Solid form of a macrocyclic farnesyltransferase inhibitor and its formulation, as well as a method for preparing a macrocyclic compound and its solid form, and a method for using it.

Abstract

This disclosure relates to 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, a pharmaceutical composition comprising the same, a method for preparing the same, and a method for using the same to treat farnesylated protein-dependent cancer.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of priority of International Patent Application PCT / CN2023 / 097389, filed on 31 May 2023, which is incorporated herein by reference in its entirety.

[0002] Provided herein are 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, a pharmaceutical composition containing the same, a method for preparing the same, and a method for treating farnesylated protein-dependent cancer using the same. [Overview of the Initiative]

[0003] In one embodiment, compound 1:

[0004] [ka] Or a solid form comprising a pharmaceutically acceptable salt and / or solvate thereof.

[0005] In another embodiment, the compound is a pharmaceutically acceptable salt of compound 1, or an isotopic substitution thereof, or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt.

[0006] In another embodiment, the pharmaceutical composition comprises i) a solid form containing compound 1 in an amount of about 0.1 mg to about 200 mg, or a pharmaceutically acceptable salt and / or solvate thereof, and ii) one or more pharmaceutically acceptable excipients.

[0007] In another embodiment, a method for preparing a pharmaceutical composition as provided herein, comprising: i) optionally crushing a 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 disintegrant, a flow enhancer, and a first portion of a filler to form a first blend; iii) crushing the first blend to form a crushed first blend; iv) crushing a second portion of the filler; v) blending the crushed first blend and the crushed second portion of the filler to form a second blend; vi) blending the second blend with a lubricant to form a smoothed blend; and vii) optionally compressing the smoothed blend into a tablet using a rotary press.

[0008] In another embodiment, a method for preparing a pharmaceutical composition as provided herein, comprising: i) optionally crushing a 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 flow enhancer, and a disintegrant to form a first blend; iii) decoagulating 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 smoothed in-granule blend; v) forming granules from the in-granule blend using, for example, a roller press and a screen; vi) blending the granules with a second portion of a disintegrant and a second portion of a lubricant to form a smoothed final blend; and vii) optionally compressing the smoothed final blend into tablets using a rotary press.

[0009] In another embodiment, a method for preparing a pharmaceutical composition as provided herein, comprising: i) optionally crushing a 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 flow enhancer, 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 smoothed final blend; and v) optionally compressing the smoothed final blend into tablets using a rotary press.

[0010] In another embodiment, compound 1:

[0011] [ka] or a process for preparing such pharmaceutically acceptable form, (a) Racemic compound 19:

[0012] [ka] The diastereomer salt of compound 1 and compound 2 are obtained by reacting the chiral acid in a solvent.

[0013] [ka] This involves forming a diastereomer salt of, The reaction involves one of two diastereomer salts selectively precipitating from the solvent, while the other diastereomer salt is selectively soluble in the solvent. (b) Separating the precipitate from the solvent, (c) To provide compound 1 by reacting the diastereomer salt of compound 1 with a base, (d) A process comprising optionally recrystallizing compound 1 from ACN / water in an optionally ratio of approximately 2:1 to approximately 1:5, and optionally approximately 1:1 to approximately 1:3.

[0014] In another embodiment, compound 1:

[0015] [ka] or a process for preparing the pharmaceutically acceptable form thereof, compound 18A:

[0016] [ka] Compound 19 is obtained by reacting a cyanide equivalent and a palladium catalyst with a zinc source and / or a phosphine ligand, optionally in the presence of a zinc source and / or a phosphine ligand.

[0017] [ka] To provide, The process includes purifying racemic compound 19 by chiral separation to provide compound 1.

[0018] In another embodiment, a process for preparing compound 9, wherein compound 7:

[0019] [ka] Reacting it with a demethylating agent, compound 8:

[0020] [ka] To form, The process includes reacting compound 8 with TBSCl and a base to form compound 9.

[0021] In another embodiment, compound 11:

[0022] [ka] A process for preparing compound 23:

[0023] [ka] The process involves reacting with TBSCl in the presence of a base to form compound 11.

[0024] In another embodiment, compound 19:

[0025] [ka] A process for preparing, Compound 17:

[0026] [ka] Chlorinated with a chlorinating agent, compound 18:

[0027] [ka] To form, The process includes reacting compound 18 with an ammonia equivalent to form compound 19.

[0028] In another embodiment, compound 14:

[0029] [ka] A process for preparing, Compound 13:

[0030] [ka] The process involves reacting under deprotection conditions to form compound 14.

[0031] In another embodiment, compound 12:

[0032] [ka] A process for preparing, Compound 11:

[0033] [ka] Compound 9:

[0034] [ka] And condense it, This is a process that includes forming compound 12.

[0035] In another embodiment, the process for preparing compound 13 is a process comprising coupling compound 12 with 1-methylimidazole to form compound 13.

[0036] In another aspect, the following:

[0037] [ka] Compounds selected from, and their salts.

[0038] In another embodiment, compound 1 or compound 2 is (R)-crosiphos, (S)-crosiphos, (+)-tartaric acid, (-)-tartaric acid, (+)-camphor sulfonic acid, (-)-camphor sulfonic acid, L-(-)-di-p-anisioyltartaric acid, D-(+)-di-p-anisioyltartaric acid, L-(-)-di-toluoyltartaric acid, D-(+)-di-toluoyltartaric acid, (R)-BINAP phosphate, (S)-BINAP phosphate, di-benzoyl-l-tartaric acid, or di-benzoyl-D-tartrate.

[0039] In another embodiment, a method for inhibiting farnesyltransferase, comprising contacting farnesyltransferase with an effective amount of a solid form of Compound 1 provided herein, a pharmaceutically acceptable salt of Compound 1, or an isotopic variant thereof, or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt provided herein, or a pharmaceutical composition provided herein containing thereof, wherein optionally, the farnesyltransferase is present in a cell, optionally, the contact of farnesyltransferase occurs intracellularly, optionally, the cell is within a subject, optionally, the cell is a mammalian cell, optionally, the cell is a human cell, and optionally, the subject is suffering from a farnesylated protein-dependent cancer.

[0040] In another embodiment, a method for treating farnesylated protein-dependent cancer in a subject, comprising administering to a subject having farnesylated protein-dependent cancer a therapeutically effective amount of compound 1 provided herein in solid form, a pharmaceutically acceptable salt of compound 1, or an isotopic substitution thereof, or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt provided herein, or a pharmaceutical composition provided herein, wherein the subject is optionally human. [Brief explanation of the drawing]

[0041] [Figure 1]This provides a representative X-ray powder diffraction (XRPD) pattern of the amorphous form of the free base of compound 1. [Figure 2] This provides a typical Oak Ridge Thermal Ellipsoid Plot (ORTEP) of the single-crystal analysis of form 1 of the hemihydrate of the free base of compound 1. [Figure 3] This provides a representative XRPD pattern of form 1 of the hemihydrate of the free base of compound 1. [Figure 4] Representative DSC and TGA thermograms of form 1 of the hemihydrate of the free base of compound 1 are provided. [Figure 5] This provides a representative XRPD pattern of form 2 of the benzoate of compound 1. [Figure 6] Representative DSC and TGA thermograms of form 2 of the benzoate of compound 1 are provided. [Figure 7] This provides a representative XRPD pattern of form 3 of the besylate (benzenesulfonic acid) salt of compound 1. [Figure 8] Representative DSC and TGA thermograms of form 3 of the besylate (benzenesulfonic acid) salt of compound 1 are provided. [Figure 9] This provides a representative XRPD pattern of form 4 of the chloride salt of compound 1. [Figure 10] Representative DSC and TGA thermograms of form 4 of the chloride salt of compound 1 are provided. [Figure 11] This provides a representative XRPD pattern of form 5 of the chloride salt of compound 1. [Figure 12] Representative DSC and TGA thermograms of form 5 of the chloride salt of compound 1 are provided. [Figure 13] This provides a representative XRPD pattern of form 6 of the citrate of compound 1. [Figure 14] Representative DSC and TGA thermograms of form 6 of the citrate salt of compound 1 are provided. [Figure 15]This provides a representative XRPD pattern of form 7 of the citrate of compound 1. [Figure 16] Representative DSC and TGA thermograms of form 7 of the citrate of compound 1 are provided. [Figure 17] This provides a representative XRPD pattern of form 8 of the fumarate of compound 1. [Figure 18] Representative DSC and TGA thermograms of form 8 of the fumarate of compound 1 are provided. [Figure 19] This provides a representative XRPD pattern of form 9 of the gentisic acid salt of compound 1. [Figure 20] Representative DSC and TGA thermograms of form 9 of compound 1 gentisic acid are provided. [Figure 21] This provides a representative XRPD pattern of form 10 of the gentisic acid salt of compound 1. [Figure 22] Representative DSC and TGA thermograms of form 10 of compound 1's gentisic acid salt are provided. [Figure 23] This provides a representative XRPD pattern of form 11 of the glycolate salt of compound 1. [Figure 24] Representative DSC and TGA thermograms of form 11 of the glycolate of compound 1 are provided. [Figure 25] This provides a representative XRPD pattern of form 12 of the 1-hydroxy-2-naphthoate salt of compound 1. [Figure 26] Representative DSC and TGA thermograms of form 12 of the 1-hydroxy-2-naphthoate salt of compound 1 are provided. [Figure 27] This provides a representative XRPD pattern of form 13 of the 1-hydroxy-2-naphthoate salt of compound 1. [Figure 28] Representative DSC and TGA thermograms of form 13 of compound 1's 1-hydroxy-2-naphthoate are provided. [Figure 29] This provides a representative XRPD pattern of form 14 of the malate salt of compound 1. [Figure 30]Representative DSC and TGA thermograms of form 14 of the malate salt of compound 1 are provided. [Figure 31] This provides a representative XRPD pattern of form 15 of the malate salt of compound 1. [Figure 32] Representative DSC and TGA thermograms of form 15 of the malate salt of compound 1 are provided. [Figure 33] This provides a representative XRPD pattern of form 16 of the maleate of compound 1. [Figure 34] Representative DSC and TGA thermograms of form 16 of the maleate of compound 1 are provided. [Figure 35] This provides a representative XRPD pattern of form 17 of the maleate of compound 1. [Figure 36] Representative DSC and TGA thermograms of form 17 of the maleate of compound 1 are provided. [Figure 37] This provides a representative XRPD pattern of form 18 of the mesylate salt of compound 1. [Figure 38] Representative DSC and TGA thermograms of form 18 of the mesylate of compound 1 are provided. [Figure 39] This provides a representative XRPD pattern of form 19 of the oxalate of compound 1. [Figure 40] Representative DSC and TGA thermograms of form 19 of the oxalate of compound 1 are provided. [Figure 41] This provides a representative XRPD pattern of form 20 of the phosphate of compound 1. [Figure 42] Representative DSC and TGA thermograms of form 20 of the phosphate of compound 1 are provided. [Figure 43] This provides a representative XRPD pattern of form 21 of the tartrate salt of compound 1. [Figure 44] Representative DSC and TGA thermograms of form 21 of compound 1's tartrate are provided. [Figure 45] This provides a representative XRPD pattern of form 22 of the tartrate salt of compound 1. [Figure 46] Representative DSC and TGA thermograms of form 22 of the tartrate salt of compound 1 are provided. [Figure 47] This provides a representative XRPD pattern of form 23 of the tosylate of compound 1. [Figure 48] Representative DSC and TGA thermograms of form 23 of the tosylate of compound 1 are provided. [Figure 49] This provides a representative XRPD pattern of form 24 of the free base anhydride of compound 1. [Figure 50] Representative DSC and TGA thermograms of form 24 of the free base anhydride of compound 1 are provided. [Figure 51] An exemplary process for preparing tablets having the strength (free base equivalent) of Compound 1, or pharmaceutically acceptable salts and / or solvates thereof, in amounts of 0.2 mg, 1 mg, 10 mg, and 50 mg is shown.

[0042] 5. Modes for Carrying Out the Invention Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art. If there are multiple definitions of a term herein, the definition in this section shall prevail unless otherwise specified.

[0043] As used herein, and in the specification and the appended claims, the indefinite articles "a" and "an," and the definite article "the," include multiple referents and single referents, unless the context clearly indicates otherwise.

[0044] Where a range is used herein for physical properties such as molecular weight or chemical properties such as chemical formula, it is intended to include all combinations and partial combinations of the range, including the number of endpoints on the limits of both ranges, as well as specific embodiments therein. Where used herein, unless otherwise specified, the terms “about” and “approximately” indicate that the value or range of value may deviate to an extent reasonable to those skilled in the art while still describing a particular solid form, for example, when used in relation to a range of numerical values ​​or values ​​provided to characterize a particular solid form, such as a particular temperature or temperature range, e.g., melting, dehydration, desolvation, or glass transition temperature; mass change, e.g., mass change as a function of temperature or humidity; e.g., solvent or water content in mass or as a percentage; or describing a peak position, for example, in analysis by IR, Raman spectroscopy, or XRPD. For example, in certain embodiments, the terms “about” and “approximately” indicate, when used in this context, that a 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 enumerated value or range of values. For example, in some embodiments, the value of the XRPD peak position may vary by up to ±0.2 degrees 2θ while still describing a particular XRPD peak. For example, in some embodiments, the value of 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 particular temperature. As used herein, a tilde (i.e., “~”) preceding a numerical value or range of values ​​indicates “about” or “approximately”.

[0045] The term "between" includes the number of endpoints on both limits of a range. For example, a range described as "3-5" includes the numbers "3" and "5".

[0046] As used herein, the term “API correction factor” is understood to refer to a correction factor calculation used to characterize a particular lot of an active pharmaceutical ingredient (API), determined based on the purity of the API, the amount of any water and any residual solvent present, and the residue on ignition (ROI). API Correction Factor = (Purity of API) * (1 - Water Content - Residual Solvent - ROI). The purity of the API is determined by methods known in the art, e.g., HPLC and / or 1 The water content is determined using 1H NMR. The water content is determined using methods known in the art, e.g., Karl Fischer analysis. The ROI is determined using methods known in the art, e.g., ignition of the sample and heating of the residue at a high temperature such as about 450 to about 600°C, and weighing of the residue. The API correction factor used herein 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 embodiments, the API correction factor is at least 0.97, or about 0.97 to about 0.98.

[0047] As used herein, the terms “administer,” “dosage,” or “administer” refer to the act of delivering or causing a compound or pharmaceutical composition to be delivered to a subject’s body by the methods described herein or by other methods known in the art. Administering a compound or pharmaceutical composition includes prescribing a compound or pharmaceutical composition to be delivered into a patient’s body. 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); transdermal dosage forms including creams, jellies, powders, or patches; oral dosage forms; inhalation powders, sprays, suspensions, and rectal suppositories. In some embodiments, the form of administration is an oral dosage form such as a tablet.

[0048] When used herein, “pharmaceutically acceptable forms” of the compounds disclosed herein include, but are not limited to, pharmaceutically acceptable salts, solvates, isomers, and isotopic substitutions (i.e., isotopically labeled derivatives) of the compounds disclosed herein, and combinations thereof (e.g., solvates, or isomers and / or isotopic substitutions of pharmaceutically acceptable salts of the compound, or solvates, salts, or solvates of salts of such compounds). In some embodiments, “pharmaceutically acceptable forms” include, but are not limited to, pharmaceutically acceptable salts, solvates, isomers (e.g., tautomers or stereoisomers), and isotopic substitutions (i.e., isotopically labeled derivatives) of Compound 1 disclosed herein, and combinations thereof.

[0049] In some embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term “pharmaceutically acceptable salts” refers to salts that, within reasonable medical judgment, are free from excessive toxicity, irritation, allergic reactions, etc., are suitable for use in contact with the target tissue, and correspond 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 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, e.g., 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, e.g., suitable inorganic or organic addition acids (sometimes called conjugate acids). In some embodiments, pharmaceutically acceptable salts include, but are not limited to, benzoates, besilates, chlorides, citrates, fumarates, gentisides, glutarates, glycolates, hippurates, 1-hydroxy-2-naphthoates, malates, maleates, mesilates, oxalates, phosphates, sulfates, tartrates, or tosilates. In some embodiments, a pharmaceutically acceptable salt of compound 1, or its pharmaceutically acceptable solvates and / or isotopic substitutions, in molar ratios ranging from about 2:1 to about 1:2, or comprising compound 1, or its pharmaceutically acceptable solvates and / or isotopic substitutions, and conjugate acids (pharmaceutically acceptable salts). In some embodiments, the solid form comprises a pharmaceutically acceptable salt of compound 1, or a pharmaceutically acceptable solvate and / or isotopically substituted form thereof, and a conjugate acid (pharmaceutically 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 its 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 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 its 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 its 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 isotope-substituted compound to its 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. The molar ratios are 8:1, approximately 0.7:1, approximately 0.6:1, approximately 0.5:1, approximately 1:0.5, approximately 1:0.6, approximately 1:0.7, approximately 1:0.8, approximately 1:0.9, approximately 1:1.1, approximately 1:1.2, approximately 1:1.3, approximately 1:1.4, approximately 1:1.5, approximately 1:1.6, approximately 1:1.7, approximately 1:1.8, approximately 1:1.9, or approximately 1:2, for example, approximately 2:1, approximately 1:1, or approximately 1:2. In some embodiments, the molar ratio of compound 1 or its pharmaceutically acceptable solvate to its conjugate acid is approximately 1:2. In some embodiments, the molar ratio of compound 1 or its pharmaceutically acceptable solvate to its conjugate acid is approximately 1:1. In some embodiments, the molar ratio of compound 1 or its pharmaceutically acceptable solvate to its conjugate acid is approximately 2:1.

[0050] In some embodiments, the pharmaceutically acceptable form of a compound disclosed herein excludes the salt form of the compound disclosed herein (i.e., not a salt) and is sometimes referred to as the free form or free base form of the compound disclosed herein. In some embodiments, the free base form of a compound disclosed herein is the pharmaceutically acceptable solvate and / or isotopic substitution form of the compound. In some embodiments, the free base form of a compound disclosed herein is the pharmaceutically acceptable solvate form of the compound.

[0051] 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 further comprising stoichiometric or non-stoichiometric amounts of solvent bound by non-covalent intermolecular forces. In some embodiments, a solvate is a crystalline form of a molecule, atom, and / or ion further comprising solvent or multiple solvent molecules incorporated into a crystal lattice structure. Solvent molecules in a solvate may exist in regular and / or irregular arrangements. In some embodiments, a solvate may contain either stoichiometric or non-stoichiometric amounts of solvent molecules. For example, a solvate having non-stoichiometric amounts of solvent molecules may result from a partial loss of solvent from a solvate. A solvate may result as a dimer or oligomer containing more than one molecule or compound ABC within a crystal lattice structure. A solvate may be a solvate of the disclosed compound or a pharmaceutically acceptable salt thereof. When the solvent is water, the solvate is a "hydrate." In some embodiments, the solvate is a hydrate. Pharmaceutically acceptable solvates and hydrates may contain, for example, 0.1, 0.25, 0.50, 0.75, or 1 solvent or water molecule, or complexes may contain 1 to about 100, or 1 to about 10, or 1 to about 2, about 3, or about 4 solvent or water molecules. In some embodiments, a pharmaceutically acceptable solvate of compound 1, or its pharmaceutically acceptable salt and / or isotopic substitution form, is or contains compound 1, or its pharmaceutically acceptable salt and / or isotopic substitution 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 the solvent is in the range of about 0.1:1 to about 1:2.In some embodiments, the molar ratio of compound 1 to the 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, for example, about 2:1, about 1:1, or about 1:2. In some embodiments, the molar ratio of compound 1 to the solvent is about 1:2 (i.e., disolvate). In some embodiments, the molar ratio of compound 1 to the solvent is about 1:1 (i.e., monosolvate). In some embodiments, the molar ratio of compound 1 to the solvent is about 2:1 (i.e., hemisolvate). In some embodiments, the pharmaceutically acceptable solvent (solvate) is a hydrate, hemihydrate, isobutyl acetate solvate, isopropyl acetate solvate, tetrahydrofuran solvate, acetone solvate, acetonitrile solvate, or a combination thereof, or may contain them. For example, in some embodiments, the pharmaceutically acceptable solvate is water, and the molar ratio of compound 1 to the solvent is about 1:2 (also referred to as hemihydrate). In some embodiments, the pharmaceutically acceptable solvate of compound 1, or its pharmaceutically acceptable salt and / or isotopic substitution form, is the solid form of compound 1.

[0052] In some embodiments, the term “pharmaceutically acceptable salt or solvate” of a compound disclosed herein includes, but is not limited to, pharmaceutically acceptable salts and / or solvates of a compound disclosed herein, and combinations thereof (e.g., solvates of pharmaceutically acceptable salts), and further includes the compound or solvates, salts, or isotopic substitutions thereof of such a compound or solvates of a salt (i.e., isotopically labeled derivatives).

[0053] In some embodiments, the pharmaceutically acceptable forms of the compounds disclosed herein exclude the solvate forms of the compounds disclosed herein (sometimes referred to as non-solvates). For example, the pharmaceutically acceptable forms of the compounds disclosed herein may not contain water (sometimes referred to as anhydrouses). In some embodiments, the non-solvate forms of the compounds disclosed herein are the pharmaceutically acceptable salts and / or isotopic substitution forms of the compounds. In some embodiments, the non-solvate forms of the compounds disclosed herein are the pharmaceutically acceptable salt forms of the compounds. Unless otherwise specified, the non-solvate forms of the compounds are understood to have a residual amount of solvate 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 a compound has a residual amount of water 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.

[0054] In some embodiments, the pharmaceutically acceptable form is an isomer. “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. “Stereoisomer” is an isomer that differs only in the way in which atoms are arranged in space. Stereoiomers include, for example, enantiomers, diastereomers, and atopisomers. Atropisomers are stereoisomers that arise due to bound rotation around a single bond, where an energy difference due to steric strain or other factors creates a barrier to rotation sufficient to allow for the identification and potential isolation of individual conformational isomers. As used herein, the term “isomer” includes any and all geometric isomers and stereoisomers. For example, “isomers” include cis and trans isomers of geometric double bonds, also called E and Z isomers; atrop isomers; R and S enantiomers; diastereomers, (d)-isomers and (l)-isomers, racemic mixtures thereof; and other mixtures thereof, which are included within the scope of this disclosure.

[0055] References to compounds disclosed herein having one or more stereocenters without specifying a particular chirality (e.g., R-enantiomer or S-enantiomer) are understood to refer to the compound as a racemic mixture (or mixture of diastereomers), while the inclusion of an R- or S- designation is further understood to refer to an enantiomerically concentrated form of the compound, e.g., an enantiomerically concentrated form of the compound, or an enantiomer excess of a particular enantiomer of the compound, in accordance with the above considerations regarding enantiomerically concentrated forms and enantiomer excesses. Notation of a compound having an R or S designation is understood to include an enantiomerically concentrated or enantiomer excess of a particular enantiomer of the compound, and is not limited to 100% of a single particular enantiomer of the compound.

[0056] Please note that if there is a discrepancy between the shown structure and its name, the shown structure will be given greater weight.

[0057] An "enantiomer" is a pair of stereoisomers that are mirror images of each other and cannot be superimposed. A mixture of any proportion of enantiomer pairs may be known as a "racemic" mixture. The terms "(±)" or "(rac)" are used to indicate a racemic mixture, where appropriate. A "diastereoisomer" is a stereoisomer that has at least two chiral atoms but is not a mirror image of each other. Absolute stereochemistry can be determined according to the Cahn-Ingold-Prelog RS system. If a compound is an enantiomer, the stereochemistry at each chiral carbon can be determined by either R or S. A divided compound whose absolute configuration is unknown can be represented as (+) or (-) depending on the direction in which it rotates plane-polarized light at the wavelength of the sodium D line (dextrorotatory or levorotatory). Certain compounds described herein contain one or more chiral centers and thus may result in enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- in terms of absolute stereochemistry at each chiral atom. The chemical substances, pharmaceutical compositions, and methods of the present invention include all such possible isomers, including racemic mixtures, optically substantially pure forms, and intermediate mixtures.

[0058] Stereoisomers, such as optically active (+) and (-) isomers, or optically active (R) and (S) isomers, can be synthesized or prepared asymmetrically, for example, using chiral synthons or chiral reagents, or they can be separated using techniques such as chromatography on a chiral stationary phase. For example, stereoisomers can be isolated from a mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts. Alternatively, preferred isomers can be prepared by asymmetric synthesis. 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(ELEliel,Ed.,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 See Techniques: A Practical Approach (John Wiley & Sons, 2008) and Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0059] It should be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. Therefore, those skilled in the art will recognize that administration of the (R) form of a compound is equivalent to administration of the (S) form of a compound that undergoes epimerization in vivo.

[0060] In some embodiments, the pharmaceutically acceptable form is a tautomer. As used herein, the term “tautomer” refers to a type of isomer comprising two or more interconvertible compounds resulting from the formal transfer of at least one hydrogen atom and at least one change in valence (e.g., single bond to double bond, triple bond to double bond, or triple bond to single bond, or vice versa). “Tautomerization” includes prototropic or proton transfer tautomerization, which is considered a subset of acid-base chemistry. “Prototropic tautomerization” or “proton transfer tautomerization” involves the transfer of protons with a change in bond order. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. If tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be reached. Tautomerization (i.e., a reaction that yields a tautomer pair) can be catalyzed by an acid or a base, or it can occur without the action or presence of an external agent. The concentrations of isomers depend on the environment in which the compound is found, and may differ depending, for example, whether the compound is a solid or in an organic solution or aqueous solution. Exemplary tautomerizations include, but are not limited to, keto-enols; amide-imides; lactam-lactimes; enamine-imines; and tautomerizations of (different) enamines. For example, in aqueous solution, pyrazoles may exhibit the following isomers, called tautomers of each other:

[0061] [ka]

[0062] As will be readily understood by those skilled in the art, a wide variety of functional groups and other structures may exhibit tautomerism, and all tautomers of a compound are within the scope of the compounds provided herein.

