disclosed herein include making compound 18: , The ammonia equivalent reacts to form compound 19. In some embodiments, the ammonia equivalent is NH3, optionally in an amount of about 15 equivalents to about 50 equivalents, or about 40 equivalents to 50 equivalents. In some embodiments, the reaction of compound 18 is carried out in a polar solvent. In some embodiments, the polar solvent is selected from IPA, EtOH, MeOH, 1,4-dioxane, DMI, and mixtures thereof. In some embodiments, the polar solvent is MeOH. In some embodiments, the reaction of compound 18 is carried out at a temperature of about 0°C to about 40°C.

[0466] In some embodiments, the method disclosed herein includes chlorinating compound 17 with a chlorinating agent: , To form compound 18. In some embodiments, the chlorinating agent is thionyl chloride, POCl3, PCl3, or oxalyl chloride. In some embodiments, the chlorinating agent is thionyl chloride. In some embodiments, the chlorinating agent is used in an amount of about 2 equivalents to about 3.5 equivalents. In some embodiments, the chlorination of compound 17 is carried out in a polar aprotic solvent. In some embodiments, the polar aprotic solvent is DMI. In some embodiments, the chlorination of compound 17 is carried out at a temperature of about 10°C to about 60°C.

[0467] In some embodiments, the methods disclosed herein include making compound 16: , The reaction with a cyanide equivalent and a palladium catalyst, optionally in the presence of a zinc source and / or a phosphine ligand, provides compound 17. In some embodiments, the cyanide source is Cu(CN)₂ or Zn(CN)₂. In some embodiments, the cyanide source is Zn(CN)₂. In some embodiments, the cyanide source is used in an amount from about 1 equivalent to about 1.7 equivalents. In some embodiments, the palladium catalyst is [PdCl(allyl)]₂, Pd₂(dba)₃, Pd(OAc)₂, Pd(PPh₃)₄, Pd(dppf)₂Cl₂, PdCl₂, or combinations thereof, or Pd₂(dba)₃ and Pd(OAc)₂. In some embodiments, the phosphine ligand is PPh₃, R-BINAP, or dppf, or dppf. In some embodiments, the phosphine ligand is present in an amount from about 0.02 equivalents to about 0.15 equivalents. In some embodiments, the zinc source is zinc metal. In some embodiments, the reaction of compound 16 is carried out at a temperature of about 60°C to about 110°C or about 90°C to about 110°C. In some embodiments, the reaction of compound 16 is carried out in a polar solvent. In some embodiments, the polar solvent is DMA or DMF.

[0468] In some embodiments, this document provides a method for preparing compound 1: , Or a pharmaceutically acceptable form thereof, the method comprising making compound 18A: , The reaction with a cyanide equivalent and a palladium catalyst, optionally in the presence of a zinc source and / or a phosphine ligand, yields compound 19: , And the racemic compound 19 is purified by chiral separation to provide compound 1. In some embodiments, the cyanide source is Cu(CN)2 or Zn(CN)2. In some embodiments, the cyanide source is Zn(CN)2. In some embodiments, the cyanide source is used in an amount of about 1 equivalent to about 1.7 equivalents. In some embodiments, the palladium catalyst is [PdCl(allyl)]2, Pd2(dba)3, Pd(OAc)2, Pd(PPh3)4, Pd(dppf)2Cl2, PdCl2, or combinations thereof, or Pd2(dba)3 and Pd(OAc)2. In some embodiments, the phosphine ligand is PPh3, R-BINAP, or dppf. In some embodiments, the phosphine ligand is dppf. In some embodiments, the phosphine ligand is present in an amount of about 0.02 equivalents to about 0.15 equivalents. In some embodiments, the zinc source is zinc metal. In some embodiments, the reaction of compound 18A is carried out at a temperature of about 60°C to about 110°C or about 90°C to about 110°C. In some embodiments, the reaction of compound 18A is carried out in a polar solvent. In some embodiments, the polar solvent is DMA or DMF.

[0469] In some embodiments, the methods disclosed herein include making compound 17A: , The compound 17A reacts with an ammonia equivalent to form compound 18A. In some embodiments, the ammonia equivalent is NH3. In some embodiments, the ammonia equivalent is used in amounts from about 15 equivalents to about 50 equivalents, or from about 17 equivalents to 21 equivalents. In some embodiments, the reaction of compound 17A is carried out in a polar solvent. In some embodiments, the polar solvent is selected from IPA, EtOH, MeOH, 1,4-dioxane, DMI, and mixtures thereof. In some embodiments, the polar solvent is IPA. In some embodiments, the reaction of compound 17A is carried out at a temperature from about 0°C to about 40°C.

[0470] In some embodiments, the methods disclosed herein include chlorinating compound 16 with a chlorinating agent: , To form compound 17A. In some embodiments, the chlorinating agent is thionyl chloride, POCl3, PCl3, or oxalyl chloride. In some embodiments, the chlorinating agent is thionyl chloride. In some embodiments, the chlorinating agent is used in an amount of about 2 equivalents to about 3.5 equivalents. In some embodiments, the chlorination of compound 16 is carried out in a polar aprotic solvent. In some embodiments, the polar aprotic solvent is DMI. In some embodiments, the chlorination of compound 16 is carried out at a temperature of about 10°C to about 60°C.

[0471] In some embodiments, the methods disclosed herein include making compound 15X: , The compound 15 or its salt is cyclized in the presence of a base to form compound 16, wherein X is a leaving group selected from -Cl, -Br, -I, -OTs, or -OMs, optionally wherein X is -Cl (compound 15). In some embodiments, the base is Cs2CO3, K2CO3, or Li2CO3. In some embodiments, the base is Cs2CO3. In some embodiments, the base is KH2PO4. In some embodiments, X is -OH, and the reaction is carried out under Mitsunobu conditions. In some embodiments, compound 15X is used in the form of a free base, and the base is present in an amount of about 1.5 equivalents to 4 equivalents. In some embodiments, compound 15X is used in the form of a salt, and the base is present in an amount of about 4 equivalents to 12 equivalents. In some embodiments, the reaction of compound 15X is carried out in a polar aprotic solvent. In some embodiments, the polar aprotic solvent is DME, DMF, MTBE, DMAc, or diethylene glycol dimethyl ether or mixtures thereof, for example, the polar aprotic solvent is DMF or DMAc. In some embodiments, the reaction of compound 15X is carried out at a temperature of about 40°C to about 80°C.

[0472] In some embodiments, the methods disclosed herein include making compound 14: , The compound 15X or its salt reacts with a hydroxyl activator to form compound 15X or its salt. In some embodiments, the hydroxyl activator is thionyl chloride, POCl3, PCl3, or oxalyl chloride (X is -Cl), NaBr or LiBr (X is -Br), TsCl (X is -OTs), or MsCl (X is -OMs). In some embodiments, the hydroxyl activator is thionyl chloride, and X is -Cl. In some embodiments, the hydroxyl activator is used in an amount of about 2 equivalents to about 4 equivalents or about 3 equivalents. In some embodiments, the reaction of compound 14 is carried out in a polar aprotic solvent, such as selected from THF, 2-MeTHF, DMF, or DMA. In some embodiments, the reaction of compound 14 is carried out at a temperature of about 10°C to about 60°C.

[0473] In some embodiments, the method includes reacting compound 14 or a salt thereof under Mitsunobu conditions to form compound 16. In some embodiments, the Mitsunobu conditions include a dialkyl azodicarbonate and a trialkylphosphine or triarylphosphine, for example, the dialkyl azodicarbonate is DEAD or DIAD, and the trialkylphosphine or triarylphosphine is triphenylphosphine.

[0474] In some embodiments, the methods disclosed herein include making compound 13PG: , Deprotection is performed under suitable deprotection conditions to form compound 14 or a salt thereof, wherein each PG is independently a hydroxyl protecting group. In some embodiments, both PG groups are silyl protecting groups, such as tert-butyldimethylsilyl, triisopropylsilyl, triethylsilyl, or tert-butyldiphenylsilyl. In some embodiments, both PG groups are triisopropylsilyl or tert-butyldimethylsilyl (compound 13). In some embodiments, deprotection conditions include optionally TBAF, MSA, MSA / H2O, or HCl / H2O in a polar solvent. In some embodiments, the solvent is THF, ACN, EtOAc, acetone, toluene, or mixtures thereof. In some embodiments, deprotection conditions include 3NHCl in THF or THF / toluene (optionally about 4:1 to about 1:4 THF / toluene, or about 2:1 to about 3:1 THF / toluene). In some embodiments, deprotection of compound 13PG is carried out at a temperature of about 0°C to about 40°C.

[0475] In some embodiments, the methods disclosed herein include coupling compound 12PG: , Each PG is independently protected by a hydroxyl group. In some embodiments, both PG groups are silyl protecting groups, such as tert-butyldimethylsilyl, triisopropylsilyl, triethylsilyl, or tert-butyldiphenylsilyl. In some embodiments, both PG groups are triisopropylsilyl or tert-butyldimethylsilyl (compound 12), and 1-methylimidazole is used to form compound 13PG. In some embodiments, the coupling of compound 12PG is carried out at a temperature of about -50°C to about -90°C. In some embodiments, the reaction includes metallizing 1-methylimidazole at the 5-position to form a reactive substance, and mixing the reactive substance with compound 12PG, optionally wherein the reactive substance is (1-methyl-2-(protecting group)-1H-imidazol-5-yl)lithium, optionally wherein the 1-methyl-2-(protecting group)-1H-imidazol-5-yl)lithium is (1-methyl-2-(triethylsilyl)-1H-imidazol-5-yl)lithium. In some embodiments, metallization includes reacting 1-methylimidazole with (i) BuLi, (ii) TESCl, and (iii) BuLi to form (1-methyl-2-(triethylsilyl)-1H-imidazol-5-yl)lithium. In some embodiments, the metallization and coupling are carried out at a temperature of about -30°C to about -90°C.

[0476] In some embodiments, the methods disclosed herein include making compound 11PG: , With compound 9PG: , A condensation is performed to form compound 12PG, wherein each PG is independently a hydroxyl protecting group, and optionally the PG groups in compounds 9PG and 11PG are both silyl protecting groups, such as tert-butyldimethylsilyl, triisopropylsilyl, triethylsilyl, or tert-butyldiphenylsilyl, and optionally both PG groups are either triisopropylsilyl or tert-butyldimethylsilyl (compounds 9 and 11). In some embodiments, the method includes reacting compound 9PG with a metallizing agent such as BuLi or isopropylMgCl / LiCl to form a reactive substance. In some embodiments, the metallizing agent is optionally used in a polar aprotic solvent in an amount of about 1 equivalent to about 1.3 equivalents. In some embodiments, the polar aprotic solvent is THF. In some embodiments, the method further includes mixing the reactive substance with compound 11PG. In some embodiments, the reaction of compound 9PG and the mixing with compound 11PG are carried out at a temperature of about -60°C to about -85°C.

[0477] In some embodiments, the method disclosed herein includes making compound 8: , The compound 9PG reacts with a hydroxyl protecting agent to form compound 9PG. In some embodiments, PG is a silyl protecting group. In some embodiments, the hydroxyl protecting agent is a silyl chloride agent. In some embodiments, PG is tert-butyldimethylsilyl and the hydroxyl protecting agent is TBSCl. In some embodiments, the reaction of compound 8 is carried out in the presence of a base, optionally in a polar aprotic solvent, optionally wherein the base is imidazole, TEA, TEA / DMAP, DIPEA, or pyridine. In some embodiments, the polar aprotic solvent is DCM or THF.

[0478] In some embodiments, the method disclosed herein includes making compound 7: , The compound 7 reacts with a demethylating agent to form compound 8. In some embodiments, the demethylating agent is BCl3 or BBr3. In some embodiments, the demethylating agent is used, optionally in the presence of a phase transfer agent, in an amount of about 1.5 to 2.5 equivalents. In some embodiments, the phase transfer agent is a tetraalkylammonium salt, such as tetrabutylammonium iodide, optionally in a polar aprotic solvent. In some embodiments, the polar aprotic solvent is THF. In some embodiments, the reaction of compound 7 is carried out at a temperature of about 0°C to about 40°C.

[0479] In some embodiments, the method disclosed herein includes making compound 6: , The compound 6 reacts with a dehydrating agent to form compound 7. In some embodiments, the dehydrating agent is POCl3, oxalyl chloride, thionyl chloride, PCl3, or PCl5; for example, POCl3 is a dehydrating agent. In some embodiments, the dehydrating agent is optionally used in a polar aprotic solvent in an amount of about 2 equivalents to about 6 equivalents. In some embodiments, the polar aprotic solvent is ACN, THF, 2-MeTHF, toluene, or DCM. In some embodiments, the reaction of compound 6 is carried out at a temperature of about 40°C to about 85°C.

[0480] In some embodiments, the method disclosed herein includes making compound 5: , The compound 6 is reacted with (i) a base and (ii) an acid to form compound 6. In some embodiments, the base is potassium tert-butoxide or sodium tert-butoxide. In some embodiments, the base is used in an amount from about 1.5 equivalents to about 3 equivalents. In some embodiments, the acid is HCl or H₂SO₄. In some embodiments, the acid is used in stoichiometric or catalytic amounts. In some embodiments, the reaction of compound 5 is carried out in a polar solvent. In some embodiments, the polar solvent is THF or toluene. In some embodiments, step (i) is carried out at a temperature from about 10°C to about 40°C. In some embodiments, step (ii) is carried out at a temperature from about 10°C to about 75°C.

[0481] In some embodiments, the method disclosed herein includes making compound 4: , Acetylation is performed in the presence of an acetyling agent to form compound 5. In some embodiments, the acetyling agent is (a) Ac₂O or (b) AcCl and a base. In some embodiments, the base is TEA or DIPEA. In some embodiments, (a) or (b) is carried out in a polar solvent such as DCM or toluene, optionally at a temperature of about 15°C to about 110°C, or (c) in water and an organic solvent such as Et₂O or DCM, using AcCl. In some embodiments, the post-reaction work-up may include adding water, separating the layers, and washing the organic phase with an aqueous solution of NaHCO₃ and an aqueous solution of NaCl. The resulting organic solution, such as a toluene solution, can be used directly in the next step.

[0482] In some embodiments, the methods disclosed herein include treating compound 3 with a reducing agent: , To form compound 4. In some embodiments, the reducing agent is TiCl3 and a proton source. In some embodiments, the proton source is water. In some embodiments, TiCl3 is optionally used in a polar aprotic solvent in an amount of about 1.5 equivalents to about 3 equivalents. In some embodiments, the polar aprotic solvent is THF. In some embodiments, the reducing agent is H2 and a hydrogenation catalyst. In some embodiments, the hydrogenation catalyst is Pd / C or Pt / C.

[0483] In some embodiments, the methods disclosed herein include reacting 1-bromo-4-nitrobenzene with 2-(3-methoxyphenyl)acetonitrile in the presence of a base to form compound 3. In some embodiments, the base is NaOH, KOH, or an alkoxide base. In some embodiments, the alkoxide base is sodium methoxide, sodium ethoxide, or potassium tert-butoxide, optionally in an amount of about 2 equivalents to about 10 equivalents, optionally in a polar solvent. In some embodiments, the polar solution is MeOH, EtOH, MeOH / DCM, or EtOH / DCM, optionally at a temperature of about 0°C to about 60°C. In some embodiments, post-treatment may include washing with an aqueous solution of Na₂S₂O₃, optionally prior to quenching by adding an aqueous solution of NaOCl. In some embodiments, the crude material may be purified by diluting with MeOH, stirring at a temperature of about 30°C to about 60°C, then concentrating to about 4.5V-5.5V, cooling, and filtering the resulting solid.

[0484] In some embodiments, the methods disclosed herein include making compound 23: , The reaction proceeds with a hydroxyl protecting agent to form compound 11PG. In some embodiments, PG is a silyl protecting group and the hydroxyl protecting agent is a silyl chloride agent. In some embodiments, PG is tert-butyldimethylsilyl and the hydroxyl protecting agent is TBSCl in the presence of a base. In some embodiments, the base is imidazole, TEA, TEA / DMAP, DIPEA, or pyridine, optionally in a polar aprotic solvent. In some embodiments, the polar aprotic solvent is DCM or THF.

[0485] In some embodiments, the method disclosed herein includes making compound 22: , The compound 23 is formed by reacting with morpholine under amide coupling conditions. In some embodiments, the amide coupling conditions include a carbodiimide and a base. In some embodiments, the carbodiimide is EDC, EDCI, or DCC. In some embodiments, the base is TEA, DIPEA, or TEA / DMAP. In some embodiments, the amide coupling conditions include BOP, PyBOP, HOAt, HOBt, or T3P.

[0486] In some embodiments, the methods disclosed herein include compound 21 by the following process: , Conversion to Compound 22: Compound 21 is treated with an alkali and water. In some embodiments, the alkali is Na₂CO₃, K₂CO₃, NaOH, or KOH, optionally in a polar protic solvent. In some embodiments, the polar protic solvent is water, MeOH, EtOH, IPA, or a mixture thereof. In some embodiments, the polar protic solvent is EtOH / water. In some embodiments, the treatment of Compound 21 is carried out at a temperature of about 50°C to about 110°C. In some embodiments, Compound 21 is mixed with methyl 4-bromo-3-(dibromomethyl)benzoate, and the conversion further includes mixing the product of the treatment step with a reducing agent. In some embodiments, the reducing agent is NaBH₄, NaCNBH₃, or BH₃·DMS.

[0487] In some embodiments, the method disclosed herein includes making compound 20: , The compound 20 reacts with a brominating agent and a free radical initiator to form compound 21. In some embodiments, the brominating agent is NBS, Br2, NaBrO3 / HBr, or 1,3-dibromo-5,5-dimethylhydantoin, and the free radical initiator is light, heat, or AIBN. In some embodiments, the brominating agent is NBS, and the free radical initiator is light. In some embodiments, the reaction of compound 20 is carried out in a continuous flow reactor having a photolysis flow cell with wavelengths in the range of about 300 nm to about 500 nm. In some embodiments, the reaction of compound 20 produces a mixture of compound 21 and methyl 4-bromo-3-(dibromomethyl)benzoate.

[0488] In some embodiments, this document provides a method for preparing compound 9, the method comprising making compound 7: , Reacts with a demethylating agent to form compound 8: , Compound 8 is then reacted with TBSCl and a base to form compound 9. In some embodiments, the demethylating agent is BCl3 or BBr3, optionally in an amount of about 1.5 to 2.5 equivalents, optionally in the presence of a phase transfer agent. In some embodiments, the phase transfer agent is a tetraalkylammonium salt, such as tetrabutylammonium iodide, optionally in a polar aprotic solvent. In some embodiments, the polar aprotic solvent is THF. In some embodiments, the reaction of compound 7 is carried out at a temperature of about 0°C to about 40°C. In some embodiments, the base is imidazole, TEA, TEA / DMAP, DIPEA, or pyridine. In some embodiments, the reaction is carried out in a polar aprotic solvent. In some embodiments, the polar aprotic solvent is DCM or THF.

[0489] In some embodiments, the method disclosed herein includes making compound 6: , The compound 6 reacts with a dehydrating agent to form compound 7. In some embodiments, the dehydrating agent is POCl3, oxalyl chloride, thionyl chloride, PCl3, or PCl5. In some embodiments, the dehydrating agent is POCl3. In some embodiments, the dehydrating agent is optionally used in a polar aprotic solvent in an amount of about 2 equivalents to about 6 equivalents. In some embodiments, the polar aprotic solvent is ACN, THF, 2-MeTHF, toluene, or DCM. In some embodiments, the reaction of compound 6 is carried out at a temperature of about 40°C to about 85°C.

[0490] In some embodiments, this document provides a method for preparing compound 11: , The method includes making compound 23: , The compound 11 is formed by reacting with TBSCl in the presence of a base. In some embodiments, the base is imidazole, TEA, TEA / DMAP, DIPEA, or pyridine. In some embodiments, the reaction of compound 11 is carried out in a polar aprotic solvent. In some embodiments, the polar aprotic solvent is DCM or THF.

[0491] In some embodiments, this document provides a method for preparing compound 19: , The method includes chlorinating compound 17 with a chlorinating agent: , To form compound 18: , Compound 18 is then reacted with an ammonia equivalent to form compound 19. In some embodiments, the chlorinating agent is thionyl chloride, POCl3, PCl3, or oxalyl chloride. In some embodiments, the chlorinating agent is thionyl chloride. In some embodiments, the chlorinating agent is used in an amount of about 2 equivalents to about 3.5 equivalents. In some embodiments, chlorination is carried out in a polar aprotic solvent. In some embodiments, the polar aprotic solvent is DMI. In some embodiments, the chlorination of compound 17 is carried out at a temperature of about 10°C to about 60°C.

[0492] In some embodiments, the ammonia equivalent is NH3. In some embodiments, the ammonia equivalent is used in an amount of about 15 equivalents to about 50 equivalents, or about 40 equivalents to 50 equivalents. In some embodiments, the reaction of compound 18 is carried out in a polar solvent, wherein the polar solvent is optionally selected from IPA, EtOH, MeOH, 1,4-dioxane, DMI, and mixtures thereof. In some embodiments, the polar solvent is MeOH. In some embodiments, the reaction of compound 18 is carried out at a temperature of about 0°C to about 40°C.

[0493] In some embodiments, this document provides a method for preparing compound 14: , The method includes making compound 13: , Deprotection is performed under deprotection conditions to form compound 14. In some embodiments, the deprotection conditions include optionally TBAF, MSA, MSA / H2O, or HCl / H2O in a polar solvent. In some embodiments, the solvent is THF, ACN, EtOAc, acetone, toluene, or a mixture thereof. In some embodiments, the deprotection conditions include 3N HCl in THF or THF / toluene (optionally about 4:1 to about 1:4 THF / toluene, or about 2:1 to about 3:1 THF / toluene). In some embodiments, deprotection of compound 14 is performed at a temperature of about 0°C to about 40°C.

[0494] In some embodiments, this document provides a method for preparing compound 12: , The method includes making compound 11: , With compound 9: , Condensation is performed to form compound 12. In some embodiments, the method includes reacting compound 9 with a metallizing agent such as BuLi or isopropylMgCl / LiCl to form a reactive substance. In some embodiments, the metallizing agent is optionally used in a polar aprotic solvent in an amount of about 1 equivalent to about 1.3 equivalents. In some embodiments, the polar aprotic solvent is THF. In some embodiments, the reactive substance is mixed with compound 11, optionally wherein the reaction of compound 9 and the mixing of the reactive substance with compound 11 are carried out at a temperature of about -60°C to about -85°C.