[0063] In some embodiments, the pharmaceutically acceptable forms are isotopically substituted forms. As used herein, the term "isotopically substituted form" refers to an isotopically enriched compound that is identical to those listed herein except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Unless otherwise specified, the structures shown herein also mean 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, such as, respectively 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 are included, and each of these is also within the scope of this specification. For example, a compound having this structure except for the substitution or enrichment of hydrogen by deuterium or tritium in one or more atoms in the molecule is within the scope of this disclosure. In some embodiments, isotopically labeled compounds are provided herein in which one or more hydrogen atoms are replaced by deuterium or enriched with deuterium. In some embodiments, isotopically labeled compounds are provided herein in which one or more hydrogen atoms are replaced by tritium or enriched with deuterium. Further, deuterium (i.e., 2Substitution with heavier isotopes, such as H, can result in certain therapeutic benefits arising from greater metabolic stability (e.g., increased in vivo half-life or reduced dose required). Disclosed isotope-labeled compounds can generally be prepared by substituting an isotope-labeled reagent with an isotope-labeled reagent. Isotope-enriched compounds, such as Compound 1 or its pharmaceutically acceptable forms, including the solid form of Compound 1 or its pharmaceutically acceptable forms, can generally be prepared by substituting an isotope-unenriched reagent with a reagent enriched with the appropriate isotope, using procedures known to those skilled in the art. Unless otherwise specified, structures shown herein also mean compounds that differ only in the presence of one or more isotope-enriched atoms. For example, substitution or enrichment of hydrogen with deuterium or tritium in one or more atoms in the molecule, or in one or more atoms in the molecule 13 C or 14 Compounds having the present structure except for carbon substitution or enrichment by C are within the scope of this disclosure. In some embodiments, isotope-labeled compounds in which one or more hydrogen atoms are replaced with deuterium or enriched with deuterium are provided herein. In some embodiments, isotope-labeled compounds in which one to three hydrogen atoms are replaced with deuterium or enriched with deuterium are provided herein. In some embodiments, isotope-labeled compounds in which one or more hydrogen atoms are replaced with tritium or enriched with deuterium are provided herein. In some embodiments, one or more carbon atoms 13 It was replaced by C, or 13 Isotope-labeled compounds enriched with 1C are provided herein. In some embodiments, one or more carbon atoms are 14 It was replaced by C, or 14 Isotope-labeled compounds enriched with 1C are provided herein.

[0064] When a compound is concentrated with deuterium, the deuterium-to-hydrogen ratio on the deuterated atoms of the molecule substantially exceeds the naturally occurring deuterium-to-hydrogen ratio.

[0065] As used herein, unless otherwise specified, the terms “solid form” and related terms refer primarily to physical forms that are not liquid or gaseous. As used herein, the terms “solid form” and “solid forms” encompass semi-solids. Solid forms may be crystalline, amorphous, partially crystalline, partially amorphous, or mixtures of forms.

[0066] The solid forms provided herein may have varying degrees of crystallinity or lattice order. The solid forms provided herein are not limited by any particular degree of crystallinity or lattice order, and may be 0 to 100% crystalline. Methods for determining the degree of crystallinity are known to those skilled in the art, such as those described in Suryanarayanan, R., *X-Ray Power Diffractometry, Physical Characterization of Pharmaceutical Salts*, HGBrittain, Editor, Mercel Dekkter, Murray Hill, NJ, 1995, pp. 187-199 (which is incorporated herein by reference in its entirety). In some embodiments, the solid forms provided herein are about 0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% crystalline, for example, about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% crystalline, or higher.

[0067] Where used herein, unless otherwise specified, the term “crystalline” and related terms, when used to describe a substance, component, product, or form, mean that the substance, component, product, or form is substantially crystalline when determined, for example, by X-ray diffraction. For example, Remington: The Science and Practice of Pharmacy, 21 stedition, Lippincott, Williams and Wilkins, Baltimore, MD (2005); The United States Pharmacopeia, 23 rd See edition, 1843–1844 (1995).

[0068] Where used herein, unless otherwise specified, the terms “crystal form,” “crystal forms,” and related terms refer to crystalline solid forms. Crystal forms include, but are not limited to, single-component and multi-component crystal forms, as well as polymorphs, solvates, hydrates, and other molecular complexes, and salts, solvates of salts, hydrates of salts, cocrystals of salts, other molecular complexes of salts, and their polymorphs. In certain embodiments, the crystal form of a substance may not substantially include amorphous forms and / or other crystal forms. In certain embodiments, the crystal form of a substance may contain, by weight, one or more amorphous forms and / or other crystal forms in amounts less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%. In certain embodiments, the crystalline form of a substance may be physically and / or chemically pure. In certain 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.

[0069] A “single-component” solid form containing a compound consists essentially of that compound. A “multi-component” solid form containing a compound contains a significant amount of one or more additional species, such as ions and / or molecules, within that solid form. For example, in certain embodiments, a crystalline multi-component solid form containing a compound further includes one or more species non-covalently bonded at regular positions in a crystal lattice. As another example, in certain embodiments, an amorphous multi-component solid form containing a compound further includes one or more polymers, the compound being dispersed in a solid matrix containing the polymers.

[0070] The crystalline form of a substance can be obtained by many methods. Such methods, but are not limited to, include melt recrystallization, melt cooling, solvent recrystallization, recrystallization in confined spaces such as nanopores or capillaries, recrystallization on surfaces or templates such as polymers, recrystallization in the presence of additives such as cocrystal pair molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, grinding, and solvent droplet grinding.

[0071] Unless otherwise specified, the terms “polymorph,” “polymorphic form,” “polymorphs,” and “polymorphic forms” as used herein, and related terms, refer to two or more crystalline forms consisting of essentially the same molecule, multiple identical molecules, or ions. Similar to different crystalline forms, different polymorphs may have different physical properties, such as melting point, 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 physical properties exhibited by polymorphs may affect pharmaceutical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rate (an important factor in bioavailability). Differences in stability can arise from changes in chemical reactivity (e.g., differential oxidation, where a dosage form discolors more rapidly when composed of one polymorph than when composed of another), or from mechanical changes (e.g., tablets crumble during storage as a kinetically preferred polymorph is converted to a thermodynamically more stable polymorph), or from both (e.g., tablets of one polymorph are more prone to decomposition at high humidity). As a result of differences in solubility / dissolution, in extreme cases, some polymorphic transitions may lead to a lack of potency, or in other extreme cases, toxicity. In addition, the physical properties of the crystals can be important in processing (e.g., one polymorph may be more likely to form solvates or may be more difficult to filter and wash to remove impurities, and particle shape and size distribution may differ between polymorphs).

[0072] Where used herein, unless otherwise specified, the terms “amorphous,” “amorphous form,” and related terms mean that the substance, component, or product in question is substantially not crystalline when determined by X-ray diffraction. In particular, the term “amorphous form” describes a disordered solid form, i.e., a solid form lacking long-range crystalline order. In certain embodiments, the amorphous form of a substance may not substantially contain other amorphous forms and / or other crystalline forms. In other embodiments, the amorphous form of a substance may contain, by weight, one or more other amorphous forms and / or crystalline forms less than 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%. In certain embodiments, the amorphous form of a substance may be physically and / or chemically pure. In certain 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 certain embodiments, the amorphous form of a substance may contain additional components or constituents (e.g., additives, polymers, or excipients that may help to further stabilize the amorphous form). In certain embodiments, the amorphous form may be a solid solution.

[0073] The amorphous form of a substance can be obtained by many methods. Such methods, but are not limited to, include heating, melt-cooling, rapid melt-cooling, solvent evaporation, rapid solvent evaporation, desolvation, sublimation, grinding, ball mill grinding, low-temperature grinding, spray drying, and freeze-drying.

[0074] Techniques for characterizing crystalline and amorphous morphologies 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, such as infrared (IR) and Raman spectroscopy, nuclear magnetic resonance (NMR) spectroscopy of solids and solutions, optical microscopy, hot-stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility measurement, dissolution measurement, elemental analysis, and Karl Fischer analysis. Characteristic unit cell parameters may be determined using one or more techniques, including X-ray diffraction and neutron diffraction, including single-crystal diffraction and powder diffraction. Useful techniques for analyzing powder diffraction data include, for example, profile refinement such as Rietveld refinement, which can be used to analyze diffraction peaks associated with a single phase in samples containing more than one solid phase. Other useful methods for analyzing powder diffraction data include unit cell indexing, which allows those skilled in the art to determine unit cell parameters from a sample containing crystalline powder. In some embodiments, the XRPD pattern is obtained using CuKα radiation. In some embodiments, the peaks enumerated for the XRPD pattern have relative intensities greater than about 5%, greater than about 10%, greater than about 15%, or greater than about 20%. In some embodiments, the gradient rate (heating rate) of the DSC is about 10°C / min. In some embodiments, slower heating rates, such as 0.5–2.0°C / min, can be used for more accurate DSC testing. Sample pans used in DSC testing include, for example, aluminum, platinum, and stainless steel pans. The pans may have different configurations, e.g., open pans, pinhole pans, or sealed pans. In some embodiments, the gradient rate of the TGA is about 10°C / min.

[0075] Unless otherwise specified, the terms "X-ray powder diffraction," "powder X-ray diffraction," "PXRD," and "XRPD" are used interchangeably in this application.

[0076] A solid morphology may exhibit distinct physical characterization data specific to a particular solid morphology, such as a crystalline morphology, as provided herein. This characterization data may be obtained by 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. The data provided by these techniques may be used to identify a particular solid morphology. A person skilled in the art can determine whether a solid morphology is one of those provided herein by performing one of these characterization techniques and determining whether the obtained data "matches" or "substantially matches" reference data provided herein, which is identified as characteristic of a particular solid morphology. Characterization data that "matches" or "substantially matches" that of a reference solid morphology will be understood by a person skilled in the art to correspond to the same solid morphology as the reference solid morphology. In analyzing whether the data "matches" or "substantially matches," a person skilled in the art understands that specific characterization data points may vary to a reasonable extent, while still describing a given solid morphology, due, for example, experimental errors and routine inter-sample analytical variability. For example, an XRPD pattern, DSC thermogram, or TGA thermal curve that "matches" or "substantially matches" one or more figures in this specification showing an XRPD pattern, DSC thermogram, or TGA thermal curve, respectively, will be considered by those skilled in the art to represent the single-crystal morphology of the same compound as the sample of the compound that provided the pattern, thermogram, or thermal curve in one or more figures provided herein. Therefore, an XRPD pattern, DSC thermogram, or TGA thermal curve that matches or substantially matches may be identical to one of the figures, or more likely, to some extent different from one or more of the figures. For example, an XRPD pattern that differs to some extent from one or more of the figures may not necessarily show each of the lines 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 typically result from 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 a crystalline compound is in the same or different form as disclosed herein by comparing the XRPD pattern, DSC thermogram, or TGA thermal curve of the sample with the corresponding XRPD pattern, DSC thermogram, or TGA thermal curve disclosed herein.

[0077] When used without further limitation, “substantially pure” means that the compound has a purity higher than about 90 weight percent, for example, about 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 weight percent, based on the weight of the compound, and also contains a purity equal to about 100 weight percent. The remaining substance may contain other forms of the compound and / or reaction impurities and / or processing impurities resulting from its preparation. If the compound is “substantially pure” with respect to the presence of other remaining material, it may be referred to as “substantially physically pure.” Where applicable, “substantially pure” means that the indicated compound contains less than about 10 weight%, less than about 5 weight%, less than about 4 weight%, less than about 3 weight%, less than about 2 weight%, less than about 1 weight%, less than about 0.5 weight%, or less than about 0.1 weight of the indicated impurities. In some embodiments, the solid forms provided herein, e.g., crystalline or amorphous forms, are substantially pure, i.e., substantially free of other solid forms and / or other chemical compounds, and contain one or more other solid forms and / or other chemical compounds in amounts less than about 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.75%, 0.5%, 0.25%, or 0.1% by weight percent. For example, in some embodiments, the solid form of compound 1 is substantially pure (e.g., having a purity of at least about 90% by weight, at least about 95% by weight, at least about 96% by weight, at least about 97% by weight, at least about 98% by weight, or at least about 99% by weight). Purity can be evaluated using techniques known in the art, for example, by an HPLC assay.

[0078] "Substantially pure" may also be eligible. If a compound is "substantially pure" with respect to the absence of chemical impurities (e.g., 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 absence of other stereoisomers, such as other enantiomers, it may be referred to as "substantially stereoisomerically pure," for example, "substantially enantiomerically pure." As used herein, unless otherwise indicated, the term stereoisomerically pure means one stereoisomer of a compound that substantially does not contain other stereoisomers of that compound.

[0079] As used herein, unless otherwise indicated, a chemical compound, solid form, or composition that is "substantially free" of another chemical compound, solid form, or composition means that, in certain embodiments, the chemical compound, solid form, or composition contains, in amounts less than 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% of another chemical compound, solid form, or composition.

[0080] As used herein, unless otherwise specified, a solid form that is "substantially physically pure" substantially contains no other solid forms. In certain embodiments, a crystalline form that is substantially physically pure contains, by weight, one or more other solid forms in amounts of 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 less than 0.01%. Detection of other solid forms can be achieved by any method apparent to those skilled in the art, including but not limited to diffraction analysis, thermal analysis, elemental combustion analysis, and / or spectroscopic analysis.

[0081] As used herein, unless otherwise specified, a solid form that is "substantially chemically pure" is substantially free from other chemical compounds (i.e., chemical impurities). In certain embodiments, a solid form that is substantially physically pure contains, by weight, one or more other chemical compounds in amounts of 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 less than 0.01%. Detection of other chemical compounds can be achieved by any method apparent to those skilled in the art, including, but not limited to, chemical analysis methods such as mass spectrometry, spectroscopic analysis, thermal analysis, elemental combustion analysis, and / or chromatographic analysis.

[0082] For example, in some embodiments, an enantiomer may be provided substantially without the corresponding enantiomer and may also be referred to as “optically concentrated,” “enantiomerically concentrated,” “enantiomerically pure,” and “non-racemic,” as interchangeably used herein, where the amount of one enantiomer is greater than the amount of that one enantiomer in a control mixture of racemic compositions (e.g., greater than 1:1 by weight). A typical enantiomerically pure compound includes more than about 80% by weight of one enantiomer of the compound and less than about 20% by weight of the other enantiomer of the compound, more than about 90% by weight of one enantiomer of the compound and less than about 10% by weight of the other enantiomer of the compound, more than about 95% by weight of one enantiomer of the compound and less than about 5% by weight of the other enantiomer of the compound, or more than about 97% by weight of one enantiomer of the compound and less than about 3% by weight of the other enantiomer of the compound.

[0083] For example, an enantiomerically concentrated preparation of an S enantiomer means a preparation of a compound having an S enantiomer in more than about 50% by weight, for example, more than about 60% by weight, more than about 70% by weight, or more than about 80% by weight, relative to the total weight of the preparation (e.g., the total weight of the S and R isomers). In some embodiments, the concentration may be much greater than about 80% by weight, providing a "substantially enantiomerically concentrated," "substantially enantiomerically pure," or "substantially non-racemic" preparation, which means a preparation of a composition having one enantiomer in more than about 85% by weight, for example, 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, relative to the total weight of the preparation. In some embodiments, the solid form of compound 1 (i.e., (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2) 2 ,4 4 -Dicarbonitrile) is enantiomerically pure (i.e., compound 2 (i.e., (R)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2) 2 ,4 4 -Substantially free of dicarbonitrides). In some embodiments, the solid form of compound 1 is substantially enantiomerically pure, with other enantiomers (e.g., compound 2, R enantiomer) present in amounts 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. In some embodiments, the solid form of compound 1 is substantially enantiomerically pure (e.g., having an enantiomer 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).

[0084] The use of stereoisomerically pure forms of such compounds, as well as mixtures of those forms, are encompassed by the embodiments provided herein. For example, mixtures containing equal or unequal amounts of enantiomers of a particular compound may be used in the methods and compositions provided herein.

[0085] The "enantiomer excess" or "% enantiomer excess" of a composition, for example, a composition containing a mixture of enantiomers of a compound, can be calculated using the following formula. In the example below, a mixture containing 90% of one enantiomer (e.g., S enantiomer) and 10% of another enantiomer (e.g., R enantiomer) is said to have an 80% enantiomer excess. ee = (90 - 10) / 100 = 80%.

[0086] For example, in some embodiments, the compounds described herein are a mixture (racemate) of enantiomers of the compound and contain an enantiomer excess of 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% of one enantiomer relative to another, such as an excess of the S enantiomer relative to the R enantiomer. For example, the compounds provided herein may have a single enantiomer with an excess of about 95% ee, for example, about 96% ee, about 97% ee, about 98% ee, about 98.5% ee, about 99% ee, or about 99.5% ee. In some embodiments, the enantiomer mixture (racemate) of the compound has an enantiomer excess of one enantiomer relative to the other, for example, an enantiomer excess of the S enantiomer relative to the R enantiomer, which is 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 about 99% to about 99.5%.

[0087] As used herein, the term “pharmaceutically acceptable excipient” is understood to mean a carrier, excipient, or diluent approved by a federal or state regulatory authority for use in animals, more specifically in humans, or listed in the United States Pharmacopeia or other commonly recognized pharmacopoeias. The term “carrier” refers to a diluent, adjuvant (e.g., Freund’s adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic agent is administered. Such pharmaceutical carriers may be sterile liquids (e.g., water and oils (including oils of petroleum, animal, plant, or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.))). Water is a particular carrier for pharmaceutical compositions administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. For example, the terms pharmaceutically acceptable carrier, excipient, or diluent include any and all solvents, dispersion media, coatings, antimicrobial and antifungal agents, isotonic agents and absorption retarders. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions disclosed herein is intended. Auxiliary active components can also be incorporated into pharmaceutical compositions. Typical compositions and dosage forms include one or more excipients. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on various factors well known in the art, including, but not limited to, how the dosage form is administered to the patient and the specific active components in the dosage form. Examples of excipients that can be used in the oral dosage forms provided herein include, but are not limited to, fillers, flow enhancers, disintegrants, lubricants, or binders, or combinations thereof.

[0088] Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the periodic table, CAS versions, Handbook of Chemistry and Physics 75th ed., inside cover, and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry, as well as specific functional parts and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry, 5th ed., 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 ed., Cambridge University Press, Cambridge, 1987.

[0089] The term "protecting group" has a conventional meaning in organic synthesis, and is, for example, a group that selectively blocks one or more reaction sites in a polyfunctional compound, so that the chemical reaction can be selectively carried out on another unprotected reaction site, and the group can be easily removed after the selective reaction is complete. Various protecting groups are disclosed, for example, in T. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Fourth Edition, John Wiley & Sons, New York (2006), which is incorporated herein by reference in its entirety. For example, the hydroxy-protected form is when at least one of the hydroxyl groups present in the compound is protected by a hydroxy-protecting group. Similarly, amines and other reaction groups can be protected in the same manner.

[0090] Where used herein, unless otherwise indicated, the term “process” as provided herein refers to a method provided herein that is useful for preparing the compounds described herein or their solid forms provided herein (e.g., crystalline, partially crystalline, or amorphous). Modifications of the methods provided herein (e.g., starting materials, reagents, protecting groups, solvents, temperature, reaction time, purification) are also provided herein. In general, the technical teachings of one embodiment provided herein can be combined with those disclosed in any other embodiment provided herein.

[0091] As used herein, unless otherwise indicated, terms such as “add,” “react,” and “process” in the context of a process such as a reaction process or a crystallization process mean bringing one reactant, reagent, solvent, catalyst, or reactive group into contact with another reactant, reagent, solvent, catalyst, or reactive group. Reactants, reagents, solvents, catalysts, and reactive groups can be added individually, simultaneously, or separately, and in any order. Each reactant, reagent, solvent, catalyst, or reactive group can be added at once, delivered all at once or over a period of time, or delivered in separate parts, which may be delivered all at once or over a period of time. They can be added in or without heat, and optionally under an inert atmosphere. “Reacting” can refer to formation in a system or an intramolecular reaction in which the reactive groups are within the same molecule.

[0092] As used herein, the term “combine” means associating one or more chemical entities with one or more other chemical entities. Combining 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 (the same or different chemical entities). The act of combining includes one or more processes with one or more compounds (the same or different chemical entities) in which one or more compounds react (e.g., bond formation or cleavage; salt formation, solvate formation, chelation, or other non-bonding modification association). The act of combining may include the modification of one or more compounds, such as isomerization (e.g., tautomerization, splitting of one isomer from another isomer, or racemization).

[0093] As used herein, unless otherwise indicated, the term “convert” means subjecting a compound to reaction conditions suitable for the formation of a desired compound.

[0094] As used herein, the term “recover” includes, but is not limited to, the act of obtaining one or more compounds by collection during and / or after process steps disclosed herein, and the act of obtaining one or more compounds by separation of one or more compounds from one or more other chemical entities during and / or after process steps disclosed herein. The term “collection” means any act known in the art for this purpose, but is not limited to, filtration, decantation of a mother liquor from a solid to obtain one or more compounds, and evaporation of a liquid medium in a solution or other mixture to obtain a solid, oil, or other residue containing one or more compounds. The solid may be crystalline, amorphous, partially crystalline, or amorphous, a powder, granular, of varying particle sizes, or of uniform particle size, among other features known in the art. The oil may vary in color and viscosity and may include one or more solid forms as a heterogeneous mixture, among other features known in the art. The term “separation” means any act known in the art for this purpose, including, but not limited to, crystallization with or without the addition of seed crystals, or other precipitation techniques (e.g., adding a poor solvent to a solution to induce precipitation of a compound; heating a solution and then cooling it to induce precipitation of a compound; scratching the surface of a solution with an instrument to induce precipitation of a compound), and distillation techniques to isolate one or more compounds from a solution or mixture. Recovery of one or more compounds may include preparing their salts, solvates, hydrates, chelates, or other complexes, and then collecting or separating them as described above.

[0095] 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 supporting ligands) are added to a reaction mixture such that the formation of the active catalyst occurs in situ. Those skilled in the art will know that even when the metal source and supporting ligands are added to the reaction mixture in the form of a single chemical entity (e.g., Pd(dppf)Cl2), further activation and / or reaction in situ may be required to produce the active catalyst. Nevertheless, as used herein, the term “catalyst” includes, but is not limited to, a chemical composition in which more than one component of an active catalyst (e.g., a metal center and supporting ligands) are added to a reaction mixture in the form of a single chemical entity (e.g., Pd(dppf)Cl2), even when further activation and / or reaction in situ is required to produce the active catalyst.

[0096] Where used herein, unless otherwise specified, the terms “solvent,” “organic solvent,” or “inert solvent,” as used in the context of a process such as a reaction process or a crystallization process, mean an inert solvent under the conditions of the reaction described, respectively. Unless otherwise specified, for each gram of limiting reagent, 1 cc (or mL) of solvent constitutes a volume equivalent (or “vol.”).

[0097] As used herein, the term “selectively precipitated” refers to the precipitate formed when a mixture of compound 1 and compound 2 (e.g., compound 19) is reacted with a chiral acid in a solvent to form a pair of diastereomer salts, wherein the precipitate is enantiomerically concentrated with either compound 1 or compound 2 and has, for example, an increased %ee compared to the starting mixture. As used herein, the term “selectively soluble” refers to the mother liquor formed when a mixture of compound 1 and compound 2 (e.g., compound 19) is reacted with a chiral acid in a solvent to form a pair of diastereomer salts, wherein the mother liquor is enantiomerically concentrated with either compound 1 or compound 2 and has, for example, an increased %ee compared to the starting mixture.

[0098] As used herein, 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 diagnoses and 200,000 deaths worldwide annually, and approximately 54,000 new cases in the United States annually. This cancer is also the most common cancer in Central Asia. HNSCC has two distinct etiologies and corresponding tumor subtypes. The first subtype is associated with smoking and alcohol consumption and is unrelated to human papillomavirus (HPV- or HPV-negative). The second subtype is associated with infection by high-risk HPV (HPV- or HPV-positive). The second subtype is mainly limited to oropharyngeal cancer. HPV- tumors are a distinct entity with a better prognosis and may require differential treatment. A significant proportion of HNSCC, particularly 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 a surrogate marker for HPV infection in HNSCC, especially in the oropharynx. More accurate HPV tests are available, based on E6 / E7 detection (Liang C, et al. Cancer Res. 2012;72:5004-5013).

[0099] As used herein, the terms “HRAS mutation” or “H-Ras mutation” refer to activating mutations in the HRAS gene or the H-Ras protein. An H-Ras mutation may refer to either a genetic alteration in the DNA sequence of the HRAS gene that causes oncogenic activation of the corresponding H-Ras protein, or an alteration in the amino acid sequence of the H-Ras protein that causes such oncogenic activation. Therefore, as used herein, the terms “HRAS mutation” or “H-Ras mutation” do not refer to alterations in the HRAS gene that do not cause oncogenic activation of the H-Ras protein, or alterations in the H-Ras protein sequence that do not cause such oncogenic activation, although such mutations may also be present in a sample or subject. Thus, a sample or subject that does not have an “H-Ras mutation” as used herein may still have an HRAS gene mutation that does not affect the activity of the H-Ras protein or an alteration that impairs the activity of the H-Ras protein, or it may have an H-Ras protein mutation that does not affect its activity or an alteration that impairs its activity. A sample or subject may have multiple copies of the HRAS gene. A sample or subject may also have both wild-type and mutant H-Ras proteins. As used herein, a sample or subject having an H-Ras mutation may also have a copy of the wild-type HRAS gene and / or wild-type H-Ras protein. As used herein, a sample or subject determined to have “wild-type H-Ras” refers to a sample or subject having only the wild-type HRAS gene and wild-type H-Ras protein, and not having an H-Ras mutation. In some embodiments, the mutant HRAS gene encodes a mutant H-Ras protein, and the HRAS gene mutation is or includes a modification in a codon encoding an amino acid substitution at a specific position selected from the group consisting of G12, G13, Q61, Q22, K117, A146, and any combination thereof in the corresponding mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation in a codon encoding an amino acid substitution at the G12 position in the mutant H-Ras protein.In some embodiments, an HRAS gene mutation is a mutation in the codon encoding the G12R substitution in the mutant H-Ras protein. An HRAS gene mutation may be a mutation in the codon encoding the G12C, G12D, G12A, G12V, G12S, G12F, G12R, or G12N substitution in the mutant H-Ras protein. In some embodiments, an HRAS gene mutation is a mutation in the codon encoding the G12V substitution in the mutant H-Ras protein. In some embodiments, an HRAS gene mutation is a mutation in the codon encoding the amino acid substitution at the G13 position in the mutant H-Ras protein. An HRAS gene mutation may be a mutation in the codon encoding the G13A, G13C, G13V, G13D, G13R, G13S, G13N, or G13V substitution in the mutant H-Ras protein. In some embodiments, an HRAS gene mutation is a mutation in the codon encoding the G13C substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation in the codon encoding the G13R substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation in the codon encoding the amino acid substitution at the Q61 position in the mutant H-Ras protein. The HRAS gene mutation may be a mutation in the codon encoding the Q61E, Q61K, Q61H, Q61L, Q61P, or Q61R substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation in the codon encoding the Q61L substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation in the codon encoding the Q61R substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation in the codon encoding the amino acid substitution at the Q22 position in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation in the codon encoding the Q22K or Q22T substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation in the codon encoding an amino acid substitution at the K117 position in the mutant H-Ras protein.In some embodiments, the HRAS gene mutation is a mutation in the codon encoding a K117N or K117L substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation in the codon encoding an amino acid substitution at the A146 position in the mutant H-Ras protein. The HRAS gene mutation may be a mutation in the codon encoding an A146V, A146T, or A146P substitution in the mutant H-Ras protein. In some embodiments, the HRAS gene mutation is a mutation in the codon encoding an A146P substitution in the mutant H-Ras protein. In some embodiments, the mutation may be a mutation in another codon that results in activation of the H-Ras protein.

[0100] As used herein, unless otherwise indicated, the term “subject” to which the administration is intended may be, but is not limited to, animals including humans (e.g., males or females of any age group, such as adult subjects or adolescent subjects; primates (e.g., crab-eating macaques, rhesus macaques), 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, quail, 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 human. In some embodiments, the subject is an adult. In some embodiments, the subject is a patient, e.g., a human patient. In some embodiments, the subject may be a patient, e.g., a patient with farnesylated protein-dependent cancer.

[0101] As used herein, the terms “prevention” and “preventing” are used herein to refer to an approach to obtaining a beneficial outcome or desired outcome, including but not limited to a preventive benefit. For a preventive benefit, the compounds and pharmaceutical compositions disclosed herein may be administered to patients at risk of developing certain diseases or to patients reporting one or more physiological symptoms of a disease or disorder, even if a diagnosis of the disease or disorder has not been made.

[0102] The term “therapeutic effect” encompasses the therapeutic and / or preventive benefits described herein, when used herein. Preventive effects include delaying or eliminating the onset of a disease or disorder, delaying or eliminating the onset of symptoms of a disease or disorder, slowing, halting, or reversing the progression of a disease or disorder, or any combination thereof.

[0103] As used herein, the terms “to treat,” “to treat,” “treatment,” and “to improve” are interchangeable herein. These terms refer to approaches to obtain beneficial results or desired outcomes, including but not limited to therapeutic benefits. A therapeutic benefit means the elimination or improvement of the underlying disorder being treated. A therapeutic benefit is achieved by the elimination or improvement of one or more physiological symptoms associated with the underlying disorder, such that improvement is observed in the patient, even though the patient may still have the underlying disease or disorder. For example, as used in relation to a patient with farnesylated protein-dependent cancer, it refers to an effect that reduces the severity of cancer or slows or delays the progression of cancer, including (a) inhibiting cancer growth or stopping cancer development, and (b) causing cancer regression or delaying or minimizing one or more symptoms associated with the presence of cancer.

[0104] This disclosure can be better understood by referring to the following detailed description and exemplary examples, which are intended to illustrate non-limiting embodiments.

[0105] 5.1 Compound In some embodiments, compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 2 ,4 4 -It can be named dicarbonitrine, and has the following structure

[0106] [ka] Compound 1 having the above is provided herein.

[0107] In some embodiments, compound 2 is (R)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 2 ,4 4 -It can be named dicarbonitrine, and has the following structure

[0108] [ka] Compound 2 having the above characteristics is provided herein.

[0109] In some embodiments, compound 19 is (3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 2 ,4 4 -It can be named dicarbonitrine, and has the following structure

[0110] [ka] Compound 19 having the above is provided herein. As used herein, compound 19 represents a racemic mixture of compound 1 and compound 2, but non-equal mixtures of compound 1 and compound 2 are also intended as described herein.

[0111] The useful compounds described herein include compounds 1, 2, and 19, as well as their pharmaceutically acceptable forms, for example, compound 1 and its pharmaceutically acceptable forms.

[0112] When used herein, the compounds disclosed herein include, but are not limited to, the free base form or pharmaceutically acceptable salts thereof of such compounds, and their solvates or hydrates, as well as isotopic substitutions. In some embodiments, the free base or pharmaceutically acceptable salt of compound 1, or its hydrate or solvate and / or isotopic substitutions are intended. Throughout this application, disclosures including compound 1, compound 2, compound 19, or any intermediate compounds disclosed herein in their synthesis are understood to also include the isotopic substitutions of such compounds provided herein.

[0113] Compounds 1, 2, and 19 provided herein, as well as the synthesis and specific use, inhibitory activity, and metabolic stability of their pharmaceutically acceptable forms, are described in International Patent Application PCT / US2022 / 80565, which is incorporated herein by reference in its entirety. Improved processes for preparing Compounds 1, 2, and 19, as well as their pharmaceutically acceptable forms, are provided herein. In some embodiments, the compound for use in the therapeutic or inhibitory methods provided herein is Compound 1 or a pharmaceutically acceptable form thereof. In some embodiments, the compound for use in the therapeutic or inhibitory methods provided herein is a pharmaceutically acceptable salt of Compound 1, or a pharmaceutically acceptable solvate and / or isotope-substituted compound thereof. In some embodiments, the compound or solid form for use in the therapeutic or inhibitory methods provided herein is Compound 1 or a solid form of its pharmaceutically acceptable form. In some embodiments, the compound for use in the therapeutic or inhibitory methods provided herein is Compound 1 or a crystalline solid form of its pharmaceutically acceptable form. Throughout this application, any disclosure including the use of Compound 1 or a pharmaceutically acceptable form thereof applies equally to Compound 2 or a pharmaceutically acceptable form thereof, or to Compound 19 or a pharmaceutically acceptable form thereof.

[0114] In some embodiments, intermediate compounds, such as those disclosed in the synthesis of compound 1 as provided herein, or compounds in pharmaceutically acceptable forms thereof, are provided herein.

[0115] 5.2 Solid form Possible pharmaceutical solids include crystalline and amorphous solids. Amorphous solids are characterized by the lack of long-range structural order, while crystalline solids are characterized by structural periodicity. The desired class of pharmaceutical solid depends on the specific application. Amorphous solids may be selected, for example, based on an enhanced solubility profile, while crystalline solids may be desirable for properties such as physical or chemical stability (see, e.g., SRVippagunta 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 various physical and chemical properties, which can offer advantages or disadvantages in processing, formulation, stability, and bioavailability, among other important pharmaceutical characteristics.

[0116] Whether crystalline or amorphous, the potential solid forms of pharmaceutical compounds can include mono-component solids and multi-component solids. Mono-component solids consist essentially of the pharmaceutical compound in the absence of other compounds. Diversity within mono-component crystalline materials can potentially arise from polymorphism, where multiple three-dimensional configurations exist for a particular pharmaceutical compound (see, for example, SRByrn et al., Solid State Chemistry of Drugs, (1999) SSCI, West Lafayette).

[0117] Further diversity in the potential solid forms of pharmaceutical compounds can arise from the possibility of multi-component solids. Crystalline solids containing two or more ionic species are called salts (see, e.g., Handbook of Pharmaceutical Salts: Properties, Selection and Use, PHStahl and CGWermuth, Eds., (2002), Wiley, Weinheim). Further types of multi-component solids that may potentially offer other property improvements to pharmaceutical compounds or their salts include, in particular, hydrates, solvates, cocrystals, and clathrates (see, e.g., SRByrn et al., Solid State Chemistry of Drugs, (1999) SSCI, West Lafayette). Multi-component crystalline forms are potentially susceptible to pleomorphism, and a given multi-component composition may exist in more than one three-dimensional crystalline configuration. The discovery of solid forms is crucial in the development of safe, effective, stable, and marketable pharmaceutical compounds.

[0118] In particular, it is impossible to predict a priori whether a crystalline form of a compound exists, much less whether such a form possesses properties suitable for pharmaceutical development (physical properties, stability, solubility, purity, etc.), or how to successfully prepare them. (For example, Braga and Grepioni, 2005, "Making crystals from crystals: a green route to crystal engineering and polymorphism," Chem.Commun.:3635-3645 (Regarding crystal engineering, if the instructions are not very precise and / or other external factors affect the process, the results can be unpredictable); Jones et al., 2006, "Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement," MRS Bulletin 31:875-879 (Currently, even for the simplest molecules, it is generally impossible to computationally predict the number of observable polymorphs); Price, 2004, "The computational prediction of pharmaceutical crystal structures and polymorphism," Advanced Drug Delivery Reviews) See 56:301-319 ("Price"); and Bernstein, 2004, "Crystal Structure Prediction and Polymorphism," ACA Transactions 39:14-23 (see also: large-scale trading still needs to be learned and performed before it can be stated with any degree of confidence that it is possible to predict crystal structures, much less polymorphisms).

[0119] The diversity of possible solid forms brings potential diversity to the physical and chemical properties of a given pharmaceutical compound. The discovery and selection of solid forms are crucial in the development of effective, stable, and marketable pharmaceutical products.

[0120] The solid forms provided herein are useful as active pharmaceutical components for the preparation of formulations for use in animals or humans. Therefore, the embodiments herein encompass the use of these solid forms as final drug products. Certain embodiments, in particular, provide solid forms useful for producing final dosage forms having improved properties required for the manufacture, processing, formulation, and / or storage of the final drug product, such as powder flow properties, compressibility, tableting properties, stability properties, and excipient compatibility. Certain embodiments herein provide pharmaceutical compositions comprising single-component crystalline forms and / or multi-component crystalline forms comprising Compound 1 and pharmaceutically acceptable excipients.

[0121] Solid forms and related terms primarily refer to physical forms that are not liquid or gaseous. A solid form may be crystalline, or a mixture of crystalline and amorphous forms. A “single-component” solid form containing a particular compound consists essentially of that compound. A “multi-component” solid form containing a particular compound comprises that compound and one or more additional species in significant amounts, such as ions and / or molecules, within the solid form, e.g., solvent molecules. The solid forms provided herein may be crystalline or intermediate (e.g., a mixture of crystalline and amorphous forms). Therefore, the crystalline forms described herein may have varying degrees of crystallinity or lattice order. The solid forms described herein are not limited by any particular degree of crystallinity or lattice order and may be 0 to 100% crystalline. Methods for determining the degree of crystallinity are known to those skilled in the art, such as those described in Suryanarayanan, R., X-Ray Powder Diffractometry, Physical Characterization of Pharmaceutical Solids, HGBrittain, Editor, Marcel Dekker, Murray Hill, NJ, 1995, pp. 187-199 (the entire text of which is incorporated herein by reference). In some embodiments, the solid forms described herein are 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.

[0122] A solid form may exhibit distinct physical characterization data specific to a particular solid form, such as a crystalline form described herein. This characterization data can be obtained by various techniques known to those skilled in the art, including, for example, XRPD, DSC, TGA, and NMR spectroscopy. The data provided by these techniques can be used to identify a particular solid form. A person skilled in the art can determine whether a solid form is one of those described herein by performing one of these characterization techniques and determining whether the obtained data is "substantially similar" to the reference data provided herein, which is identified as characteristic of a particular solid form. Characterization data that is "substantially similar" to that of a reference solid form will be understood by those skilled in the art to correspond to the same solid form as the reference solid form. In analyzing whether the data is "substantially similar," a person skilled in the art understands that specific characterization data points may vary to a reasonable extent, while still describing a given solid form, due to, for example, experimental errors and routine inter-sample analysis.

[0123] In some embodiments, compound 1:

[0124] [ka] A solid form comprising a pharmaceutically acceptable salt or solvate thereof is provided herein. In some embodiments, the solid form comprising compound 1 or a pharmaceutically acceptable salt or solvate thereof may be in a crystalline form, substantially crystalline form, partially crystalline form, a mixture of crystalline forms, or an amorphous form. In some embodiments, the solid form is crystalline. In some embodiments, the solid form is amorphous. In some embodiments, the solid form is not amorphous. 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 the free base of compound 1. In some embodiments, the solid form is the 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 non-solvate of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the solid form is the anhydride of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the solid form is the 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 enantiomerically pure. In some embodiments, the solid form of compound 1 or a pharmaceutically acceptable salt and / or solvate thereof has an enantiomer purity of at least about 98% (e.g., about 98.5%, about 99%, or about 99.5%).

[0125] In some embodiments, the pharmaceutically acceptable solvate in solid form is selected from the group consisting of hydrate, hemihydrate, isobutyl acetate solvate, isopropyl acetate solvate, tetrahydrofuran solvate, acetone solvate, acetonitrile solvate, or combinations thereof. In some embodiments, the pharmaceutically acceptable solvate 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 the pharmaceutically acceptable solvent in the solid form 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 the solvent in the 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 the solvent in the 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 salt in the solid form to the solvent is about 1:2 (i.e., disolvate). In some embodiments, the molar ratio of compound 1 or its pharmaceutically acceptable salt in the solid form to the solvent is about 1:1 (i.e., monosolvate). In some embodiments, the molar ratio of compound 1 or its pharmaceutically acceptable salt in the solid form to the solvent is about 2:1 (i.e., hemisolvate). In some embodiments, the solvent is water, and compound 1 or its pharmaceutically acceptable salt and water are present in the solid form in a molar ratio of about 2:1 (hemihydrate). In some embodiments, the solid form is the hemihydrate of compound 1 or its pharmaceutically acceptable salt.

[0126] In some embodiments, the pharmaceutically acceptable salt in solid form is selected from the group consisting of benzoates, besilates, chlorides, citrates, fumarates, gentisinates, glycolates, 1-hydroxy-2-naphthoates, malates, maleates, mesilates, oxalates, phosphates, tartrates, or tosilates. 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-naphthoate. In some embodiments, compound 1 or its pharmaceutically acceptable solvate and pharmaceutically acceptable salt (conjugate acid) in solid form are present in a molar ratio ranging from 2:1 to 1:2. 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 2:1 to about 1:1. In some embodiments, the molar ratio of compound 1 or its pharmaceutically acceptable solvate in solid form to its conjugate acid is in the range of about 1:1 to about 1:2.

[0127] 5.2.1 Form 1 of Compound 1 In some embodiments, form 1 of compound 1 is provided herein. In some embodiments, form 1 of compound 1 is the crystalline free base hemihydrate of compound 1. In some embodiments, form 1 of compound 1 substantially does not contain amorphous compound 1. In some embodiments, form 1 of compound 1 substantially does not contain other crystalline forms (i.e., polymorphs) of compound 1. In some embodiments, form 1 of compound 1 substantially does not contain salt forms of compound 1. In some embodiments, form 1 of compound 1 is provided as a substantially pure form 1 of compound 1.

[0128] A typical XRPD pattern of compound 1, form 1, is shown in Figure 3.

[0129] In some embodiments, Form 1 has an enantiomer 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 crystalline or higher, with about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% being crystalline.

[0130] In some embodiments, Embodiment 1 has an X-ray powder diffraction (XRPD) pattern with peaks at approximately 9.0, 12.8, 16.6, and 18.4°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 8.6, 12.0, 18.1, and 23.2°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 16.1, 17.1, 24.1, and 25.6°2θ. In some embodiments, the XRPD pattern includes 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.

[0131] In some embodiments, solid forms comprising the free base hemihydrate of compound 1 are provided herein, characterized by one, two, three, four, five, six, seven, eight, nine, ten, or all of the XRPD peaks located at approximate positions (e.g., 2θ ± 0.2°) of 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 when measured using CuKα radiation. In some embodiments, the solid form is characterized by at least three of the peaks. In some embodiments, the solid form is characterized by at least five of the peaks. In some embodiments, the solid form is characterized by at least seven of the peaks. In some embodiments, the solid form is characterized by at least nine of the peaks. In some embodiments, the solid form is characterized by at least eleven of the peaks. In some embodiments, the solid form is characterized by all of the peaks.

[0132] In some embodiments, Embodiment 1 has an XRPD pattern that substantially matches the XRPD pattern shown in Figure 3.

[0133] In some embodiments, Embodiment 1 is

[0134]

number

[0135]

number

[0136] Representative overlays of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms for form 1 of compound 1 are shown in Figure 4.

[0137] In some embodiments, when Embodiment 1 is characterized by a DSC using a temperature gradient of about 10°C / min, it shows a thermal (endothermal) event with an onset temperature of about 83°C, a thermal (endothermal) event with an onset temperature of about 212°C, and / or endothermal peaks at about 137°C and about 221°C. In some embodiments, Embodiment 1 is characterized by a DSC thermogram substantially shown in the DSC thermogram shown in Figure 4.

[0138] In some embodiments, Embodiment 1, when characterized by TGA, shows no weight loss when heated to below about 75°C. In some embodiments, Embodiment 1, when characterized by TGA, shows a weight loss of about 1.8% when heated from about 75°C to about 170°C. In some embodiments, Embodiment 1 is characterized by a TGA thermogram substantially shown in the TGA thermogram shown in Figure 4.

[0139] In some embodiments, Form 1 has a purity of at least 98%, 98.5%, 99%, or 99.5%.

[0140] In some embodiments, Form 1 has solubility of approximately 4.69, 5.04, and 3.67 mg / mL in SGF medium at 0.5 hours, 2 hours, and 24 hours, respectively. In some embodiments, Form 1 has solubility of approximately 0.29, 0.31, and 0.33 mg / mL in FeSSIF medium at 0.5 hours, 2 hours, and 24 hours, respectively.

[0141] In some embodiments, Embodiment 1 is prepared according to the procedure of Embodiment 1.

[0142] All combinations of the embodiments described above are incorporated in this application.

[0143] 5.2.2 Form 2 of Compound 1 In some embodiments, a second form of compound 1 is provided herein. In some embodiments, the second form of compound 1 is the crystalline benzoate of compound 1. In some embodiments, the second form has a compound 1 / benzoate molar ratio of about 1:1. In some embodiments, the second form of compound 1 is substantially free of amorphous compound 1. In some embodiments, the second form of compound 1 is substantially free of other crystalline forms (i.e., polymorphs) of compound 1. In some embodiments, the second form of compound 1 is provided as a substantially pure form 2 of compound 1.

[0144] A typical XRPD pattern for form 2 of compound 1 is shown in Figure 5.

[0145] In some embodiments, Form 2 has an enantiomer 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%, or higher.

[0146] In some embodiments, Embodiment 2 has an X-ray powder diffraction (XRPD) pattern with peaks at approximately 4.7, 17.0, and 19.4°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 12.7, 16.6, 17.8, 18.9, and 21.4°2θ. In some embodiments, the XRPD pattern further 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.

[0147] In some embodiments, solid forms comprising the benzoate of compound 1 are provided herein, characterized by one, two, three, four, five, six, seven, eight, nine, ten, or all of the XRPD peaks located at approximate positions (e.g., 2θ ± 0.2°) of 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 when measured using CuKα radiation. In some embodiments, the solid form is characterized by at least three of the peaks. In some embodiments, the solid form is characterized by at least five of the peaks. In some embodiments, the solid form is characterized by at least seven of the peaks. In some embodiments, the solid form is characterized by at least nine of the peaks. In some embodiments, the solid form is characterized by at least eleven of the peaks. In some embodiments, the solid form is characterized by at least thirteen of the peaks. In some embodiments, the solid form is characterized by all of the peaks.

[0148] In some embodiments, Embodiment 2 has an XRPD pattern that substantially matches the XRPD pattern shown in Figure 5.

[0149] Representative overlays of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms for form 2 of compound 1 are shown in Figure 6.

[0150] In some embodiments, when characterized by a DSC using a temperature gradient of about 10°C / min, embodiment 2 shows a thermal (endothermic) event with an onset temperature of about 209°C and / or an endothermic peak at about 216°C. In some embodiments, embodiment 2 is characterized by a DSC thermogram substantially shown in the DSC thermogram shown in Figure 6.

[0151] In some embodiments, Form 2, when characterized by TGA, shows no weight loss when heated up to less than about 180 °C. In some embodiments, Form 2 is characterized by a TGA thermogram substantially as shown in the TGA thermogram shown in FIG. 6.

[0152] In some embodiments, Form 2 has (a) a purity of at least 98%, 98.5%, 99%, or 99.5%, (b) solubilities of about 4.17, 4.47, and 4.49 mg / mL in SGF medium at 0.5 h, 2 h, and 24 h, respectively, (c) solubilities of about 0.72, 0.68, and 0.54 mg / mL in FeSSIF medium at 0.5 h, 2 h, and 24 h, respectively, or (d) any combination of (a)-(c).

[0153] In some embodiments, Form 2 is prepared according to the procedure of Example 2.

[0154] All combinations of the above-described embodiments are included in this application.

[0155] 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 the crystalline besylate of Compound 1. In some embodiments, Form 3 has a molar ratio of Compound 1 / benzenesulfonic acid of about 1:0.9. In some embodiments, Form 3 of Compound 1 substantially does not contain amorphous Compound 1. In some embodiments, Form 3 of Compound 1 substantially does not contain other crystalline forms (i.e., polymorphs) of Compound 1. In some embodiments, Form 3 of Compound 1 is provided as a substantially pure Form 3 of Compound 1.

[0156] A representative XRPD pattern of Form 3 of Compound 1 is shown in FIG. 7.

[0157] In some embodiments, Form 3 has an enantiomeric purity of about 98%, about 98.5%, about 99%, or about 99.5%, or more. 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 more.

[0158] In some embodiments, Form 3 has an X-ray powder diffraction (XRPD) pattern that includes peaks at approximately 7.6, 8.9, and 14.3° 2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 17.9, and 19.7° 2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 21.0, and 24.8° 2θ. In some embodiments, the XRPD pattern includes peaks at approximately 7.6, 8.9, 14.3, 17.9, 19.7, 21.0, and 24.8° 2θ.

[0159] In some embodiments, provided herein is a solid form comprising a besylate of Compound 1, characterized by 1, 2, 3, 4, 5, 6, or all of the XRPD peaks located at approximately the positions (e.g., 2θ ± 0.2°) of 7.6, 8.9, 14.3, 17.9, 19.7, 21.0, and 24.8° 2θ when measured using CuKα radiation. In some embodiments, the solid form is characterized by at least 3 of the peaks. In some embodiments, the solid form is characterized by at least 5 of the peaks. In some embodiments, the solid form is characterized by all of the peaks. <,

[0160] In some embodiments, Form 3 has an XRPD pattern that substantially matches the XRPD pattern shown in Figure 7.

[0161] Representative overlays of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms for form 3 of compound 1 are shown in Figure 8.

[0162] In some embodiments, when embodiment 3 is characterized by a DSC using a temperature gradient of about 10°C / min, it shows a thermal (endothermic) event with an onset temperature of about 186°C and / or an endothermic peak at about 206°C. In some embodiments, embodiment 3 is characterized by a DSC thermogram substantially shown in the DSC thermogram shown in Figure 8.

[0163] In some embodiments, when characterized by TGA, Embodiment 3 exhibits a weight loss of approximately 5.7% when heated over a range of approximately 95 to approximately 230°C. In some embodiments, Embodiment 3 is characterized by a TGA thermogram substantially shown in the TGA thermogram shown in Figure 8.

[0164] In some embodiments, Embodiment 3 is prepared according to the procedure of Embodiment 3.

[0165] All combinations of the embodiments described above are incorporated in this application.

[0166] 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 the crystalline hydrochloride salt of compound 1. In some embodiments, form 4 has a compound 1 / hydrochloride molar ratio of about 1:1, and optionally, 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 (i.e., polymorphs) of compound 1. In some embodiments, form 4 of compound 1 is provided as a substantially pure form 4 of compound 1.

[0167] A typical XRPD pattern for form 4 of compound 1 is shown in Figure 9.