[0495] In some embodiments, this document provides a method for preparing compound 13, the method comprising coupling compound 12 with 1-methylimidazole to form compound 13. In some embodiments, the method comprises metallizing 1-methylimidazole at the 5-position to form a reactive substance, and mixing the reactive substance with compound 12. In some embodiments, the reactive substance is (1-methyl-2-(protecting group)-1H-imidazol-5-yl)lithium, optionally wherein 1-methyl-2-(protecting group)-1H-imidazol-5-yl)lithium is (1-methyl-2-(triethylsilyl)-1H-imidazol-5-yl)lithium. In some embodiments, metallization comprises reacting 1-methylimidazole with (i) BuLi, (ii) TESCl, and (iii) BuLi to form (1-methyl-2-(triethylsilyl)-1H-imidazol-5-yl)lithium. In some embodiments, metallization is carried out at a temperature of about -30°C to about -90°C. In some implementations, coupling is carried out at temperatures of about -30°C to about -90°C.

[0496] In some embodiments, where a transition metal catalyst is used in one or more steps of the method disclosed herein, the method may include reducing the amount of transition metal material (such as palladium-based or zinc-based material) from the reaction products or subsequent reaction products. In some embodiments, compound 1 or an intermediate in the synthetic method is reduced such that compound 1 conforms to the "Guideline on the Specification Limits for Residues of Metal Catalysts" (European Medicines Agency). Preauthorisation Evaluation of Medicines for Human Use London, January 2007 (Document reference CPMP / SWP / QWP / 4446 / 00, revised version). In some embodiments, the method includes reducing the amount of palladium and / or zinc in compound 1 or an intermediate. In some embodiments, reducing the amount of palladium and / or zinc mixed with reaction products such as compound 1 includes treating the reaction product / transition metal mixture with an adsorbent and an extractant or crystallizer, or a combination thereof. In some embodiments, reducing the amount of palladium includes treating the reaction product with an extractant and then treating the resulting material with an adsorbent. In some embodiments, the reaction product may be treated with an adsorbent once, more than once, or twice.

[0497] Examples of adsorbents include, but are not limited to, trithiocyanate (trimercaptotriazine; TMT), TMT derivatives (such as solid TMT, polystyrene-bonded TMT, silica-bonded TMT, SiliaMetS...). ® DMT, TMT or TMT-3Na bound to thiol porous polystyrene, and derivatized silica gels (such as silica gel-joint-thiol, silica gel-(CH2)3-SH, silica gel-(CH2)3-S-(CH2)2-SH, or silica gel-joint-amine, such as silica gel-(CH2)3-NH2, or silica gel-(CH2)3-[NH-(CH2)2] 1-2 -NH2, or silica gel -(CH2)3-NHC(S)NHCH3, such as silica gel-connector-amine, such as SiliciaMetS ® Metal purifiers), polystyrene-bonded ethylenediamine, and derivatized polyolefin fibers (e.g., grafted with acrylic acid, vinylpyridine, styrene sulfonic acid, styrene thiols, styrene diphenylphosphine, ethyl mercaptoacrylate, or α-hydroxythiols of acrylic acid, such as Smopex). ® Metal removers), activated carbon (such as DARCO) ® KB-G and DARCO ®KB-WJ) or glass bead sponges. Examples of crystallizing agents include, but are not limited to, N-acetylcysteine, thiourea, 2-methylthiourea, thioglycerol, hemimaleate, or Bu3P. Examples of extractants include, but are not limited to, N-acetylcysteine, L-cysteine, and Bu3P in lactic acid. See, for example, Garrett et al. Adv. Synth. Catal 2004, 346, 889-900.

[0498] Examples of other adsorbents suitable for zinc removal include zinc chelating agents such as EDTA and EDTA derivatives, such as tetrasodium EDTA, and SiliaMetS. ® Metal scavengers, such as SiliaMetS DEAM, SiliaMetS diamine, SiliaMetS SOTA, SiliaMetS imidazole, and SiliaMetS triamine.

[0499] In some embodiments, compound 1 is treated with a mixture of tetrasodium EDTA and TMT-3Na in water at a temperature of about 20°C to about 40°C, and then optionally purified by column chromatography.

[0500] In some embodiments, after reduction, the amount of palladium and / or in the reaction products is about 100 ppm or less, or about 10 ppm, or undetectable. In some embodiments, the presence and / or amount of residual heavy metal (e.g., palladium or zinc) impurities are determined using methods known in the art. In some embodiments, the presence and / or amount of residual heavy metal (e.g., palladium or zinc) impurities are determined using inductively coupled plasma mass spectrometry (ICP-MS). In some embodiments, the United States Pharmacopeia General Rules are used. <232> The techniques described in Elemental Impurities - Limits determine the presence and / or amount of residual heavy metal (e.g., palladium) impurities.

[0501] In some embodiments, this document provides a compound selected from the following: And its salt.

[0502] In some embodiments, this document provides a compound selected from: compound 1 or compound 2 ( R )-chlorocyclic phosphate, ( S ()-chlorocyclic phosphate, (+)-tartrate, (-)-tartrate, (+)-camphor sulfonate, (-)-camphor sulfonate, L-(-)-di-p-methoxybenzoyl tartrate, D-(+)-di-p-methoxybenzoyl tartrate, L-(-)-di-toluyl tartrate, D-(+)-di-toluyl tartrate, ( R)-BINAP phosphate, ( S The salt is benzoyl-1-tartrate, benzoyl-D-tartrate, or benzoyl-BINAP phosphate. In some embodiments, the salt is benzoyl-1-tartrate or benzoyl-D-tartrate of compound 1 or compound 2. In some embodiments, the salt is an L-DBTA salt of compound 1.

[0503] 5.6 Applications and Methods 5.6.1 Therapeutic Uses and Methods RAS isoforms associate with the inner surface of the plasma membrane to transduce extracellular signals. To become active, RAS undergoes several post-translational modifications. The first step in activation is the farnesylation of the C-terminal cysteine ​​residue in the CAAX box (where C represents cysteine, A represents an aliphatic amino acid, and X represents any amino acid). Rowinsky, EK et al., J. Clin. Oncol. 1999, 17, 3631–3652. Farnesyltransferases (FTases) recognize the CAAX motif and transfer 15-carbon farnesyl isoprene from the farnesyl diphosphate to the cysteine ​​residue. The AAX amino acid is then cleaved by Ras-convertase I, and the farnesylated cysteine ​​is carboxymethylated by isoprene-cysteine ​​carboxymethyltransferase. Prior, IA et al., J. Cell Sci. 2001, 114, 1603–1608. Further palmitoylation (KRAS4A, NRAS, and HRAS) or the presence of a multibasic domain (KRAS4B) results in protein anchoring in the plasma membrane. Hancock, JF et al., Cell 1990, 63, 133–139. Observations suggest that isopentenylation is required for the function of all RAS isotypes, including their mutant forms. However, some farnesylated proteins—including KRAS and NRAS—can be rescued from membrane displacement by alternative isopentenylation with geranylgeranyltransferase (GGTase) in the presence of farnesyltransferase inhibitors (FTI). Zhang, FL et al., J. Biol. Chem. 1997, 272, 10232–10239; Whyte, DB et al., J. Biol. Chem. 1997, 272, 14459–14464. Conversely, third-family member HRAS is not a GGTase substrate, and therefore its membrane localization and cellular function are attenuated by FTI (Whyte, DB, et al.). Therefore, targeting enriched patient tumor populations using FTI, such as farnesylation-dependent tumors like HRAS, or tumors with HRAS mutations, should provide clinical benefit.

[0504] One specific FTI in clinical development is tipifranib. The efficacy of tipifranib has been examined in a range of cell- and patient-derived xenograft models of head and neck squamous cell carcinoma (HNSCC). Gilardi, M. et al., Mol. Cancer Ther. 2020, 19, 1784–1796. Genomic analysis has revealed HRAS mutations in 6% of HNSCC patients at initial diagnosis (Hoadley, KA et al., Cell 2018, 173, 291–304) and in 15% of patients during the period of acquiring resistance to cetuximab (Braig, F. et al., Oncotarget 2016, 7, 42988–42995), and HRAS mutations have been demonstrated to be associated with reduced response to cetuximab treatment in HNSCC patients. "Rampias, T. et al., Clin. Cancer Res. 2014, 20, 2933–2946."

[0505] HRAS mutations are also recurrent in other cancer types, including urothelial carcinoma and salivary gland tumors, and 24% of patients with HRAS-mutant metastatic urothelial carcinoma treated with tilpifaib experienced an objective response. Furthermore, among 13 patients with recurrent / metastatic salivary gland tumors (SGT) treated with tilpifaib, one patient experienced an objective response, and seven others had stable disease that was considered the best response. (Ho, AL et al., J. Clin. Oncol. 2020, 38, 6504). Other tumor types exhibiting recurrent HRAS-driven mutations include squamous cell carcinoma of the lung, thyroid carcinoma, pheochromocytoma, and paraganglioma. (Hoadley, KA et al.)

[0506] In some embodiments, a pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable solvate thereof, or a solid form comprising compound 1 or a pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable solvate thereof, is a farnesyltransferase inhibitor. In some embodiments, the pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable solvate thereof, or a solid form comprising compound 1 or a pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable solvate thereof, is a selective farnesyltransferase inhibitor relative to inhibition of geranylgeranyltransferase type 1 (such as geranylgeranyltransferase type 1). In some embodiments, a method for inhibiting farnesyltransferase is provided herein, the method comprising contacting the farnesyltransferase with an effective amount of a pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable solvate thereof, or a solid form comprising compound 1 or a pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable solvate thereof. In some embodiments, the method of inhibiting farnesyltransferase includes contacting the farnesyltransferase with an effective amount of a pharmaceutical composition as disclosed herein, the pharmaceutical composition comprising a pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable solvate thereof, or a solid form comprising compound 1 or a pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the contact of the farnesyltransferase occurs in cells. In some embodiments, the farnesyltransferase is present in cells. In some embodiments, the cells are in a subject. In some embodiments, the cells are mammalian cells. In some embodiments, the cells are human cells. In some embodiments, the subject has a cancer dependent on farnesylated proteins. In some embodiments, the subject is a human.

[0507] In some embodiments, the method inhibits farnesylation of the H-Ras protein. In some embodiments, the H-Ras protein is mutated. In some embodiments, the HRas protein mutation is or contains a modification in the corresponding mutated H-Ras protein that encodes an amino acid substitution at a specific position in the codon selected from G12, G13, Q61, Q22, K117, A146, and any combination thereof. In some embodiments, inhibition of farnesylation of the H-Ras protein (such as a mutated H-Ras protein) occurs intracellularly. In some embodiments, the cells are in a subject. In some embodiments, the cells are mammalian cells. In some embodiments, the cells are human cells. In some embodiments, inhibition of farnesyltransferases present in the cells occurs in a subject suffering from a farnesylation-dependent cancer. In some embodiments, the farnesylation-dependent cancer is a solid tumor. In some embodiments, the farnesylation-dependent cancer is a cancer dependent on one or more farnesylation proteins. In some embodiments, the farnesylation-dependent cancer is dependent on the farnesylation protein for the progression and / or survival of said cancer. In some embodiments, the farnesylated protein-dependent cancer is a farnesylated H-Ras protein-dependent cancer. In some embodiments, the farnesylated protein-dependent cancer has an H-Ras protein mutation. In some embodiments, the HRas protein mutation is or includes a modification in the corresponding mutant H-Ras protein that encodes an amino acid substitution at a specific position in the codon selected from G12, G13, Q61, Q22, K117, A146, and any combination thereof. In some embodiments, the farnesylated protein-dependent cancer is head and neck cancer. In some embodiments, the head and neck cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, head and neck cancers such as HNSCC are dependent on one or more farnesylated proteins, such as farnesylated H-Ras proteins. In some embodiments, head and neck cancers such as HNSCC have an H-Ras protein mutation. In some embodiments, the farnesylated protein-dependent cancer is carcinoma, melanoma, sarcoma, or chronic granulomatous disease. For example, in some embodiments, the cancers dependent on farnesylation proteins are thyroid cancer, head and neck cancer, urothelial carcinoma, salivary gland cancer, upper gastrointestinal cancer, bladder cancer, breast cancer, ovarian cancer, brain cancer, stomach cancer, prostate cancer, lung cancer, colon cancer, skin cancer, liver cancer, or pancreatic cancer. In some embodiments, the cancer is squamous cell carcinoma (SCC). For example, in some embodiments, the SCC is head and neck SCC (HNSCC), lung SCC (LSCC), thyroid SCC (TSCC), esophageal SCC (ESCC), bladder SCC (BSCC), or urothelial carcinoma (UC). In some embodiments, the SCC is HNSCC. In some embodiments, the SCC is human papillomavirus (HPV) negative SCC.In some embodiments, HNSCC is HPV-negative HNSCC. For example, in some embodiments, HNSCC is tracheal HNSCC, maxillary HNSCC, or oral HNSCC. In some embodiments, SCC, such as HNSCC, lung SCC, thyroid SCC, esophageal SCC, bladder SCC, or urothelial carcinoma, is dependent on one or more farnesylated proteins, such as farnesylated H-Ras protein. In some embodiments, HNSCC is dependent on one or more farnesylated proteins, such as farnesylated H-Ras protein. In some embodiments, SCC, such as HNSCC, lung SCC, thyroid SCC, esophageal SCC, bladder SCC, or urothelial carcinoma, has an H-Ras protein mutation. In some embodiments, HNSCC has an H-Ras protein mutation. In some embodiments, the subject is a human.

[0508] In some embodiments, this document provides a method of treating a subject with a farnesylation-dependent cancer, the method comprising administering to a subject suffering from a farnesylation-dependent cancer a therapeutically effective amount of a pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable solvate thereof, or a solid form comprising compound 1 or a pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable solvate thereof. In some embodiments, the method of treating a subject with a farnesylation-dependent cancer comprises administering to a subject suffering from a farnesylation-dependent cancer a therapeutically effective amount of a pharmaceutical composition as disclosed herein, the pharmaceutical composition comprising a pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable solvate thereof, or a solid form comprising compound 1 or a pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the farnesylation-dependent cancer is a solid tumor. In some embodiments, the farnesylation-dependent cancer is cancer dependent on one or more farnesylations. In some embodiments, the farnesylation-dependent cancer is dependent on farnesylations for progression and / or survival of said cancer. In some embodiments, the farnesylated protein-dependent cancer is a farnesylated H-Ras protein-dependent cancer. In some embodiments, the farnesylated protein-dependent cancer has an H-Ras protein mutation. In some embodiments, the HRas protein mutation is or includes a modification in the corresponding mutant H-Ras protein that encodes an amino acid substitution at a specific position in the codon selected from G12, G13, Q61, Q22, K117, A146, and any combination thereof. In some embodiments, the farnesylated protein-dependent cancer is head and neck cancer. In some embodiments, the head and neck cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, head and neck cancers such as HNSCC are dependent on one or more farnesylated proteins, such as farnesylated H-Ras proteins. In some embodiments, head and neck cancers such as HNSCC have an H-Ras protein mutation. In some embodiments, the farnesylated protein-dependent cancer is carcinoma, melanoma, sarcoma, or chronic granulomatous disease. For example, in some embodiments, the cancers dependent on farnesylation proteins are thyroid cancer, head and neck cancer, urothelial carcinoma, salivary gland cancer, upper gastrointestinal cancer, bladder cancer, breast cancer, ovarian cancer, brain cancer, stomach cancer, prostate cancer, lung cancer, colon cancer, skin cancer, liver cancer, or pancreatic cancer. In some embodiments, the cancers dependent on farnesylation proteins are squamous cell carcinomas (SCC). For example, in some embodiments, SCC is head and neck SCC (HNSCC), lung SCC (LSCC), thyroid SCC (TSCC), esophageal SCC (ESCC), bladder SCC (BSCC), or urothelial carcinoma (UC). In some embodiments, SCC is HNSCC.In some embodiments, the SCC is a human papillomavirus (HPV) negative SCC. In some embodiments, the HNSCC is an HPV negative HNSCC. For example, in some embodiments, the HNSCC is a tracheal HNSCC, a maxillary HNSCC, or an oral HNSCC. In some embodiments, the SCC, such as HNSCC, lung SCC, thyroid SCC, esophageal SCC, bladder SCC, or urothelial carcinoma, is dependent on one or more farnesylated proteins, such as farnesylated H-Ras protein. In some embodiments, the HNSCC is dependent on one or more farnesylated proteins, such as farnesylated H-Ras protein. In some embodiments, the SCC, such as HNSCC, lung SCC, thyroid SCC, esophageal SCC, bladder SCC, or urothelial carcinoma, has an H-Ras protein mutation. In some embodiments, the HNSCC has an H-Ras protein mutation. In some embodiments, the subject is a human.

[0509] In some embodiments, such as the methods for treating farnesylated protein-dependent cancers disclosed herein, the presence or absence of H-Ras mutations has been determined prior to treatment. In some embodiments, determining the presence or absence of H-Ras mutations includes analyzing nucleic acids obtained from a sample from a subject. In some embodiments, the sample is a tissue biopsy. In some embodiments, the sample is a tumor biopsy. In some embodiments, H-Ras mutations are determined by sequencing, polymerase chain reaction (PCR), DNA microarray, mass spectrometry (MS), single nucleotide polymorphism (SNP) assay, denaturing high-performance liquid chromatography (DHPLC), or restriction fragment length polymorphism (RFLP) assay. In some embodiments, H-Ras mutations are determined by PCR. In some embodiments, H-Ras mutations are determined by sequencing.

[0510] In some embodiments, a pharmaceutically acceptable salt of compound 1 as disclosed herein, or a pharmaceutically acceptable solvate thereof, or a solid form comprising compound 1 or a pharmaceutically acceptable salt or solvate thereof, is metabolically stable, for example, metabolically stable to the liver of a subject, such as to the liver of a human.

[0511] 5.6.2 Dosage and Regimen The compounds described herein can be delivered in the form of pharmaceutical compositions comprising a therapeutically effective amount of a pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable solvate thereof, or a solid form comprising compound 1 or a pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the therapeutically effective amount in the pharmaceutical composition is determined based on the free base equivalent of a pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable solvate thereof, or a solid form comprising compound 1 or a pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable solvate thereof. The pharmaceutical compositions disclosed herein are intended to be administered via suitable routes, including but not limited to oral, parenteral, rectal, topical, and local administration. In some embodiments, the selected dose level will depend on various factors, including, for example, the activity of the particular compound used, the route of administration, the time of administration, the excretion or metabolic rate of the particular compound used, the rate and extent of absorption, the duration of treatment, other drugs, compounds, and / or materials used in combination with the particular compound used, the age, sex, weight, condition, general health, and medical history of the patient being treated, and similar factors well known in the medical field.

[0512] The appropriate daily dose of the compounds described herein administered to a subject will be the amount of the compounds described herein, which, in some embodiments, may be the lowest dose effective in producing a therapeutic effect. Such effective doses will generally depend on the factors described herein. In some embodiments, a therapeutically effective amount of a pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable solvate thereof, or a solid form containing compound 1 or a pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable solvate thereof as an active ingredient, may be administered as a single dose or subdivided into more than one dose of about 0.01 mg / kg to about 500 mg / kg per day, or more particularly in amounts of about 0.01 mg / kg to about 400 mg / kg per day, such as about 0.01 mg / kg to about 300 mg / kg per day, about 0.01 mg / kg to about 200 mg / kg per day, about 0.01 mg / kg to 100 mg / kg per day, about 0.01 mg / kg to about 50 mg / kg per day, about 0.01 mg / kg to about 25 mg / kg per day, or about 0.01 mg / kg to about 10 mg / kg per day. The dosage can be approximately 0.01 mg / kg, 0.025 mg / kg, 0.05 mg / kg, 0.075 mg / kg, 0.1 mg / kg, 0.25 mg / kg, 0.5 mg / kg, 0.75 mg / kg, 1 mg / kg, 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 50 mg / kg, 75 mg / kg, 100 mg / kg, 200 mg / kg, 300 mg / kg, 400 mg / kg, or 500 mg / kg per day.For example, in some embodiments, a pharmaceutically acceptable salt or pharmaceutically acceptable solvate of compound 1 disclosed herein, or a solid form comprising compound 1 or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, may be administered at doses or therapeutically effective amounts of about 0.01 mg / kg to about 25 mg / kg daily, about 0.01 mg / kg to about 20 mg / kg daily, about 0.01 mg / kg to about 15 mg / kg daily, about 0.01 mg / kg to about 10 mg / kg daily, about 0.01 mg / kg to about 7.5 mg / kg daily, or about 0.01 mg / kg to about [missing information - likely a dosage range]. Amounts of 5 mg / kg or from about 0.01 mg / kg to about 2.5 mg / kg per day, such as about 0.01 mg / kg per day, about 0.025 mg / kg per day, about 0.05 mg / kg per day, about 0.075 mg / kg per day, about 0.1 mg / kg per day, about 0.25 mg / kg per day, about 0.5 mg / kg per day, about 0.75 mg / kg per day, about 1 mg / kg per day, about 2.5 mg / kg per day, about 5 mg / kg per day, about 7.5 mg / kg per day, about 10 mg / kg per day, about 15 mg / kg per day, or about 20 mg / kg per day. In some embodiments, a therapeutically effective amount of a pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable solvate thereof, or a solid form comprising compound 1 or a pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable solvate thereof, is included in the pharmaceutical composition as described herein. The actual dose level of the active ingredient in the pharmaceutical compositions described herein can be varied to obtain an amount of active ingredient that is effective in achieving the desired therapeutic response for a particular subject (such as a human patient), the composition, and the mode of administration without being toxic to the subject. In some cases, dose levels below the lower limit of the range described above may be sufficient, while in other cases, larger doses may be used without causing any harmful side effects, for example, by dividing such larger doses into several smaller doses administered throughout the day. The dose may reflect the amount of the compound, or the amount of the compound in a particular pharmaceutical form, or the equivalent of the free base form of a particular pharmaceutical form.

[0513] In some embodiments, treatment is administered in combination with radiotherapy or radiation therapy in the form of a pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable solvate thereof, or in a solid form containing compound 1 or a pharmaceutically acceptable salt of compound 1 or a pharmaceutically acceptable solvate thereof.