[0168] In some embodiments, form 4 has an enantiomer 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%, or higher.

[0169] In some embodiments, Embodiment 4 has an X-ray powder diffraction (XRPD) pattern with peaks at approximately 5.3, 16.7, 19.1, and 26.0°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 5.3, 16.7, 19.1, and 26.0°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 5.3, 16.7, 19.1, and 26.0°2θ. In some embodiments, the XRPD pattern includes 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.

[0170] In some embodiments, solid forms comprising the hydrochloride salt of compound 1 are provided herein, characterized by one, two, three, four, five, six, seven, eight, nine, ten, or all of the XRPD peaks located at approximate positions (e.g., 2θ ± 0.2°) of 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 when measured using CuKα radiation. In some embodiments, the solid form is characterized by at least three of the peaks. In some embodiments, the solid form is characterized by at least five of the peaks. In some embodiments, the solid form is characterized by at least seven of the peaks. In some embodiments, the solid form is characterized by at least nine of the peaks. In some embodiments, the solid form is characterized by at least eleven of the peaks. In some embodiments, the solid form is characterized by all of the peaks.

[0171] In some embodiments, Embodiment 4 has an XRPD pattern that substantially matches the XRPD pattern shown in Figure 9.

[0172] Figure 10 shows representative overlays of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms for form 4 of compound 1.

[0173] In some embodiments, when Embodiment 4 is characterized by a DSC using a temperature gradient of about 10°C / min, it shows thermal (endothermic) events with starting temperatures of about 28°C, about 98°C, and about 242°C, and / or endothermic peak temperatures of about 64°C and about 116°C, and about 258°C (two overlapping peaks), respectively. In some embodiments, Embodiment 4 is characterized by a DSC thermogram substantially shown in the DSC thermogram shown in Figure 10.

[0174] In some embodiments, Form 4, when characterized by TGA, shows a weight loss of about 3.2% when heated from room temperature to about 90 °C and a weight loss of about 2.7% when heated from about 90 °C to 140 °C. In some embodiments, Form 4 is characterized by a TGA thermogram substantially as shown in the TGA thermogram shown in FIG. 10.

[0175] In some embodiments, Form 4 is prepared according to the procedure of Example 4.

[0176] All combinations of the above-described embodiments are included in this application.

[0177] 5.2.5 Form 5 of Compound 1 In some embodiments, Form 5 of Compound 1 is provided herein. In some embodiments, Form 5 of Compound 1 is the crystalline hydrochloride salt of Compound 1. In some embodiments, Form 4 has a compound 1 / hydrochloric acid molar ratio of about 1:1 and optionally the solid form is a hydrate. In some embodiments, Form 5 of Compound 1 substantially does not contain amorphous Compound 1. In some embodiments, Form 5 of Compound 1 substantially does not contain other crystalline forms (i.e., polymorphs) of Compound 1. In some embodiments, Form 5 of Compound 1 is provided as substantially pure Form 5 of Compound 1.

[0178] A representative XRPD pattern of Form 5 of Compound 1 is shown in FIG. 11.

[0179] In some embodiments, Form 5 has an enantiomeric purity of about 98%, about 98.5%, about 99%, or about 99.5%, or more. 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, about 90%, about 95%, about 96%, about 97%, about 98%, about 9,8.5%, about 99%, or about 99.5% of Form 5 is crystalline or more.

[0180] In some embodiments, Embodiment 5 has an X-ray powder diffraction (XRPD) pattern with peaks at approximately 6.3, 8.4, 15.1, and 23.5°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 10.7 and 17.9°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 20.8 and 21.6°2θ. In some embodiments, the XRPD pattern includes peaks at approximately 6.3, 8.4, 10.7, 15.1, 17.9, 20.8, 21.6, and 23.5°2θ.

[0181] In some embodiments, solid forms comprising the hydrochloride salt of compound 1 are provided herein, characterized by one, two, three, four, five, six, seven, eight, nine, ten, or all of the XRPD peaks located at approximate positions of 6.3, 8.4, 10.7, 15.1, 17.9, 20.8, 21.6, and 23.5°2θ (e.g., 2θ ± 0.2°) when measured using CuKα radiation. In some embodiments, the solid form is characterized by at least three of the peaks. In some embodiments, the solid form is characterized by at least five of the peaks. In some embodiments, the solid form is characterized by at least seven of the peaks. In some embodiments, the solid form is characterized by all of the peaks.

[0182] In some embodiments, Embodiment 5 has an XRPD pattern that substantially matches the XRPD pattern shown in Figure 11.

[0183] Representative overlays of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms for form 5 of compound 1 are shown in Figure 12.

[0184] In some embodiments, when embodiment 5 is characterized by a DSC using a temperature gradient of about 10°C / min, it shows a thermal (endothermic) event with an onset temperature of about 244°C and / or an endothermic peak temperature of about 247°C. In some embodiments, embodiment 5 is characterized by a DSC thermogram substantially shown in the DSC thermogram shown in Figure 12.

[0185] In some embodiments, Embodiment 5, when characterized by TGA, exhibits a weight loss of about 5.3% before reaching about 130°C and a weight loss of about 12% over the range of about 175 to about 300°C. In some embodiments, Embodiment 5 is characterized by a TGA thermogram substantially shown in the TGA thermogram shown in Figure 12.

[0186] In some embodiments, Embodiment 5 is prepared according to the procedure of Embodiment 5.

[0187] All combinations of the embodiments described above are incorporated in this application.

[0188] 5.2.6 Form 6 of Compound 1 In some embodiments, form 6 of compound 1 is provided herein. In some embodiments, form 6 of compound 1 is the crystalline citrate of compound 1. In some embodiments, form 6 has a compound 1 / citrate molar ratio of about 1:0.8, and optionally, 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 (i.e., polymorphs) of compound 1. In some embodiments, form 6 of compound 1 is provided as a substantially pure form 6 of compound 1.

[0189] A typical XRPD pattern for form 6 of compound 1 is shown in Figure 13.

[0190] In some embodiments, form 6 has an enantiomer 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%, or higher.

[0191] In some embodiments, Embodiment 6 has an X-ray powder diffraction (XRPD) pattern with peaks at approximately 12.0, 16.6, and 18.1°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 12.9, 19.5, and 23.3°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 24.2, 25.6, and 26.1°2θ. In some embodiments, the XRPD pattern includes peaks at approximately 12.0, 12.9, 16.6, 18.1, 19.5, 23.3, 24.2, 25.6, and 26.1°2θ.

[0192] In some embodiments, solid forms of compound 1 citrate are provided herein, characterized by one, two, three, four, five, six, seven, eight, nine, ten, or all of the XRPD peaks located at approximate positions (e.g., 2θ ± 0.2°) of 12.0, 12.9, 16.6, 18.1, 19.5, 23.3, 24.2, 25.6, and 26.1°2θ when measured using CuKα radiation. In some embodiments, the solid form is characterized by at least three of the peaks. In some embodiments, the solid form is characterized by at least five of the peaks. In some embodiments, the solid form is characterized by at least seven of the peaks. In some embodiments, the solid form is characterized by all of the peaks.

[0193] In some embodiments, Embodiment 6 has an XRPD pattern that substantially matches the XRPD pattern shown in Figure 13.

[0194] Representative overlays of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms for form 6 of compound 1 are shown in Figure 14.

[0195] In some embodiments, when Embodiment 6 is characterized by a DSC using a temperature gradient of approximately 10°C / min, it shows thermal (endothermic) events with start temperatures of approximately 92°C and 144°C, and / or endothermic peak temperatures of approximately 102°C and 177°C, respectively. In some embodiments, Embodiment 6 is characterized by a DSC thermogram substantially shown in the DSC thermogram shown in Figure 14.

[0196] In some embodiments, when characterized by TGA, embodiment 6 exhibits a weight loss of approximately 5.1% when heated from approximately 26°C to approximately 150°C. In some embodiments, embodiment 6 is characterized by a TGA thermogram substantially shown in the TGA thermogram shown in Figure 14.

[0197] In some embodiments, Embodiment 6 is prepared according to the procedure of Embodiment 6.

[0198] All combinations of the embodiments described above are incorporated in this application.

[0199] 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 the crystalline citrate of compound 1. In some embodiments, form 7 has a compound 1 / citrate molar ratio of about 1:1, and optionally, 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 (i.e., polymorphs) of compound 1. In some embodiments, form 7 of compound 1 is provided as a substantially pure form 7 of compound 1.

[0200] A typical XRPD pattern for form 7 of compound 1 is shown in Figure 15.

[0201] In some embodiments, form 7 has an enantiomer 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%, or higher.

[0202] In some embodiments, Embodiment 7 has an X-ray powder diffraction (XRPD) pattern with peaks at approximately 11.0, 15.0, 19.0, 22.1, 27.7, and 29.8°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 22.1, 24.2, 24.6, 25.2, 25.8, and 26.5°2θ. In some embodiments, the XRPD pattern further 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 embodiments, the XRPD pattern 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.

[0203] In some embodiments, a solid form of compound 1 citrate is provided herein, characterized by one, two, three, four, five, six, seven, eight, nine, ten, or all of the XRPD peaks located at approximate positions of 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 (e.g., 2θ±0.2°) when measured using CuKα radiation. In some embodiments, the solid form is characterized by at least three of the peaks. In some embodiments, the solid form is characterized by at least five of the peaks. In some embodiments, the solid form is characterized by at least seven of the peaks. In some embodiments, the solid form is characterized by at least nine of the peaks. In some embodiments, the solid form is characterized by at least 11 of the peaks. In some embodiments, the solid form is characterized by at least 13 of the peaks. In some embodiments, the solid form is characterized by all of the peaks.

[0204] In some embodiments, Embodiment 7 has an XRPD pattern that substantially matches the XRPD pattern shown in Figure 15.

[0205] Representative overlays of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms for form 7 of compound 1 are shown in Figure 16.

[0206] In some embodiments, when Embodiment 7 is characterized by a DSC using a temperature gradient of about 10°C / min, it shows thermal (endothermic) events with starting temperatures of about 41°C, about 135°C, and about 169°C, and / or endothermic peak temperatures of about 58°C, about 139°C, and about 188°C, respectively. In some embodiments, Embodiment 7 is characterized by a DSC thermogram substantially shown in the DSC thermogram shown in Figure 16.

[0207] In some embodiments, when characterized by TGA, embodiment 7 exhibits a weight loss of about 2.8% when heated from about 25°C to about 100°C. In some embodiments, embodiment 7 is characterized by a TGA thermogram substantially shown in the TGA thermogram shown in Figure 16.

[0208] In some embodiments, Embodiment 7 is prepared according to the procedure of Embodiment 7.

[0209] All combinations of the embodiments described above are incorporated in this application.

[0210] 5.2.8 Form 8 of Compound 1 In some embodiments, form 8 of compound 1 is provided herein. In some embodiments, form 8 of compound 1 is the crystalline fumarate of compound 1. In some embodiments, form 8 has a compound 1 / fumarate molar ratio of about 1:1, and optionally the solid form is a solvate, and optionally 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 (i.e., polymorphs) of compound 1. In some embodiments, form 8 of compound 1 is provided as a substantially pure form 8 of compound 1.

[0211] A typical XRPD pattern for form 8 of compound 1 is shown in Figure 17.

[0212] In some embodiments, form 8 has an enantiomer 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 crystalline or higher, with about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% being crystalline.

[0213] In some embodiments, Embodiment 8 has an X-ray powder diffraction (XRPD) pattern with peaks at approximately 8.6, 10.9, 16.7, and 23.3°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 4.9, 11.4, and 17.6°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 12.7, 14.6, and 26.0°2θ. In some embodiments, the XRPD pattern includes 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.

[0214] In some embodiments, solid forms comprising a fumarate of compound 1 are provided herein, characterized by one, two, three, four, five, six, seven, eight, nine, ten, or all of the XRPD peaks located at approximate positions (e.g., 2θ ± 0.2°) of 4.9, 8.6, 10.9, 11.4, 12.7, 14.6, 16.7, 17.6, 23.3, and 26.0°2θ when measured using CuKα radiation. In some embodiments, the solid form is characterized by at least three of the peaks. In some embodiments, the solid form is characterized by at least five of the peaks. In some embodiments, the solid form is characterized by at least seven of the peaks. In some embodiments, the solid form is characterized by at least nine of the peaks. In some embodiments, the solid form is characterized by all of the peaks.

[0215] In some embodiments, Embodiment 8 has an XRPD pattern that substantially matches the XRPD pattern shown in Figure 17.

[0216] Figure 18 shows representative overlays of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms for form 8 of compound 1.

[0217] In some embodiments, when Embodiment 8 is characterized by a DSC using a temperature gradient of approximately 10°C / min, it shows a thermal (endothermic) event with an onset temperature of approximately 28°C and / or an endothermic peak at approximately 100°C, and a thermal (endothermic) event with an onset temperature of approximately 206°C and / or a peak temperature at approximately 214°C. In some embodiments, Embodiment 8 is characterized by a DSC thermogram substantially shown in the DSC thermogram shown in Figure 18.

[0218] In some embodiments, when characterized by TGA, embodiment 8 exhibits a weight loss of about 2.0% when heated from about 24.5°C to about 150°C. In some embodiments, embodiment 8 is characterized by a TGA thermogram substantially shown in the TGA thermogram shown in Figure 18.

[0219] In some embodiments, form 8 has a purity of at least 98%, 98.5%, 99%, or 99.5%.

[0220] In some embodiments, form 8 has solubility of approximately 5 mg / mL or more, 5 mg / mL or more, and 5 mg / mL or more in the SGF medium at 0.5 hours, 2 hours, and 24 hours, respectively. In some embodiments, form 8 has solubility of approximately 1.27, 1.26, and 1.15 mg / mL in the FeSSIF medium at 0.5 hours, 2 hours, and 24 hours, respectively.

[0221] In some embodiments, Embodiment 8 is prepared according to the procedure of Embodiment 8.

[0222] All combinations of the embodiments described above are incorporated in this application.

[0223] 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 gentisic acid salt of compound 1. In some embodiments, form 9 has a compound 1 / gentisic acid molar ratio of about 1:1, and optionally, 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 (i.e., polymorphs) of compound 1. In some embodiments, form 9 of compound 1 is provided as a substantially pure form 9 of compound 1.

[0224] A typical XRPD pattern of compound 1, form 9, is shown in Figure 19.

[0225] In some embodiments, form 9 has an enantiomer 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%, or higher.

[0226] In some embodiments, form 9 has an X-ray powder diffraction (XRPD) pattern with peaks at approximately 8.0, 9.6, 16.5, 17.6, 18.7, and 24.6°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 11.7, 12.2, 19.9, and 26.5°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 13.8, 15.4, 16.1, 20.8, and 21.7°2θ. In some embodiments, the XRPD pattern 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.

[0227] In some embodiments, solid forms of compound 1 containing gentisic acid salt are provided herein, characterized by one, two, three, four, five, six, seven, eight, nine, ten, or all of the XRPD peaks located at approximate positions of 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 (e.g., 2θ ± 0.2°) when measured using CuKα radiation. In some embodiments, the solid form is characterized by at least three of the peaks. In some embodiments, the solid form is characterized by at least five of the peaks. In some embodiments, the solid form is characterized by at least seven of the peaks. In some embodiments, the solid form is characterized by at least nine of the peaks. In some embodiments, the solid form is characterized by at least eleven of the peaks. In some embodiments, the solid form is characterized by at least 13 of the peaks. In some embodiments, the solid form is characterized by all of the peaks.

[0228] In some embodiments, Embodiment 9 has an XRPD pattern that substantially matches the XRPD pattern shown in Figure 19.

[0229] Representative overlays of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms for form 9 of compound 1 are shown in Figure 20.

[0230] In some embodiments, when embodiment 9 is characterized by a DSC using a temperature gradient of about 10°C / min, it shows thermal (endothermic) events with start temperatures of about 56°C and about 256°C, and / or endothermic peak temperatures of about 81°C and about 263°C, respectively. In some embodiments, embodiment 9 is characterized by a DSC thermogram substantially shown in the DSC thermogram shown in Figure 20.

[0231] In some embodiments, when characterized by TGA, embodiment 9 exhibits a weight loss of about 2.2% when heated from about 26.5°C to about 100°C. In some embodiments, embodiment 9 is characterized by a TGA thermogram substantially shown in the TGA thermogram shown in Figure 20.

[0232] In some embodiments, Embodiment 9 is prepared according to the procedure of Embodiment 9.

[0233] All combinations of the embodiments described above are incorporated in this application.

[0234] 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 gentisic acid salt of compound 1. In some embodiments, form 10 has a compound 1 / gentisic acid molar ratio of about 1:1, and the solid form is an anhydride. 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 (i.e., polymorphs) of compound 1. In some embodiments, form 10 of compound 1 is provided as a substantially pure form 10 of compound 1.

[0235] A typical XRPD pattern of compound 1, form 10, is shown in Figure 21.

[0236] In some embodiments, form 10 has an enantiomer 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%, or higher.

[0237] In some embodiments, Embodiment 10 has an X-ray powder diffraction (XRPD) pattern with peaks at approximately 4.7, 13.2, and 16.9°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 8.39, 17.5, 18.6, 21.8, and 25.3°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 11.8, 12.6, 19.0, 19.4, and 23.8°2θ. In some embodiments, the XRPD pattern includes 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.

[0238] In some embodiments, solid forms of compound 1 containing gentisic acid salt are provided herein, characterized by one, two, three, four, five, six, seven, eight, nine, ten, or all of the XRPD peaks located at approximate positions (e.g., 2θ ± 0.2°) of 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 when measured using CuKα radiation. In some embodiments, the solid form is characterized by at least three of the peaks. In some embodiments, the solid form is characterized by at least five of the peaks. In some embodiments, the solid form is characterized by at least seven of the peaks. In some embodiments, the solid form is characterized by at least nine of the peaks. In some embodiments, the solid form is characterized by at least eleven of the peaks. In some embodiments, the solid form is characterized by all of the peaks.

[0239] In some embodiments, Embodiment 10 has an XRPD pattern that substantially matches the XRPD pattern shown in Figure 21.

[0240] Representative overlays of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms for form 10 of compound 1 are shown in Figure 22.

[0241] In some embodiments, when embodiment 10 is characterized by a DSC using a temperature gradient of about 10°C / min, it shows a thermal (endothermic) event with an onset temperature of about 240°C and / or an endothermic peak temperature of about 245°C. In some embodiments, embodiment 10 is characterized by a DSC thermogram substantially shown in the DSC thermogram shown in Figure 22.

[0242] In some embodiments, when characterized by TGA, embodiment 10 exhibits a weight loss of about 0.4% when heated from about 120°C to about 200°C. In some embodiments, embodiment 10 is characterized by a TGA thermogram substantially shown in the TGA thermogram shown in Figure 22.

[0243] In some embodiments, Embodiment 10 is prepared according to the procedure of Embodiment 10.

[0244] All combinations of the embodiments described above are incorporated in this application.

[0245] 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 compound 1 / glycolate molar ratio of about 1:1, and optionally, 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 (i.e., polymorphs) of compound 1. In some embodiments, form 11 of compound 1 is provided as a substantially pure form 11 of compound 1.

[0246] A typical XRPD pattern of compound 1, form 11, is shown in Figure 23.

[0247] In some embodiments, form 11 has an enantiomer 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%, or higher.

[0248] In some embodiments, Embodiment 11 has an X-ray powder diffraction (XRPD) pattern with peaks at approximately 7.4, 12.6, 16.7, and 23.8°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 16.2, 23.4, 25.7, and 28.9°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 19.0, 20.3, and 26.1°2θ. In some embodiments, the XRPD pattern includes 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.

[0249] In some embodiments, solid forms comprising a glycolate of compound 1 are provided herein, characterized by one, two, three, four, five, six, seven, eight, nine, ten, or all of the XRPD peaks located at approximate positions (e.g., 2θ ± 0.2°) of 7.4, 12.6, 16.2, 16.7, 19.0, 20.3, 23.4, 23.8, 25.7, 26.1, and 28.9°2θ when measured using CuKα radiation. In some embodiments, the solid form is characterized by at least three of the peaks. In some embodiments, the solid form is characterized by at least five of the peaks. In some embodiments, the solid form is characterized by at least seven of the peaks. In some embodiments, the solid form is characterized by at least nine of the peaks. In some embodiments, the solid form is characterized by all of the peaks.

[0250] In some embodiments, Embodiment 11 has an XRPD pattern that substantially matches the XRPD pattern shown in Figure 23.

[0251] Representative overlays of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms for form 11 of compound 1 are shown in Figure 24.

[0252] In some embodiments, when Embodiment 11 is characterized by a DSC using a temperature gradient of about 10°C / min, it shows thermal (endothermic) events with starting temperatures of about 35°C, about 116°C, and about 152°C, and / or endothermic peak temperatures of about 59°C, about 94°C, and about 170°C, respectively. In some embodiments, Embodiment 11 is characterized by a DSC thermogram substantially shown in the DSC thermogram shown in Figure 24.

[0253] In some embodiments, when characterized by TGA, embodiment 11 exhibits a weight loss of about 1.7% when heated from about 27°C to about 80°C and a weight loss of about 3.2% when heated from about 110°C to about 200°C. In some embodiments, embodiment 11 is characterized by a TGA thermogram substantially shown in the TGA thermogram shown in Figure 24.

[0254] In some embodiments, form 11 is prepared according to the procedure of Example 11.

[0255] All combinations of the embodiments described above are incorporated in this application.

[0256] 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 the crystalline 1-hydroxy-2-naphthoate of compound 1. In some embodiments, form 12 has a compound 1 / 1-hydroxy-2-naphthoate molar ratio of about 1:1, and optionally, 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 (i.e., polymorphs) of compound 1. In some embodiments, form 12 of compound 1 is provided as a substantially pure form 12 of compound 1.

[0257] A typical XRPD pattern for form 12 of compound 1 is shown in Figure 25.

[0258] In some embodiments, form 12 has an enantiomer 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%, or higher.

[0259] In some embodiments, Embodiment 12 has an X-ray powder diffraction (XRPD) pattern with peaks at approximately 6.2, 11.2, 14.4, and 22.3°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 5.1, 14.9, and 18.3°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 5.6 and 25.3°2θ. In some embodiments, the XRPD pattern includes peaks at approximately 5.1, 5.6, 6.2, 11.2, 14.4, 14.9, 18.3, 22.3, and 25.3°2θ.

[0260] In some embodiments, solid forms of compound 1 containing 1-hydroxy-2-naphthoate are provided herein, characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all of the XRPD peaks located at approximate positions (e.g., 2θ ± 0.2°) of 5.1, 5.6, 6.2, 11.2, 14.4, 14.9, 18.3, 22.3, and 25.3°2θ when measured using CuKα radiation. In some embodiments, the solid form is characterized by at least 3 of the peaks. In some embodiments, the solid form is characterized by at least 5 of the peaks. In some embodiments, the solid form is characterized by at least 7 of the peaks. In some embodiments, the solid form is characterized by at least 8 of the peaks. In some embodiments, the solid form is characterized by all of the peaks.

[0261] In some embodiments, Embodiment 12 has an XRPD pattern that substantially matches the XRPD pattern shown in Figure 25.

[0262] Representative overlays of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms for form 12 of compound 1 are shown in Figure 26.

[0263] In some embodiments, when embodiment 12 is characterized by a DSC using a temperature gradient of about 10°C / min, it shows thermal (endothermic) events with start temperatures of about 25°C and about 178°C, and / or endothermic peak temperatures of about 32°C and about 186°C, respectively. In some embodiments, embodiment 12 is characterized by a DSC thermogram substantially shown in the DSC thermogram shown in Figure 26.

[0264] In some embodiments, when characterized by TGA, embodiment 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. In some embodiments, embodiment 12 is characterized by a TGA thermogram substantially shown in the TGA thermogram shown in Figure 26.

[0265] In some embodiments, form 12 is prepared according to the procedure of Example 12.

[0266] All combinations of the embodiments described above are incorporated in this application.

[0267] 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 the crystalline 1-hydroxy-2-naphthoate of compound 1. In some embodiments, form 13 has a compound 1 / 1-hydroxy-2-naphthoate molar ratio of about 1:1, and the solid form is the anhydride. In some embodiments, form 13 of compound 1 substantially does not contain amorphous compound 1. In some embodiments, form 13 of compound 1 substantially does not contain other crystalline forms (i.e., polymorphs) of compound 1. In some embodiments, form 13 of compound 1 is provided as a substantially pure form 13 of compound 1.

[0268] A typical XRPD pattern for form 13 of compound 1 is shown in Figure 27.

[0269] In some embodiments, form 13 has an enantiomer 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 crystalline or higher, with about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% crystalline.

[0270] In some embodiments, Embodiment 13 has an X-ray powder diffraction (XRPD) pattern with peaks at approximately 16.6, 18.1, 19.1, and 24.7°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 8.9, 12.5, 14.7, 19.7, 21.6, and 29.7°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 11.8, 12.0, 15.4, 23.3, 25.8, and 27.9°2θ. In some embodiments, the XRPD pattern 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.

[0271] In some embodiments, solid forms of compound 1 containing 1-hydroxy-2-naphthoate are provided herein, characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all of the XRPD peaks located at approximate positions (e.g., 2θ ± 0.2°) of 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 when measured using CuKα radiation. In some embodiments, the solid form is characterized by at least 3 of the peaks. In some embodiments, the solid form is characterized by at least 5 of the peaks. In some embodiments, the solid form is characterized by at least 7 of the peaks. In some embodiments, the solid form is characterized by at least 9 of the peaks. In some embodiments, the solid form is characterized by at least 11 of the peaks. In some embodiments, the solid form is characterized by at least 13 of the peaks. In some embodiments, the solid form is characterized by at least 15 of the peaks. In some embodiments, the solid form is characterized by all of the peaks.

[0272] In some embodiments, embodiment 13 has an XRPD pattern that substantially matches the XRPD pattern shown in Figure 27.

[0273] Representative overlays of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms for form 13 of compound 1 are shown in Figure 28.

[0274] In some embodiments, when embodiment 13 is characterized by a DSC using a temperature gradient of about 10°C / min, it shows a thermal (endothermic, melting / decomposition) event with an onset temperature of about 187°C and / or an endothermic peak at about 194°C. In some embodiments, embodiment 13 is characterized by a DSC thermogram substantially shown in the DSC thermogram shown in Figure 28.

[0275] In some embodiments, embodiment 13 exhibits no weight loss below approximately 160°C when characterized by TGA. In some embodiments, embodiment 13 is characterized by a TGA thermogram substantially shown in the TGA thermogram shown in Figure 28.

[0276] In some embodiments, form 13 has a purity of at least 98%, 98.5%, 99%, or 99.5%.

[0277] In some embodiments, Form 13 has solubility of approximately 3.86, 4.05, and 4.12 in SGF medium at 0.5 hours, 2 hours, and 24 hours, respectively. In some embodiments, Form 13 has solubility of approximately 0.74, 0.82, and 0.78 mg / mL in FeSSIF medium at 0.5 hours, 2 hours, and 24 hours, respectively.

[0278] In some embodiments, form 13 is prepared according to the procedure of Example 13.

[0279] All combinations of the embodiments described above are incorporated in this application.

[0280] 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 the crystalline malate of compound 1. In some embodiments, form 14 has a compound 1 / malate molar ratio of about 1:1, and optionally, 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 (i.e., polymorphs) of compound 1. In some embodiments, form 14 of compound 1 is provided as a substantially pure form 14 of compound 1.

[0281] A typical XRPD pattern of form 14 of compound 1 is shown in Figure 29.

[0282] In some embodiments, form 14 has an enantiomer 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 crystalline or higher, with about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% crystalline.

[0283] In some embodiments, Embodiment 14 has an X-ray powder diffraction (XRPD) pattern with peaks at approximately 4.7, 16.9, 17.3, 20.8, and 22.7°2θ. In some embodiments, the XRPD pattern further 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 further includes peaks at approximately 10.9, 14.1, 18.4, 24.9, 26.1, 26.7, and 27.1°2θ. In some embodiments, the XRPD pattern 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.

[0284] In some embodiments, solid forms of compound 1 malate are provided herein, characterized by one, two, three, four, five, six, seven, eight, nine, ten, or all of the XRPD peaks located at approximate positions (e.g., 2θ ± 0.2°) of 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, the solid form is characterized by at least three of the peaks. In some embodiments, the solid form is characterized by at least five of the peaks. In some embodiments, the solid form is characterized by at least seven of the peaks. In some embodiments, the solid form features at least 9 of the peaks. In some embodiments, the solid form features at least 11 of the peaks. In some embodiments, the solid form features at least 13 of the peaks. In some embodiments, the solid form features at least 15 of the peaks. In some embodiments, the solid form features at least 17 of the peaks. In some embodiments, the solid form features at least 19 of the peaks. In some embodiments, the solid form features all of the peaks.

[0285] In some embodiments, Embodiment 14 has an XRPD pattern that substantially matches the XRPD pattern shown in Figure 29.

[0286] Representative overlays of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms for form 14 of compound 1 are shown in Figure 30.

[0287] In some embodiments, when embodiment 14 is characterized by a DSC using a temperature gradient of about 10°C / min, it shows thermal (endothermic) events with starting temperatures of about 28°C and about 178°C, and / or endothermic peak temperatures of about 69°C and about 216°C, respectively. In some embodiments, embodiment 14 is characterized by a DSC thermogram substantially shown in the DSC thermogram shown in Figure 30.

[0288] In some embodiments, when characterized by TGA, embodiment 14 exhibits a weight loss of about 3.6% when heated from about 30°C to about 120°C. In some embodiments, embodiment 14 is characterized by a TGA thermogram substantially shown in the TGA thermogram shown in Figure 30.

[0289] In some embodiments, embodiment 14 is prepared according to the procedure of embodiment 14.

[0290] All combinations of the embodiments described above are incorporated in this application.

[0291] 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 the crystalline malate of compound 1. In some embodiments, form 15 has a compound 1 / malate molar ratio of about 1:1, and 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 (i.e., polymorphs) of compound 1. In some embodiments, form 15 of compound 1 is provided as a substantially pure form 15 of compound 1.

[0292] A typical XRPD pattern of compound 1, form 15, is shown in Figure 31.

[0293] In some embodiments, form 15 has an enantiomer 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%, or higher.

[0294] In some embodiments, Embodiment 15 has an X-ray powder diffraction (XRPD) pattern with peaks at approximately 11.1, 12.5, 16.6, and 17.8°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 8.39, 22.0, 23.3, and 25.5°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 13.9, 14.7, and 24.1°2θ. In some embodiments, the XRPD pattern includes 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.

[0295] In some embodiments, solid forms of compound 1 malate are provided herein, characterized by one, two, three, four, five, six, seven, eight, nine, ten, or all of the XRPD peaks located at approximate positions (e.g., 2θ ± 0.2°) of 8.39, 11.1, 12.5, 13.9, 14.7, 16.6, 17.8, 22.0, 23.3, 24.1, and 25.5°2θ when measured using CuKα radiation. In some embodiments, the solid form is characterized by at least three of the peaks. In some embodiments, the solid form is characterized by at least five of the peaks. In some embodiments, the solid form is characterized by at least seven of the peaks. In some embodiments, the solid form is characterized by at least nine of the peaks. In some embodiments, the solid form is characterized by all of the peaks.

[0296] In some embodiments, embodiment 15 has an XRPD pattern that substantially matches the XRPD pattern shown in Figure 31.

[0297] Representative overlays of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms for form 15 of compound 1 are shown in Figure 32.

[0298] In some embodiments, when embodiment 15 is characterized by a DSC using a temperature gradient of about 10°C / min, it shows thermal (endothermic) events with starting temperatures of about 127°C and about 159°C, and / or endothermic peak temperatures of about 145°C and about 182°C, respectively. In some embodiments, embodiment 15 is characterized by a DSC thermogram substantially shown in the DSC thermogram shown in Figure 32.

[0299] In some embodiments, when characterized by TGA, embodiment 15 exhibits a weight loss of about 3.1% when heated from about 90°C to about 160°C and a weight loss of about 3.6% when heated from about 160°C to about 190°C. In some embodiments, embodiment 15 is characterized by a TGA thermogram substantially shown in the TGA thermogram shown in Figure 32.

[0300] In some embodiments, form 15 is prepared according to the procedure of Example 15.

[0301] All combinations of the embodiments described above are incorporated in this application.

[0302] 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 the crystalline maleate of compound 1. In some embodiments, form 16 has a compound 1 / maleate molar ratio of about 1:1, and optionally, 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 (i.e., polymorphs) of compound 1. In some embodiments, form 16 of compound 1 is provided as a substantially pure form 16 of compound 1.

[0303] A typical XRPD pattern of compound 1, form 16, is shown in Figure 33.

[0304] In some embodiments, form 16 has an enantiomer 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%, or higher.

[0305] In some embodiments, Embodiment 16 has an X-ray powder diffraction (XRPD) pattern with peaks at approximately 12.2, 12.6, 26.1, and 29.2°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 4.8, 16.7, 24.7, and 25.2°2θ. In some embodiments, the XRPD pattern further 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.

[0306] In some embodiments, solid forms comprising the maleate of compound 1 are provided herein, characterized by one, two, three, four, five, six, seven, eight, nine, ten, or all of the XRPD peaks located at approximate positions (e.g., 2θ ± 0.2°) of 4.8, 12.2, 12.6, 14.5, 16.7, 17.3, 24.3, 24.7, 25.2, 26.1, and 29.2°2θ when measured using CuKα radiation. In some embodiments, the solid form is characterized by at least three of the peaks. In some embodiments, the solid form is characterized by at least five of the peaks. In some embodiments, the solid form is characterized by at least seven of the peaks. In some embodiments, the solid form is characterized by at least nine of the peaks. In some embodiments, the solid form is characterized by all of the peaks.

[0307] In some embodiments, embodiment 16 has an XRPD pattern that substantially matches the XRPD pattern shown in Figure 33.

[0308] Representative overlays of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms for form 16 of compound 1 are shown in Figure 34.

[0309] In some embodiments, when embodiment 16 is characterized by a DSC using a temperature gradient of about 10°C / min, it shows thermal (endothermic) events with start temperatures of about 26°C and about 198°C, and / or endothermic peak temperatures of about 53°C and about 206°C, respectively. In some embodiments, embodiment 16 is characterized by a DSC thermogram substantially shown in the DSC thermogram shown in Figure 34.

[0310] In some embodiments, when characterized by TGA, embodiment 16 exhibits a weight loss of about 1.8% when heated from about 24°C to about 100°C. In some embodiments, embodiment 16 is characterized by a TGA thermogram substantially shown in the TGA thermogram shown in Figure 34.

[0311] In some embodiments, embodiment 16 is prepared according to the procedure of embodiment 16.

[0312] All combinations of the embodiments described above are incorporated in this application.

[0313] 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 the crystalline maleate of compound 1. In some embodiments, form 17 has a compound 1 / maleate molar ratio of about 1:1, and optionally, 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 (i.e., polymorphs) of compound 1. In some embodiments, form 17 of compound 1 is provided as a substantially pure form 17 of compound 1.

[0314] A typical XRPD pattern for form 17 of compound 1 is shown in Figure 35.

[0315] In some embodiments, form 17 has an enantiomer 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%, or higher.

[0316] In some embodiments, Embodiment 17 has an X-ray powder diffraction (XRPD) pattern with peaks at approximately 9.5, 15.2, and 18.6°2θ. In some embodiments, the XRPD pattern further 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 further includes peaks at approximately 12.8, 14.4, 24.0, 25.2, and 25.7°2θ. In some embodiments, the XRPD pattern 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.

[0317] In some embodiments, solid forms comprising the maleate of compound 1 are provided herein, characterized by one, two, three, four, five, six, seven, eight, nine, ten, or all of the XRPD peaks located at approximate positions (e.g., 2θ ± 0.2°) of 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 when measured using CuKα radiation. In some embodiments, the solid form is characterized by at least three of the peaks. In some embodiments, the solid form is characterized by at least five of the peaks. In some embodiments, the solid form is characterized by at least seven of the peaks. In some embodiments, the solid form is characterized by at least nine of the peaks. In some embodiments, the solid form is characterized by at least eleven of the peaks. In some embodiments, the solid form is characterized by at least 13 of the peaks. In some embodiments, the solid form is characterized by all of the peaks.

[0318] In some embodiments, embodiment 17 has an XRPD pattern that substantially matches the XRPD pattern shown in Figure 35.

[0319] Representative overlays of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms for form 17 of compound 1 are shown in Figure 36.

[0320] In some embodiments, when embodiment 17 is characterized by a DSC using a temperature gradient of about 10°C / min, it shows thermal (endothermic) events with start temperatures of about 27°C and about 195°C, and / or endothermic peak temperatures of about 60°C and about 205°C, respectively. In some embodiments, embodiment 17 is characterized by a DSC thermogram substantially shown in the DSC thermogram shown in Figure 36.

[0321] In some embodiments, when characterized by TGA, embodiment 17 exhibits a weight loss of about 1.2% when heated from about 26°C to about 100°C. In some embodiments, embodiment 17 is characterized by a TGA thermogram substantially shown in the TGA thermogram shown in Figure 36.

[0322] In some embodiments, Embodiment 17 is prepared according to the procedure of Embodiment 17.

[0323] All combinations of the embodiments described above are incorporated in this application.

[0324] 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 mesylate of compound 1. In some embodiments, form 18 has a compound 1 / methanesulfonic acid molar ratio of about 1:0.8, and optionally, 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 (i.e., polymorphs) of compound 1. In some embodiments, form 18 of compound 1 is provided as a substantially pure form 18 of compound 1.

[0325] A representative XRPD pattern of compound 1, form 18, is shown in Figure 37.

[0326] In some embodiments, form 18 has an enantiomer 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%, or higher.

[0327] In some embodiments, embodiment 18 has an X-ray powder diffraction (XRPD) pattern with peaks at approximately 9.0, 9.2, 18.6, and 19.2°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 17.5, 18.1, and 23.1°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 20.4, 21.0, and 21.2°2θ. In some embodiments, the XRPD pattern includes 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.

[0328] In some embodiments, solid forms comprising a mesylate of compound 1 are provided herein, characterized by one, two, three, four, five, six, seven, eight, nine, ten, or all of the XRPD peaks located at approximate positions (e.g., 2θ ± 0.2°) of 9.0, 9.2, 17.5, 18.1, 18.6, 19.2, 20.4, 21.0, 21.2, and 23.1°2θ when measured using CuKα radiation. In some embodiments, the solid form is characterized by at least three of the peaks. In some embodiments, the solid form is characterized by at least five of the peaks. In some embodiments, the solid form is characterized by at least seven of the peaks. In some embodiments, the solid form is characterized by at least nine of the peaks. In some embodiments, the solid form is characterized by all of the peaks.

[0329] In some embodiments, embodiment 18 has an XRPD pattern that substantially matches the XRPD pattern shown in Figure 37.

[0330] Representative overlays of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms for form 18 of compound 1 are shown in Figure 38.

[0331] In some embodiments, when embodiment 18 is characterized by a DSC using a temperature gradient of about 10°C / min, it shows a thermal (endothermic) event with an onset temperature of about 142°C and / or an endothermic peak temperature of about 146°C. In some embodiments, embodiment 18 is characterized by a DSC thermogram substantially shown in the DSC thermogram shown in Figure 38.

[0332] In some embodiments, when characterized by TGA, embodiment 18 exhibits a weight loss of about 5.6% when heated from near room temperature to about 145°C and a weight loss of about 9.5% when heated from about 145°C to about 200°C. In some embodiments, embodiment 18 is characterized by a TGA thermogram substantially shown in the TGA thermogram shown in Figure 38.

[0333] In some embodiments, embodiment 18 is prepared according to the procedure of embodiment 18.

[0334] All combinations of the embodiments described above are incorporated in this application.

[0335] 5.2.19 Form 19 of Compound 1 In some embodiments, form 19 of compound 1 is provided herein. In some embodiments, form 19 of compound 1 is the crystalline oxalate of compound 1. In some embodiments, form 19 has a compound 1 / oxalate molar ratio of about 1:1, and optionally, 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 (i.e., polymorphs) of compound 1. In some embodiments, form 19 of compound 1 is provided as a substantially pure form 19 of compound 1.

[0336] A typical XRPD pattern of compound 1, form 19, is shown in Figure 39.

[0337] In some embodiments, form 19 has an enantiomer 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%, or higher.

[0338] In some embodiments, embodiment 19 has an X-ray powder diffraction (XRPD) pattern with peaks at approximately 4.7, 13.2, 19.8, and 25.0°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 8.5, 11.4, 14.2, 15.7, and 17.1°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 8.8, 9.7, 20.5, and 25.9°2θ. In some embodiments, the XRPD pattern includes 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.

[0339] In some embodiments, solid forms comprising the oxalate of compound 1 are provided herein, characterized by one, two, three, four, five, six, seven, eight, nine, ten, or all of the XRPD peaks located at approximate positions (e.g., 2θ ± 0.2°) of 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 when measured using CuKα radiation. In some embodiments, the solid form is characterized by at least three of the peaks. In some embodiments, the solid form is characterized by at least five of the peaks. In some embodiments, the solid form is characterized by at least seven of the peaks. In some embodiments, the solid form is characterized by at least nine of the peaks. In some embodiments, the solid form is characterized by at least eleven of the peaks. In some embodiments, the solid form is characterized by all of the peaks.

[0340] In some embodiments, embodiment 19 has an XRPD pattern that substantially matches the XRPD pattern shown in Figure 39.

[0341] Representative overlays of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms for form 19 of compound 1 are shown in Figure 40.

[0342] In some embodiments, when embodiment 19 is characterized by a DSC using a temperature gradient of about 10°C / min, it shows thermal (endothermic) events with starting temperatures of about 92°C, about 137°C, and about 194°C, and / or endothermic peak temperatures of about 137°C, about 190°C, and about 194°C, respectively. In some embodiments, embodiment 19 is characterized by a DSC thermogram substantially shown in the DSC thermogram shown in Figure 40.

[0343] In some embodiments, when characterized by TGA, embodiment 19 exhibits a weight loss of about 7.4% when heated from about 90°C to about 190°C and a weight loss of about 19.0% when heated from about 190°C to about 240°C. In some embodiments, embodiment 19 is characterized by a TGA thermogram substantially shown in the TGA thermogram shown in Figure 40.

[0344] In some embodiments, embodiment 19 is prepared according to the procedure of embodiment 19.

[0345] All combinations of the embodiments described above are incorporated in this application.

[0346] 5.2.20 Form 20 of Compound 1 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, and optionally, 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 (i.e., polymorphs) of compound 1. In some embodiments, form 20 of compound 1 is provided as a substantially pure form 20 of compound 1.

[0347] A typical XRPD pattern of compound 1, form 20, is shown in Figure 41.

[0348] In some embodiments, form 20 has an enantiomer 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%, or higher.

[0349] In some embodiments, Embodiment 20 has an X-ray powder diffraction (XRPD) pattern with peaks at approximately 9.4, 15.1, 16.6, and 18.2°2θ. In some embodiments, the XRPD pattern further 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 further includes peaks at approximately 11.1, 12.8, 22.0, 24.4, 25.3, 26.9, and 31.7°2θ. In some embodiments, the XRPD pattern includes 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.

[0350] In some embodiments, solid forms of compound 1 phosphate are provided herein, characterized by one, two, three, four, five, six, seven, eight, nine, ten, or all of the XRPD peaks located at approximate positions of 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 (e.g., 2θ±0.2°) when measured using CuKα radiation. In some embodiments, the solid form is characterized by at least three of the peaks. In some embodiments, the solid form is characterized by at least five of the peaks. In some embodiments, the solid form is characterized by at least seven of the peaks. In some embodiments, the solid form is characterized by at least nine of the peaks. In some embodiments, the solid form features at least 11 of the peaks. In some embodiments, the solid form features at least 13 of the peaks. In some embodiments, the solid form features at least 15 of the peaks. In some embodiments, the solid form features at least 17 of the peaks. In some embodiments, the solid form features all of the peaks.

[0351] In some embodiments, Embodiment 20 has an XRPD pattern that substantially matches the XRPD pattern shown in Figure 41.

[0352] Representative overlays of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms for form 20 of compound 1 are shown in Figure 42.

[0353] In some embodiments, when embodiment 20 is characterized by a DSC using a temperature gradient of about 10°C / min, it shows a thermal (endothermic) event with an onset temperature of about 34°C and / or an endothermic peak temperature of about 74°C. In some embodiments, embodiment 20 is characterized by a DSC thermogram substantially shown in the DSC thermogram shown in Figure 42.

[0354] In some embodiments, when characterized by TGA, embodiment 20 exhibits a weight loss of about 4.5% when heated from about 25°C to about 110°C. In some embodiments, embodiment 20 is characterized by a TGA thermogram substantially shown in the TGA thermogram shown in Figure 42.

[0355] In some embodiments, form 20 is prepared according to the procedure of Example 20.

[0356] All combinations of the embodiments described above are incorporated in this application.

[0357] 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 the crystalline tartrate of compound 1. In some embodiments, form 21 has a compound 1 / tartrate molar ratio of about 1:1, and optionally, 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 (i.e., polymorphs) of compound 1. In some embodiments, form 21 of compound 1 is provided as a substantially pure form 21 of compound 1.

[0358] A typical XRPD pattern of compound 1, form 21, is shown in Figure 43.

[0359] In some embodiments, form 21 has an enantiomer 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%, or higher.

[0360] In some embodiments, Embodiment 21 has an X-ray powder diffraction (XRPD) pattern with peaks at approximately 13.2, 16.9, 17.2, 17.7, 18.4, and 25.3°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 8.3, 12.3, 20.9, and 24.0°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 14.5, 19.9, and 22.4°2θ. In some embodiments, the XRPD pattern includes 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.

[0361] In some embodiments, solid forms comprising the tartrate of compound 1 are provided herein, characterized by one, two, three, four, five, six, seven, eight, nine, ten, or all of the XRPD peaks located at approximate positions (e.g., 2θ ± 0.2°) of 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 when measured using CuKα radiation. In some embodiments, the solid form is characterized by at least three of the peaks. In some embodiments, the solid form is characterized by at least five of the peaks. In some embodiments, the solid form is characterized by at least seven of the peaks. In some embodiments, the solid form is characterized by at least nine of the peaks. In some embodiments, the solid form is characterized by at least eleven of the peaks. In some embodiments, the solid form is characterized by all of the peaks.

[0362] In some embodiments, embodiment 21 has an XRPD pattern that substantially matches the XRPD pattern shown in Figure 43.

[0363] Representative overlays of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms for form 21 of compound 1 are shown in Figure 44.

[0364] In some embodiments, when embodiment 21 is characterized by a DSC using a temperature gradient of about 10°C / min, it shows a thermal (endothermic) event with start temperatures of about 29°C and about 201°C, and / or endothermic peak temperatures of about 70°C and about 204°C. In some embodiments, embodiment 21 is characterized by a DSC thermogram substantially shown in the DSC thermogram shown in Figure 44.

[0365] In some embodiments, when characterized by TGA, embodiment 21 exhibits a weight loss of about 6.8% when heated from about 30°C to about 140°C. In some embodiments, embodiment 21 is characterized by a TGA thermogram substantially shown in the TGA thermogram shown in Figure 44.

[0366] In some embodiments, form 21 is prepared according to the procedure of Example 21.

[0367] All combinations of the embodiments described above are incorporated in this application.

[0368] 5.2.22 Form 22 of Compound 1 In some embodiments, form 22 of compound 1 is provided herein. In some embodiments, form 22 of compound 1 is the crystalline tartrate of compound 1. In some embodiments, form 22 has a compound 1 / tartrate molar ratio 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 (i.e., polymorphs) of compound 1. In some embodiments, form 22 of compound 1 is provided as a substantially pure form 22 of compound 1.

[0369] A typical XRPD pattern of compound 1, form 22, is shown in Figure 45.

[0370] In some embodiments, form 22 has an enantiomer 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%, or higher.

[0371] In some embodiments, Embodiment 22 has an X-ray powder diffraction (XRPD) pattern with peaks at approximately 10.6, 11.2, 16.6, 17.6, 18.1, and 22.5°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 8.5, 14.6, 22.0, 25.2, 25.6, and 29.9°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 12.3, 14.2, 23.7, 23.9, and 27.4°2θ. In some embodiments, the XRPD pattern includes 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.

[0372] In some embodiments, solid forms comprising the tartrate of compound 1 are provided herein, characterized by one, two, three, four, five, six, seven, eight, nine, ten, or all of the XRPD peaks located at approximate positions (e.g., 2θ ± 0.2°) of 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 when measured using CuKα radiation. In some embodiments, the solid form is characterized by at least three of the peaks. In some embodiments, the solid form is characterized by at least five of the peaks. In some embodiments, the solid form is characterized by at least seven of the peaks. In some embodiments, the solid form is characterized by at least nine of the peaks. In some embodiments, the solid form is characterized by at least eleven of the peaks. In some embodiments, the solid form is characterized by at least 13 of the peaks. In some embodiments, the solid form is characterized by at least 15 of the peaks. In some embodiments, the solid form is characterized by all of the peaks.

[0373] In some embodiments, Embodiment 22 has an XRPD pattern that substantially matches the XRPD pattern shown in Figure 45.

[0374] Representative overlays of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms for form 22 of compound 1 are shown in Figure 46.

[0375] In some embodiments, when embodiment 22 is characterized by a DSC using a temperature gradient of about 10°C / min, it shows thermal (endothermic) events with starting temperatures of about 27°C, about 106°C, and about 209°C, and / or endothermic peak temperatures of about 51°C, about 141°C, and about 222°C. In some embodiments, embodiment 22 is characterized by a DSC thermogram substantially shown in the DSC thermogram shown in Figure 46.

[0376] In some embodiments, when characterized by TGA, embodiment 22 exhibits a weight loss of about 2.8% when heated from about 80°C to about 170°C. In some embodiments, embodiment 22 is characterized by a TGA thermogram substantially shown in the TGA thermogram shown in Figure 46.

[0377] In some embodiments, form 22 is prepared according to the procedure of Example 22.

[0378] All combinations of the embodiments described above are incorporated in this application.

[0379] 5.2.23 Form 23 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 tosylate of compound 1. In some embodiments, form 23 has a compound 1 / toluenesulfonic acid molar ratio of about 1:0.8, and optionally, 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 (i.e., polymorphs) of compound 1. In some embodiments, form 23 of compound 1 is provided as a substantially pure form 23 of compound 1.

[0380] A typical XRPD pattern of compound 1, form 23, is shown in Figure 47.

[0381] In some embodiments, form 23 has an enantiomer 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%, or higher.