[0514] It should be understood that the subheadings throughout this document do not limit the topics discussed to those chapters, but rather apply to and are intended to apply to every embodiment disclosed in this application.

[0515] The compounds disclosed herein, including illustrative compounds and intermediate compounds, were described using ChemDraw.® Version 18.1.4.4 or later is used for naming.

[0516] 6. Example abbreviation : Analytical methods XRPD: XRPD diffraction patterns were collected using an X-ray diffractometer (instrument: PANalytical, Empyrean; radiation, Cu Kα). Detector, PIXcel 1D Scan angle, 3°–40° (2θ); Scan step, 0.013° (2θ); Tube voltage / current, 45kV / 40mA; Diverging slit, 1 / 8°; Rotate, open; Sample holder, zero-background sample tray). Samples are prepared on zero-background silicon wafers by gently pressing them onto a flat surface.

[0517] PLM: Optical microscopy analysis was performed using an ECLIPSE LV100POL microscope (Nikon, Japan). Each sample was placed on a slide with a drop of oil and covered with a coverslip. The samples were observed using polarized light through a 4-20× objective lens.

[0518] DSC: DSC analysis was performed using a TA instrument (Discovery DSC 250). Approximately 1-3 mg of sample was placed in an aluminum dish with pinholes and heated from 25°C to 300°C at a heating rate of 10°C / min under a N2 purge gas flow rate of 50 mL / min.

[0519] TGA: TGA analysis was performed using a TA instrument (Discovery TGA 55). Approximately 1-5 mg of sample was loaded onto a pre-equilibrated aluminum tray and heated from room temperature to 300°C at a heating rate of 10°C / min under a N2 purge gas flow rate of 40 mL / min (equilibration chamber) and 60 mL / min (sample chamber).

[0520] HPLC: Unless otherwise instructed, HPLC analysis of all polymorphs, salts, and solubility in media experiments was performed on an Agilent 1260 series instrument using a Waters XBridge Shield RP18 4.6*150mm, 3.5μm column at 40°C. Mobile phase A: 0.1% aqueous solution of H3PO4; mobile phase B: MeOH:ACN 3:7 v / v; flow rate 1.5 mL / min; injection volume 5 μL; DAD detector wavelength 210 nm; and gradients: 12 min, 100% A; 3 min, 50% A; 2.1 min, 5% A; 5 min, 100% A.

[0521] HPLC: Unless otherwise instructed, all HPLC analyses for chiral salt screening experiments were performed on an Agilent 1290 series HPLC instrument with a Waters XBridge BEHC18 XP (2.1 × 50 mm, 2.5 μm) column at a flow rate of 0.6 mL / min. DAD detector wavelengths were 215 nm and 252 nm. Mobile phase A: 10 mM NH4OAc (water / MeOH / ACN 900 / 60 / 40); Mobile phase B: 10 mM NH4OAc (water / MeOH / ACN 100 / 540 / 360), with gradients of 80% A for 1.5 min and 0% A for 1.5 min.

[0522] UPC: Unless otherwise indicated, UPC analysis is performed on the Waters Acquity UPC equipped with a UV detector and a QDA detector. 2 The system used a Daicel Chiralpak ID-3 (3.0×150mm, 3μm) column with mobile phase A: 65% CO2 and mobile phase B: 35% MeOH + 0.2% NH4OH (25% aqueous solution). The isocratic pump program was used, with a run time of 10 minutes, a flow rate of 1.2 mL / min, UV detection at 250 nm, and a column temperature of 40 °C.

[0523] The following examples are presented in an illustrative rather than limiting manner. Unless otherwise stated, the raw material used to prepare compounds 1-24 as detailed in Examples 1-24 is compound 1 (amorphous, free base) prepared according to Example 52.

[0524] Example 1: Preparation of free base hemihydrate of compound 1 (form 1) .

[0525] Method A: Compound 1 free base (20 mg) was characterized as amorphous by polarized light microscopy and XRPD. Figure 1 ).

[0526] The material was diluted with (a) acetone / H2O (1 / 9 v / v), (b) ACN / H2O (1 / 9 v / v), or THF / H2O (1 / 9 v / v) (0.5 mL). The resulting mixture was stirred at 50 °C for 4 days (acetone / H2O) or 11 days (ACN / H2O or THF / H2O). The resulting solid was collected by filtration and analyzed by XRPD to identify it as the free base hemihydrate of compound 1 (form 1).

[0527] Method B: Amorphous compound 1 free base (250 mg) was mixed with 3 mL acetone / H₂O (1 / 9, v / v) at 50 °C for 17 hours. The resulting suspension was stirred at room temperature for 1 hour and then filtered. The solid was collected and dried under vacuum at 40 °C for 4 hours. Compound 1 free base hemihydrate was obtained in 91% yield and with 99.61% purity (HPLC), with 0.4% residual acetone. 1 HNMR, Bruker, 400MHz, DMSO-d6).

[0528] Method C: Purified water (3V) was added to a solution of the free base of compound 1 in ACN (3V) over 1 hour at 45℃±5℃, followed by the addition of seed crystals of the free base hemihydrate of compound 1 (form 1). The resulting mixture was stirred at 45℃±5℃ for 0.5 hours, then treated with purified water (6V) for 2 hours. The resulting mixture was stirred at 45℃±5℃ for 2 hours, then cooled to 25℃±5℃ and stirred for 7 hours. The resulting solid was collected by filtration, washed with purified water, and dried under vacuum at 60℃ for 8 days to obtain the free base hemihydrate of compound 1 (form 1). HPLC: 98.8% compound 1, 0.4% compound 2.

[0529] Method D: Single-crystal analysis of the free base hemihydrate of compound 1 (form 1). The crystal structure of form 1 was collected and resolved. The crystalline free base hemihydrate of compound 1 was dissolved in 0.3 mL of ACN / H₂O at 50 °C at 60 °C. The solution was filtered at room temperature, and the filtrate was covered with a pinhole membrane and kept at room temperature for 20 hours to allow for evaporative crystallization. The resulting plate-like crystals with aggregates were collected and analyzed by single-crystal X-ray diffraction (180 K, Rigaku XtaLAB Synergy-DW diffractometer, with Cu Kα radiation). The analysis is performed. All non-hydrogen atoms can be located directly from the difference Fourier plot. The framework hydrogen atoms are geometrically positioned and constrained to the parent atom using a riding model. The SHELXL program is used to achieve this through the use of full matrix techniques. F 2 The final structural refinement is achieved by minimizing the sum of squared deviations from the mean. The single-crystal structure of form 1 has the characteristics of equation 2 (C). 29H 20 N6O) H2O (hemihydrate) P Monoclinic crystals in space group 21. For example... Figure 2 As shown, analysis confirmed that each asymmetric unit contains two compound molecules and one water molecule, the unit cell contains two asymmetric units, and chiral carbon " S "Absolute configuration. Table 1 provides a summary of the structural data for compound 1 (form 1)." 1 HNMR (300MHz, DMSO-d6) δ 8.43 (s, 1H), 8.26 (s, 1H), 8.16 (s, 1H), 7.74 (d, J = 87.4Hz, 3H), 7.48 –7.19 (m, 3H), 7.12 –7.03 (m, 1H), 5.50 (d, J= 12.8Hz, 2H), 3.60 (s, 2H).

[0530] Analytical data (XRPD) of the material obtained from method B are provided. Figure 3 ); DSC / TGA ( Figure 4 Methods A, C, and D produce materials with consistent analytical data.

[0531] DSC: The product exhibits a thermal (endothermic) event with an onset temperature of about 83°C and an endothermic peak at about 138°C, and a thermal (endothermic, melting) event with an onset temperature of about 212°C and an endothermic peak at about 221°C. TGA: The product does not exhibit weight loss when heated below about 75°C, and exhibits a weight loss of about 1.8% when heated from about 75°C to about 170°C.

[0532] Example 2: Preparation of Compound 1 Benzoate (Form 2) .

[0533] Method A: Amorphous compound 1 free base (30 mg) was mixed with 0.5 mL of (a) IPA, (b) acetone, (c) IPAc, or (d) ACN / water (19 / 1) at room temperature and treated with benzoic acid (1.1 equivalents). The resulting mixture was stirred at room temperature for 16 hours. For (b), 1 mL of n-heptane was added, and the mixture was stirred again at 50 °C for 24 hours. In each case, the resulting solid was collected by filtration and dried under vacuum at 40 °C for 4 hours to provide compound 1 benzoate (form 2). Analytical data (XRPD, Figure 5 DSC / TGA Figure 6 (a) 1HNMR (Bruker, 400MHz, DMSO-d6) showed 0.2% by weight of residual IPA.

[0534] Method B: Amorphous compound 1 free base (350 mg) and benzoic acid (86.6 mg, 1 equivalent) were added to 3.5 mL of acetone at room temperature. The resulting mixture was stirred at room temperature for 5 minutes, then seeded with 4 wt% of compound 1 benzoate (form 2) and stirred for 4 hours. The resulting suspension was treated with n-heptane (7 mL) and stirred for 20 hours. The resulting solid was collected by filtration and dried under vacuum at 40 °C for 4 hours to provide compound 1 benzoate (form 2). Characterization data were obtained as follows. The analytical data of the material obtained from Method B are comparable to those of the material obtained from Method A. 1 HNMR (Bruker, 400MHz, DMSO-d6) showed 0.5% by weight of residual acetone.

[0535] 1 HNMR (400MHz, DMSO- d 6) δ 8.44 (s, 1H), 8.25 (d , J = 8.9Hz, 1H), 8.16(s, 1H), 8.05 –7.79 (m, 3H), 7.69 –7.54 (m, 2H), 7.54 –7.35 (m, 3H), 7.30 –7.00 (m, 3H), 6.31 (s, 1H), 5.49 (d, J =12.7Hz, 2H), 3.59 (s, 3H).

[0536] DSC: The product exhibits thermal (endothermic, melting / decomposition) events with an onset temperature of approximately 209 °C and a peak temperature of approximately 216 °C. TGA: The product does not exhibit weight loss when heated below approximately 180 °C. Based on these data, compound 1 benzoate (form 2) was identified as the anhydrous form.

[0537] Example 3: Preparation of compound 1 benzenesulfonate (benzenesulfonic acid) (form 3) .

[0538] Amorphous compound 1, free base (30 mg), and benzenesulfonic acid (1.0 equivalent) were mixed with IPAc (0.5 mL) and stirred for 4 days at room temperature. The mixture was concentrated, treated with acetone (0.2 mL), and stirred for 4 days at room temperature, followed by treatment with n-heptane (1 mL). The resulting solid was collected and dried to give compound 1 benzenesulfonate (form 3). Analytical data (XRPD, Figure 7 DSC / TGA Figure 8 ).

[0539] 1 HNMR (400MHz, DMSO- d 6) δ 8.95 (s, 1H), 8.52 –8.14 (m, 3H), 7.98 (s, 2H), 7.66 –7.53 (m, 2H), 7.46 (t, J = 7.9Hz, 1H), 7.41 –7.21 (m, 4H), 7.11(dd, J = 8.2, 2.4Hz, 1H), 6.89 (s, 1H), 5.86 –5.22 (m, 2H), 3.43 (s, 3H), 1.24 (s, 2H), 1.17 (d, J = 6.2Hz, 1H).

[0540] DSC: The product exhibits multiple thermal events, including an onset temperature of approximately 186 °C and a peak temperature of approximately 206 °C (endothermic). TGA: The product exhibits a 5.7% weight loss upon heating in the range of approximately 95 °C to approximately 230 °C. These data, along with... 1 HNMR data (Bruker, 400 MHz, DMSO-d6) identified a substance in which compound 1 was present in a molar ratio of 1:0.9 to acid, as well as residual IPAc (3%), n-heptane (1.3%), and acetone (0.2%), indicating that it was in solvated form.

[0541] Example 4: Preparation of chloride salt of compound 1 (form 4) .

[0542] Amorphous compound 1 in its free base form (30 mg) was mixed with IPA (0.5 mL), treated with HCl solution (1 M, prepared by diluting concentrated HCl in IPA), and stirred at room temperature for 4 days. The resulting solid was separated by centrifugation and vacuum dried at 40 °C for 4 hours to provide the chloride salt of compound 1 (form 4). Analytical data (XRPD, Figure 9 DSC / TGA Figure 10 Purity, 98.9% (HPLC). 1 0.3% residual IPA was identified by HNMR (Bruker, 400MHz, DMSO-d6).

[0543] 1 H-NMR (400MHz, DMSO- d 6) δ 8.73 (s, 1H), 8.31 (d, J = 8.8Hz, 2H), 8.21(s, 1H), 7.97 (s, 2H), 7.46 (t,J = 7.9Hz, 1H), 7.41 –7.16 (m, 2H), 7.10 (dd, J = 8.2, 2.4Hz, 1H), 6.79 (s, 1H), 5.52 (d, J = 10.5Hz, 2H), 4.14 –3.54 (m,3H).

[0544] DSC: Four endothermic peaks were observed, with onset temperatures of approximately 28 °C, 98 °C, and 242 °C, and peak temperatures at approximately 64 °C and 116 °C (water and residual solvent loss), and at approximately 258 °C (two overlapping peaks; melting, decomposition). TGA: The product exhibited two stages of weight loss, 3.2% before 90 °C and 2.7% in the range of 90 °C to 140 °C. These data indicate that form 4 is a hydrate.

[0545] Example 5: Preparation of chloride salt of compound 1 (form 5) .

[0546] Form 5 was prepared using the procedure described for Example 4, with ACN used instead of IPA. Analytical data (XRPD, Figure 11 DSC / TGA Figure 12 Purity, 98.9% (HPLC).

[0547] 1 HNMR (400MHz, DMSO- d 6) δ 8.95 (s, 1H), 8.51 –8.15 (m, 3H), 7.99 (s, 2H), 7.46 (t, J = 7.9Hz, 1H), 7.26 (d, J = 7.5Hz, 2H), 7.11 (dd, J = 8.1,2.4Hz, 1H), 6.88 (s, 1H), 5.52 (d, J = 11.2Hz, 2H), 3.77 (dt, J = 12.2, 6.2 Hz, 3H).

[0548] DSC: The product exhibits multiple thermal events, including a thermal (endothermic) event with an onset temperature of approximately 244 °C and a peak temperature of approximately 247 °C, indicating losses of water and residual solvent. TGA: The product exhibits a 5.3% weight loss (loss of water and residual solvent) up to 130 °C and approximately 12% weight loss in the range from approximately 175 °C to approximately 300 °C. 1 HNMR indicates a trace level of residual ACN (0.3%).

[0549] Example 6: Preparation of compound 1 citrate (form 6) .

[0550] Amorphous compound 1, a free base (30 mg), was mixed with IPAc (0.5 mL) at room temperature and treated with citric acid (1.1 equivalents). After 19 hours, the resulting solid was separated by filtration and dried under vacuum at 40 °C for 4 hours. Analytical data (XRPD, Figure 13 DSC / TGA Figure 14 ).

[0551] 1 HNMR (400MHz, DMSO- d 6) δ 8.43 (s, 1H), 8.25 (d, J = 8.9Hz, 1H), 8.16(s, 1H), 7.81 (d, J = 71.5Hz, 3H), 7.43 (t, J = 7.9Hz, 2H), 7.23 (d, J =7.5Hz, 2H), 7.08 (dd, J = 8.3, 2.4Hz, 1H), 6.36 (s, 1H), 5.49 (d, J = 12.2Hz,2H), 3.60 (s, 3H), 2.78 –2.57 (m, 3H), 1.96 (s, 1H), 1.17 (d, J = 6.3Hz, 2H).

[0552] DSC: The product exhibits multiple endothermic peaks, including onset temperatures of approximately 92°C and 144°C, and peak temperatures of approximately 102°C and 177°C. TGA: The product exhibits approximately 5.1% weight loss in the temperature range of approximately 26°C to approximately 150°C. Based on these data and 1 ¹H NMR results (Bruker, 400 MHz, DMSO-d6) identified compound 1, citrate (form 6), as an IPAc solvate. The molar ratio of base to acid was 1:0.8. Example 7: Preparation of compound 1 citrate (form 7) .

[0553] The product was prepared as described in Example 6, using ACN / H2O (19 / 1) instead of IPAc. Analytical data (XRPD, Figure 15 DSC / TGA Figure 16 ).

[0554] 1HNMR (400MHz, DMSO-d6) δ 8.42 (s, 1H), 8.25 (d, J = 8.9Hz, 1H), 8.16(s, 1H), 7.81 (d, J = 62.1Hz, 3H), 7.43 (t, J = 7.9Hz, 2H), 7.23 (d, J =7.5Hz, 2H), 7.11 –7.01 (m, 1H), 6.35 (s, 1H), 5.49 (d, J = 12.6Hz, 2H), 3.61(s, 3H), 2.74 (d, J = 15.4Hz, 2H), 2.64 (d, J = 15.4Hz, 2H).

[0555] DSC: The product exhibits four endothermic peaks, including onset temperatures of approximately 41°C, 135°C, and 169°C, and peak temperatures of approximately 58°C, 139°C, and 188°C. TGA: The product exhibits approximately 2.8% weight loss in the temperature range of 25°C to approximately 100°C. 1 HNMR (Bruker, 400MHz, DMSO-d6) indicates approximately 0.2% residual ACN. These data indicate that form 7 is a hydrate.

[0556] Example 8: Preparation of compound 1 fumarate (form 8) .

[0557] Method A: Amorphous compound 1, free base (30 mg), was mixed with acetone (0.5 mL), treated with fumaric acid (1.1 equivalents), and stirred at room temperature for 19 hours. The resulting mixture was treated with n-heptane (1 mL) and stirred at 50 °C for 20 hours. The resulting solid was separated by filtration and dried under vacuum at 40 °C for 4 hours.

[0558] Method B: Amorphous compound 1, free base (30 mg), was mixed with ACN / water (19 / 1, 0.5 mL), treated with 1.1 equivalents of fumaric acid (1.1 equivalents), and stirred at room temperature for 2 hours. ACN / water (19 / 1, 0.3 mL) was added, and the mixture was stirred again for 17 hours. The resulting solid was separated by filtration and dried under vacuum at 40 °C for 4 hours. Analytical data (XRPD, ...) are provided. Figure 17 DSC / TGA Figure 18 ). 1 HNMR (Bruker, 400MHz, DMSO-d6) indicated 0.2% residual ACN.

[0559] Method C: Amorphous compound 1 free base (350 mg) and fumaric acid (90 mg, 1.1 equivalents) were mixed in acetone (3.5 mL) and the mixture was stirred at room temperature for 30 minutes. The resulting solution was added dropwise to a dispersion of compound 1 fumarate (form 8) seed crystals in n-heptane. After stirring at room temperature for 24 hours, the resulting solid was separated by filtration and dried under vacuum at 40 °C for 5 hours. To remove residual acetone, the solid was ground with a mortar and pestle and further dried under vacuum at 90 °C for 3 hours.

[0560] The materials obtained from methods A and C show results comparable to those provided by the materials from method B.

[0561] 1 HNMR (400MHz, DMSO- d 6) δ 8.44 (s, 1H), 8.25 (d, J = 8.9Hz, 1H), 8.16(s, 1H), 8.01 –7.52 (m, 3H), 7.43 (t, J = 7.9Hz, 2H), 7.22 (d, J = 7.5Hz, 1H), 7.08 (dd, J = 8.3, 2.4Hz, 1H), 6.62 (s, 2H), 6.32 (s, 1H), 5.49 (d, J =13.2Hz, 2H), 3.59 (s, 4H).

[0562] DSC: The product exhibits thermal (endothermic, dehydration) events with an onset temperature of about 28°C and a peak temperature of about 100°C, and thermal (endothermic, melting / decomposition) events with an onset temperature of about 206°C and a peak temperature of about 214°C. TGA: The product exhibits a weight loss of about 2.0% when heated from about 24.5°C to about 150.0°C.

[0563] Example 9: Preparation of gentianate (form 9) of compound 1 .

[0564] As described in Example 6, the product was prepared using gentianic acid and IPA or IPAc as solvents. Analytical data (XRPD, Figure 19 DSC / TGA Figure 20 ).

[0565] 1 HNMR (400MHz, DMSO- d 6) δ 9.03 (s, 1H), 8.42 (s, 1H), 8.25 (d,J =8.9Hz, 1H), 8.16 (s, 1H), 7.82 (d, J = 53.1Hz, 3H), 7.43 (t, J = 7.9Hz, 2H),7.29 –7.00 (m, 4H), 6.91 (dd, J = 8.8, 3.1Hz, 1H), 6.74 (d, J = 8.8Hz, 1H), 6.37 (s, 1H), 5.50 (d, J = 12.6Hz, 2H), 1.17 (d, J = 6.2Hz, 1H).

[0566] DSC: The product exhibits two endothermic peaks (desolvation, IPAc; melting / decomposition) with onset temperatures of approximately 56°C and 256°C, and peak temperatures of approximately 81°C and 263°C, respectively. TGA: The product exhibits a 2.2% weight loss in the range of approximately 26.5°C to approximately 100°C. 1 HNMR (Bruker, 400MHz, DMSO-d6) indicated the presence of residual IPAc (approximately 1.9%), which together indicated the solvate form.

[0567] Example 10: Preparation of gentianate of compound 1 (form 10) .

[0568] As described in Example 6, the product was prepared using gentian acid and acetone or ACN / H2O (19 / 1) as solvents. Data from the ACN / H2O experiments are provided below. Analytical data (XRPD, Figure 21 DSC / TGA Figure 22 ). 1 HNMR (Bruker, 400MHz, DMSO-d6) indicated residual IPAc (0.4%).

[0569] 1HNMR (400MHz, DMSO-d6) δ 9.04 (s, 1H), 8.42 (s, 1H), 8.25 (d, J =8.9Hz, 1H), 8.16 (s, 1H), 7.82 (d, J = 54.8Hz, 3H), 7.43 (t, J = 7.9Hz, 2H), 7.28 –6.96 (m, 4H), 6.91 (dd, J = 8.8, 3.1Hz, 1H), 6.74 (d, J = 8.9Hz, 1H), 6.37 (s, 1H), 5.49 (d, J = 12.6Hz, 2H).

[0570] DSC ( Figure 22 The product exhibits an endothermic peak (melting / decomposition) with an onset temperature of approximately 240°C and a peak temperature of approximately 245°C. TGA ( Figure 22 The product exhibits a weight loss of approximately 0.4% when heated in the range of approximately 120°C to 200°C. This indicates that the product is in anhydrous form.