[0382] In some embodiments, Embodiment 23 has an X-ray powder diffraction (XRPD) pattern with peaks at approximately 8.5, 14.6, 18.1, and 21.7°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 6.8, 17.7, and 23.8°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 18.8 and 22.9°2θ. In some embodiments, the XRPD pattern includes peaks at approximately 6.8, 8.5, 14.6, 17.7, 18.1, 18.8, 21.7, 22.9, and 23.8°2θ.

[0383] In some embodiments, solid forms of compound 1 toluenesulfonic acid tosylate are provided herein, characterized by one, two, three, four, five, six, seven, eight, or all of the XRPD peaks located at approximate positions (e.g., 2θ ± 0.2°) of 6.8, 8.5, 14.6, 17.7, 18.1, 18.8, 21.7, 22.9, and 23.8°2θ when measured using CuKα radiation. In some embodiments, the solid form is characterized by at least three of the peaks. In some embodiments, the solid form is characterized by at least five of the peaks. In some embodiments, the solid form is characterized by at least seven of the peaks. In some embodiments, the solid form is characterized by at least eight of the peaks. In some embodiments, the solid form is characterized by all of the peaks.

[0384] In some embodiments, embodiment 23 has an XRPD pattern that substantially matches the XRPD pattern shown in Figure 47.

[0385] Representative overlays of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms for form 23 of compound 1 are shown in Figure 48.

[0386] In some embodiments, when embodiment 23 is characterized by a DSC using a temperature gradient of about 10°C / min, it shows thermal (endothermic) events with start temperatures of about 83°C and about 186°C, and / or endothermic peak temperatures of about 120°C and about 202°C, respectively. In some embodiments, embodiment 23 is characterized by a DSC thermogram substantially shown in the DSC thermogram shown in Figure 48.

[0387] In some embodiments, when characterized by TGA, embodiment 23 exhibits a weight loss of about 1.8% when heated from near room temperature to about 100°C and a weight loss of about 5.6% when heated from about 100°C to about 180°C. In some embodiments, embodiment 23 is characterized by a TGA thermogram substantially shown in the TGA thermogram shown in Figure 48.

[0388] In some embodiments, form 23 is prepared according to the procedure of Example 23.

[0389] All combinations of the embodiments described above are incorporated in this application.

[0390] 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 the crystalline anhydride of compound 1. In some embodiments, form 24 of compound 1 substantially does not contain amorphous compound 1. In some embodiments, form 24 of compound 1 substantially does not contain other crystalline forms (i.e., polymorphs) of compound 1. In some embodiments, form 24 of compound 1 substantially does not contain salt forms of compound 1. In some embodiments, form 24 of compound 1 is provided as a substantially pure form 24 of compound 1.

[0391] A typical XRPD pattern of compound 1, form 24, is shown in Figure 49.

[0392] In some embodiments, form 24 has an enantiomer 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 crystalline or higher, with about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5% crystalline.

[0393] In some embodiments, Embodiment 24 has an X-ray powder diffraction (XRPD) pattern with peaks at approximately 9.5, 11.8, 14.6, and 20.9°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 14.8, 16.4, 22.3, and 23.8°2θ. In some embodiments, the XRPD pattern further includes peaks at approximately 16.6, 17.1, 24.2, and 25.1°2θ. In some embodiments, the XRPD pattern includes 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.

[0394] In some embodiments, solid forms comprising the anhydride of compound 1 are provided herein, characterized by one, two, three, four, five, six, seven, eight, nine, ten, or all of the XRPD peaks located at approximate positions (e.g., 2θ ± 0.2°) of 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 when measured using CuKα radiation. In some embodiments, the solid form is characterized by at least three of the peaks. In some embodiments, the solid form is characterized by at least five of the peaks. In some embodiments, the solid form is characterized by at least seven of the peaks. In some embodiments, the solid form is characterized by at least nine of the peaks. In some embodiments, the solid form is characterized by at least eleven of the peaks. In some embodiments, the solid form is characterized by all of the peaks.

[0395] In some embodiments, embodiment 24 has an XRPD pattern that substantially matches the XRPD pattern shown in Figure 49.

[0396] Representative overlays of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms for form 24 of compound 1 are shown in Figure 50.

[0397] In some embodiments, when embodiment 24 is characterized by a DSC using a temperature gradient of about 10°C / min, it shows a thermal (endothermic) event with an onset temperature of about 240°C and / or an endothermic peak at about 246°C. In some embodiments, embodiment 24 is characterized by a DSC thermogram substantially shown in the DSC thermogram shown in Figure 50.

[0398] In some embodiments, embodiment 24 exhibits no weight loss when heated to about 200°C, when characterized by TGA. In some embodiments, embodiment 24 is characterized by a TGA thermogram substantially shown in the TGA thermogram shown in Figure 50.

[0399] In some embodiments, embodiment 24 is prepared according to the procedure of embodiment 14.

[0400] All combinations of the embodiments described above are incorporated in this application.

[0401] 5.3 pharmaceutically acceptable salts of Compound 1 In some embodiments, compound 1:

[0402] [ka] Pharmacologically acceptable salts, Pharmacopoeia of compound 1 or its isotopic substitutions, or pharmaceutically acceptable solvates of pharmaceutically acceptable salts are provided herein. In some embodiments, pharmaceutically acceptable salts are benzoates, besilates, chlorides, citrates, fumarates, gentisinates, glutarates, glycolates, hippurates, 1-hydroxy-2-naphthoates, malates, maleates, mesylates, oxalates, phosphates, sulfates, tartrates, or tosylates. In some embodiments, pharmaceutically acceptable salts of compound 1, or their pharmaceutically acceptable solvates, are substantially pure. In some embodiments, pharmaceutically acceptable salts of compound 1, or their pharmaceutically acceptable solvates, are substantially chemically pure. In some embodiments, pharmaceutically acceptable salts of compound 1, or their pharmaceutically acceptable solvates, are substantially physically pure. In some embodiments, pharmaceutically acceptable salts of compound 1, or their pharmaceutically acceptable solvates, are substantially enantiomerically pure. In some embodiments, a pharmaceutically acceptable salt of compound 1, or a pharmaceutically acceptable solvate thereof, has an enantiomer purity of at least about 98% (e.g., about 98.5%, about 99%, or about 99.5%). In some embodiments, a 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, a 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, a 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, a 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 the non-solvate of the pharmaceutically acceptable salt of compound 1. In some embodiments, the pharmaceutically acceptable salt of compound 1 is the anhydrous of the 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, and the pharmaceutically acceptable solvate is a hydrate, hemihydrate, isobutyl acetate solvate, isopropyl acetate solvate, tetrahydrofuran solvate, acetone solvate, acetonitrile solvate, or a combination thereof. In some embodiments, the pharmaceutically acceptable solvate is a hydrate. In some embodiments, a 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, a 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.

[0403] In some embodiments, the pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 2 ,4 4 - Dicarbonitrile benzoate, or a pharmaceutically acceptable solvate thereof. In some embodiments, the benzoate of compound 1 has a compound 1 / benzoate molar ratio in the range of about 2:1 to about 1:2, for example, 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 / benzoate molar ratio of about 1:1.

[0404] In some embodiments, the pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 2 ,4 4 - Dicarbonitrile besyl salt, or a pharmaceutically acceptable solvate thereof.

[0405] In some embodiments, the pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 2 ,4 4 - Dicarbonitric chloride salts, or pharmaceutically acceptable solvates thereof.

[0406] In some embodiments, the pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 2 ,4 4 - Dicarbonitrile citrate, or a pharmaceutically acceptable solvate thereof.

[0407] In some embodiments, the pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 2 ,4 4 -Dicarbonitrile 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, for example, 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.

[0408] In some embodiments, the pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 2 ,4 4 - Dicarbonitrile gentisinate, or a pharmaceutically acceptable solvate thereof.

[0409] In some embodiments, the pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 2 ,4 4 - Dicarbonitrile glutarate, or a pharmaceutically acceptable solvate thereof.

[0410] In some embodiments, the pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 2 ,4 4 - Dicarbonitrile glycolate, or a pharmaceutically acceptable solvate thereof.

[0411] In some embodiments, the pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 2 ,4 4 - Dicarbonitrile hippurate, or a pharmaceutically acceptable solvate thereof.

[0412] In some embodiments, the pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 2 ,4 4-Dicarbonitrile 1-hydroxy-2-naphthoate, or a pharmaceutically acceptable solvate thereof.

[0413] In some embodiments, the 1-hydroxy-2-naphthoate of compound 1 has a compound 1 / 1-hydroxy-2-naphthoate molar ratio in the range of about 2:1 to about 1:2, for example, about 2:1 to about 1:1, or about 1:1 to about 1:2. In some embodiments, the 1-hydroxy-2-naphthoate of compound 1 has a compound 1 / 1-hydroxy-2-naphthoate molar ratio of about 1:1.

[0414] In some embodiments, the pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 2 ,4 4 - Dicarbonitrile malate, or a pharmaceutically acceptable solvate thereof.

[0415] In some embodiments, the pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 2 ,4 4 - Dicarbonitrile maleate, or a pharmaceutically acceptable solvate thereof.

[0416] In some embodiments, the pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 2 ,4 4 - Dicarbonitrile mesylate, or a pharmaceutically acceptable solvate thereof.

[0417] In some embodiments, the pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 2 ,4 4 - Dicarbonitrile oxalate, or a pharmaceutically acceptable solvate thereof.

[0418] In some embodiments, the pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 2 ,4 4 - Dicarbonitrile phosphate, or a pharmaceutically acceptable solvate thereof.

[0419] In some embodiments, the pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 2 ,4 4 - Dicarbonitric sulfate, or a pharmaceutically acceptable solvate thereof.

[0420] In some embodiments, the pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 2 ,4 4 - Dicarbonitrile tartrate, or a pharmaceutically acceptable solvate thereof.

[0421] In some embodiments, the pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 2 ,4 4- Dicarbonitrile tosylate, or a pharmaceutically acceptable solvate thereof.

[0422] 5.4 Pharmaceutical Compositions and Preparation Methods In some embodiments, i) an amount of compound 1 ranging from about 0.1 mg to about 200 mg,

[0423] [ka] ii) a pharmaceutically acceptable salt and / or solvate thereof, and ii) one or more pharmaceutically acceptable excipients are provided herein. 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 contains a solid form of compound 1 as disclosed herein. In some embodiments, the pharmaceutical composition contains any one of forms 1 to 24 of compound 1 as disclosed herein. In some embodiments, the pharmaceutical composition contains a solid form of compound 1 as disclosed herein, including crystalline, free base, and hemihydrate. In some embodiments, the pharmaceutical composition contains 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-dried 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, one or more pharmaceutically acceptable excipients include fillers, flow enhancers, disintegrants, lubricants, or binders, or a combination thereof.

[0424] In some embodiments, the pharmaceutical composition includes a filler. In some embodiments, the filler is present in an amount of about 40 to about 95% (w / w) (or weight percent, referring to the weight of a particular component per unit of the total weight of the composition, typically, for tablet compositions, relative to the weight of the uncoated core tablet). In some embodiments, the filler is silicified microcrystalline cellulose, microcrystalline cellulose, D-mannitol, or a combination thereof. In some embodiments, the filler is silicified microcrystalline cellulose.

[0425] In some embodiments, the pharmaceutical composition includes a flow promoter. In some embodiments, the amount of the flow promoter is colloidal silicon dioxide. In some embodiments, the colloidal silicon dioxide is present in an amount of about 0.5 to about 5% (w / w), or about 0.5, about 1.0, or about 1.5% (w / w), or about 1.0% (w / w).

[0426] In some embodiments, the pharmaceutical composition includes a disintegrant. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the disintegrant is present in an amount of about 1 to about 6% (w / w), or about 2.0%, about 2.5%, about 3.0%, about 3.5%, or about 4.0% (w / w), or about 3.0% (w / w). In some embodiments, the pharmaceutical composition includes a lubricant.

[0427] In some embodiments, the lubricant is magnesium stearate. In some embodiments, the lubricant is present in amounts of about 0.5 to about 2.5% (w / w), or about 0.5, about 1.0, about 1.5, or about 2.0% (w / w), or about 1.0% (w / w), or about 1.5% (w / w).

[0428] In some embodiments, the pharmaceutical composition includes a binder. In some embodiments, the binder is povidone. In some embodiments, the binder is present in an amount of about 3 to about 10% (w / w) and about 3 to about 15 mg.

[0429] In some embodiments, pharmaceutical compositions are provided herein in which (a) a solid form is present in an amount of about 0.1 mg to about 25 mg free base equivalent and silicified microcrystalline cellulose is present in an amount of about 70 to about 97% (w / w), or (b) a solid form is present in an amount of about 25 mg to about 200 mg free base equivalent and silicified microcrystalline cellulose is present in an amount of about 40 to about 70% (w / w). In some embodiments, the solid form is present in an amount of about 0.2 mg free base equivalent and silicified microcrystalline cellulose is present in an amount of about 75 to about 95% (w / w) and about 73 to about 75.4 mg. In some embodiments, 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 to about 95% (w / w) and in (a) about 80 to about 380 mg, or (b) about 80 to about 90 mg, or (c) about 370 to about 378 mg. In some embodiments, 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 to about 95% (w / w) and in about 75 to about 85 mg. In some embodiments, 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 to about 50% (w / w) and in about 40 to about 50 mg, or the silicified microcrystalline cellulose is present in an amount of about 60 to about 70% (w / w) and in about 60 to about 70 mg.

[0430] In some embodiments, the pharmaceutical composition comprises (a) a core tablet containing about 0.21 mg of Compound 1 (Form 1), about 75.4 mg of silicified microcrystalline cellulose, about 0.8 mg of colloidal silicon dioxide, 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 composition with a strength of 0.2 mg of Compound 1 (free base equivalent).

[0431] In some embodiments, the pharmaceutical composition comprises (a) a core tablet containing about 1.03 mg of Compound 1 (Form 1), about 377 mg of silicified microcrystalline cellulose, about 4.0 mg of colloidal silicon dioxide, 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 composition with a strength of 1 mg of Compound 1 (free base equivalent).

[0432] In some embodiments, the pharmaceutical composition comprises (a) a core tablet containing about 10.3 mg of Compound 1 (Form 1), about 84.2 mg of silicified microcrystalline cellulose, about 1.0 mg of colloidal silicon dioxide, 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 composition with a strength of 10 mg of Compound 1 (free base equivalent).

[0433] In some embodiments, the pharmaceutical composition comprises (a) a core tablet containing about 51.5 mg of Compound 1 (Form 1), about 43.0 mg of silicified microcrystalline cellulose, about 1.0 mg of colloidal silicon dioxide, 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 intragranular portion containing 51.5 mg of Compound 1 (Form 1), about 43.0 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 containing about 1.0 mg of croscarmellose sodium and about 0.5 mg of magnesium stearate. In some embodiments, these pharmaceutical compositions are compositions with a Compound 1 (free base equivalent) strength of 50 mg.

[0434] In some embodiments, the pharmaceutical composition comprises (a) a core tablet containing about 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 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 intragranular portion containing 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 containing about 1.0 mg of croscarmellose sodium and about 0.5 mg of magnesium stearate. In some embodiments, these pharmaceutical compositions are compositions with a Compound 1 (free base equivalent) strength of 50 mg.

[0435] In some embodiments, the pharmaceutical composition comprises (a) a core tablet containing about 1.0 mg of Compound 1 (Form 1), about 5.0 mg of povidone, about 89 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. In some embodiments, the pharmaceutical composition is a composition with a strength of 1 mg of Compound 1 (free base equivalent).

[0436] In some embodiments, the pharmaceutical composition comprises (a) a core tablet containing about 10 mg of Compound 1 (Form 1), about 5.0 mg of povidone, about 80 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. In some embodiments, the composition is a 10 mg Compound 1 (free base equivalent) strength composition.

[0437] In some embodiments, the pharmaceutical composition comprises (a) a core tablet containing 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. In some embodiments, the pharmaceutical composition comprises (a) a core tablet containing about 51.5 mg of Compound 1 (Form 1), about 10.0 mg of povidone, about 128.5 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. In some embodiments, the core tablet comprises (a) an intragranular portion containing Compound 1 (Form 1), silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and povidone, and (b) an extragranular portion containing magnesium stearate. In some embodiments, the composition is a 50 mg Compound 1 (free base equivalent) strength composition.

[0438] In some embodiments, a method for preparing a pharmaceutical composition as disclosed herein is provided, the method comprising: i) optionally crushing a 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 flow enhancer, and a filler to form a first blend; iii) crushing the first blend to form a crushed first blend; iv) crushing a second portion of the filler; v) blending the crushed first blend and the crushed 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. In some embodiments, the method comprises crushing a solid form of compound 1 or a pharmaceutically acceptable salt and / or solvate thereof. In some embodiments, the method further comprises viiii) coating the compressed tablets. In some embodiments, the coating is a spray-dried film coating. In some embodiments, the method further comprises ix) packaging the film-coated tablets in a container. In some embodiments, the amount of compound 1, or a pharmaceutically acceptable salt and / or solvate thereof, in solid form present in the pharmaceutical composition is about 0.2 mg, about 1 mg, or about 10 mg free base equivalent.

[0439] In some embodiments, a method for preparing a pharmaceutical composition as disclosed herein is provided, the method comprising: i) optionally crushing a 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 flow enhancer, and a disintegrant to form a first blend; iii) decoagulating 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 smoothed in-granule blend; v) forming granules from the in-granule blend using, for example, a roller press and a screen; vi) blending the granules with a second portion of a disintegrant and a second portion of a lubricant to form a smoothed final blend; and vii) optionally compressing the smoothed final blend into a tablet using a rotary press. In some embodiments, the method comprises crushing a solid form of compound 1, or a pharmaceutically acceptable salt and / or solvate thereof. In some embodiments, the method further comprises viiii) coating the compressed tablets. In some embodiments, the coating is a spray-dried film coating. In some embodiments, the method further comprises ix) packaging the film-coated tablets in a container. In some embodiments, the amount of compound 1, or a pharmaceutically acceptable salt and / or solvate thereof in solid form present in the film-coated tablets is 50 mg free base equivalent.

[0440] In some embodiments, a method for preparing a pharmaceutical composition as disclosed herein is provided, the method comprising: i) optionally crushing a 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 flow enhancer, 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 smoothed final blend; and v) optionally compressing the smoothed final blend into tablets using a rotary press. In some embodiments, the method comprises crushing a solid form of compound 1 or a pharmaceutically acceptable salt and / or solvate thereof. In some embodiments, the method further comprises vii) coating the compressed tablets. In some embodiments, the coating is a spray-dried film coating. In some embodiments, the method further includes viiii) packaging the film-coated tablets in a container. In some embodiments, the amount of compound 1, or a pharmaceutically acceptable salt and / or solvate thereof, in solid form present in the film-coated tablets is 1 mg, 10 mg, or 50 mg free base equivalent. In some embodiments, the dried granules are ground and then blended with a lubricant to form a smoothed final blend. In some embodiments, the granules are ground using a screen of about 0.5 mm to about 2 mm mesh, or about 1 mm mesh. In some embodiments, the wet granules are ground before drying, for example, using a 3 / 8 inch screen.

[0441] 5.5 Synthesis In some embodiments, compound 1:

[0442] [ka] Or a process for preparing a pharmaceutically acceptable form thereof, comprising one or more of the following steps shown in schemes A to F, is provided herein.

[0443] Scheme A.

[0444] [ka]

[0445] Scheme B.

[0446] [ka]

[0447] Scheme C.

[0448] [ka]

[0449] Scheme D.

[0450] [ka]

[0451] Scheme E.

[0452] [ka]

[0453] Scheme F.

[0454] [ka]

[0455] In some embodiments, a process for preparing compound 1 or a pharmaceutically acceptable form thereof, (a) Racemic compound 19:

[0456] [ka] The diastereomer salt of compound 1 and compound 2 are obtained by reacting the chiral acid in a solvent.

[0457] [ka] Forms a diastereomer salt of The reaction involves one of two diastereomer salts selectively precipitating from the solvent, while the other diastereomer salt is selectively soluble in the solvent. (b) Separating the precipitate from the solvent, (c) To provide compound 1 by reacting the diastereomer salt of compound 1 with a base, (d) A process is provided herein that optionally includes recrystallizing compound 1 from ACN / water in an optionally 2:1 to 1:5 ratio and optionally 1:1 to 1:3 ratio.

[0458] In some embodiments, the chiral acid is (R)-crosiphos, (S)-crosiphos, (+)-tartaric acid, (-)-tartaric acid, (+)-camphorsulfonic acid, (-)-camphorsulfonic acid, L-(-)-di-p-anisioyltartaric acid, D-(+)-di-p-anisioyltartaric acid, L-(-)-di-toluoyltartaric acid, D-(+)-di-toluoyltartaric acid, (R)-BINAP phosphate, (S)-BINAP phosphate, di-benzoyl-l-tartaric acid, or di-benzoyl-D-tartaric acid. In some embodiments, the chiral acid is dibenzoyl-D-tartaric acid or dibenzoyl-L-tartaric acid, and the solvent is acetone or DCM. In some embodiments, the chiral acid is (R)-BINAP phosphate or (S)-BINAP phosphate, and the solvent is dioxane, acetone, ACN, IPAc, MEK, THF, 2-MeTHF, dioxolane, or glycan, for example, in some embodiments the solvent is THF or dioxolane. In some embodiments, the chiral acid is dibenzoyl-D-tartaric acid, and the diastereomer salt of compound 1 is a diastereomer salt that is selectively soluble in the solvent. In some embodiments, the chiral acid is dibenzoyl-L-tartaric acid, and the diastereomer salt of compound 1 is a diastereomer salt that selectively precipitates from the solvent. In some embodiments, the base is Na2CO3, K2CO3, NaOH, or KOH, or the base is Na2CO3. In some embodiments, the solvent is DCM.

[0459] In some embodiments, the method disclosed herein involves compound 18:

[0460] [ka] The process involves reacting with an ammonia equivalent to form compound 19. In some embodiments, the ammonia equivalent is optionally about 15 to about 50 equivalents, or about 40 to 50 equivalents, of NH3. 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 to about 40°C.

[0461] In some embodiments, the method disclosed herein involves compound 17:

[0462] [ka] The process 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 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 to about 60°C.

[0463] In some embodiments, the method disclosed herein involves compound 16:

[0464] [ka] The present invention provides compound 17 by reacting a cyanide equivalent with a palladium catalyst in the presence of an optionally selected zinc source and / or a phosphine ligand. 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 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 a combination 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 used in an amount of about 0.02 to about 0.15 equivalents. In some embodiments, the zinc source is metal zinc. In some embodiments, the reaction of compound 16 is carried out at a temperature of about 60 to about 110°C, or about 90 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.

[0465] In some embodiments, compound 1:

[0466] [ka] or a process for preparing the pharmaceutically acceptable form thereof, compound 18A:

[0467] [ka] Compound 19 is obtained by reacting a cyanide equivalent and a palladium catalyst with a zinc source and / or a phosphine ligand, optionally in the presence of a zinc source and / or a phosphine ligand.

[0468] [ka] To provide, A process is provided herein that includes purifying a racemic compound 19 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 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 a combination 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 used in an amount of about 0.02 to about 0.15 equivalents. In some embodiments, the zinc source is metal zinc. In some embodiments, the reaction of compound 18A is carried out at a temperature of about 60 to about 110°C, or about 90 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 method disclosed herein involves compound 17A

[0470] [ka] The process involves reacting 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 an amount of about 15 to about 50 equivalents, or about 17 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 of about 0 to about 40°C.

[0471] In some embodiments, the method disclosed herein involves compound 16:

[0472] [ka] The process includes 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 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 to about 60°C.

[0473] In some embodiments, the method disclosed herein involves compound 15X

[0474] [ka] The method includes cyclizing a salt thereof (wherein X is a leaving group selected from -Cl, -Br, -I, -OTs, or -OMs, and optionally X is -Cl (compound 15)) in the presence of a base to form compound 16. 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 free base form, and this base is present in an amount of about 1.5 to 4 equivalents. In some embodiments, compound 15X is used in salt form, and this base is present in an amount of about 4 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 diglyme, or a mixture 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 to about 80°C.

[0475] In some embodiments, the method disclosed herein involves compound 14:

[0476] [ka] The method includes reacting a salt thereof with a hydroxyl activator to form compound 15X or a salt thereof. In some embodiments, the hydroxyl activator is thionyl chloride, POCl3, PCl3, or oxalyl chloride (where X is -Cl), NaBr or LiBr (where X is -Br), TsCl (where X is -OTs), or MsCl (where X is -OMs). In some embodiments, the hydroxyl activator is thionyl chloride, where X is -Cl. In some embodiments, the hydroxyl activator is used in an amount of about 2 to about 4 equivalents, or about 3 equivalents. In some embodiments, the reaction of compound 14 is carried out in a polar aprotic solvent selected from, for example, THF, 2-MeTHF, DMF, or DMA. In some embodiments, the reaction of compound 14 is carried out at a temperature of about 10 to about 60°C.

[0477] In some embodiments, the process includes reacting compound 14 or a salt thereof under Mitsunobu conditions to form compound 16. In some embodiments, the Mitsunobu conditions include a dialkyl azodicarboxylate and a trialkyl- or triarylphosphine, for example, the dialkyl azodicarboxylate is DEAD or DIAD, and the trialkyl- or triarylphosphine is triphenylphosphine.

[0478] In some embodiments, the method disclosed herein involves compound 13PG

[0479] [ka] The process involves deprotecting a PG (wherein each PG is independently a hydroxyl protecting group) under appropriate deprotection conditions to form compound 14 or a salt thereof. In some embodiments, both PG groups are silyl protecting groups such as tert-butyldimethylsilyl, tri-isopropylsilyl, triethylsilyl, or tert-butyldiphenylsilyl. In some embodiments, both PG groups are tri-isopropylsilyl or tert-butyldimethylsilyl (compound 13). In some embodiments, the deprotection conditions optionally include TBAF, MSA, MSA / H2O, or HCl / H2O in a polar solvent. In some embodiments, the solvent is THF, ACN, RINKAN, acetone, toluene, or a mixture thereof. In some embodiments, the deprotection conditions include 3N HCl in THF or THF / toluene (optionally, THF / toluene in a ratio of about 4:1 to about 1:4, or THF / toluene in a ratio of about 2:1 to about 3:1). In some embodiments, the deprotection of compound 13PG is carried out at a temperature of about 0 to about 40°C.

[0480] In some embodiments, the method disclosed herein involves compound 12PG

[0481] [ka] The method involves coupling (wherein each PG is independently a hydroxyl protecting group). In some embodiments, both PG groups are silyl protecting groups such as tert-butyldimethylsilyl, tri-isopropylsilyl, triethylsilyl, or tert-butyldiphenylsilyl. In some embodiments, both PG groups are tri-isopropylsilyl or tert-butyldimethylsilyl (compound 12), where 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 to about -90°C. In some embodiments, the reaction comprises metallizing 1-methylimidazole at the 5-position to form a reactive species, and mixing the reactive species with compound 12PG, wherein the reactive species is optionally (1-methyl-2-(protecting group)-1H-imidazole-5-yl)lithium, and optionally 1-methyl-2-(protecting group)-1H-imidazole-5-yl)lithium is (1-methyl-2-(triethylsilyl)-1H-imidazole-5-yl)lithium. In some embodiments, the metallization comprises reacting 1-methylimidazole with (i)BuLi, (ii)TESCl, and (iii)BuLi to form (1-methyl-2-(triethylsilyl)-1H-imidazole-5-yl)lithium. In some embodiments, the metallization and coupling are carried out at a temperature of about -30 to about -90°C.

[0482] In some embodiments, the method disclosed herein involves compound 11PG

[0483] [ka] Compound 9PG

[0484] [ka] The method comprises condensing compound 9PG with (wherein each PG is independently a hydroxyl protecting group, optionally both PG groups in compound 9PG and compound 11PG are silyl protecting groups such as tert-butyldimethylsilyl, tri-isopropylsilyl, triethylsilyl, or tert-butyldiphenylsilyl, optionally both PG groups are tri-isopropylsilyl or tert-butyldimethylsilyl (compound 9 and compound 11)) to form compound 12PG. In some embodiments, the method comprises reacting compound 9PG with a metallating agent such as BuLi or isopropylMgCl / LiCl to form a reactive species. In some embodiments, the metallating agent is optionally used in an amount of about 1 to about 1.3 equivalents in a polar aprotic solvent. In some embodiments, the polar aprotic solvent is THF. In some embodiments, the method further comprises mixing the reactive species with compound 11PG. In some embodiments, the reaction of compound 9PG and its mixing with compound 11PG are carried out at a temperature of about -60 to about -85°C.

[0485] In some embodiments, the method disclosed herein involves compound 8:

[0486] [ka] The process involves reacting with a hydroxyl protecting agent to form compound 9PG. In some embodiments, PG is a silyl protecting agent. 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, the base is optionally imidazole, TEA, TEA / DMAP, DIPEA, or pyridine in a polar aprotic solvent. In some embodiments, the polar aprotic solvent is DCM or THF.

[0487] In some embodiments, the method disclosed herein involves compound 7

[0488] [ka] The process includes reacting 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 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 optionally a tetraalkylammonium salt, such as tetrabutylammonium iodide, 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 to about 40°C.

[0489] In some embodiments, the method disclosed herein involves compound 6:

[0490] [ka] The process includes reacting 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. In some embodiments, the dehydrating agent is used in an amount of about 2 to about 6 equivalents in a polar aprotic solvent, optionally. 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 to about 85°C.

[0491] In some embodiments, the method disclosed herein involves compound 5

[0492] [ka] The process involves reacting (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 of about 1.5 to about 3 equivalents. In some embodiments, the acid is HCl or H2SO4. In some embodiments, the acid is used in a stoichiometric or catalytic amount. 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 of about 10 to about 40°C. In some embodiments, step (ii) is carried out at a temperature of about 10 to about 75°C.

[0493] In some embodiments, the method disclosed herein involves compound 4:

[0494] [ka] The process involves acetylating in the presence of an acetylating agent to form compound 5. In some embodiments, the acetylating 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 optionally carried out in a polar solvent such as DCM or toluene at a temperature of about 15 to about 110°C, or (c) water and AcCl in an organic solvent such as Et2O or DCM. In some embodiments, post-reaction treatment may include adding water, separating the layers, and washing the organic phase with aqueous NaHCO3 and aqueous NaCl solutions. The resulting organic solution, for example, a toluene solution, may be used directly in the next step.

[0495] In some embodiments, the method disclosed herein involves compound 3:

[0496] [ka] The process includes treating 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 used in an amount of about 1.5 to about 3 equivalents in a polar aprotic solvent, optionally. 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.

[0497] In some embodiments, the method disclosed herein involves 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 optionally sodium methoxide, sodium ethoxide, or potassium tert-butoxide in an optionally polar solvent in an optionally large amount of about 2 to about 10 equivalents. In some embodiments, the polar solvent is MeOH, EtOH, MeOH / DCM, or EtOH / DCM, and optionally at a temperature of about 0 to about 60°C. In some embodiments, the work-up may include washing with an aqueous Na2S2O3 solution and optionally quenching by adding an aqueous NaOCl solution beforehand. In some embodiments, the crude substance may be purified by diluting with MeOH, stirring at a temperature of about 30 to about 60°C, then concentrating to about 4.5 to 5.5V, cooling, and filtering the resulting solid.

[0498] In some embodiments, the method disclosed herein involves compound 23:

[0499] [ka] The method includes reacting with a hydroxyl protecting agent to form compound 11PG. In some embodiments, PG is a silyl protecting agent 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 optionally imidazole, TEA, TEA / DMAP, DIPEA, or pyridine in a polar aprotic solvent. In some embodiments, the polar aprotic solvent is DCM or THF.

[0500] In some embodiments, the method disclosed herein involves compound 22

[0501] [ka] The process includes reacting with morpholine under amide coupling conditions to form compound 23. 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.

[0502] In some embodiments, the method disclosed herein involves compound 21:

[0503] [ka] The process includes converting compound 21 to compound 22 by treating compound 21 with a base and water. In some embodiments, the base is optionally Na2CO3, K2CO3, NaOH, or KOH 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 to about 110°C. In some embodiments, compound 21 is in a mixture 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.

[0504] In some embodiments, the method disclosed herein involves compound 20:

[0505] [ka] The process involves reacting with a brominating agent and a 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 radical initiator is light, heat, or AIBN. In some embodiments, the brominating agent is NBS, and the radical initiator is light. In some embodiments, the reaction of compound 20 is carried out in a continuous flow reactor equipped with a photodegradation flow cell having wavelengths in the range of about 300 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.

[0506] In some embodiments, a process for preparing compound 9, wherein compound 7:

[0507] [ka] Reacting it with a demethylating agent, compound 8:

[0508] [ka] To form, A process is provided herein that includes reacting compound 8 with TBSCl and a base to form compound 9. In some embodiments, the demethylating agent is BCl3 or BBr3 in an optionally selected 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 optionally a tetraalkylammonium salt such as tetrabutylammonium iodide 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 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.

[0509] In some embodiments, the method disclosed herein involves compound 6:

[0510] [ka] The process involves reacting 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 used in an amount of about 2 to about 6 equivalents in a polar aprotic solvent, optionally. 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 to about 85°C.

[0511] In some embodiments, compound 11:

[0512] [ka] A process for preparing, Compound 23:

[0513] [ka] A process is provided herein that includes reacting with TBSCl in the presence of a base to form compound 11. 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.

[0514] In some embodiments, compound 19:

[0515] [ka] A process for preparing, Compound 17:

[0516] [ka] Chlorinated with a chlorinating agent, compound 18:

[0517] [ka] To form, A process is provided herein that includes reacting compound 18 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 to about 3.5 equivalents. In some embodiments, the 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 to about 60°C.

[0518] In some embodiments, the ammonia equivalent is NH3. In some embodiments, the ammonia equivalent is used in amounts of about 15 to about 50 equivalents, or about 40 to 50 equivalents. In some embodiments, the reaction of compound 18 is carried out in a polar solvent, which 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 to about 40°C.

[0519] In some embodiments, compound 14:

[0520] [ka] A process for preparing, Compound 13:

[0521] [ka] A process is provided herein that includes reacting under deprotection conditions to form compound 14. In some embodiments, the deprotection conditions optionally include TBAF, MSA, MSA / H2O, or HCl / H2O in a polar solvent. In some embodiments, the solvent is THF, ACN, siRNA, acetone, toluene, or a mixture thereof. In some embodiments, the deprotection conditions include 3N HCl in THF or THF / toluene (optionally, THF / toluene in a ratio of about 4:1 to about 1:4, or THF / toluene in a ratio of about 2:1 to about 3:1). In some embodiments, the deprotection of compound 14 is carried out at a temperature of about 0 to about 40°C.

[0522] In some embodiments, compound 12:

[0523] [ka] A process for preparing, Compound 11:

[0524] [ka] Compound 9:

[0525] [ka] A process is provided herein that includes condensation with to form compound 12. In some embodiments, the process includes reacting compound 9 with a metallating agent such as BuLi or isopropyl MgCl / LiCl to form a reactive species. In some embodiments, the metallating agent is used in an amount of about 1 to about 1.3 equivalents in a polar aprotic solvent, optionally. In some embodiments, the polar aprotic solvent is THF. In some embodiments, the reactive species is mixed with compound 11, optionally, the reaction of compound 9 and the mixing of the reactive species with compound 11 are carried out at a temperature of about -60 to about -85°C.

[0526] In some embodiments, a process for preparing compound 13 is provided herein, comprising coupling compound 12 with 1-methylimidazole to form compound 13. In some embodiments, this process comprises metallizing 1-methylimidazole at the 5-position to form a reactive species, and mixing the reactive species with compound 12. In some embodiments, the reactive species is (1-methyl-2-(protecting group)-1H-imidazole-5-yl)lithium, and optionally, 1-methyl-2-(protecting group)-1H-imidazole-5-yl)lithium is (1-methyl-2-(triethylsilyl)-1H-imidazole-5-yl)lithium. In some embodiments, the metallization comprises reacting 1-methylimidazole with (i)BuLi, (ii)TESCl, and (iii)BuLi to form (1-methyl-2-(triethylsilyl)-1H-imidazole-5-yl)lithium. In some embodiments, metallization is carried out at a temperature of about -30 to about -90°C. In some embodiments, coupling is carried out at a temperature of about -30 to about -90°C.

[0527] In some embodiments, if one or more steps of the processes disclosed herein use a transition metal catalyst, the process may include reducing the amount of transition metal material, such as a palladium-based material or a zinc-based material, from the reaction product or subsequent reaction products. In some embodiments, the reduction is performed on compound 1 or an intermediate in the synthesis process, and as a result, compound 1 meets the specification guidelines for transition metals or palladium ("Guideline on the Specification Limits for Residues of Metal Catalysts," European Medicines Agency Preauthorisation Evaluation of Medicines for Human Use, London, January 2007, Doc.Ref.CPMP / SWP / QWP / 4446 / 00 corr). In some embodiments, the process 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 a reaction product such as compound 1 includes treating the reaction product / transition metal mixture with an adsorbent and / or extractant, or a crystallizer, or a combination thereof. In some embodiments, reducing the amount of palladium involves 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 the adsorbent once, more than once, or twice.

[0528] Examples of adsorbents include, but are not limited to, trithiocyanuric acid (trimercaptotriazine, TMT), TMT derivatives (e.g., solid TMT, polystyrene-bonded TMT, silica gel-bonded TMT, SiliaMetS® DMT, mercaptoporous polystyrene-bonded TMT, or TMT-3Na), and derivatized silica gel (e.g., silica gel-linker-thiol, silica gel-(CH2)3-SH, silica gel-(CH2)3-S-(CH2)2-SH, or silica gel-linker-amine, e.g., silica gel-(CH2)3-NH2, or silica gel-(CH2)3-[NH-(CH2)2] 1-2Examples of crystallizing agents include -NH2, or silica gel-(CH2)3-NHC(S)NHCH3, e.g., silica gel-linker-amine, e.g., SiliaMetS® metal scavenger), polystyrene-bonded ethylenediamine, derivatized polyolefin fibers (e.g., grafted with acrylic acid, vinylpyridine, styrene sulfonic acid, styrylthiol, styryldiphenylphosphine, mercaptoethyl acrylate, or acrylate alpha-hydroxylthiol, e.g., Smopex® metal scavenger), activated carbon (e.g., DARCO® KB-G and DARCO® KB-WJ), or glass bead sponges. Examples of crystallizing agents, but not limited to, include N-acetylcysteine, thiourea, 2-methylthiourea, thioglycerol, hemimaleate, or Bu3P. Examples of extractants, but not limited to, include N-acetylcysteine, L-cysteine, and Bu3P in lactic acid. For example, see Garrett et al., Adv.Synth.Catal.2004, 346, 889-900.

[0529] Examples of additional 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 DOTA, SiliaMetS imidazole, and SiliaMetS triamine.

[0530] In some embodiments, compound 1 is treated with a mixture of tetrasodium EDTA and TMT-3Na in water at a temperature of about 20 to about 40°C, and then optionally purified by column chromatography.

[0531] In some embodiments, after reduction, the amount of palladium and / or in the reaction product is about 100 ppm or less, about 10 ppm, or undetectable. In some embodiments, the presence and / or amount of residual heavy metal (e.g., palladium or zinc) impurities is 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 is determined using inductively coupled plasma mass spectrometry (ICP-MS). In some embodiments, the presence and / or amount of residual heavy metal (e.g., palladium) impurities is determined using the US Pharmacopeia General Chapter <232> Determined using the techniques described in Elemental Impurities-Limits.

[0532] In some embodiments, the following:

[0533] [ka] Compounds selected from and salts thereof are provided herein.

[0534] In some embodiments, compounds selected from (R)-crosiphos, (S)-crosiphos, (+)-tartaric acid, (-)-tartaric acid, (+)-camphorsulfonic acid, (-)-camphorsulfonic acid, L-(-)-di-p-anisioyltartaric acid, D-(+)-di-p-anisioyltartaric acid, L-(-)-di-toluoyltartaric acid, D-(+)-di-toluoyltartaric acid, (R)-BINAP phosphate, (S)-BINAP phosphate, di-benzoyl-l-tartaric acid, or di-benzoyl-D-tartrate of compound 1 or compound 2 are provided herein. In some embodiments, the salt is di-benzoyl-l-tartrate or di-benzoyl-D-tartrate of compound 1 or compound 2. In some embodiments, the salt is L-DBTA salt of compound 1.

[0535] 5.6 Use and Method 5.6.1 Therapeutic Use and Methods RAS isoforms associate with the inner surface of the plasma membrane to transmit extracellular signals. To become active, RAS undergoes several posttranslational modifications. Among the first steps in activation is the farnesylation of cysteine ​​in the C-terminal 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. The enzyme farnesyltransferase (FTase) recognizes the CAAX motif and transfers a 15-carbon farnesyl isoprenoid from farnesyl diphosphate to a cysteine ​​residue. The AAX amino acid is then cleaved by Ras-converting enzyme I, and the farnesylated cysteine ​​is carboxymethylated by isoprenylcysteine ​​carboxylmethyltransferase. Prior, IA, et al., J. Cell Sci. 2001, 114, 1603-1608. The presence of further palmitoylation (KRAS4A, NRAS, and HRAS) or a polybasic domain (KRAS4B) leads to protein fixation in the plasma membrane. Hancock, JF, et al., Cell 1990, 63, 133-139. This observation suggests that prenylation is required for the function of all RAS isoforms, including their variant forms. However, some farnesylated proteins, including KRAS and NRAS, can be rescued from membrane displacement in the presence of farnesyltransferase inhibitors (FTIs) by alternative prenylation by the enzyme geranylgeranyltransferase (GGTase). Zhang, FL, et al., J. Biol. Chem. 1997, 272, 10232-10239; Whyte, DB, et al., J. Biol. Chem. 1997, 272, 14459-14464. Conversely, HRAS, a third family member, is not a GGTase substrate, and therefore its membrane localization and cellular function are reduced by FTI.Whyte, DB, et al. Therefore, the use of FTIs to target enriched patient populations of tumors, such as farnesylating protein-dependent tumors like HRAS, such as tumors with HRAS mutations, should provide clinical benefits.

[0536] One specific FTI currently in clinical development is tipifarnib. The efficacy of tipifarnib was investigated in a series of cell-derived 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 revealed that HRAS mutations occur in 6% of HNSCC patients at initial diagnosis (Hoadley, KA, et al., Cell 2018, 173, 291-304) and in 15% of patients during the acquisition of resistance to cetuximab (Braig, F., et al., Oncotarget 2016, 7, 42988-42995), and HRAS mutations have been shown to correlate with a reduced response in HNSCC patients to cetuximab treatment. "" Rampias, T., et al., Clin. Cancer Res. 2014, 20, 2933-2946.

[0537] HRAS also repeatedly mutates in other cancer types, including urothelial cell carcinoma and salivary gland tumors, and 24% of patients with HRAS-mutated metastatic urothelial carcinoma treated with tipifarnib experienced an objective response. In addition, of 13 patients with recurrent / metastatic salivary gland tumor (SGT) treated with tipifarnib, one experienced an objective response, and seven more had disease stability as the best response. Ho, AL, et al., J. Clin. Oncol. 2020, 38, 6504. Other tumor types showing recurrent HRAS driver mutations include lung squamous cell carcinoma, thyroid cancer, pheochromocytoma, and paraganglioma. Hoadley, KA, et al.

[0538] 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 thereof, or a pharmaceutically acceptable solvate thereof, is a farnesyltransferase inhibitor. 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 thereof, or a pharmaceutically acceptable solvate thereof, is a selective farnesyltransferase inhibitor for inhibition of geranylgeranyltransferase type 1 (e.g., geranylgeranyltransferase type 1). In some embodiments, a method for inhibiting farnesyltransferase is provided herein, comprising contacting farnesyltransferase with a solid form comprising an effective amount of a pharmaceutically acceptable salt of compound 1, or a pharmaceutically acceptable solvate thereof, or compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. In some embodiments, a method for inhibiting farnesyltransferase involves contacting farnesyltransferase with an effective amount of a pharmaceutical composition disclosed herein, 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 thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the contact of farnesyltransferase takes place in a cell. In some embodiments, farnesyltransferase is present in a cell. In some embodiments, the cell is within a subject. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell. In some embodiments, the subject has a farnesylated protein-dependent cancer. In some embodiments, the subject is human.

[0539] In some embodiments, the method inhibits farnesylation of the H-Ras protein. In some embodiments, the H-Ras protein has a mutation. In some embodiments, the H-Ras protein mutation is or includes modifications in codons encoding amino acid substitutions at specific positions selected from G12, Gl3, Q61, Q22, K117, A146, and any combination thereof in the corresponding mutant H-Ras protein. In some embodiments, the inhibition of farnesylation of the H-Ras protein, e.g., the mutant H-Ras protein, is carried out intracellularly. In some embodiments, the cells are within a subject. In some embodiments, the cells are mammalian cells. In some embodiments, the cells are human cells. In some embodiments, the inhibition of intracellular farnesyltransferase is carried out in a subject suffering from a farnesylation protein-dependent cancer. In some embodiments, the farnesylation protein-dependent cancer is a solid tumor. In some embodiments, the farnesylation protein-dependent cancer is a cancer dependent on one or more farnesylation proteins. In some embodiments, a farnesylated protein-dependent cancer is a farnesylated protein-dependent cancer in relation to the progression and / or survival of the cancer. In some embodiments, a farnesylated protein-dependent cancer is a farnesylated H-Ras protein-dependent cancer. In some embodiments, a farnesylated protein-dependent cancer has an H-Ras protein mutation. In some embodiments, an H-Ras protein mutation is or includes a modification in a codon encoding an amino acid substitution at a specific position selected from G12, Gl3, Q61, Q22, K117, A146, and any combination thereof in the corresponding mutant H-Ras protein. In some embodiments, a farnesylated protein-dependent cancer is a head and neck cancer. In some embodiments, a head and neck cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, a head and neck cancer, e.g., HNSCC, is dependent on one or more farnesylated proteins, e.g., a farnesylated H-Ras protein.In some embodiments, head and neck cancers, such as HNSCC, have H-Ras protein mutations. In some embodiments, farnesylating protein-dependent cancers are carcinomas, melanomas, sarcomas, or chronic granulomatous diseases. For example, in some embodiments, farnesylating protein-dependent cancers are thyroid cancer, head and neck cancer, urothelial carcinoma, salivary gland cancer, upper gastrointestinal tract 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, SCC is head and neck SCC (HNSCC), lung SCC (LSCC), thyroid SCC (TSCC), esophagus SCC (ESCC), bladder SCC (BSCC), or urothelial carcinoma (UC). In some embodiments, SCC is HNSCC. In some embodiments, SCC is human papillomavirus (HPV) negative SCC. In some embodiments, HNSCC is HPV negative HNSCC. For example, in some embodiments, HNSCC is tracheal HNSCC, micrognathic HNSCC, or oral HNSCC. In some embodiments, SCC, for example, HNSCC, lung SCC, thyroid SCC, esophageal SCC, bladder SCC, or urothelial carcinoma depends on one or more farnesylated proteins, for example, the farnesylated H-Ras protein. In some embodiments, HNSCC depends on one or more farnesylated proteins, for example, on farnesylated H-Ras protein. In some embodiments, SCCs, such as HNSCC, lung SCC, thyroid SCC, esophageal SCC, bladder SCC, or urothelial carcinoma, have H-Ras protein mutations. In some embodiments, HNSCC has H-Ras protein mutations. In some embodiments, the subject is human.

[0540] In some embodiments, a method for treating farnesylated protein-dependent cancer in a subject is provided herein, comprising administering to a subject having farnesylated protein-dependent cancer a solid form comprising a therapeutically effective amount of a pharmaceutically acceptable salt of compound 1, or a pharmaceutically acceptable solvate thereof, or compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. In some embodiments, a method for treating farnesylated protein-dependent cancer in a subject comprises administering to a subject having farnesylated protein-dependent cancer a therapeutically effective amount of a pharmaceutical composition disclosed herein, comprising a solid form comprising a pharmaceutically acceptable salt of compound 1, or a pharmaceutically acceptable solvate thereof, or compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, farnesylated protein-dependent cancer is a solid tumor. In some embodiments, farnesylated protein-dependent cancer is cancer dependent on one or more farnesylated proteins. In some embodiments, a farnesylated protein-dependent cancer is a farnesylated protein-dependent cancer in relation to the progression and / or survival of the cancer. In some embodiments, a farnesylated protein-dependent cancer is a farnesylated H-Ras protein-dependent cancer. In some embodiments, a farnesylated protein-dependent cancer has an H-Ras protein mutation. In some embodiments, an H-Ras protein mutation is or includes a modification in a codon encoding an amino acid substitution at a specific position selected from G12, Gl3, Q61, Q22, K117, A146, and any combination thereof in the corresponding mutant H-Ras protein. In some embodiments, a farnesylated protein-dependent cancer is a head and neck cancer. In some embodiments, a head and neck cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, a head and neck cancer, e.g., HNSCC, is dependent on one or more farnesylated proteins, e.g., a farnesylated H-Ras protein.In some embodiments, head and neck cancers, such as HNSCC, have H-Ras protein mutations. In some embodiments, farnesylating protein-dependent cancers are carcinomas, melanomas, sarcomas, or chronic granulomatous diseases. For example, in some embodiments, farnesylating protein-dependent cancers are thyroid cancer, head and neck cancer, urothelial carcinoma, salivary gland cancer, upper gastrointestinal tract 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, farnesylating protein-dependent cancer is squamous cell carcinoma (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, SCC is human papillomavirus (HPV) negative SCC. In some embodiments, HNSCC is HPV negative HNSCC. For example, in some embodiments, HNSCC is tracheal HNSCC, micrognathic HNSCC, or oral HNSCC. In some embodiments, SCC, e.g., HNSCC, lung SCC, thyroid SCC, esophageal SCC, bladder SCC, or urothelial carcinoma, depends on one or more farnesylated proteins, e.g., farnesylated H-Ras protein. In some embodiments, HNSCC depends on one or more farnesylated proteins, e.g., farnesylated H-Ras protein. In some embodiments, SCC, e.g., 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 human.

[0541] In some embodiments, as disclosed herein, the presence or absence of H-Ras mutations is determined prior to treatment in a method for treating farnesylated protein-dependent cancer. In some embodiments, determining the presence or absence of H-Ras mutations involves analyzing nucleic acids obtained from a sample derived from the 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.

[0542] 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 or solvate thereof, as disclosed herein, is metabolically stable, for example, metabolically stable to hepatic metabolism in a subject, for example, metabolically stable to hepatic metabolism in humans.

[0543] 5.6.2 Dosage and regimen The compounds described herein can be delivered in the form of a pharmaceutical composition comprising 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 thereof, 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 the pharmaceutically acceptable salt of Compound 1, or a pharmaceutically acceptable solvate thereof, or the solid form containing Compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. The pharmaceutical compositions disclosed herein are intended to be administered by appropriate routes, including but not limited to oral, parenteral, rectal, topically, and locally. In some embodiments, the selected dosage level depends on a variety of factors, including, for example, the activity of the particular compound used, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound used, the rate and degree 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, overall health and previous medical history of the patient being treated, and similar factors well known in the medical field.