[0571] Example 11: Preparation of compound 1 glycolate (form 11) .

[0572] Method A: As described in Example 6, the product was prepared using glycolic acid and IPAc as solvents. Analytical data (XRPD, Figure 23 DSC / TGA Figure 24 ). 1 HNMR (Bruker, 400MHz, DMSO-d6) indicated residual IPAc (0.4%).

[0573] Method B: Amorphous compound 1, free base (30 mg), and glycolic acid (1.1 equivalents) were mixed in acetone (0.5 mL) and stirred at room temperature for 16 hours. The solution was treated with n-heptane (1 mL) and stirred at 50 °C for 2 days. The resulting solid was separated by filtration and dried under vacuum at 40 °C for 4 hours. The data are comparable to those obtained from the product of Method A.

[0574] 1 HNMR (400MHz, DMSO- d 6) δ 8.44 (s, 1H), 8.24 (d , J = 8.9Hz, 1H), 8.16(s, 1H), 7.90 (s, 1H), 7.58 (s, 1H), 7.48 –7.17 (m, 3H), 7.08 (dd, J= 8.2,2.4Hz, 1H), 6.32 (s, 1H), 5.49 (d, J = 13.5Hz, 2H), 3.91 (s, 2H), 3.59 (s, 2H).

[0575] DSC: The product exhibits multiple endothermic events, including onset temperatures at approximately 35°C, 116°C, and 152°C, and peak temperatures at approximately 59°C, 94°C, and 170°C. TGA: The product exhibits approximately 1.7% weight loss when heated from 27°C to approximately 80°C and approximately 3.2% weight loss when heated from approximately 110°C to approximately 200°C. The data indicate that this form may be a hydrate.

[0576] Example 12: Preparation of compound 1, 1-hydroxy-2-naphthoic acid salt (form 12) .

[0577] As described in Example 6, the product was prepared using 1-hydroxy-2-naphthoic acid and IPAc. Analytical data (XRPD, Figure 25 DSC / TGA Figure 26 ).

[0578] 1 HNMR (400MHz, DMSO- d 6) δ 8.42 (s, 1H), 8.26 (dd, J = 8.7, 1.4Hz, 2H),8.17 (s, 1H), 7.85 (d, J = 8.1Hz, 3H), 7.74 (d, J = 8.7Hz, 1H), 7.66 –7.58(m, 1H), 7.52 (ddd, J = 8.2, 6.9, 1.3Hz, 1H), 7.44 (t, J = 7.9Hz, 1H), 7.26(dd, J = 19.8, 8.1Hz, 3H), 7.09 (dd, J = 8.2, 1.9Hz, 1H), 6.47 (s, 1H), 5.52(s, 2H), 4.86 (hept, J = 6.3Hz, 1H), 1.96 (s, 1H), 1.17 (d, J = 6.3Hz, 2H).

[0579] DSC: The product exhibits multiple endothermic events, including onset temperatures of approximately 25°C and 178°C, and peak temperatures of approximately 32°C and 186°C. TGA: The product exhibits a 0.5% weight loss when heated from 25°C to approximately 80°C, and a 7.4% weight loss when heated from approximately 100°C to approximately 190°C. 1 HNMR (Bruker, 400MHz, DMSO-d6) indicates the presence of residual IPAc (approximately 5.1%).

[0580] Example 13: Preparation of compound 1, 1-hydroxy-2-naphthoic acid salt (form 13) .

[0581] Method A: As described in Example 9, the product was obtained using ACN / water (19 / 1) as the solvent. XRPD analysis data are provided ( Figure 27 ).

[0582] Method B: Amorphous compound 1 free base (300 mg) and 1-hydroxy-2-naphthoic acid (1.1 equivalents) were added to ACN / H2O (19 / 1, 5 mL), and the resulting mixture was stirred for 5 minutes. The solution was seeded with compound 1 1-hydroxy-2-naphthoic acid salt (form 13), and the mixture was stirred at room temperature for 16 hours. The resulting thick suspension was diluted with ACN / H2O (19 / 1, 2.5 mL) and stirred for 2 hours. The solid was collected by filtration and dried under vacuum at 40 °C for 4 hours. DSC / TGA data are provided ( Figure 28 The materials obtained from methods A and B have comparable analytical data.

[0583] 1 HNMR (400MHz, DMSO- d 6) δ 8.42 (s, 1H), 8.26 (d, J = 9.0Hz, 2H), 8.17(s, 1H), 8.08 –7.82 (m, 3H), 7.74 (d, J = 8.7Hz, 1H), 7.62 (ddd, J = 8.2,6.8, 1.4Hz, 1H), 7.53 (ddd, J = 8.2, 6.9, 1.3Hz, 1H), 7.44 (t, J = 7.9Hz, 1H), 7.26 (dd) , J = 20.2, 8.1Hz, 3H), 7.09 (dd, J = 8.2, 2.4Hz, 1H), 6.48 (s, 1H), 5.52 (s, 2H).

[0584] DSC: The product exhibits thermal (endothermic, melting / decomposition) events with an onset temperature of approximately 187°C and a peak temperature of approximately 194°C. TGA: The product does not exhibit weight loss when heated below approximately 160°C.

[0585] Example 14: Preparation of compound 1 malate (form 14) .

[0586] Amorphous compound 1, free base (30 mg), and malic acid (1.1 equivalents) were mixed in ACN / H2O (0.5 mL) and stirred at room temperature for 2 hours. The mixture was then treated with ACN / H2O (19 / 1, 0.3 mL) and stirred at room temperature for 17 hours. The resulting solid was separated by filtration and dried under vacuum at 40 °C for 4 hours. Analytical data (XRPD, Figure 29 DSC / TGA Figure 30 ).

[0587] 1 HNMR (400MHz, DMSO- d 6) δ 8.44 (s, 1H), 8.25 (d, J = 8.9Hz, 1H), 8.16(s, 1H), 7.77 (d, J = 100.4Hz, 3H), 7.43 (t , J = 7.9Hz, 2H), 7.23 (d, J =7.6Hz, 2H), 7.08 (dd, J = 8.3, 2.4Hz, 1H), 6.33 (s, 1H), 5.49 (d, J = 12.7Hz, 2H), 4.24 (dd, J = 7.6, 5.1Hz, 1H), 3.59 (s, 3H), 2.61 (dd, J = 15.6, 5.1Hz, 1H), 2.43 (dd, J = 15.7, 7.6Hz, 1H).

[0588] DSC: The product exhibits multiple thermal events, including onset temperatures of approximately 28°C and 178°C, and peak temperatures of approximately 69°C and 216°C. TGA: The product shows a weight loss of approximately 3.6% when heated from approximately 30°C to approximately 120°C. The data indicate that this form is a hydrate.

[0589] Example 15: Preparation of compound 1 malate (form 15) .

[0590] Amorphous compound 1 (free base, 30 mg) and malic acid (1.1 equivalents) were mixed in acetone (0.5 mL) and stirred at room temperature for 19 hours. The mixture was treated with n-heptane (1 mL) and stirred at 50 °C for 2 days. The resulting solid was separated by filtration and dried under vacuum at 40 °C for 4 hours. Analytical data (XRPD) are provided. Figure 31 DSC / TGA Figure 32 ). 1 HNMR (Bruker, 400MHz, DMSO-d6) indicated residual acetone (6.0%) and n-heptane (3.7%).

[0591] 1 HNMR (400MHz, DMSO- d 6) δ 8.43 (s, 1H), 8.24 (d, J = 8.9Hz, 1H), 8.15(s, 1H), 7.77 (d, J = 94.0Hz, 3H), 7.41 (q, J = 19.6, 13.7Hz, 2H), 7.29 –7.00(m, 3H), 6.32 (s, 1H), 5.49 (d, J = 11.5Hz, 2H), 4.24 (dd, J = 7.6, 5.1Hz,1H), 3.60 (s, 2H), 2.61 (dd, J = 15.7, 5.1Hz, 1H), 2.43 (dd, J = 15.7, 7.6Hz,1H), 2.09 (s, 2H), 1.33 –1.17 (m, 1H), 0.90 –0.81 (m, 1H).

[0592] DSC: The product exhibits multiple thermal events, including onset temperatures of approximately 127°C and 159°C, and peak temperatures of approximately 145°C and 182°C. TGA: The product exhibits approximately 3.1% weight loss upon heating from approximately 90°C to approximately 160°C and approximately 3.6% weight loss upon heating from approximately 160°C to approximately 190°C. The data indicate that this form is a solvate.

[0593] Example 16: Preparation of maleate of compound 1 (form 16) .

[0594] A mixture of amorphous compound 1 (30 mg) free base and maleic acid (1.1 equivalents) in IPA (0.5 mL) was stirred at room temperature for 2 hours, then treated with IPA (0.3 mL) and stirred again for 14 hours. The resulting solid was separated by filtration and dried under vacuum at 40 °C for 4 hours. Analytical data (XRPD, Figure 33 DSC / TGA Figure 34 ).

[0595] 1 HNMR (400MHz, DMSO- d 6) δ 8.44 (d, J = 47.0Hz, 2H), 8.30 (d, J =8.8Hz, 1H), 8.20 (s, 1H), 7.95 (s, 2H), 7.45 (t, J = 7.9Hz, 1H), 7.25 (d, J =7.5Hz, 2H), 7.10 (dd, J = 8.3, 2.4Hz, 1H), 6.70 (s, 1H), 6.10 (d, J = 1.8Hz,2H), 5.74 –5.36 (m, 2H), 3.72 (s, 4H).

[0596] DSC: The product exhibits 2-3 endothermic peaks with onset temperatures of approximately 26°C and 198°C, and peak temperatures of approximately 53°C and 206°C. TGA: The product exhibits approximately 1.8% weight loss (water loss) when heated from 24°C to approximately 100°C, indicating that the material is a hydrate.

[0597] Example 17: Preparation of maleate of compound 1 (form 17) .

[0598] As described in Example 6, the product was obtained using maleic acid and ACN / H2O (19 / 1). Analytical data (XRPD, Figure 35 DSC / TGA Figure 36 ).

[0599] 1 HNMR (400MHz, DMSO- d 6) δ 8.59 –8.26 (m, 2H), 8.20 (s, 1H), 7.95 (s,2H), 7.53 –7.18 (m, 3H), 7.10 (dd, J= 8.4, 2.4Hz, 1H), 6.69 (s, 1H), 6.11(s, 2H), 5.52 (d, J = 9.9Hz, 2H), 3.72 (s, 3H).

[0600] DSC: The product exhibits multiple endothermic events, including onset temperatures of approximately 27°C and 195°C, and peak temperatures of approximately 60°C and 205°C. TGA: The product exhibits approximately 1.2% weight loss when heated from 26°C to approximately 100°C, indicating that the material is a hydrate.

[0601] Example 18: Preparation of compound 1 methanesulfonate (form 18) .

[0602] Methanesulfonic acid (1.0 equivalent) was dissolved in IPAc (0.5 mL), and amorphous compound 1 free base (30 mg) was added. The resulting mixture was stirred at room temperature for 4 days. The resulting solid was collected by centrifugation and dried under vacuum at 40 °C for 4 hours. Analytical data (XRPD, Figure 37 DSC / TGA Figure 38 Purity (99.2%, HPLC).

[0603] 1 HNMR (400MHz, DMSO- d 6) δ 8.89 (s, 1H), 8.32 (d, J = 8.6Hz, 2H), 8.22(s, 1H), 8.07 –7.73 (m, 2H), 7.46 (t, J = 7.9Hz, 1H), 7.40 –7.19 (m, 2H), 7.14 –7.06 (m, 1H), 6.86 (s, 1H), 5.54 (d, J = 11.4Hz, 2H), 4.86 (hept, J =6.3Hz, 1H), 3.36 (s, 3H), 2.29 (s, 2H), 1.96 (s, 2H), 1.17 (d, J = 6.3Hz, 5H).

[0604] DSC: The product exhibits an endothermic peak (desolvation) with an onset temperature of approximately 142 °C and a peak temperature of approximately 146 °C. TGA: The product exhibits approximately 5.6% weight loss when heated from room temperature to approximately 145 °C and approximately 9.5% weight loss when heated from approximately 145 °C to approximately 200 °C. 1¹H NMR (Bruker, 400 MHz, DMSO-d6) indicated a molar ratio of 1:0.8 (free base:acid) and the presence of residual IPAc (12%). The data indicate that this form is an IPAc solvate.

[0605] Example 19: Preparation of compound 1 oxalate (form 19) .

[0606] ACN (0.25 mL) was added to a mixture of amorphous compound 1 free base (30 mg) and oxalic acid (1.0 equivalent), and the resulting mixture was stirred at room temperature for 4 days. The resulting solid was collected by centrifugation and dried under vacuum at 40 °C for 4 hours. Analytical data (XRPD) are provided. Figure 39 DSC / TGA Figure 40 Purity, 99.1% (HPLC).

[0607] 1 HNMR (400MHz, DMSO- d 6) δ 8.64 –7.59 (m, 5H), 7.53 –6.94 (m, 4H), 6.54 (s, 1H), 5.52 (s, 2H), 2.08 (s, 2H).

[0608] DSC: The product exhibits endothermic peaks at an onset temperature of approximately 92°C (peak temperature approximately 137°C) (solvent loss), approximately 187°C (peak temperature approximately 190°C) (melting), and approximately 194°C (peak temperature approximately 202°C) (decomposition). TGA: The product exhibits approximately 7.4% weight loss (solvent loss) when heated from approximately 90°C to approximately 190°C and 19.0% weight loss (decomposition) when heated from approximately 190°C to approximately 240°C. These data and 1 ¹H NMR (Bruker, 400 MHz, DMSO-d6) (6.4% residual ACN) indicates that this form is an ACN solvate.

[0609] Example 20: Preparation of phosphate of compound 1 (form 20) .

[0610] Amorphous compound 1, a free base (30 mg), was dissolved in ACN / H₂O (19 / 1, 0.5 mL) and treated with H₃PO₄ (1 equivalent - 1.1 equivalents; 85% molar concentration in water). The resulting mixture was stirred at room temperature for 19 hours. The resulting solid was collected by filtration and dried under vacuum at 40 °C for 4 hours. Analytical data (XRPD, ...) are provided. Figure 41 DSC / TGA Figure 42 ). 1HNMR (Bruker, 400MHz, DMSO-d6) indicates 0.1% residual ACN.

[0611] 1 HNMR (400MHz, DMSO-d6) δ 8.44 (s, 1H), 8.25 (d, J = 8.9Hz, 1H), 8.16(s, 1H), 7.78 (d, J = 92.7Hz, 3H), 7.43 (t, J = 7.9Hz...

Claims

1. A solid form comprising Compound 1, or a pharmaceutically acceptable salt and / or solvate thereof: 。 2. The solid form of claim 1, wherein the solid form is crystalline.

3. The solid form of claim 1 or 2, wherein the solid form comprises the free base of Compound 1.

4. The solid form of any one of claims 1 to 3, wherein the solid form is a non-solvate of Compound 1, or a pharmaceutically acceptable salt thereof.

5. The solid form of any one of claims 1 to 3, wherein the solid form is an anhydrous form of Compound 1.

6. The solid form of any one of claims 1 to 3, wherein the solid form is a pharmaceutically acceptable solvate of Compound 1, or a pharmaceutically acceptable form thereof.

7. The solid form of claim 6, wherein the pharmaceutically acceptable solvate is selected from the group consisting of a hydrate, a hemihydrate, an isobutyl acetate solvate, an isopropyl acetate solvate, a tetrahydrofuran solvate, an acetone solvate, an acetonitrile solvate, or a combination thereof.

8. The solid form of claim 7, wherein the Compound 1 and pharmaceutically acceptable solvate are present in a molar ratio ranging from about 2: 1 to about 1 :

2.

9. The solid form of claim 8, wherein the pharmaceutically acceptable solvate is a hydrate.

10. The solid form of claim 9, wherein the Compound 1 and the hydrate are present in a molar ratio of about 2: 1 (hemihydrate).

11. The solid form of any one of claims 1 to 3 or 6 to 10, wherein the solid form is a crystalline free base hemihydrate of Compound 1.

12. The solid form of claim 11, wherein the solid form is Compound 1 (Form 1).

13. The solid form of claim 11 or claim 12, characterized by an XRPD pattern comprising peaks at approximately 9.0°, 12.8°, 16.6°, and 18.4° 2Θ when measured using Cu Ka radiation.

14. The solid form of claim 13, wherein the XRPD pattern further comprises peaks at approximately 8.6°, 12.0°, 18.1°, and 23.2° 2Θ.

15. The solid form of claim 14, wherein the XRPD pattern further comprises peaks at approximately 16.1°, 17.1°, 24.1°, and 25.6° 2Θ.

16. The solid form of any one of claims 11-15, said solid form characterized by an XRPD pattern that substantially matches the XRPD pattern illustrated in Figure 3; optionally characterized by having the approximate unit cell dimensions: α = 90°, β = 107.8° and γ = 90°, and P a unit cell of space group 21.

17. The solid form of any one of claims 11 to 16, exhibiting a thermal (endothermic) event with an onset temperature of about 83 °C and a thermal (endothermic, melting) event with an onset temperature of about 212 °C and / or an endothermic peak at about 137 °C and about 221 °C, as characterized by DSC at a temperature ramp of about 10 °C / minute.

18. The solid form of any one of claims 11-17, characterized by a differential scanning calorimogram that substantially matches the DSC pattern shown in FIG.

4.

19. The solid form of any one of claims 11-18, which exhibits no weight loss on heating below about 75 °C and a weight loss of about 1.8% on heating from about 75 °C to about 170 °C, as characterized by TGA.

20. The solid form of any one of claims 11-19, characterized by a thermogravimetric analysis pattern that substantially matches the TGA pattern shown in FIG.

4.

21. The solid form of any one of claims 11-20, wherein the solid form has: (a) a purity of at least 98%, 98.5%, 99%, or 99.5%; (b) a solubility of about 4.69 mg / mL, 5.04 mg / mL, and 3.67 mg / mL in SGF media at 0.5 hour, 2 hours, and 24 hours, respectively; or (c) a solubility of about 0.29 mg / mL, 0.31 mg / mL, and 0.33 mg / mL in FeSSIF media at 0.5 hour, 2 hours, and 24 hours, respectively; or (d) a combination of any one of (a)-(c).

22. The solid form of any one of claims 1, 2, or 4-10, wherein the solid form comprises a pharmaceutically acceptable salt of Compound 1.

23. The solid form of claim 22, wherein the pharmaceutically acceptable salt is a benzoate, besylate, chloride, citrate, fumarate, gentisate, glycolate, 1-hydroxy-2-naphthoate, malate, maleate, mesylate, oxalate, phosphate, tartrate, or tosylate salt of Compound 1.

24. The solid form of claim 23, wherein the solid form has a molar ratio of Compound 1 / conjugate acid ranging from about 2: 1 to about 1 :

2.

25. The solid form of claim 23 or claim 24, wherein the pharmaceutically acceptable salt is a benzoate salt of Compound 1.

26. The solid form of claim 25, wherein the solid form has a molar ratio of Compound 1 / benzoic acid of about 1 :

1.

27. The solid form of claim 25 or claim 26, wherein the solid form is Compound 1 (Form 2).

28. The solid form of any one of claims 25-27, characterized by an XRPD pattern comprising peaks at about 4.7°, 17.0°, and 19.4° 2Q when measured using Cu Ka radiation.

29. The solid form of claim 28, wherein the XRPD pattern further comprises peaks at about 12.7°, 16.6°, 17.8°, 18.9°, and 21.4° 2Q, optionally the XRPD pattern further comprises peaks at about 13.5°, 13.7°, 14.3°, 23.0°, 23.9°, and 24.6° 2Q.

30. The solid form of any one of claims 25-29, characterized by an XRPD pattern that substantially matches the XRPD pattern shown in FIG.

5.

31. The solid form of any one of claims 25-30, which exhibits a thermal (endothermic, melting / decomposition) event with an onset temperature of about 209 °C and / or an endothermic peak at about 216 °C, as characterized by DSC at a temperature ramp of about 10 °C / minute.

32. The solid form of any one of claims 25-31, characterized by a differential scanning calorimetry pattern that substantially matches the DSC pattern shown in FIG.

6.

33. The solid form of any one of claims 25-32, which does not exhibit a weight loss upon heating below about 180 °C, as characterized by TGA.

34. The solid form of any one of claims 25-33, characterized by a thermogravimetric analysis pattern that substantially matches the TGA pattern shown in FIG.

6.

35. The solid form of any one of claims 25-34, wherein the solid form has: (a) a purity of at least 98%, 98.5%, 99%, or 99.5%; (b) a solubility in SGF media of about 4.17 mg / mL, 4.47 mg / mL, and 4.49 mg / mL at 0.5 hour, 2 hours, and 24 hours, respectively; (c) a solubility in FeSSIF media of about 0.72 mg / mL, 0.68 mg / mL, and 0.54 mg / mL at 0.5 hour, 2 hours, and 24 hours, respectively; or (d) a combination of any one of (a)-(c).

36. The solid form of claim 23 or claim 24, wherein the pharmaceutically acceptable salt is a besylate salt of Compound 1.

37. The solid form of claim 36, wherein the solid form has a molar ratio of Compound 1 / besylate acid of about 1 :0.

9.

38. The solid form of claim 36 or claim 37, wherein the solid form is Compound 1 (Form 3).

39. The solid form of any one of claims 36-38, which: (a) is characterized by an XRPD pattern comprising peaks at about 7.6°, 8.9°, and 14.3° 2Q when measured using Cu Ka radiation, optionally the XRPD pattern further comprises peaks at about 17.9° and 19.7° 2Q, optionally the XRPD pattern further comprises peaks at about 21.0° and 24.8° 2Q; (b) is characterized by an XRPD pattern that substantially matches the XRPD pattern shown in Figure 7; (c) (i) exhibits a thermal (endothermic) event with an onset temperature of about 186 °C and / or an endothermic peak at about 206 °C, as characterized by DSC at a temperature ramp of about 10 °C / minute; or (ii) is characterized by a differential scanning calorimetry pattern that substantially matches the DSC pattern shown in Figure 8; (d) (i) exhibits a weight loss of about 5.7% upon heating in the range of about 95 °C to about 230 °C, as characterized by TGA; or (ii) is characterized by a thermogravimetric analysis pattern that substantially matches the TGA pattern shown in Figure 8; or (e) a combination of any of (a)-(d).

40. The solid form of claim 23 or claim 24, wherein the pharmaceutically acceptable salt is a hydrochloride salt of Compound 1.

41. The solid form of claim 40, wherein the solid form has a molar ratio of Compound 1 / hydrochloric acid of about 1 : 1, optionally wherein the solid form is a hydrate.

42. The solid form of claim 40 or claim 41, wherein the solid form is Compound 1 (Form 4).

43. The solid form of any one of claims 40 to 42, which: (a) is characterized by an XRPD pattern comprising peaks at approximately 5.3°, 16.7°, 19.1°, and 26.0° 2Q when measured using Cu Kα radiation, optionally the XRPD pattern further comprising peaks at approximately 8.6°, 11.2°, 12.6°, and 15.3° 2Q, optionally the XRPD pattern further comprising peaks at approximately 15.9°, 17.8°, 24.3°, and 28.2° 2Q; (b) is characterized by an XRPD pattern that substantially matches the XRPD pattern shown in Figure 9; (c) (i) exhibits a thermal (endothermic) event with onset temperatures of about 28 °C, about 98 °C, and about 242 °C and / or endothermic peak temperatures at about 64 °C and about 116 °C (water and residual solvent loss), respectively, and at about 258 °C (two overlapping peaks; melting, decomposition), as characterized by DSC at a temperature ramp of about 10 °C / minute; or (ii) is characterized by a differential scanning calorimetry pattern that substantially matches the DSC pattern shown in Figure 10; (d) (i) exhibits a weight loss of about 3.2% upon heating from room temperature to about 90 °C and a weight loss of about 2.7% upon heating from about 90 °C to 140 °C, as characterized by TGA; or (ii) is characterized by a thermogravimetric analysis pattern that substantially matches the TGA pattern shown in Figure 10; or (e) a combination of any of (a)-(d).

44. The solid form of claim 40 or claim 41, wherein the solid form is Compound 1 (Form 5).

45. The solid form of any one of claims 40, 41, or 44, which: (a) is characterized by an XRPD pattern comprising peaks at approximately 5.3°, 16.7°, 19.1°, and 26.0° 2Q when measured using Cu Kα radiation, optionally the XRPD pattern further comprising peaks at approximately 8.6°, 11.2°, 12.6°, and 15.3° 2Q, optionally the XRPD pattern further comprising peaks at approximately 15.9°, 17.8°, 24.3°, and 28.2° 2Q; (b) is characterized by an XRPD pattern that substantially matches the XRPD pattern shown in Figure 9; (c) (i) exhibits a thermal (endothermic) event with onset temperatures of about 28 °C, about 98 °C, and about 242 °C and / or endothermic peak temperatures at about 64 °C and about 116 °C (water and residual solvent loss), respectively, and at about 258 °C (two overlapping peaks; melting, decomposition), as characterized by DSC at a temperature ramp of about 10 °C / minute; or (ii) is characterized by a differential scanning calorimetry pattern that substantially matches the DSC pattern shown in Figure 10; (d) (i) exhibits a weight loss of about 3.2% upon heating from room temperature to about 90 °C and a weight loss of about 2.7% upon heating from about 90 °C to 140 °C, as characterized by TGA; or (ii) is characterized by a thermogravimetric analysis pattern that substantially matches the TGA pattern shown in Figure 10; or (e) a combination of any of (a)-(d). (a) is characterized by an XRPD pattern comprising peaks at about 6.3°, 8.4°, 15.1°, and 23.5° 2Q, optionally further comprising peaks at about 10.7° and 17.9° 2Q, optionally further comprising peaks at about 20.8° and 21.6° 2Q, when measured using Cu Ka radiation; (b) is characterized by an XRPD pattern that matches substantially the XRPD pattern shown in FIG. 11; (c) (i) exhibits a thermal (endothermic) event with an onset temperature of about 244 °C and / or an endothermic peak temperature at about 247 °C (water and residual solvent loss), as characterized by DSC at a temperature ramp of about 10 °C / minute; or (ii) is characterized by a differential scanning calorimetry pattern that matches substantially the DSC pattern shown in FIG. 12; (d) (i) exhibits a weight loss of about 5.3% prior to about 130 °C and a weight loss of about 12% in the range of about 175 °C to about 300 °C, as characterized by TGA; or (ii) is characterized by a thermogravimetric analysis pattern that matches substantially the TGA pattern shown in FIG. 12; or (e) a combination of any of (a)-(d).

46. The solid form of claim 23 or claim 24, wherein the pharmaceutically acceptable salt is a citrate salt of Compound 1.

47. The solid form of claim 46, wherein the solid form has a molar ratio of Compound 1 / citric acid of about 1 :0.8, optionally wherein the solid form is a solvate.

48. The solid form of claim 46 or claim 47, wherein the solid form is Compound 1 (Form 6).

49. The solid form of any one of claims 46-48, the solid form: (a) is characterized by an XRPD pattern comprising peaks at about 12.0°, 16.6°, and 18.1° 2Q, optionally further comprising peaks at about 12.9°, 19.5°, and 23.3° 2Q, optionally further comprising peaks at about 24.2°, 25.6°, and 26.1° 2Q, when measured using Cu Ka radiation; (b) is characterized by an XRPD pattern that matches substantially the XRPD pattern shown in FIG. 13; (c) (i) exhibits a thermal (endothermic) event with an onset temperature of about 92 °C and 144 °C and / or an endothermic peak temperature at about 102 °C and 177 °C, respectively, as characterized by DSC at a temperature ramp of about 10 °C / minute; or (ii) is characterized by a differential scanning calorimetry pattern that matches substantially the DSC pattern shown in FIG. 14; (d) (i) exhibits a weight loss of about 5.1% when heated from about 26 °C to about 150 °C, as characterized by TGA; or (ii) is characterized by a thermogravimetric analysis pattern that matches substantially the TGA pattern shown in FIG. 14; or (e) a combination of any of (a)-(d).

50. The solid form of claim 46, wherein the solid form has a molar ratio of Compound 1 / citric acid of about 1 : 1, optionally wherein the solid form is a hydrate.

51. The solid form of claim 46 or claim 50, wherein the solid form is Compound 1 (Form 7).

52. The solid form of any one of claims 46, 50, or 51, which: (a) is characterized by an XRPD pattern comprising peaks at about 11.0°, 15.0°, 19.0°, 22.1°, 27.7°, and 29.8° 2Q when measured using Cu Ka radiation, optionally further comprising peaks at about 22.1°, 24.2°, 24.6°, 25.2°, 25.8°, and 26.5° 2Q, optionally further comprising peaks at about 8.5°, 8.8°, 12.7°, 13.3°, 13.8°, 16.7°, 17.1°, 17.5°, and 17.9° 2Q; (b) is characterized by an XRPD pattern that matches substantially the XRPD pattern shown in FIG. 15; (c) (i) exhibits thermal (endothermic) events with onset temperatures of about 41 °C, about 135 °C, and about 169 °C and / or endothermic peak temperatures at about 58 °C, about 139 °C, and about 188 °C, respectively, as characterized by DSC at a temperature ramp of about 10 °C / minute; or (ii) is characterized by a differential scanning calorimetry pattern that matches substantially the DSC pattern shown in FIG. 16; (d) (i) exhibits a weight loss of about 2.8% when heated from about 25 °C to about 100 °C, as characterized by TGA; or (ii) is characterized by a thermogravimetric analysis pattern that matches substantially the TGA pattern shown in FIG. 16; or (e) a combination of any of (a)-(d).

53. The solid form of claim 23 or claim 24, wherein the pharmaceutically acceptable salt is a fumarate salt of the Compound 1.

54. The solid form of claim 53, wherein the solid form has a molar ratio of Compound 1 / fumaric acid of about 1 : 1, optionally wherein the solid form is a solvate, optionally wherein the solvate is a hydrate.

55. The solid form of claim 53 or claim 54, wherein the solid form is Compound 1 (Form 8).

56. The solid form of any one of claims 53 to 55, which is characterized by an XRPD pattern comprising peaks at about 8.6°, 10.9°, 16.7°, and 23.3° 2Q when measured using Cu Ka radiation.

57. The solid form of claim 56, wherein the XRPD pattern further comprises peaks at about 4.9°, 11.4°, and 17.6° 2Q, optionally further comprising peaks at about 12.7°, 14.6°, and 26.0° 2Q.

58. The solid form of any one of claims 53-57, characterized by an XRPD pattern that substantially matches the XRPD pattern shown in FIG.

17.

59. The solid form of any one of claims 53-58, which exhibits a thermal (endothermic, dehydration) event with an onset temperature of about 28 °C and / or an endothermic peak at about 100 °C, and a thermal (endothermic, melting / decomposition) event with an onset temperature of about 206 °C and / or a peak temperature of about 214 °C, as characterized by DSC at a temperature ramp of about 10 °C / minute.

60. The solid form of any one of claims 53-59, characterized by a differential scanning calorimetry pattern that substantially matches the DSC pattern shown in FIG.

18.

61. The solid form of any one of claims 53-60, which exhibits a weight loss of about 2.0% when heated from about 24.5 °C to about 150 °C, as characterized by TGA.

62. The solid form of any one of claims 53-61, characterized by a thermogravimetric analysis pattern that substantially matches the TGA pattern shown in FIG.

18.

63. The solid form of any one of claims 53-62, wherein the solid form has: (a) a purity of at least 98%, 98.5%, 99%, or 99.5%; (b) a solubility of about > 5 mg / mL, > 5 mg / mL, and > 5 mg / mL in SGF media at 0.5 hour, 2 hours, and 24 hours, respectively; (c) a solubility of about 1.27 mg / mL, 1.26 mg / mL, and 1.15 mg / mL in FeSSIF media at 0.5 hour, 2 hours, and 24 hours, respectively; or (d) a combination of any one of (a)-(c).

64. The solid form of claim 23 or claim 24, wherein the pharmaceutically acceptable salt is a gentisic acid salt of Compound 1.

65. The solid form of claim 64, wherein the solid form has a molar ratio of Compound 1 / gentisic acid of about 1 : 1, optionally wherein the solid form is a solvate.

66. The solid form of claim 64 or claim 65, wherein the solid form is Compound 1 (Form 9).

67. The solid form of any one of claims 64-66, which: (a) is characterized by an XRPD pattern comprising peaks at about 8.0°, 9.6°, 16.5°, 17.6°, 18.7°, and 24.6° 2Q when measured using Cu Ka radiation, optionally the XRPD pattern further comprising peaks at about 11.7°, 12.2°, 19.9°, and 26.5° 2Q, optionally the XRPD pattern further comprising peaks at about 13.8°, 15.4°, 16.1°, 20.8°, and 21.7° 2Q; (b) is characterized by an XRPD pattern that substantially matches the XRPD pattern shown in FIG. 19; (c) is characterized by an XRPD pattern that substantially matches the XRPD pattern shown in FIG. 20; or (d) is characterized by an XRPD pattern that substantially matches the XRPD pattern shown in FIG.

21. (c) (i) exhibits a thermal (endothermic) event with an onset temperature of about 56 °C and about 256 °C and / or an endothermic peak temperature at about 81 °C and about 263 °C, respectively, as characterized by DSC at a temperature ramp of about 10 °C / minute; or (ii) is characterized by a differential scanning calorimogram that matches substantially the DSC pattern set forth in FIG. 20; (d) (i) exhibits a weight loss of about 2.2% when heated from about 26.5 °C to about 100 °C, as characterized by TGA; or (ii) is characterized by a thermogravimetric analysis pattern that matches substantially the TGA pattern set forth in FIG. 20; or (e) a combination of any of (a)-(d).

68. The solid form of claim 64, wherein the solid form has a molar ratio of about 1 : 1 of Compound 1 / gentiopicrogenic acid, and wherein the solid form is an anhydrate.

69. The solid form of claim 64 or claim 68, wherein the solid form is Compound 1 (Form 10).

70. The solid form of any one of claims 64, 68, or 69, which: (a) is characterized by an XRPD pattern comprising peaks at approximately 4.7°, 13.2°, and 16.9° 2Q, optionally further comprising peaks at approximately 8.39°, 17.5°, 18.6°, 21.8°, and 25.3° 2Q, optionally further comprising peaks at approximately 11.8°, 12.6°, 19.0°, 19.4°, and 23.8° 2Q, when measured using Cu Kα radiation; (b) is characterized by an XRPD pattern that matches substantially the XRPD pattern set forth in FIG. 21; (c) (i) exhibits a thermal (endothermic) event with an onset temperature of about 240 °C and / or an endothermic peak temperature at about 245 °C, as characterized by DSC at a temperature ramp of about 10 °C / minute; or (ii) is characterized by a differential scanning calorimogram that matches substantially the DSC pattern set forth in FIG. 22; (d) (i) exhibits a weight loss of about 0.4% when heated from about 120 °C to about 200 °C, as characterized by TGA; or (ii) is characterized by a thermogravimetric analysis pattern that matches substantially the TGA pattern set forth in FIG. 22; or (e) a combination of any of (a)-(d).

71. The solid form of claim 23 or claim 24, wherein the pharmaceutically acceptable salt is a glycolate salt of the Compound 1.

72. The solid form of claim 71, wherein the solid form has a molar ratio of about 1 : 1 of Compound 1 / glycolic acid, optionally wherein the solid form is a hydrate.

73. The solid form of claim 71 or claim 72, wherein the solid form is Compound 1 (Form 11).

74. The solid form of any one of claims 71 to 73, which: (a) is characterized by an XRPD pattern comprising peaks at approximately 4.7°, 13.2°, and 16.9° 2Q, optionally further comprising peaks at approximately 8.39°, 17.5°, 18.6°, 21.8°, and 25.3° 2Q, optionally further comprising peaks at approximately 11.8°, 12.6°, 19.0°, 19.4°, and 23.8° 2Q, when measured using Cu Kα radiation; (b) is characterized by an XRPD pattern that matches substantially the XRPD pattern set forth in FIG. 21; (c) (i) exhibits a thermal (endothermic) event with an onset temperature of about 240 °C and / or an endothermic peak temperature at about 245 °C, as characterized by DSC at a temperature ramp of about 10 °C / minute; or (ii) is characterized by a differential scanning calorimogram that matches substantially the DSC pattern set forth in FIG. 22; (d) (i) exhibits a weight loss of about 0.4% when heated from about 120 °C to about 200 °C, as characterized by TGA; or (ii) is characterized by a thermogravimetric analysis pattern that matches substantially the TGA pattern set forth in FIG. 22; or (e) a combination of any of (a)-(d).

71. The solid form of claim 23 or claim 24, wherein the pharmaceutically acceptable salt is a glycolate salt of the Compound 1.

72. The solid form of claim 71, wherein the solid form has a molar ratio of about 1 : 1 of Compound 1 / glycolic acid, optionally wherein the solid form is a hydrate.

73. The solid form of claim 71 or claim 72, wherein the solid form is Compound 1 (Form 11).

74. The solid form of any one of claims 71 to 73, which: (a) is characterized by an XRPD pattern comprising peaks at about 7.4°, 12.6°, 16.7°, and 23.8° 2Q, optionally further comprising peaks at about 16.2°, 23.4°, 25.7°, and 28.9° 2Q, optionally further comprising peaks at about 19.0°, 20.3°, and 26.1° 2Q, when measured using Cu Kcx radiation; (b) is characterized by an XRPD pattern that substantially matches the XRPD pattern shown in FIG. 23; (c) (i) exhibits thermal (endothermic) events with onset temperatures of about 35 °C, about 116 °C, and about 152 °C and / or with an endothermic peak temperature at about 59 °C, about 94 °C, and about 170 °C, respectively, as characterized by DSC at a temperature ramp of about 10 °C / minute; or (ii) is characterized by a differential scanning calorimetry pattern that substantially matches the DSC pattern shown in FIG. 24; (d) (i) exhibits a weight loss of about 1.7% on heating from about 27 °C to about 80 °C and a weight loss of about 3.2% on heating from about 110 °C to about 200 °C, as characterized by TGA; or (ii) is characterized by a thermogravimetric analysis pattern that substantially matches the TGA pattern shown in FIG. 24; or (e) a combination of any of (a)-(d).

75. The solid form of claim 23 or claim 24, wherein the pharmaceutically acceptable salt is a l-hydroxy-2-naphthoate salt of Compound 1.

76. The solid form of claim 75, wherein the solid form has a molar ratio of Compound 1 / 1- hydroxy-2-naphthoic acid of about 1 : 1, optionally wherein the solid form is a solvate.

77. The solid form of claim 75 or claim 76, wherein the solid form is Compound 1 (Form 12).

78. The solid form of any one of claims 75-77, the solid form: (a) is characterized by an XRPD pattern comprising peaks at about 6.2°, 11.2°, 14.4°, and 22.3° 2Q, optionally further comprising peaks at about 5.1°, 14.9°, and 18.3° 2Q, optionally further comprising peaks at about 5.6° and 25.3° 2Q, when measured using Cu Kcx radiation; (b) is characterized by an XRPD pattern that substantially matches the XRPD pattern shown in FIG. 25; (c) (i) exhibits thermal (endothermic) events with onset temperatures of about 25 °C and about 178 °C and / or with an endothermic peak temperature at about 32 °C and about 186 °C, respectively, as characterized by DSC at a temperature ramp of about 10 °C / minute; or (ii) is characterized by a differential scanning calorimetry pattern that substantially matches the DSC pattern shown in FIG. 26; (d) (i) exhibits a weight loss of about 1.7% on heating from about 27 °C to about 80 °C and a weight loss of about 3.2% on heating from about 110 °C to about 200 °C, as characterized by TGA; or (ii) is characterized by a thermogravimetric analysis pattern that substantially matches the TGA pattern shown in FIG. 24; or (e) a combination of any of (a)-(d). (d) (i) exhibits a weight loss of about 0.5% on heating from about 25 °C to about 80 °C and a weight loss of about 7.4% on heating from about 100 °C to about 190 °C, as characterized by TGA; or (ii) is characterized by a thermogravimetric analysis profile that substantially matches the TGA profile shown in Figure 26; or (e) a combination of any of (a)-(e).

79. The solid form of claim 75, wherein the solid form has a molar ratio of Compound 1 / 1-hydroxy-2-naphthoic acid of about 1 : 1, wherein the solid form is an anhydrate.

80. The solid form of claim 75 or claim 79, wherein the solid form is Compound 1 (Form 13).

81. The solid form of any one of claims 75, 79, or 80, characterized by an XRPD pattern comprising peaks at approximately 16.6°, 18.1°, 19.1°, and 24.7° 2Q when measured using Cu Ka radiation.

82. The solid form of claim 81, wherein the XRPD pattern further comprises peaks at approximately 8.9°, 12.5°, 14.7°, 19.7°, 21.6°, and 29.7° 2Q, optionally the XRPD pattern further comprises peaks at approximately 11.8°, 12.0°, 15.4°, 23.3°, 25.8°, and 27.9° 2Q.

83. The solid form of any one of claims 75 or 79 to 82, characterized by an XRPD pattern that substantially matches the XRPD pattern shown in Figure 27.

84. The solid form of any one of claims 75 or 79 to 83, exhibiting a thermal (endothermic, melting / decomposition) event with an onset temperature of about 187 °C and / or an endothermic peak at about 194 °C, as characterized by DSC at a temperature ramp of about 10 °C / minute.

85. The solid form of any one of claims 75 or 79 to 84, characterized by a differential scanning calorimetry pattern that substantially matches the DSC pattern shown in Figure 28.

86. The solid form of any one of claims 75 or 79 to 85, which does not exhibit a weight loss below about 160 °C, as characterized by TGA.

87. The solid form of any one of claims 75 or 79 to 86, characterized by a thermogravimetric analysis profile that substantially matches the TGA profile shown in Figure 28.

88. The solid form of any one of claims 79 to 87, wherein the solid form has: (a) a purity of at least 98%, 98.5%, 99%, or 99.5%; (b) solubility in SGF media of about 3.86, 4.05, and 4.12 at 0.5 hour, 2 hours, and 24 hours, respectively; (c) solubility of about 0.74 mg / mL, 0.82 mg / mL, and 0.78 mg / mL at 0.5 hour, 2 hours, and 24 hours, respectively, in FeSSIF media; or (d) a combination of any of (a)-(c).

89. The solid form of claim 23 or claim 24, wherein the pharmaceutically acceptable salt is a malate salt of Compound 1.

90. The solid form of claim 89, wherein the solid form has a molar ratio of Compound 1 / malic acid of about 1 : 1, optionally wherein the solid form is a hydrate.

91. The solid form of claim 89 or claim 90, wherein the solid form is Compound 1 (Form 14).

92. The solid form of any one of claims 89-91, which: (a) is characterized by an XRPD pattern comprising peaks at approximately 4.7°, 16.9°, 17.3°, 20.8°, and 22.7° 2Q, optionally the XRPD pattern further comprising peaks at approximately 8.3°, 12.5°, 13.0°, 14.5°, 16.3°, 19.1°, 23.5°, 24.6°, 25.5°, and 28.2° 2Q, optionally the XRPD pattern further comprising peaks at approximately 10.9°, 14.1°, 18.4°, 24.9°, 26.1°, 26.7°, and 27.1° 2Q, when measured using Cu K a radiation; (b) is characterized by an XRPD pattern that matches substantially the XRPD pattern shown in FIG. 29; (c) (i) exhibits thermal (endothermic) events with onset temperatures of about 28 °C and about 178 °C and / or endothermic peak temperatures at about 69 °C and about 216 °C, respectively, as characterized by DSC at a temperature ramp of about 10 °C / minute; or (ii) is characterized by a differential scanning calorimetry pattern that matches substantially the DSC pattern shown in FIG. 30; (d) (i) exhibits a weight loss of about 3.6% upon heating from about 30 °C to about 120 °C, as characterized by TGA; or (ii) is characterized by a thermogravimetric analysis pattern that matches substantially the TGA pattern shown in FIG. 30; or (e) a combination of any of (a)-(d).

93. The solid form of claim 89, wherein the solid form has a molar ratio of Compound 1 / malic acid of about 1 : 1, and wherein the solid form is a solvate.

94. The solid form of claim 89 or claim 93, wherein the solid form is Compound 1 (Form 15).

95. The solid form of any one of claims 89, 93, or 94, which: (a) is characterized by an XRPD pattern comprising peaks at about 11.1°, 12.5°, 16.6°, and 17.8° 2Q, optionally further comprising peaks at about 8.39°, 22.0°, 23.3°, and 25.5° 2Q, optionally further comprising peaks at about 13.9°, 14.7°, and 24.1° 2Q, when measured using Cu Kα radiation; (b) is characterized by an XRPD pattern that substantially matches the XRPD pattern shown in FIG. 31 ; (c) (i) exhibits thermal (endothermic) events with onset temperatures of about 127 °C and about 159 °C and / or endothermic peak temperatures at about 145 °C and about 182 °C, respectively, as characterized by DSC at a temperature ramp of about 10 °C / minute; or (ii) is characterized by a differential scanning calorimetry pattern that substantially matches the DSC pattern shown in FIG. 32; (d) (i) exhibits a weight loss of about 3.1% on heating from about 90 °C to about 160 °C and a weight loss of about 3.6% on heating from about 160 °C to about 190 °C, as characterized by TGA; or (ii) is characterized by a thermogravimetric analysis pattern that substantially matches the TGA pattern shown in FIG. 32; or (e) a combination of any of (a)-(d).

96. The solid form of claim 23 or claim 24, wherein the pharmaceutically acceptable salt is a maleate salt of Compound 1.

97. The solid form of claim 96, wherein the solid form has a molar ratio of Compound 1 / maleic acid of about 1 : 1, optionally wherein the solid form is a hydrate.

98. The solid form of claim 96 or claim 97, wherein the solid form is Compound 1 (Form 16).

99. The solid form of any one of claims 96 to 98, the solid form: (a) is characterized by an XRPD pattern comprising peaks at about 12.2°, 12.6°, 26.1°, and 29.2° 2Q, optionally further comprising peaks at about 4.8°, 16.7°, 24.7°, and 25.2° 2Q, optionally further comprising peaks at about 14.5°, 17.3°, and 24.3° 2Q, when measured using Cu Kα radiation; (b) is characterized by an XRPD pattern that substantially matches the XRPD pattern shown in FIG. 33; (c) (i) exhibits thermal (endothermic) events with onset temperatures of about 26 °C and about 198 °C and / or endothermic peak temperatures at about 53 °C and about 206 °C, respectively, as characterized by DSC at a temperature ramp of about 10 °C / minute; or (ii) is characterized by a differential scanning calorimetry pattern that substantially matches the DSC pattern shown in FIG. 34; (d) (i) exhibits a weight loss of about 1.8% on heating from about 24 °C to about 100 °C, as characterized by TGA; or (ii) is characterized by a thermogravimetric analysis pattern that substantially matches the TGA pattern shown in FIG. 34; or (e) a combination of any of (a)-(d). (e) a combination of any of (a)-(d).

100. The solid form of claim 96 or claim 97, wherein the solid form is Compound 1 (Form 17).

101. The solid form of any one of claims 96, 97, or 100, which solid form: (a) is characterized by an XRPD pattern comprising peaks at about 9.5°, 15.2°, and 18.6° 2Q, optionally further comprising peaks at about 4.8°, 8.2°, 16.6°, 17.3°, 20.9°, 27.0°, and 29.1° 2Q, optionally further comprising peaks at about 12.8°, 14.4°, 24.0°, 25.2°, and 25.7° 2Q, when measured using Cu Ka radiation; (b) is characterized by an XRPD pattern that matches substantially the XRPD pattern illustrated in FIG. 35; (c) (i) exhibits thermal (endothermic) events with onset temperatures of about 27 °C and about 195 °C and / or endothermic peak temperatures at about 60 °C and about 205 °C, respectively, as characterized by DSC at a temperature ramp of about 10 °C / minute; or (ii) is characterized by a differential scanning calorimetry pattern that matches substantially the DSC pattern illustrated in FIG. 36; (d) (i) exhibits a weight loss of about 1.2% when heated from about 26 °C to about 100 °C, as characterized by TGA; or (ii) is characterized by a thermogravimetric analysis pattern that matches substantially the TGA pattern illustrated in FIG. 36; or (e) a combination of any of (a)-(d).

102. The solid form of claim 23 or claim 24, wherein the pharmaceutically acceptable salt is a methanesulfonic acid (mesylate) salt of the Compound 1.

103. The solid form of claim 102, wherein the solid form has a molar ratio of Compound 1 / mesylate of about 1 :0.8, optionally wherein the solid form is a solvate.

104. The solid form of claim 102 or claim 103, wherein the solid form is Compound 1 (Form 18).

105. The solid form of any one of claims 102 to 104, which solid form: (a) is characterized by an XRPD pattern comprising peaks at about 9.0°, 9.2°, 18.6°, and 19.2° 2Q, optionally further comprising peaks at about 17.5°, 18.1°, and 23.1° 2Q, optionally further comprising peaks at about 20.4°, 21.0°, and 21.2° 2Q, when measured using Cu Ka radiation; (b) is characterized by an XRPD pattern that matches substantially the XRPD pattern illustrated in FIG. 37; (c) (i) exhibits thermal (endothermic) events with onset temperatures of about 27 °C and about 195 °C and / or endothermic peak temperatures at about 60 °C and about 205 °C, respectively, as characterized by DSC at a temperature ramp of about 10 °C / minute; or (ii) is characterized by a differential scanning calorimetry pattern that matches substantially the DSC pattern illustrated in FIG. 36; (d) (i) exhibits a weight loss of about 1.2% when heated from about 26 °C to about 100 °C, as characterized by TGA; or (ii) is characterized by a thermogravimetric analysis pattern that matches substantially the TGA pattern illustrated in FIG. 36; or (e) a combination of any of (a)-(d). (c) (i) exhibits a thermal (endothermic) event with an onset temperature of about 142 °C and / or an endothermic peak temperature at about 146 °C, as characterized by DSC at a temperature ramp of about 10 °C / minute; or (ii) is characterized by a differential scanning calorimogram that matches substantially the DSC pattern shown in FIG. 38; (d) (i) exhibits a weight loss of about 5.6% upon heating from about room temperature to about 145 °C and a weight loss of about 9.5% upon heating from about 145 °C to about 200 °C, as characterized by TGA; or (ii) is characterized by a thermogravimetric analysis pattern that matches substantially the TGA pattern shown in FIG. 38; or (e) a combination of any of (a)-(d).

106. The solid form of claim 23 or claim 24, wherein the pharmaceutically acceptable salt is an oxalate salt of Compound 1.

107. The solid form of claim 106, wherein the solid form has a molar ratio of Compound 1 / oxalic acid of about 1 : 1, optionally wherein the solid form is a solvate.

108. The solid form of claim 106 or claim 107, wherein the solid form is Compound 1 (Form 19).

109. The solid form of any one of claims 106-108, the solid form: (a) is characterized by an XRPD pattern comprising peaks at approximately 4.7°, 13.2°, 19.8°, and 25.0° 2Q, optionally the XRPD pattern further comprising peaks at approximately 8.5°, 11.4°, 14.2°, 15.7°, and 17.1° 2Q, optionally the XRPD pattern further comprising peaks at approximately 8.8°, 9.7°, 20.5°, and 25.9° 2Q, when measured using Cu Kα radiation; (b) is characterized by an XRPD pattern that matches substantially the XRPD pattern shown in FIG. 39; (c) (i) exhibits a thermal (endothermic) event with onset temperatures of about 92 °C, about 137 °C, and about 194 °C and / or endothermic peak temperatures at about 137 °C, about 190 °C, and about 194 °C, respectively, as characterized by DSC at a temperature ramp of about 10 °C / minute; or (ii) is characterized by a differential scanning calorimogram that matches substantially the DSC pattern shown in FIG. 40; (d) (i) exhibits a weight loss of about 7.4% upon heating from about 90 °C to about 190 °C and a weight loss of about 19.0% upon heating from about 190 °C to about 240 °C, as characterized by TGA; or (ii) is characterized by a thermogravimetric analysis pattern that matches substantially the TGA pattern shown in FIG. 40; or (e) a combination of any of (a)-(d).

110. The solid form of claim 23 or claim 24, wherein the pharmaceutically acceptable salt is a phosphate salt of Compound 1.

111. The solid form of claim 110, wherein the solid form is a monophosphate salt of Compound 1, optionally wherein the solid form is a hydrate.

112. The solid form of claim 110 or claim 111, wherein the solid form is Compound 1 (Form 20).

113. The solid form of any one of claims 110 to 112, which: (a) is characterized by an XRPD pattern comprising peaks at about 9.4°, 15.1°, 16.6°, and 18.2° 2Q, optionally further comprising peaks at about 8.5°, 10.6°, 12.3°, 14.1°, 17.5°, 20.1°, 22.5°, and 23.6° 2Q, optionally further comprising peaks at about 11.1°, 12.8°, 22.0°, 24.4°, 25.3°, 26.9°, and 31.7° 2Q, when measured using Cu Ka radiation; (b) is characterized by an XRPD pattern that matches substantially the XRPD pattern illustrated in FIG. 41; (c) (i) exhibits a thermal (endothermic) event with an onset temperature of about 34 °C and / or an endothermic peak temperature at about 74 °C, as characterized by DSC at a temperature ramp of about 10 °C / minute; or (ii) is characterized by a differential scanning calorimetry pattern that matches substantially the DSC pattern illustrated in FIG. 42; (d) (i) exhibits a weight loss of about 4.5% when heated from about 25 °C to about 110 °C, as characterized by TGA; or (ii) is characterized by a thermogravimetric analysis pattern that matches substantially the TGA pattern illustrated in FIG. 42; or (e) a combination of any of (a)-(d).

114. The solid form of claim 23 or claim 24, wherein the pharmaceutically acceptable salt is a tartrate salt of Compound 1.

115. The solid form of claim 114, wherein the solid form has a molar ratio of Compound 1 / tartrate of about 1 : 1, optionally wherein the solid form is a hydrate.

116. The solid form of claim 114 or claim 115, wherein the solid form is Compound 1 (Form 21).

117. The solid form of any one of claims 110 to 112, which: (a) is characterized by an XRPD pattern comprising peaks at about 13.2°, 16.9°, 17.2°, 17.7°, 18.4°, and 25.3° 2Q, optionally further comprising peaks at about 8.3°, 12.3°, 20.9°, and 24.0° 2Q, optionally further comprising peaks at about 14.5°, 19.9°, and 22.4° 2Q, when measured using Cu Ka radiation; (b) is characterized by an XRPD pattern that matches substantially the XRPD pattern illustrated in FIG. 43; (c) (i) exhibits a thermal (endothermic) event with an onset temperature of about 34 °C and / or an endothermic peak temperature at about 74 °C, as characterized by DSC at a temperature ramp of about 10 °C / minute; or (ii) is characterized by a differential scanning calorimetry pattern that matches substantially the DSC pattern illustrated in FIG. 42; (d) (i) exhibits a weight loss of about 4.5% when heated from about 25 °C to about 110 °C, as characterized by TGA; or (ii) is characterized by a thermogravimetric analysis pattern that matches substantially the TGA pattern illustrated in FIG. 42; or (e) a combination of any of (a)-(d). (c) (i) exhibits thermal (endothermic) events with onset temperatures at about 29 °C and about 201 °C and / or endothermic peak temperatures at about 70 °C and about 204 °C, as characterized by DSC at a temperature ramp of about 10 °C per minute; or (ii) is characterized by a differential scanning calorimetry pattern that matches substantially the DSC pattern shown in FIG. 44; (d) (i) exhibits a weight loss of about 6.8% when heated from about 30 °C to about 140 °C, as characterized by TGA; or (ii) is characterized by a thermogravimetric analysis pattern that matches substantially the TGA pattern shown in FIG. 44; or (e) a combination of any of (a)-(d).

118. The solid form of claim 114, wherein the solid form has a molar ratio of Compound 1 / tartaric acid of about 1 : 1, and wherein the solid form is a solvate.

119. The solid form of claim 114 or claim 118, wherein the solid form is Compound 1 (Form 22).

120. The solid form of any one of claims 114, 118, or 119, which: (a) is characterized by an XRPD pattern comprising peaks at approximately 10.6°, 11.2°, 16.6°, 17.6°, 18.1°, and 22.5° 2Q, optionally further comprising peaks at approximately 8.5°, 14.6°, 22.0°, 25.2°, 25.6°, and 29.9° 2Q, optionally further comprising peaks at approximately 12.3°, 14.2°, 23.7°, 23.9°, and 27.4° 2Q, when measured using Cu Kα radiation; (b) is characterized by an XRPD pattern that matches substantially the XRPD pattern shown in FIG. 45; (c) (i) exhibits thermal (endothermic) events with onset temperatures at about 27 °C, about 106 °C, and about 209 °C and / or endothermic peak temperatures at about 51 °C, about 141 °C, and about 222 °C, as characterized by DSC at a temperature ramp of about 10 °C per minute; or (ii) is characterized by a differential scanning calorimetry pattern that matches substantially the DSC pattern shown in FIG. 46; (d) (i) exhibits a weight loss of about 2.8% when heated from about 80 °C to about 170 °C, as characterized by TGA; or (ii) is characterized by a thermogravimetric analysis pattern that matches substantially the TGA pattern shown in FIG. 46; or (e) a combination of any of (a)-(d).

121. The solid form of claim 23 or claim 24, wherein the pharmaceutically acceptable salt is a p-toluenesulfonic acid (tosylate) salt of Compound 1.

122. The solid form of claim 121, wherein the solid form has a molar ratio of Compound 1 / p-toluenesulfonic acid of about 1 :0.8, optionally wherein the solid form is a solvate.

123. The solid form of claim 114 or claim 115, wherein the solid form is Compound 1 (Form 23).

124. The solid form of any one of claims 121-123: (a) characterized by an XRPD pattern comprising peaks at about 8.5°, 14.6°, 18.1°, and 21.7° 2Q, optionally further comprising peaks at about 6.8°, 17.7°, and 23.8° 2Q, optionally further comprising peaks at about 18.8° and 22.9° 2Q, when measured using Cu Ka radiation; (b) characterized by an XRPD pattern substantially matching the XRPD pattern illustrated in FIG. 47; (c) (i) exhibiting thermal (endothermic) events with onset temperatures of about 83 °C and about 186 °C and / or endothermic peak temperatures at about 120 °C and about 202 °C, respectively, as characterized by DSC at a temperature ramp of about 10 °C / minute; or (ii) characterized by a differential scanning calorimetry pattern substantially matching the DSC pattern illustrated in FIG. 48; (d) (i) exhibiting a weight loss of about 1.8% upon heating from about room temperature to about 100 °C and a weight loss of about 5.6% upon heating from about 100 °C to about 180 °C, as characterized by TGA; or (ii) characterized by a thermogravimetric analysis pattern substantially matching the TGA pattern illustrated in FIG. 48; or (e) a combination of any one of (a)-(d).

125. The solid form of claim 3, wherein the solid form is an anhydrate of Compound 1 free base.

126. The solid form of claim 125, wherein the solid form is Compound 1 (Form 24).

127. The solid form of any one of claims 5, 125, or 126: (a) characterized by an XRPD pattern comprising peaks at about 9.5°, 11.8°, 14.6°, and 20.9° 2Q, optionally further comprising peaks at about 14.8°, 16.4°, 22.3°, and 23.8° 2Q, optionally further comprising peaks at about 16.6°, 17.1°, 24.2°, and 25.1° 2Q, when measured using Cu Ka radiation; (b) characterized by an XRPD pattern substantially matching the XRPD pattern illustrated in FIG. 49; (c) (i) exhibiting thermal (endothermic) events with onset temperatures of about 240 °C and / or an endothermic peak at about 246 °C, as characterized by DSC at a temperature ramp of about 10 °C / minute; or (ii) characterized by a differential scanning calorimetry pattern substantially matching the DSC pattern illustrated in FIG. 50; (d) (i) exhibiting no weight loss upon heating to about 200 °C, as characterized by TGA; or (ii) characterized by a thermogravimetric analysis pattern substantially matching the TGA pattern illustrated in FIG. 50; or (e) a combination of any one of (a)-(d).

128. A pharmaceutically acceptable salt of Compound 1: ， or an isotopolog of thereof, or a pharmaceutically acceptable solvate of said pharmaceutically acceptable salt.

129. The compound of claim 128, wherein the pharmaceutically acceptable salt is a benzoate, a besylate, a chloride, a citrate, a fumarate, a gentisate, a glutarate, a glycolate, a hippurate, a 1-hydroxy-2-naphthoate, a malate, a maleate, a mesylate, an oxalate, a phosphate, a sulfate, a tartrate, or a tosylate.

130. The compound of claim 128 or claim 129, wherein the pharmaceutically acceptable salt has a molar ratio of Compound 1 / conjugate acid ranging from about 2: 1 to about 1 :

2.

131. The compound of any one of claims 128-130, wherein the pharmaceutically acceptable salt of Compound 1 is S )-3-amino-3-(l-methyl-l H -oxa-2(4, 6)-quinolene-l, 4(l,3)-dibenzo cyclohexane-2 2 , 4 4 -dicyanobenzoic acid salt or a pharmaceutically acceptable solvate thereof.

132. The compound of claim 131, wherein the pharmaceutically acceptable salt has a molar ratio of Compound 1 / benzoic acid of about 1 :

1.

133. The compound of any one of claims 128-130, wherein the pharmaceutically acceptable salt of Compound 1 is (S)-3-amino-3-(l-methyl-lH-imidazol-5-yl)-6-oxa-2(4, 6)- quinolene- 1,4(l,3)-dibenzo cyclohexane-2 2 , 4 4 -dicarbonitrile besylate or a pharmaceutically acceptable solvate thereof.

134. The compound of any one of claims 128-130, wherein the pharmaceutically acceptable salt of Compound 1 is S )-3-amino-3-(l-methyl-l H -oxa-2(4, 6)-quinolene-l, 4(l,3)-dibenzo cyclohexane-2 2 , 4 4 -dicarbonitrile chloride salt or a pharmaceutically acceptable solvate thereof.

135. The compound of any one of claims 128-130, wherein the pharmaceutically acceptable salt of Compound 1 is ( S )-3-amino-3-(l-methyl-l H -oxa-2(4, 6)-quinolene-l, 4(l,3)-dibenzo cyclohexane-2 2 , 4 4 -dicarbonitrile citrate or a pharmaceutically acceptable solvate thereof.

136. The compound of any one of claims 128-130, wherein the pharmaceutically acceptable salt of Compound 1 is S )-3-amino-3-(l-methyl-l H -oxa-2(4, 6)-quinolene-l, 4(l,3)-dibenzo cyclohexane-2 2 , 4 4 -dicarbonitrile fumarate or a pharmaceutically acceptable solvate thereof.

137. The compound of claim 136, wherein the pharmaceutically acceptable salt has a molar ratio of Compound 1 / fumaric acid of about 1 :

1.

138. The compound of any one of claims 128-130, wherein the pharmaceutically acceptable salt of Compound 1 is ( S) -3-amino-3-(l-methyl-l H -oxa-2(4, 6)-quinol-1, 4(1,3)-diphenoxazin-2 2 , 4 4 -dicarbonitrile gentisate salt or a pharmaceutically acceptable solvate thereof.

139. The compound of any one of claims 128-130, wherein the pharmaceutically acceptable salt of Compound 1 is S )-3-amino-3-(l-methyl-l H -oxa-2(4, 6)-quinolene-l, 4(l,3)-dibenzo cyclohexane-2 2 , 4 4 -dicarbonitrile glutarate salt or a pharmaceutically acceptable solvate thereof.

140. The compound of any one of claims 128-130, wherein the pharmaceutically acceptable salt of Compound 1 is S )-3-amino-3-(l-methyl-l H -oxa-2(4, 6)-quinolene-l, 4(l,3)-dibenzo cyclohexane-2 2 , 4 4 -dicarbonitrile glycolate or a pharmaceutically acceptable solvate thereof.

141. The compound of any one of claims 128-130, wherein the pharmaceutically acceptable salt of Compound 1 is S )-3-amino-3-(l-methyl-l H -oxa-2(4, 6)-quinolene-l, 4(l,3)-dibenzo cyclohexane-2 2 , 4 4 -dicarbonitrile hippurate or a pharmaceutically acceptable solvate thereof.

142. The compound of any one of claims 128-130, wherein the pharmaceutically acceptable salt of Compound 1 is S )-3-amino-3-(l-methyl-l H -oxa-2(4, 6)-quinolene-1, 4(1,3)-dibenzo cyclohexane-2 2 , 4 4 -dicarbonitrile 1 -hydroxy-2-naphthoate or a pharmaceutically acceptable solvate thereof.

143. The compound of claim 142, wherein the pharmaceutically acceptable salt has a molar ratio of Compound 1 / 1-hydroxy-2-naphthoic acid of about 1 :

1.

144. The compound of any one of claims 128-130, wherein the pharmaceutically acceptable salt of Compound 1 is S )-3-amino-3-(l-methyl-l H -oxa-2(4, 6)-quinolene-l, 4(l,3)-dibenzo cyclohexane-2 2 , 4 4 -dicyanomaleate or a pharmaceutically acceptable solvate thereof.

145. The compound of any one of claims 128-130, wherein the pharmaceutically acceptable salt of Compound 1 is ( S )-3-amino-3-(l-methyl-l H - imidazol-5-yl)-6-oxa-2(4, 6)-quinolene-1, 4(1,3)-dibenzo cyclohexane-2 2 , 4 4 -dicarbonitrile maleate salt or a pharmaceutically acceptable solvate thereof.

146. The compound of any one of claims 128-130, wherein the pharmaceutically acceptable salt of Compound 1 is S) -3-amino-3-(l-methyl-l H - imidazol-5-yl)-6-oxa-2(4, 6)- quinolene- 1,4(l,3)-dibenzo cyclohexane-2 2 , 4 4 -dicyanomethanesulfonate or a pharmaceutically acceptable solvate thereof.

147. The compound of any one of claims 128-130, wherein the pharmaceutically acceptable salt of Compound 1 is S) -3-amino-3-(l-methyl-l H - imidazol-5-yl)-6-oxa-2(4, 6)- quinolene- 1,4(l,3)-dibenzo cyclohexane-2 2 , 4 4 -dicarbonitrile oxalate salt or a pharmaceutically acceptable solvate thereof.

148. The compound of any one of claims 128-130, wherein the pharmaceutically acceptable salt of Compound 1 is S )-3-amino-3-(l-methyl-l H -oxa-2(4, 6)-quinolene-1, 4(1,3)-dibenzo cyclohexane-2 2 , 4 4 -dicarbonitrile phosphate or a pharmaceutically acceptable solvate thereof.

149. The compound according to any one of claims 128 to 130, wherein the pharmaceutically acceptable salt of Compound 1 is ( S )-3-amino-3-(l-methyl-l H -oxa-2(4, 6)-quinolene-l, 4(1, 3)-dibenzo-cyclohexane-2 2 , 4 4 -dicarbonitrile sulfate or a pharmaceutically acceptable solvate thereof.

150. The compound according to any one of claims 128 to 130, wherein the pharmaceutically acceptable salt of Compound 1 is ( S )-3-amino-3-(1-methyl-1 H -oxa-2(4, 6)-quinolene-1, 4(1, 3)-dibenzo-cyclohexane-2 2 , 4 4 -dicarbonitrile tartrate salt or a pharmaceutically acceptable solvate thereof.

151. The compound according to any one of claims 128 to 130, wherein the pharmaceutically acceptable salt of Compound 1 is S )-3-amino-3-(l-methyl-l H -oxa-2(4, 6)-quinolene-l, 4(l,3)-dibenzo-cyclohexane-2 2 , 4 4 -dicyanotoluene sulfonate or a pharmaceutically acceptable solvate thereof.

152. The compound of any one of claims 128-151, wherein the pharmaceutically acceptable salt of Compound 1 is a non-solvate of the pharmaceutically acceptable salt of Compound 1.

153. The compound of any one of claims 128-151, wherein the pharmaceutically acceptable salt of Compound 1 is an anhydrate of the pharmaceutically acceptable salt of Compound 1.

154. The compound of any one of claims 128-151, wherein the pharmaceutically acceptable salt of Compound 1 is a pharmaceutically acceptable solvate of the pharmaceutically acceptable salt of Compound 1.

155. The compound of claim 154, wherein the pharmaceutically acceptable solvate is a hydrate, a hemi-hydrate, isobutyl acetate, isopropyl acetate, tetrahydrofuran solvate, acetone solvate, acetonitrile solvate, or a combination thereof.

156. The compound of claim 154, wherein the pharmaceutically acceptable solvate has a molar ratio of Compound 1 / solvent ranging from about 2: 1 to about 1 :

2.

157. The compound of claim 156, wherein the molar ratio of Compound 1 / solvent is about 1 :

1.

158. The compound of any one of claims 154-157, wherein the pharmaceutically acceptable solvate is a hydrate.

159. A pharmaceutical composition comprising: i) a solid form comprising Compound 1, or a pharmaceutically acceptable salt and / or solvate thereof: ， in an amount of about 0.1 mg to about 200 mg, and ii) one or more pharmaceutically acceptable excipients.

160. The pharmaceutical composition of claim 159, wherein the solid form is crystalline.

161. The pharmaceutical composition of claim 159 or claim 160, wherein the amount of Compound 1 is about 0.2 mg free base equivalent.

162. The pharmaceutical composition of claim 159 or claim 160, wherein the amount of Compound 1 is about 1.0 mg free base equivalent.

163. The pharmaceutical composition of claim 159 or claim 160, wherein the amount of Compound 1 is about 10 mg free base equivalent.

164. The pharmaceutical composition of claim 159 or claim 160, wherein the amount of Compound 1 is about 50 mg free base equivalent.

165. The pharmaceutical composition of any one of claims 159 to 164, wherein the solid form is according to any one of claims 3 to 127.

166. The pharmaceutical composition of claim 165, wherein the solid form is according to claim 11.

167. The pharmaceutical composition of claim 165, wherein the solid form is Compound 1 (Form 1).

168. The pharmaceutical composition of any one of claims 159 to 167, wherein the pharmaceutical composition is formulated as an immediate release oral dosage form.

169. The pharmaceutical composition of any one of claims 159 to 168, wherein the pharmaceutical composition is a tablet.

170. The pharmaceutical composition of claim 169, wherein the tablet is a coated tablet.

171. The pharmaceutical composition of any one of claims 159 to 170, wherein the one or more pharmaceutically acceptable excipients comprise a filler, a glidant, a disintegrant, a lubricant, or a binder, or a combination thereof.

172. The pharmaceutical composition of any one of claims 159 to 170, wherein the pharmaceutical composition comprises a filler.

173. The pharmaceutical composition of claim 172, wherein the filler is present in an amount of about 40% w / w to about 95% w / w.

174. The pharmaceutical composition of claim 172 or claim 173, wherein the filler is silicified microcrystalline cellulose, microcrystalline cellulose, D-mannitol, or a combination thereof.

175. The pharmaceutical composition of any one of claims 172 to 174, wherein the filler is silicified microcrystalline cellulose.

176. The pharmaceutical composition of claim 175, wherein (a) the solid form is present in an amount of about 0.1 mg to about 25 mg free base equivalent, and the silicified microcrystalline cellulose is present in an amount of about 70% w / w to about 97% w / w, or (b) the solid form is present in an amount of about 25 mg to about 200 mg free base equivalent, and the silicified microcrystalline cellulose is present in an amount of about 40% w / w to about 70% w / w.

177. The pharmaceutical composition of claim 176, wherein the solid form is present in an amount of about 0.2 mg free base equivalent, and the silicified microcrystalline cellulose is present in an amount of about 75% w / w to about 95% w / w and about 73 mg to about 75.4 mg.

178. The pharmaceutical composition of claim 176, wherein the solid form is present in an amount of about 1.0 mg free base equivalent and the silicified microcrystalline cellulose is present in an amount of about 75% w / w to about 95% w / w and (a) about 80 mg to about 380 mg, or (b) about 80 mg to about 90 mg, or (c) about 370 mg to about 378 mg.

179. The pharmaceutical composition of claim 176, wherein the solid form is present in an amount of about 10 mg free base equivalent and the silicified microcrystalline cellulose is present in an amount of about 75% w / w to about 95% w / w and about 75 mg to about 85 mg.

180. The pharmaceutical composition of claim 176, wherein the solid form is present in an amount of about 50 mg free base equivalent and the silicified microcrystalline cellulose is present in an amount of about 40% w / w to about 50% w / w and about 40 mg to about 50 mg, or the silicified microcrystalline cellulose is present in an amount of about 60% w / w to about 70% w / w and about 60 mg to about 70 mg.

181. The pharmaceutical composition of any one of claims 159 to 180, wherein the pharmaceutical composition comprises a glidant.

182. The pharmaceutical composition of claim 181, wherein the amount of glidant is colloidal silicon dioxide.

183. The pharmaceutical composition of claim 182, wherein the colloidal silicon dioxide is present in an amount of about 0.5% w / w to about 5% w / w, or about 0.5% w / w, about 1.0% w / w, or about 1.5% w / w, or about 1.0% w / w.

184. The pharmaceutical composition of any one of claims 159 to 183, wherein the pharmaceutical composition comprises a disintegrant.

185. The pharmaceutical composition of claim 184, wherein the disintegrant is croscarmellose sodium.

186. The pharmaceutical composition of claim 184 or 185, wherein the disintegrant is present in an amount of about 1% w / w to about 6% w / w, or about 2.0% w / w, about 2.5% w / w, about 3.0% w / w, about 3.5% w / w, or about 4.0% w / w, or about 3.0% w / w.

187. The pharmaceutical composition of any one of claims 159 to 186, wherein the pharmaceutical composition comprises a lubricant.

188. The pharmaceutical composition of claim 187, wherein the lubricant is magnesium stearate.

189. The pharmaceutical composition of claim 187 or claim 188, wherein the lubricant is present in an amount of about 0.5% w / w to about 2.5% w / w, or about 0.5% w / w, about 1.0% w / w, about 1.5% w / w, or about 2.0% w / w, or about 1.0% w / w, or about 1.5% w / w.

190. The pharmaceutical composition of any one of claims 159 to 189, wherein the pharmaceutical composition comprises a binder.

191. The pharmaceutical composition of claim 190, wherein the binder is povidone.

192. The pharmaceutical composition of claim 190 or claim 191, wherein the binder is present in an amount of about 3% w / w to about 10% w / w and about 3 mg to about 15 mg.

193. The pharmaceutical composition of claim 192, comprising: (a) a core tablet comprising about 0.21 mg Compound 1 (Form 1), about 75.4 mg silicified microcrystalline cellulose, about 0.8 mg colloidal silicon dioxide, about 2.4 mg croscarmellose sodium, and about 1.2 mg magnesium stearate; and (b) a tablet coating.

194. The pharmaceutical composition of claim 192, comprising: (a) a core tablet comprising about 1.03 mg Compound 1 (Form 1), about 377.0 mg silicified microcrystalline cellulose, about 4.0 mg colloidal silicon dioxide, about 12.0 mg croscarmellose sodium, and about 6.0 mg magnesium stearate; and (b) a tablet coating.

195. The pharmaceutical composition of claim 192, comprising: (a) a core tablet comprising about 10.3 mg Compound 1 (Form 1), about 84.2 mg silicified microcrystalline cellulose, about 1.0 mg colloidal silicon dioxide, about 3.0 mg croscarmellose sodium, and about 1.5 mg magnesium stearate; and (b) a tablet coating.

196. The pharmaceutical composition of claim 192, comprising: (a) a core tablet comprising about 51.5 mg Compound 1 (Form 1), about 43.0 mg silicified microcrystalline cellulose, about 1.0 mg colloidal silicon dioxide, about 3.0 mg croscarmellose sodium, and about 1.5 mg magnesium stearate; and (b) a tablet coating; or (a) a core tablet comprising about 51.4 mg Compound 1 (Form 1), about 43.1 mg silicified microcrystalline cellulose, about 1.0 mg colloidal silicon dioxide, about 3.0 mg croscarmellose sodium, and about 1.5 mg magnesium stearate; and (b) a tablet coating.

197. The pharmaceutical composition of claim 196, wherein the core tablet comprises: (a) an intragranular portion comprising 51.5 mg Compound 1 (Form 1), about 43.0 mg silicified microcrystalline cellulose, about 1.0 mg colloidal silicon dioxide, about 2.0 mg croscarmellose sodium, and about 1.0 mg magnesium stearate; and (b) an extragranular portion comprising about 1.0 mg croscarmellose sodium and about 0.5 mg magnesium stearate; or (a) an intragranular portion comprising 51.4 mg Compound 1 (Form 1), about 43.1 mg silicified microcrystalline cellulose, about 1.0 mg colloidal silicon dioxide, about 2.0 mg croscarmellose sodium, and about 1.0 mg magnesium stearate; and (b) an extragranular portion comprising about 1.0 mg croscarmellose sodium and about 0.5 mg magnesium stearate. ​ (a) an intragranular portion comprising 51.4 mg of Compound 1 (Form 1), about 43.1 mg of silicified microcrystalline cellulose, about 1.0 mg of colloidal silicon dioxide, about 2.0 mg of croscarmellose sodium, and about 1.0 mg of magnesium stearate; and (b) an extragranular portion comprising about 1.0 mg of croscarmellose sodium and about 0.5 mg of magnesium stearate.

198. The pharmaceutical composition of claim 192, comprising: (a) a core tablet comprising about 1.03 mg of Compound 1 (Form 1), about 5.0 mg of povidone, about 88.97 mg of silicified microcrystalline cellulose, about 1.0 mg of colloidal silicon dioxide, about 3.0 mg of croscarmellose sodium, and about 1.0 mg of magnesium stearate; and (b) a tablet coating.

199. The pharmaceutical composition of claim 192, comprising: (a) a core tablet comprising about 10.3 mg of Compound 1 (Form 1), about 5.0 mg of povidone, about 79.7 mg of silicified microcrystalline cellulose, about 1.0 mg of colloidal silicon dioxide, about 3.0 mg of croscarmellose sodium, and about 1.0 mg of magnesium stearate; and (b) a tablet coating.

200. The pharmaceutical composition of claim 192, comprising: (a) a core tablet comprising about 52 mg of Compound 1 (Form 1), about 10.0 mg of povidone, about 128 mg of silicified microcrystalline cellulose, about 2.0 mg of colloidal silicon dioxide, about 6.0 mg of croscarmellose sodium, and about 2.0 mg of magnesium stearate; and (b) a tablet coating.

201. The pharmaceutical composition of claim 200, wherein the core tablet comprises: (a) an intragranular portion comprising the Compound 1 (Form 1), the silicified microcrystalline cellulose, the colloidal silicon dioxide, the croscarmellose sodium, and the povidone; and (b) an extragranular portion comprising the magnesium stearate.

202. The pharmaceutical composition of any one of claims 170-201, wherein the tablet coating is a spray-dried film coating.

203. The pharmaceutical composition of any one of claims 170-201, wherein the tablet coating comprises a polymer, a plasticizer, and a pigment.

204. The pharmaceutical composition of any one of claims 170-201, wherein the tablet coating comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc.

205. A method of making the pharmaceutical composition of any one of claims 169-201, the method comprising: i) optionally, deagglomerating the solid form of Compound 1 or a pharmaceutically acceptable salt and / or solvate thereof; ii) mixing the solid form of Compound 1 or a pharmaceutically acceptable salt and / or solvate thereof with a first portion of a disintegrant, a glidant, and a filler to form a first blend; iii) deagglomerating the first blend to form a deagglomerated first blend; iv) deagglomerating a second portion of the filler; v) blending the deagglomerated first blend and the deagglomerated second portion of the filler to form a second blend; vi) blending the second blend with a lubricant to form a lubricated blend; and vii) optionally compressing the lubricated blend into a tablet using a rotary press.

206. The method of claim 205, wherein the method further comprises viii) coating the compressed tablet.

207. The method of claim 206, wherein the coating is a spray-dried film coating.

208. The method of any one of claims 205 to 207, optionally wherein the method further comprises ix) packaging the film-coated tablet into a container.

209. The method of any one of claims 205 to 208, wherein the amount of the solid form of Compound 1, or a pharmaceutically acceptable salt and / or solvate thereof, present in the pharmaceutical composition is about 0.2 mg, about 1 mg, or about 10 mg free base equivalent.

210. A method of making the pharmaceutical composition of any one of claims 169 to 201, the method comprising: i) optionally, deagglomerating the solid form of Compound 1, or a pharmaceutically acceptable salt and / or solvate thereof; ii) mixing the solid form of Compound 1, or a pharmaceutically acceptable salt and / or solvate thereof, with a first portion of a filler, a glidant, and a disintegrant to form a first blend; iii) deagglomerating the first blend and then blending the first blend to form a second blend; iv) blending the second blend with a first portion of a lubricant to form a lubricated intra-granular blend; v) forming granules from the intra-granular blend; vi) blending the granules with a second portion of the disintegrant and a second portion of the lubricant to form a lubricated final blend; and vii) optionally compressing the lubricated final blend into a tablet using a rotary press.

211. The method of claim 210, wherein the method further comprises viii) coating the compressed tablet; optionally, wherein forming granules from the intra-granular blend is performed using a roller compactor and a screen.

212. The method of claim 211, wherein the coating is a spray-dried film coating.

213. The method of any one of claims 210 to 212, optionally wherein the method further comprises ix) packaging the film-coated tablet into a container.

214. The method of any one of claims 210 to 213, wherein the amount of the solid form of Compound 1, or a pharmaceutically acceptable salt and / or solvate thereof, present in the film-coated tablet is 50 mg free base equivalent.

215. A method of making the pharmaceutical composition of any one of claims 169 to 201, the method comprising: i) optionally, deagglomerating the solid form of Compound 1, or a pharmaceutically acceptable salt and / or solvate thereof; ii) granulating the solid form of Compound 1, or a pharmaceutically acceptable salt and / or solvate thereof, a filler, a glidant, and a disintegrant with a binder and water to form wet granules; iii) drying the wet granules to form dry granules; iv) blending the granules with a lubricant to form a lubricated final blend; and v) optionally compressing the lubricated final blend into tablets with a rotary press.

216. The method of claim 215, wherein the method further comprises vii) coating the compressed tablets; optionally, wherein forming granules from the intra-granular blend is performed with a high shear granulator and a screen.

217. The method of claim 216, wherein the coating is a spray-dried film coating.

218. The method of any one of claims 215 to 217, optionally, wherein the method further comprises viii) packaging the film-coated tablets into a container.

219. The method of any one of claims 215 to 218, wherein the amount of the solid form of Compound 1, or a pharmaceutically acceptable salt and / or solvate thereof, present in the film-coated tablets is 1 mg, 10 mg, or 50 mg free base equivalent.

220. A method for preparing Compound 1: or a pharmaceutically acceptable form thereof, the method comprising: ， (a) reacting racemic Compound 19: with a chiral acid in a solvent to form a diastereomeric salt of Compound 1 and a diastereomeric salt of Compound 2: wherein one of the two diastereomeric salts selectively precipitates from the solvent and the other of the two diastereomeric salts is selectively soluble in the solvent; (b) separating the precipitate from the solvent; ， (c) reacting the diastereomeric salt of Compound 1 with a base to provide Compound 1, and ， (d) optionally, recrystallizing Compound 1, optionally from ACN / water in a ratio of about 2: 1 to about 1 :5, optionally about 1 : 1 to about 1 :

3.

223. The method of claim 222, wherein the chiral acid is dibenzoyl-D-tartaric acid and the diastereomeric salt of Compound 1 is the diastereomeric salt that is selectively soluble in the solvent.

224. The method of claim 222, wherein the chiral acid is dibenzoyl-L-tartaric acid and the diastereomeric salt of Compound 1 is the diastereomeric salt that selectively precipitates from the solvent.

225. The method of any one of claims 220 to 224, wherein the base is Na2C03, K2C03, NaOH, or KOH, or wherein the base is Na2C03.

221. The method of claim 220, wherein the chiral acid is ( R )-chlorocyclophosphoric acid, ( S )-chlorocyclophosphoric acid, (+)-tartaric acid, (-)-tartaric acid, (+)-camphorsulfonic acid, (-)-camphorsulfonic acid, L-(-)-di-p- methoxybenzoyltartaric acid, D-(+)-di-p-methoxybenzoyltartaric acid, L-(-)-di-toluoyltartaric acid, D-(+)-di-toluoyltartaric acid, ( R )-BINAP phosphoric acid, ( S )-BINAP phosphoric acid, dibenzoyl-l-tartaric acid, or dibenzoyl-D-tartaric acid.

222. The method of claim 220, wherein (a) the chiral acid is dibenzoyl-D-tartaric acid or dibenzoyl-L-tartaric acid and the solvent is acetone or DCM, or (b) the chiral acid is ( R )-BINAP phosphoric acid or ( S )-BINAP phosphoric acid and the solvent is dioxane, acetone, ACN, IPAc, MEK, THF, 2-MeTHF, dioxolane, or ethylene glycol dimethyl ether, or the solvent is THF or dioxolane.

226. The method of any one of claims 222 to 225, wherein the solvent is DCM.

227. The method of any one of claims 220 to 226, comprising reacting Compound 18: ​ ​ ​ ， with an amine equivalent to form compound 19.

228. The method of claim 227, wherein the amine equivalent is NH3, optionally in an amount of about 15 equivalents to about 50 equivalents, or about 40 equivalents to 50 equivalents, wherein the reaction of compound 18 is conducted in a polar solvent, wherein the polar solvent is optionally selected from IPA, EtOH, MeOH, 1, 4-dioxane, DMI, and mixtures thereof, optionally wherein the polar solvent is MeOH, optionally wherein the reaction of compound 18 is conducted at a temperature of about 0 °C to about 40 °C.

229. The method of claim 227 or claim 228, comprising chlorinating compound 17 with a chlorinating agent: ， to form compound 18.

230. The method of claim 229, wherein the chlorinating agent is thionyl chloride, POCl3, PCI3, or oxalyl chloride, optionally wherein the chlorinating agent is thionyl chloride, optionally used in an amount of about 2 equivalents to about 3.5 equivalents, optionally wherein the chlorination of compound 17 is conducted in a polar aprotic solvent, optionally wherein the polar aprotic solvent is DMI, and optionally the chlorination of compound 17 is conducted at a temperature of about 10 °C to about 60 °C.

231. The method of claim 229 or claim 230, comprising reacting compound 16: ， with a cyanide equivalent and a palladium catalyst, optionally in the presence of a zinc source and / or a phosphine ligand, to provide compound 17.

232. The method of claim 231, wherein: (a) the cyanide source is Zn(CN)2, optionally in an amount of about 1 equivalent to about 1.7 equivalents; (b) the palladium catalyst is [PdCl(allyl)]2, Pd2(dba)3, Pd(OAc)2, Pd(PPh3)4, Pd(dppf)2Cl2, PdCl2, or a combination thereof, or is Pd2(dba)3and Pd(OAc)2; (c) the phosphine ligand is PPh3, R-BINAP, or dppf, or is dppf, optionally wherein the phosphine ligand is present in an amount of about 0.02 equivalents to about 0.15 equivalents; (d) the zinc source is zinc metal; (e) the reaction of compound 16 is conducted at a temperature of about 60 °C to about 110 °C, or about 90 °C to about 110 °C; (f) the reaction of compound 16 is conducted in a polar solvent, optionally wherein the polar solvent is DMA or DMF; or (g) any combination of (a)-(f).

233. A method for making compound 1: ， or a pharmaceutically acceptable form thereof, the method comprising reacting compound 18A: ， with a cyanide equivalent and a palladium catalyst, optionally in the presence of a zinc source and / or a phosphine ligand, to provide compound 19: ， and purifying racemic compound 19 by chiral separation to provide compound 1.

234. The method of claim 233, wherein: (a) the cyanide source is Zn(CN)2, optionally in an amount of about 1 equivalent to about 1.7 equivalents; (b) the palladium catalyst is [PdCl(allyl)]2, Pd2(dba)3, Pd(OAc)2, Pd(PPh3)4, Pd(dppf)2Cl2, PdCl2, or a combination thereof, or is Pd2(dba)3and Pd(OAc)2; (c) the phosphine ligand is PPh3, R-BINAP, or dppf, or is dppf, optionally wherein the phosphine ligand is present in an amount of about 0.02 equivalents to about 0.15 equivalents; (d) the zinc source is zinc metal; (e) the reaction of compound 18A is conducted at a temperature of about 60 °C to about 110 °C, or about 90 °C to about 110 °C; (f) the reaction of compound 18A is conducted in a polar solvent, optionally wherein the polar solvent is DMA or DMF; or (g) any combination of (a)-(f).

235. The method of claim 233 or claim 234, comprising reacting compound 17A: ， with an ammonia equivalent to form compound 18A.

236. The method of claim 235, wherein the ammonia equivalent is NH3, optionally in an amount of about 15 equivalents to about 50 equivalents, or about 17 equivalents to 21 equivalents, wherein the reaction of compound 17A is conducted in a polar solvent, wherein the polar solvent is optionally selected from the group consisting of IPA, EtOH, MeOH, 1, 4-dioxane, DMI, and mixtures thereof, optionally wherein the polar solvent is IPA, optionally wherein the reaction of compound 17A is conducted at a temperature of about 0 °C to about 40 °C.

237. The method of claim 235 or claim 236, comprising chlorinating compound 16 with a chlorinating agent: ， to form compound 17A.

238. The method of claim 237, wherein the chlorinating agent is thionyl chloride, POCl3, PCI3, or oxalyl chloride, optionally wherein the chlorinating agent is thionyl chloride, optionally used in an amount of about 2 equivalents to about 3.5 equivalents, optionally wherein the chlorination of compound 16 is conducted in a polar aprotic solvent, optionally wherein the polar aprotic solvent is DMI, and optionally the chlorination of compound 16 is conducted at a temperature of about 10 °C to about 60 °C.

239. The method of any one of claims 231, 232, 237, or 238, comprising cyclizing compound 15X: or a salt thereof, in the presence of a base to form compound 16, wherein X is a leaving group selected from the group consisting of -Cl, -Br, -I, -OTs, or -OMs, optionally wherein X is -Cl (compound 15).

240. The method of claim 239, wherein the base is Cs2CO3, K2CO3, or Li2CO3, optionally wherein the base is Cs2CO3, optionally wherein (a) compound 15X is used as a free base and the base is present in an amount of about 1.5 equivalents to 4 equivalents, or (b) compound 15X is used as a salt and the base is present in an amount of about 4 equivalents to 12 equivalents, optionally wherein the reaction of compound 15X is performed in a polar aprotic solvent, optionally wherein the polar aprotic solvent is DME, DMF, MTBE, DMAc, or diethyleneglycol dimethyl ether, or a mixture thereof, optionally wherein the polar aprotic solvent is DMF or DMAc, optionally wherein the reaction of compound 15X is performed at a temperature of about 40 °C to about 80 °C.

241. The method of claim 239 or claim 240, comprising reacting compound 14: or a salt thereof, with a hydroxyl activating agent to form compound 15X or a salt thereof. ， 242. The method of claim 241, wherein the hydroxyl activating agent is thionyl chloride, POCl3, PCI3, or oxalyl chloride (X is -Cl), NaBr or LiBr (X is -Br), TsCl (X is -OTs), or MsCl (X is -OMs), optionally wherein the hydroxyl activating agent is thionyl chloride and X is -Cl, optionally wherein the thionyl chloride is used in an amount of about 2 equivalents to about 4 equivalents or about 3 equivalents, optionally wherein the reaction of compound 14 is performed in a polar aprotic solvent, optionally selected from THF, 2-MeTHF, DMF, or DMA, optionally the reaction of compound 14 is performed at a temperature of about 10 °C to about 60 °C.

243. The method of any one of claims 231, 232, 237, or 238, comprising reacting compound 14 or a salt thereof under Mitsunobu conditions to form compound 16, optionally wherein the Mitsunobu conditions comprise a dialkyl azodicarboxylate and a trialkyl phosphine or triaryl phosphine, optionally wherein the dialkyl azodicarboxylate is DEAD or DIAD and the trialkyl phosphine or triaryl phosphine is triphenyl phosphine.

244. The method of any one of claims 241 to 243, comprising deprotecting compound 13PG: under suitable deprotection conditions to form compound 14 or a salt thereof, wherein each PG is independently a hydroxyl protecting group. ​ ， ​ 245. The method of claim 244, wherein both PG groups are silyl protecting groups, such as tert-butyldimethylsilyl, triisopropylsilyl, triethylsilyl, or tert-butyldiphenylsilyl, optionally wherein both PG groups are triisopropylsilyl or tert-butyldimethylsilyl (Compound 13), and wherein the deprotection conditions comprise TBAF, MSA, MSA / H2O, or HC1 / H2O, optionally in a polar solvent, optionally wherein the solvent is THF, ACN, EtOAc, acetone, toluene, or a mixture thereof, optionally wherein the deprotection conditions comprise 3N HC1 in THF or THF / toluene (optionally about 4: 1 to about 1 :4 THF / toluene, or about 2: 1 to about 3: 1 THF / toluene), optionally the deprotection of the Compound 13PG is carried out at a temperature of about 0 °C to about 40 °C.

246. The method of claim 244 or claim 245, comprising coupling Compound 12PG: ， with 1-methylimidazole to form Compound 13PG, wherein each PG is independently a hydroxyl protecting group, optionally wherein both PG groups are silyl protecting groups, such as tert-butyldimethylsilyl, triisopropylsilyl, triethylsilyl, or tert-butyldiphenylsilyl, optionally wherein both PG groups are triisopropylsilyl or tert-butyldimethylsilyl (Compound 12), optionally wherein the coupling of the Compound 12PG is carried out at a temperature of about -50 °C to about -90 °C.

247. The method of claim 246, wherein the reaction comprises metallating 1-methylimidazole at the 5-position to form a reactive species, and mixing the reactive species with Compound 12PG, optionally wherein the reactive species is (1-methyl-2-(protecting group)- lH-imidazol-5-yl)lithium, optionally wherein the (1-methyl-2-(protecting group)- lH-imidazol-5-yl)lithium is (1-methyl-2-(triethylsilyl)-lH-imidazol-5-yl)lithium, optionally wherein the metallating comprises reacting 1-methyl-imidazole with (i) BuLi, (ii) TESCl, and (iii) BuLi to form the (1-methyl-2-(triethylsilyl)-lH-imidazol-5-yl)lithium, optionally wherein the metallating and the coupling are carried out at a temperature of about -30 °C to about -90 °C.

248. The method of any one of claim 246 or claim 247, comprising coupling Compound 11PG: ， with Compound 9PG: ， condensing to form compound 12PG, wherein each PG is independently a hydroxyl protecting group, optionally wherein the PG groups in compound 9PG and compound 11PG are both silyl protecting groups, such as tert-butyldimethylsilyl, triisopropylsilyl, triethylsilyl, or tert-butyldiphenylsilyl, optionally wherein both PG groups are triisopropylsilyl or tert-butyldimethylsilyl (compound 9 and compound 11).

249. The method of claim 248, comprising reacting compound 9PG with a metalating agent, such as BuLi or isopropyl MgCl / LiCl, optionally in a polar aprotic solvent to form a reactive species, optionally wherein the metalating agent is used in an amount of about 1 equivalent to about 1.3 equivalents, optionally wherein the polar aprotic solvent is THF, and mixing the reactive species with compound 11PG, optionally wherein the reaction of compound 9PG and mixing with compound 11PG is carried out at a temperature of about -60 °C to about -85 °C.

250. The method of claim 248 or claim 249, comprising reacting compound 8: ， with a hydroxyl protecting group reagent to form compound 9PG.

251. The method of claim 250, wherein PG is a silyl protecting group and the hydroxyl protecting group reagent is a silyl chloride reagent, optionally wherein PG is tert-butyldimethylsilyl and the hydroxyl protecting group reagent is TBSCl, wherein the reaction of compound 8 is carried out in the presence of a base, optionally in a polar aprotic solvent, optionally wherein the base is imidazole, TEA, TEA / DMAP, DIPEA, or pyridine, optionally wherein the polar aprotic solvent is DCM or THF.

252. The method of claim 250 or claim 251, comprising reacting compound 7: ， with a demethylating agent to form compound 8.

253. The method of claim 252, wherein the demethylating agent is BCl3 or BBr3, optionally in an amount of about 1.5 equivalents to 2.5 equivalents, optionally in the presence of a phase transfer agent, optionally in a polar aprotic solvent, optionally wherein the phase transfer agent is a tetraalkylammonium salt, such as tetrabutylammonium iodide, optionally wherein the polar aprotic solvent is THF, optionally the reaction of compound 7 is carried out at a temperature of about 0 °C to about 40 °C.

254. The method of claim 252 or claim 253, comprising reacting compound 6: ， with a dehydrating reagent to form compound 7.

255. The method of claim 254, wherein the dehydrating reagent is POCl3, oxalyl chloride, thionyl chloride, PCI3, or PCI5, optionally wherein the dehydrating reagent is POCl3, optionally in an amount of about 2 equivalents to about 6 equivalents, optionally in a polar aprotic solvent, optionally wherein the polar aprotic solvent is ACN, THF, 2-MeTHF, toluene, or DCM, optionally the reaction of compound 6 is carried out at a temperature of about 40 °C to about 85 °C.

256. The method of claim 254 or claim 255, comprising reacting compound 5: ， with (i) a base and (ii) an acid to form compound 6.

257. The method of claim 256, wherein the base is potassium tert-butoxide or sodium tert-butoxide, optionally in an amount of about 1.5 equivalents to about 3 equivalents, and the acid is HC1 or H2SO4, wherein the acid is used in a stoichiometric amount or a catalytic amount, optionally wherein the reaction of compound 5 is carried out in a polar solvent, optionally wherein the polar solvent is THF or toluene, optionally wherein step (i) is carried out at a temperature of about 10 °C to about 40 °C and step (ii) is carried out at a temperature of about 10 °C to about 75 °C.

258. The method of claim 256 or claim 257, comprising acetylating compound 4: ， in the presence of an acetylating agent to form compound 5.

259. The method of claim 258, wherein the acetylating agent is (a) Ac2O or (b) AcCl and a base, optionally wherein the base is TEA or DIPEA, optionally wherein (a) or (b) is carried out in a polar solvent such as DCM or toluene, optionally at a temperature of about 15 °C to about 110 °C; or (c) AcCl in water and an inorganic solvent such as Et20 or DCM.

260. The method of claim 258 or claim 259, comprising treating compound 3: ， with a reducing agent to form compound 4.

261. The method of claim 260, wherein the reducing agent is (a) TiCl3and a proton source, optionally wherein the proton source is water, optionally wherein the TiCl3is used in an amount of about 1.5 equivalents to about 3 equivalents, optionally in a polar aprotic solvent, optionally wherein the polar aprotic solvent is THF; or (b) H2and a hydrogenation catalyst, optionally wherein the hydrogenation catalyst is Pd / C or Pt / C.

262. The method of claim 260 or claim 261, comprising reacting 1-bromo-4- nitrobenzene with 2-(3-methoxyphenyl)acetonitrile in the presence of a base to form compound 3.

263. The method of claim 262, wherein the base is NaOH, KOH, or an alkoxide base, optionally wherein the alkoxide base is sodium methoxide, sodium ethoxide, or potassium tert-butoxide, optionally in an amount of about 2 equivalents to about 10 equivalents, optionally in a polar solvent, optionally wherein the polar solvent is MeOH, EtOH, MeOH / DCM, or EtOH / DCM, optionally at a temperature of about 0 °C to about 60 °C.

264. The method of any one of claims 248-263, comprising reacting compound 23: ， with a hydroxyl protecting group reagent to form compound 11PG.

265. The method of claim 264, wherein PG is a silyl protecting group and the hydroxyl protecting group reagent is a silyl chloride reagent, optionally wherein PG is tert-butyldimethylsilyl and the hydroxyl protecting group reagent is TBSCl, in the presence of a base, optionally in a polar aprotic solvent, optionally wherein the base is imidazole, TEA, TEA / DMAP, DIPEA, or pyridine, optionally wherein the polar aprotic solvent is DCM or THF.

266. The method of claim 264 or claim 265, comprising reacting compound 22: ， with morpholine under amide coupling conditions to form compound 23.

267. The method of claim 266, wherein the amide coupling conditions comprise (a) a carbodiimide and a base, optionally wherein the carbodiimide is EDC, EDCI, or DCC, optionally wherein the base is TEA, DIPEA, or TEA / DMAP, or (b) BOP, PyBOP, HOAt, HOBt, or T3P.

268. The method of claim 266 or claim 267, comprising converting compound 21: ， to compound 22: treating compound 21 with a base and water.

269. The method of claim 268, wherein the base is Na2CO3, K2CO3, NaOH, or KOH, optionally in a polar protic solvent, optionally wherein the polar protic solvent is water, MeOH, EtOH, IPA, or a mixture thereof, optionally wherein the polar protic solvent is EtOH / water, optionally at a temperature of about 50 °C to about 110 °C.

270. The method of claim 268 or claim 269, wherein compound 21 is mixed with methyl 4-bromo-3-(dibromomethyl)benzoate, and the converting further comprises mixing the product of the treating step with a reducing agent, optionally wherein the reducing agent is NaBH4, NaCNBH3, or BH3-DMS.

271. The method of claim 269 or claim 270, comprising reacting compound 20: ， with a brominating agent and a radical initiator to form compound 21.

272. The method of claim 271, wherein the brominating agent is NBS, Br2, NaBrO3 / HBr, or 1, 3-dibromo-5, 5-dimethylhydantoin, and the radical initiator is light, heat, or AIBN, optionally wherein the brominating agent is NBS and the radical initiator is light, optionally wherein the reaction of Compound 20 is performed in a continuous flow reactor with a photolysis flow cell having a wavelength in a range of about 300 nm to about 500 nm, optionally wherein the reaction of Compound 20 produces a mixture of Compound 21 and methyl 4-bromo-3-(dibromomethyl)benzoate.

273. A method for making Compound 9, the method comprising reacting Compound 7: with a demethylating agent to form Compound 8: and reacting Compound 8 with TBSCl and a base to form Compound 9. ， 274. The method of claim 273, wherein: ， (a) the demethylating agent is BC13 or BBr3, optionally in an amount of about 1.5 equivalents to 2.5 equivalents, optionally in the presence of a phase transfer agent, optionally in a polar aprotic solvent, optionally wherein the phase transfer agent is a tetraalkylammonium salt, such as tetrabutylammonium iodide, optionally wherein the polar aprotic solvent is THF, optionally the reaction of Compound 7 is performed at a temperature of about 0 °C to about 40 °C; and / or (b) the base is imidazole, TEA, TEA / DMAP, DIPEA, or pyridine, and optionally wherein the reaction is performed in a polar aprotic solvent, optionally wherein the polar aprotic solvent is DCM or THF.

275. The method of claim 273 or claim 274, the method comprising reacting Compound 6: with a dehydrating agent to form Compound 7.

276. The method of claim 275, wherein the dehydrating agent is POCl3, oxalyl chloride, thionyl chloride, PCI3, or PCI5, optionally wherein the dehydrating agent is POCl3, optionally in an amount of about 2 equivalents to about 6 equivalents, optionally in a polar aprotic solvent, optionally wherein the polar aprotic solvent is ACN, THF, 2-MeTHF, toluene, or DCM, optionally the reaction of Compound 6 is performed at a temperature of about 40 °C to about 85 °C.

277. A method for making Compound 11: ， the method comprising reacting Compound 23: with TBSCl in the presence of a base to form Compound 11.

278. The method of claim 277, wherein the base is imidazole, TEA, TEA / DMAP, DIPEA, or pyridine, optionally wherein the reaction of Compound 11 is performed in a polar aprotic solvent, optionally wherein the polar aprotic solvent is DCM or THF.

279. A method for making Compound 19: ， the method comprising chlorinating Compound 17 with a chlorinating agent: to form Compound 18: and reacting Compound 18 with an ammonia equivalent to form Compound 19. ， 280. The method of claim 279, wherein: ​ ​ ， ​ ， ​ ， ​ ​ (a) the chlorinating agent is thionyl chloride, POCI3, PCI3, or oxalyl chloride, optionally wherein the chlorinating agent is thionyl chloride, optionally used in an amount of about 2 equivalents to about 3.5 equivalents, optionally wherein the chlorination is carried out in a polar aprotic solvent, optionally wherein the polar aprotic solvent is DMI, and optionally wherein the chlorination of compound 17 is carried out at a temperature of about 10 °C to about 60 °C; and / or (B) the ammonia equivalent is NH3, optionally in an amount of about 15 equivalents to about 50 equivalents, or about 40 equivalents to 50 equivalents, wherein the reaction of compound 18 is carried out in a polar solvent, wherein the polar solvent is optionally selected from IPA, EtOH, MeOH, 1, 4-dioxane, DMI, and mixtures thereof, optionally wherein the polar solvent is MeOH, optionally wherein the reaction of compound 18 is carried out at a temperature of about 0 °C to about 40 °C.

281. A method for preparing compound 14: ， the method comprising deprotecting compound 13: ， under deprotection conditions to form compound 14.

282. The method of claim 281, wherein the deprotection conditions comprise TBAF, MSA, MSA / H2O, or HC1 / H2O, optionally in a polar solvent, optionally wherein the solvent is THF, ACN, EtOAc, acetone, toluene, or mixtures thereof, optionally wherein the deprotection conditions comprise 3N HC1 in THF or THF / toluene (optionally about 4: 1 to about 1:4 THF / toluene, or about 2: 1 to about 3: 1 THF / toluene), optionally wherein the deprotection of compound 14 is carried out at a temperature of about 0 °C to about 40 °C.

283. A method for preparing compound 12: ， the method comprising condensing compound 11: ， with compound 9: ， to form compound 12.

284. The method of claim 283, comprising reacting compound 9 with a metalating agent such as BuLi or isopropyl MgCl / LiCl, optionally in a polar aprotic solvent, to form a reactive species, optionally wherein the metalating agent is used in an amount of about 1 equivalent to about 1.3 equivalents, optionally wherein the polar aprotic solvent is THF, and mixing the reactive species with compound 11, optionally wherein the reaction of compound 9 and the mixing of the reactive species with compound 11 is carried out at a temperature of about -60 °C to about -85 °C.

285. A method for preparing compound 13, the method comprising coupling compound 12 with 1-methylimidazole to form compound 13.

286. The method of claim 285, comprising metallating 1-methylimidazole at the 5- position to form a reactive species, and mixing the reactive species with Compound 12, optionally wherein the reactive species is (1-methyl-2-(protecting group)-1H-imidazol-5- yl)lithium, optionally wherein the (1-methyl-2-(protecting group)-1H-imidazol-5- yl)lithium is (1-methyl-2-(triethylsilyl)-1H-imidazol-5-yl)lithium, optionally wherein the metallating comprises reacting 1-methyl-imidazole with (i) BuLi, (ii) TESCl, and (iii) BuLi to form the (1-methyl-2-(triethylsilyl)-1H-imidazol-5-yl)lithium, optionally wherein the metallating is performed at a temperature of about -30 °C to about -90 °C, optionally wherein the coupling is performed at a temperature of about -30 °C to about -90 °C.

287. A compound selected from the following: and salts thereof.

288. A compound 1 or compound 2 ( R )-chlorocyclic phosphate, ( S ()-chlorocyclic phosphate, (+)-tartrate, (-)-tartrate, (+)-camphor sulfonate, (-)-camphor sulfonate, L-(-)-di-p-methoxybenzoyl tartrate, D-(+)-di-p-methoxybenzoyl tartrate, L-(-)-di-toluyl tartrate, D-(+)-di-toluyl tartrate, ( R )-BINAP phosphate, ( S )-BINAP phosphate, benzoyl-1-tartrate or benzoyl-D-tartrate.

289. The salt of claim 288, wherein the salt is a dibenzoyl-l-tartaric acid salt or a dibenzoyl-D-tartaric acid salt of Compound 1 or Compound 2.

290. The salt of claim 288, wherein the salt is a Compound 1 L-DBTA salt.

291. A method of inhibiting farnesyltransferase, comprising contacting the farnesyltransferase with an effective amount of a solid form of any one of claims 1-127, a pharmaceutically acceptable salt of the compound of any one of claims 128-158, or a pharmaceutically acceptable solvate of an isotopologue or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 159-204, optionally wherein the farnesyltransferase is present in a cell, optionally wherein the contacting of the farnesyltransferase occurs in a cell, optionally wherein the cell is in a subject, optionally wherein the cell is a mammalian cell, optionally wherein the cell is a human cell, and optionally wherein the subject has a cancer that depends on farnesylated proteins.

292. A method of treating a cancer that depends on farnesylated proteins in a subject, comprising administering to a subject having a cancer that depends on farnesylated proteins a therapeutically effective amount of a solid form of any one of claims 1-127, a pharmaceutically acceptable salt of the compound of any one of claims 128-158, or a pharmaceutically acceptable solvate of an isotopologue or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 159-204, optionally wherein the subject is a human.

293. The method of claim 291 or claim 292, wherein the farnesylation- dependent protein-dependent cancer is a farnesylation-dependent H-Ras protein- dependent cancer, optionally wherein the farnesylation-dependent protein-dependent cancer has an H-Ras protein mutation, optionally wherein the H-Ras protein mutation is or comprises a modification in the codon encoding an amino acid substitution at a particular position selected from G12, Gl3, Q61, Q22, K117, A146, and any combination thereof in the corresponding mutant H-Ras protein; optionally wherein the presence or absence of the H-Ras mutation has been determined by analyzing nucleic acid obtained from a sample from the subject, optionally wherein the sample is a tissue biopsy or is a tumor biopsy, optionally wherein the H-Ras mutation has been determined by sequencing, polymerase chain reaction (PCR), DNA microarray, mass spectrometry (MS), single nucleotide polymorphism (SNP) assay, denaturing high-performance liquid chromatography (DHPLC), or restriction fragment length polymorphism (RFLP) assay.

294. The method of any one of claims 291 to 293, wherein the farnesylation- dependent protein-dependent cancer is a thyroid cancer, a head and neck cancer, a urothelial cancer, a salivary gland cancer, an upper gastrointestinal cancer, a bladder cancer, a breast cancer, an ovarian cancer, a brain cancer, a gastric cancer, a prostate cancer, a lung cancer, a colon cancer, a skin cancer, a liver cancer, or a pancreatic cancer.

295. The method of any one of claims 291 to 293, wherein the farnesylation- dependent protein-dependent cancer is a head and neck cancer, optionally wherein the head and neck cancer is a head and neck squamous cell carcinoma (HNSCC); or wherein the farnesylation-dependent protein-dependent cancer is a squamous cell carcinoma (SCC), optionally wherein the SCC is a head and neck SCC (HNSCC), a lung SCC (LSCC), a thyroid SCC (TSCC), an esophageal SCC (ESCC), a bladder SCC (BSCC), or a urothelial carcinoma (UC), optionally wherein the SCC is a HNSCC, optionally wherein the HNSCC is a tracheal HNSCC, a maxillary HNSCC, an oral HNSCC.

296. The method of any one of claims 291 to 295, wherein the farnesylation- dependent protein-dependent cancer is a solid tumor.

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