[0544] The appropriate daily dose of the compound described herein administered to a subject would, in some embodiments, be the amount of the compound that is the minimum effective dose to produce a therapeutic effect. Such an effective dose generally depends on the factors described herein. In some embodiments, a pharmaceutically acceptable salt of compound 1 in a therapeutically effective amount, or a pharmaceutically acceptable solvate thereof, or a solid form containing compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, is available as an active component, subdivided into single doses or more than one dose, in amounts ranging from approximately 0.01 mg / kg to a maximum of approximately 500 mg / kg per day, or more specifically, approximately 0.01 to approximately 400 mg / kg per day, for example, approximately 0.01 to approximately 300 mg / kg per day, approximately 0.01 to approximately 200 mg / kg per day, approximately 0.01 to approximately 100 mg / kg per day, approximately 0.01 to approximately 50 mg / kg per day, approximately 0.01 to approximately 25 mg / kg per day, or approximately 0.01 to approximately 10 mg / kg per day, for example. For example, the daily dose would 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, 100 mg / kg, 200 mg / kg, 300 mg / kg, 400 mg / kg, or 500 mg / kg.For example, in some embodiments, a pharmaceutically acceptable salt of compound 1 in a drug dose or therapeutically effective amount, or a pharmaceutically acceptable solvate thereof, or a solid form containing compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, is disclosed herein in doses of approximately 0.01 to 25 mg / kg per day, approximately 0.01 to 20 mg / kg per day, approximately 0.01 to 15 mg / kg per day, approximately 0.01 to 10 mg / kg per day, approximately 0.01 to 7.5 mg / kg per day, approximately 0.01 to 5 mg / kg per day The amount is in the form of kg, or about 0.01 to about 2.5 mg / kg per day, for example, about 0.01 mg / kg, about 0.025 mg / kg, about 0.05 mg / kg, about 0.075 mg / kg, about 0.1 mg / kg, about 0.25 mg / kg, about 0.5 mg / kg, about 0.75 mg / kg, about 1 mg / kg, about 2.5 mg / kg, about 5 mg / kg, about 7.5 mg / kg, about 10 mg / kg, about 15 mg / kg, and about 20 mg / kg per day. In some embodiments, a pharmaceutically acceptable 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 thereof, or a pharmaceutically acceptable solvate thereof, is included in the pharmaceutical composition described herein. The actual dosage levels of the active components in the pharmaceutical compositions described herein can be varied to obtain an amount of the active component effective in achieving a desired therapeutic response for a particular subject, composition, and mode of administration, such as a human patient, without being toxic to the subject. In some cases, dosage levels lower than the lower limit of the aforementioned range may be more than sufficient, while in other cases, even higher doses can be used without causing any adverse side effects, for example, by dividing such higher doses into several smaller doses for administration throughout the day. The dosage may reflect the amount of the compound, or the amount of the compound in a particular pharmaceutical form, or the free base form equivalent of a particular pharmaceutical form.

[0545] In some embodiments, a treatment in solid form comprising a pharmaceutically acceptable salt of compound 1, or a pharmaceutically acceptable solvate thereof, or compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, is administered in combination with radiotherapy or radiation therapy.

[0546] The subheadings throughout this specification are not intended to limit the subject matter discussed to those sections only, but rather to apply to and be intended to apply to each embodiment disclosed in this application.

[0547] The compounds disclosed herein, including example compounds and intermediate compounds, were named using ChemDraw® version 18.1.4.4 or later. [Examples]

[0548] Abbreviation:

[0549] [Table 1]

[0550] Analysis method XRPD: XRPD diffraction diagrams are produced using an X-ray diffractometer (equipment: PAlytical, Empiren, radiation).

[0551]

number

[0552] PLM: Optical microscopy analysis was performed using an ECLIPSE LV100POL microscope (Nikon, Japan). Each sample was placed on a glass slide with one drop of immersion oil and covered with a glass slip. The samples were observed using polarized 4-20x objective lenses.

[0553] DSC: DSC analysis was performed using a TA instrument (Discovery DSC 250). Approximately 1-3 mg of sample was placed in an aluminum pan with a pinhole 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.

[0554] TGA: TGA analysis was performed using a TA instrument (Discovery TGA 55). Approximately 1-5 mg of sample was placed in a pre-measured aluminum pan and heated from room temperature to 300°C at a heating rate of 10°C per minute under N2 purge gas flow rates of 40 mL / min (balance chamber) and 60 mL / min (sample chamber).

[0555] HPLC: Unless otherwise specified, HPLC analysis for all polymorphs, salts, and solubility experiments in the medium was performed using an Agilent 1260 series instrument with a Waters XBridge Shield RP18 4.6*150 mm, 3.5 μm column, column temperature 40°C, mobile phase A: 0.1% H3PO4 in water, B: MeOH:ACN 3:7 (v / v), flow rate 1.5 mL / min, injection volume 5 μL, DAD detector at wavelength 210 nm, and gradients of 12 min, 100% A, 3 min, 50% A, 2.1 min, 5% A, and 5 min, 100% A.

[0556] HPLC: Unless otherwise specified, HPLC analysis of all chiral salt screening experiments was performed using 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 detectors at wavelengths of 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 a gradient of 80% A for 1.5 minutes and 0% A for 1.5 minutes.

[0557] UPC: Unless otherwise specified, UPC analysis is performed using Waters Acquity UPC with UV and QDA detectors. 2 The system was operated using a Daicel Chiralpak ID-3 (3.0 × 150 mm, 3 μm) column, mobile phase A: 65% CO2, mobile phase B: 35% MeOH + 0.2% NH4OH (25%, aqueous solution), isocratic pump program, runtime 10 minutes, flow rate 1.2 mL / min, UV detection at 250 nm, and column temperature 40°C.

[0558] The following examples are provided as illustrations only and are not limiting. Unless otherwise specified, the starting material for Compound 1 used in the preparations of Forms 1 to 24, as detailed in Examples 1 to 24, was Compound 1 (amorphous, free base) prepared according to Example 52.

[0559] Example 1: Preparation of free base hemihydrate of compound 1 (Form 1). Method A: The free base of compound 1 (20 mg) was characterized as amorphous by polarized light microscopy and XRPD (Figure 1).

[0560] This substance 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 as the free base hemihydrate (Form 1) of compound 1 by XRPD analysis.

[0561] Method B: Free base (250 mg) of amorphous compound 1 was mixed with 3 mL of 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 high pressure at 40°C for 4 hours. The free base hemihydrate of compound 1 was obtained with 0.4% residual acetone in yield 91% and purity 99.61% (HPLC). 1 HNMR, Bruker, 400MHz, DMSO-d6).

[0562] Method C: To a solution of the free base of compound 1 in ACN (3V) at 45±5℃, purified water (3V) was added over 1 hour, followed by the addition of a seed crystal of the free base hemihydrate of compound 1 (Form 1). The resulting mixture was stirred at 45±5℃ for 0.5 hours, and 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 oven-dried under high pressure 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.

[0563] Method D: Single-crystal analysis of free base hemihydrate of compound 1 (form 1). The crystal structure of form 1 was collected and analyzed. Free base hemihydrate of crystalline compound 1 was dissolved in ACN / H2O (0.3 mL) at 60°C at 50.0 mg / mL. The solution was filtered at room temperature, the filtrate was covered with a pinhole film, and the solution was kept at room temperature for 20 hours to allow evaporation and crystallization. The resulting plate-like crystals with aggregates were collected and single-crystal X-ray diffraction (180 K, Rigaku XtaLAB Synergy-DW diffractometer, CuKα radiation) was used.

[0564]

number

[0565] [Table 2]

[0566] 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).

[0567] Analytical data for the substance obtained by Method B are provided (XRPD, Figure 3) and DSC / TGA (Figure 4). Methods A, C, and D produced substances with consistent analytical data.

[0568] DSC: The product exhibited a thermal (endothermic) event with an endothermic peak at an onset temperature of approximately 83°C and approximately 138°C, as well as a thermal (endothermic, melting) event with an endothermic peak at an onset temperature of approximately 212°C and approximately 221°C. TGA: The product showed no weight loss when heated below approximately 75°C, and showed a weight loss of approximately 1.8% when heated between approximately 75°C and approximately 170°C.

[0569] Example 2: Preparation of the benzoate (Form 2) of Compound 1. Method A: Amorphous compound 1 and free base (30 mg) were mixed at room temperature with 0.5 mL of (a) IPA, (b) acetone, (c) IPAc, or (d) ACN / water (19 / 1), treated with benzoic acid (1.1 equivalents), and 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 further at 50°C for 24 hours. In each case, the resulting solid was collected by filtration and dried under high pressure at 40°C for 4 hours to obtain the benzoate of compound 1 (Form 2). Analytical data are provided (XRPD, Figure 5, DSC / TGA, Figure 6). For (a) 1 1H NMR (Bruker, 400 MHz, DMSO-d6) showed 0.2 wt% residual IPA.

[0570] Method B: Free base of amorphous compound 1 (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 4% by weight of benzoate of compound 1 (Form 2) was added as a seed crystal, and the mixture was 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 high pressure at 40°C for 4 hours to obtain benzoate of compound 1 (Form 2). Characterization data was obtained as follows. The analytical data of the substance obtained by Method B were equivalent to that of the substance obtained by Method A. 1 1H NMR (Bruker, 400 MHz, DMSO-d6) showed 0.5 wt% residual acetone.

[0571] 1HNMR(400MHz,DMSO-d6)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).

[0572] DSC: The product exhibited a thermal (endothermic, melting / decomposition) event with an onset temperature of approximately 209°C and a peak temperature of approximately 216°C. TGA: The product showed no weight loss even when heated to below approximately 180°C. Based on these data, the benzoate (form 2) of compound 1 was identified as an anhydrous form.

[0573] Example 3: Preparation of the besylate (benzenesulfonic acid) salt (Form 3) of Compound 1. Free base (30 mg) of amorphous compound 1 and benzenesulfonic acid (1.0 equivalent) were mixed with IPAc (0.5 mL) at room temperature and stirred for 4 days. The mixture was concentrated, treated with acetone (0.2 mL), stirred at room temperature for 4 days, and then treated with n-heptane (1 mL). The resulting solid was collected and dried to obtain the besylate of compound 1 (Form 3). Analytical data are provided (XRPD, Figure 7; DSC / TGA, Figure 8).

[0574] 1 HNMR(400MHz,DMSO-d6)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).

[0575] DSC: The product exhibited multiple thermal events, including a thermal (endothermic) event with an onset temperature of approximately 186°C and a peak temperature of approximately 206°C. TGA: The product showed a weight loss of 5.7% when heated over a range of approximately 95 to 230°C. These data are as follows: 1 Along with HNMR data (Bruker, 400 MHz, DMSO-d6), we identified a substance with a molar ratio of compound 1 to acid of 1:0.9, containing residual IPAc (3%), n-heptane (1.3%), and acetone (0.2%), indicating that this is a solvated form.

[0576] Example 4: Preparation of chloride salt (Form 4) of compound 1. Free base form (30 mg) of amorphous compound 1 was mixed with IPA (0.5 mL), treated with HCl solution (1 M, prepared by diluting concentrated HCl with IPA), and stirred at room temperature for 4 days. The resulting solid was isolated by centrifugation and dried under high pressure at 40°C for 4 hours to obtain the chloride salt of compound 1 (form 4). Analytical data is provided (XRPD, Figure 9; DSC / TGA, Figure 10). Purity, 98.9% (HPLC). 1 1H NMR (Bruker, 400 MHz, DMSO-d6) identified 0.3% residual IPA.

[0577] 1 H-NMR(400MHz,DMSO-d6)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),7.41-7.1 6(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).

[0578] DSC: Four endothermic peaks were observed, with onset temperatures of approximately 28 °C, 98 °C, and 242 °C, and peak temperatures of approximately 64 °C and 116 °C (loss of water and residual solvent), and approximately 258 °C (two overlapping peaks, melting, decomposition), respectively. TGA: The product showed two-step weight losses of 3.2% before 90 °C and 2.7% over the range of 90 - 140 °C. These data indicated Form 4 as a hydrate.

[0579] Example 5: Preparation of the chloride salt of Compound 1 (Form 5). Form 5 was prepared using the procedure described in Example 4, using ACN instead of IPA. Analytical data are provided (XRPD, Figure 11, DSC / TGA, Figure 12). Purity, 98.9% (HPLC).

[0580] 1 HNMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.51 - 8.15 (m, 3H), 7.99 (s, 2H), 7.46 (t, J = 7.9 Hz, 1H), 7.26 (d, J = 7.5 Hz, 2H), 7.11 (dd, J = 8.1, 2.4 Hz, 1H), 6.88 (s, 1H), 5.52 (d, J = 11.2 Hz, 2H), 3.77 (dt, J = 12.2, 6.2 Hz, 3H).

[0581] DSC: The product showed multiple thermal events, including a thermal (endothermic) event with an onset temperature of approximately 244 °C and a peak temperature of approximately 247 °C, and showed loss of water and residual solvent. TGA: The product showed a 5.3% weight loss (loss of water and residual solvent) before 130 °C and approximately 12% weight loss over the range of approximately 175 - approximately 300 °C. 1 HNMR showed trace levels of residual ACN (0.3%).

[0582] Example 6: Preparation of the citrate salt of Compound 1 (Form 6). The free base (30 mg) of amorphous compound 1 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 isolated by filtration and dried under high pressure at 40°C for 4 hours. Analytical data are provided (XRPD, Figure 13; DSC / TGA, Figure 14).

[0583] 1 HNMR(400MHz,DMSO-d6)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(d d,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).

[0584] DSC: The product showed multiple endothermic peaks, including peaks with onset temperatures of approximately 92°C and 144°C, and peak temperatures of approximately 102°C and 177°C, respectively. TGA: The product showed a weight loss of approximately 5.1% over a range of approximately 26°C to approximately 150°C. Based on these data, 1 Based on the 1H NMR results (Bruker, 400 MHz, DMSO-d6), the citrate of compound 1 (form 6), with a base-to-acid molar ratio of 1:0.8, was identified as the IPAc solvate.

[0585] Example 7: Preparation of the citrate of compound 1 (form 7). The product was prepared as described in Example 6, using ACN / H2O(19 / 1) instead of IPAc. Analytical data are provided (XRPD, Figure 15; DSC / TGA, Figure 16).

[0586] 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).

[0587] DSC: The product exhibited four endothermic peaks, each with an onset temperature of approximately 41, 135, and 169°C, and peak temperatures of approximately 58, 139, and 188°C. TGA: The product showed a weight loss of approximately 2.8% over the range of 25 to approximately 100°C. 1 1H NMR (Bruker, 400 MHz, DMSO-d6) showed approximately 0.2% residual ACN. These data indicated that form 7 was a hydrate.

[0588] Example 8: Preparation of fumarate of compound 1 (form 8). Method A: Free base (30 mg) of amorphous compound 1 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 isolated by filtration and dried under high pressure at 40°C for 4 hours.

[0589] Method B: Free base (30 mg) of amorphous compound 1 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 for a further 17 hours. The resulting solid was isolated by filtration and dried under high pressure at 40°C for 4 hours. Analytical data are provided (XRPD, Figure 17, DSC / TGA, Figure 18). 1 1HNMR (Bruker, 400 MHz, DMSO-d6) showed 0.2% residual ACN.

[0590] Method C: The free base of amorphous compound 1 (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 seed crystals of the fumarate of compound 1 (Form 8) in n-heptane. After stirring at room temperature for 24 hours, the resulting solid was isolated by filtration and dried at 40 °C under high vacuum for 5 hours. To remove residual acetone, the solid was pulverized with a mortar and pestle and further dried at 90 °C under high vacuum for 3 hours.

[0591] The substances obtained from Methods A and C showed results equivalent to the data provided for the substance of Method B.

[0592] 1 HNMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.25 (d, J = 8.9 Hz, 1H), 8.16 (s, 1H), 8.01 - 7.52 (m, 3H), 7.43 (t, J = 7.9 Hz, 2H), 7.22 (d, J = 7.5 Hz, 1H), 7.08 (dd, J = 8.3, 2.4 Hz, 1H), 6.62 (s, 2H), 6.32 (s, 1H), 5.49 (d, J = 13.2 Hz, 2H), 3.59 (s, 4H).

[0593] DSC: The product showed a thermal (endothermic, dehydration) event with an onset temperature of about 28 °C and a peak temperature of about 100 °C, and a thermal (endothermic, melting / decomposition) event with an onset temperature of about 206 °C and a peak temperature of about 214 °C. TGA: The product showed a weight loss of about 2.0% when heated from about 24.5 °C to about 150.0 °C.

[0594] Example 9: Preparation of the gentisate of compound 1 (Form 9). The product was prepared as described in Example 6 using gentisic acid and IPA or IPAc as the solvent. Analytical data are provided (XRPD, Figure 19, DSC / TGA, Figure 20).

[0595] 1HNMR(400MHz,DMSO-d6)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).

[0596] DSC: The products exhibited two endothermic peaks (desolvation, IPAc, melting point / 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 showed a weight loss of 2.2% over the range of approximately 26.5°C to 100°C. 1 1HNMR (Bruker, 400 MHz, DMSO-d6) showed residual IPAc (approximately 1.9%), indicating a solvate form collectively.

[0597] Example 10: Preparation of gentisinate of compound 1 (form 10). The product was prepared as described in Example 6, using gentisic acid and acetone or ACN / H2O(19 / 1) as the solvent. Data from the ACN / H2O experiment are provided below. Analytical data are provided (XRPD, Figure 21; DSC / TGA, Figure 22). 1 1HNMR (Bruker, 400MHz, DMSO-d6) showed residual IPAc (0.4%).

[0598] 1 HNMR(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).

[0599] DSC (Figure 22): The product showed one 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 showed a weight loss of approximately 0.4% when heated over a range of approximately 120–200°C. Its form was shown as anhydrous.

[0600] Example 11: Preparation of glycolate of compound 1 (form 11). Method A: The product was prepared using glycolic acid and IPAc as the solvent, as described in Example 6. Analytical data are provided (XRPD, Figure 23; DSC / TGA, Figure 24). 1 1HNMR (Bruker, 400MHz, DMSO-d6) showed residual IPAc (0.4%).

[0601] Method B: Free base (30 mg) of amorphous compound 1 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 isolated by filtration and dried under high pressure at 40°C for 4 hours. The data were equivalent to those obtained from the product of Method A.

[0602] 1 HNMR(400MHz,DMSO-d6)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).

[0603] DSC: The product exhibited multiple endothermic events, including peaks with starting temperatures of approximately 35, 116, and 152°C, and peak temperatures of approximately 59, 94, and 170°C, respectively. TGA: The product showed a weight loss of approximately 1.7% when heated from 27°C to approximately 80°C and a weight loss of approximately 3.2% when heated from approximately 110°C to approximately 200°C. The data indicated that its form could be a hydrate.

[0604] Example 12: Preparation of 1-hydroxy-2-naphthoate of compound 1 (form 12). The product was prepared using 1-hydroxy-2-naphthoic acid and IPAc as described in Example 6. Analytical data are provided (XRPD, Figure 25; DSC / TGA, Figure 26).

[0605] 1 HNMR (400 MHz, DMSO-d6)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).

[0606] DSC: The product exhibited multiple endothermic events, including peaks with start temperatures of approximately 25°C and 178°C, and peak temperatures of approximately 32°C and 186°C, respectively. TGA: The product showed a weight loss of 0.5% when heated from 25°C to approximately 80°C, and a weight loss of 7.4% when heated from approximately 100°C to approximately 190°C. 1 HNMR (Bruker, 400 MHz, DMSO-d6) showed the presence of residual IPAc (approximately 5.1%).

[0607] Example 13: Preparation of 1-hydroxy-2-naphthoate of compound 1 (form 13). Method A: The product was obtained using ACN / water (19 / 1) as the solvent, as described in Example 9. XRPD analysis data is provided (Figure 27).

[0608] Method B: Free base (300 mg) of amorphous compound 1 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 treated with a seed crystal of 1-hydroxy-2-naphthoate of compound 1 (Form 13), and the mixture was stirred at room temperature for 16 hours. The resulting concentrated 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 high pressure at 40°C for 4 hours. DSC / TGA data is provided (Figure 28). The substances obtained by Methods A and B had equivalent analytical data.

[0609] 1 HNMR(400MHz,DMSO-d6)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(dd d,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).

[0610] DSC: The product exhibited a thermal (endothermic, melting / decomposition) event with an onset temperature of approximately 187°C and a peak temperature of approximately 194°C. TGA: The product showed no weight loss even when heated to below approximately 160°C.

[0611] Example 14: Preparation of the malate salt of compound 1 (Form 14). Free base (30 mg) of amorphous compound 1 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 treated with ACN / H2O (19 / 1, 0.3 mL) and stirred at room temperature for 17 hours. The resulting solid was isolated by filtration and dried under high pressure at 40°C for 4 hours. Analytical data are provided (XRPD, Figure 29; DSC / TGA, Figure 30).

[0612] 1 HNMR(400MHz,DMSO-d6)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).

[0613] DSC: The product exhibited multiple thermal events, including peaks with starting temperatures of approximately 28°C and 178°C, and peak temperatures of approximately 69°C and 216°C, respectively. TGA: The product showed a weight loss of approximately 3.6% when heated from approximately 30°C to approximately 120°C. The data indicated that its form was a hydrate.

[0614] Example 15: Preparation of the malate salt of compound 1 (Form 15). Free base (30 mg) of amorphous compound 1 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 isolated by filtration and dried under high pressure at 40°C for 4 hours. Analytical data are provided (XRPD, Figure 31; DSC / TGA, Figure 32). 1 1HNMR (Bruker, 400 MHz, DMSO-d6) showed residual acetone (6.0%) and n-heptane (3.7%).

[0615] 1 HNMR (400 MHz, DMSO-d6)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,2 H),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).

[0616] DSC: The product exhibited multiple thermal events, including peaks with starting temperatures of approximately 127°C and 159°C, and peak temperatures of approximately 145°C and 182°C. TGA: The product showed 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. The data indicated that its form was a solvate.

[0617] Example 16: Preparation of the maleate salt of compound 1 (form 16). A mixture of free base (30 mg) of amorphous compound 1 in IPA (0.5 mL) and maleic acid (1.1 equivalents) was stirred at room temperature for 2 hours, then treated with IPA (0.3 mL), and stirred for a further 14 hours. The resulting solid was isolated by filtration and dried under high pressure at 40°C for 4 hours. Analytical data are provided (XRPD, Figure 33; DSC / TGA, Figure 34).

[0618] 1HNMR(400MHz,DMSO-d6)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).

[0619] DSC: The product showed 2-3 endothermic peaks at starting temperatures of approximately 26°C and 198°C, and peak temperatures of approximately 53°C and 206°C. TGA: When heated from 24°C to approximately 100°C, the product showed a weight loss of approximately 1.8% (water loss), indicating that this substance is a hydrate.

[0620] Example 17: Preparation of the maleate salt of compound 1 (form 17). The product was obtained using maleic acid and ACN / H2O(19 / 1) as described in Example 6. Analytical data are provided (XRPD, Figure 35; DSC / TGA, Figure 36).

[0621] 1 HNMR(400MHz,DMSO-d6)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).

[0622] DSC: The product exhibited multiple endothermic events, including peaks with starting temperatures of approximately 27°C and 195°C, and peak temperatures of approximately 60°C and 205°C, respectively. TGA: When heated from approximately 26°C to approximately 100°C, the product showed a weight loss of approximately 1.2%, indicating that this substance is a hydrate.

[0623] Example 18: Preparation of the mesylate salt of compound 1 (Form 18). Methanesulfonic acid (1.0 equivalent) was dissolved in IPAc (0.5 mL), and the free base of amorphous compound 1 (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 high pressure at 40°C for 4 hours. Analytical data is provided (XRPD, Figure 37; DSC / TGA, Figure 38). Purity (99.2%, HPLC).

[0624] 1 HNMR(400MHz,DMSO-d6)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).

[0625] DSC: The product exhibited an endothermic peak with an onset temperature of approximately 142°C and a peak temperature (desolvation) of approximately 146°C. TGA: The product showed a weight loss of approximately 5.6% when heated from room temperature to approximately 145°C, and a weight loss of approximately 9.5% when heated from approximately 145°C to approximately 200°C. 1 1HNMR (Bruker, 400 MHz, DMSO-d6) showed a molar ratio of 1:0.8 (free base:acid) and residual IPAc (12%). The data indicated that its form was IPAc solvate.

[0626] Example 19: Preparation of oxalate of compound 1 (form 19). ACN (0.25 mL) was added to a mixture of free base of amorphous compound 1 (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 high pressure at 40°C for 4 hours. Analytical data is provided (XRPD, Figure 39; DSC / TGA, Figure 40). Purity, 99.1% (HPLC).

[0627] 1HNMR (400MHz, DMSO-d6) 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).

[0628] DSC: The product showed endothermic peaks at initiation temperatures of approximately 92°C (peak temperature of approximately 137°C) (solvent loss), approximately 187°C (peak temperature of approximately 190°C) (melting), and approximately 194°C (peak temperature of approximately 202°C) (decomposition). TGA: The product showed a weight loss of approximately 7.4% (solvent loss) when heated from approximately 90°C to approximately 190°C, and a weight loss of 19.0% (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) indicated that its form was ACN solvate.

[0629] Example 20: Preparation of the phosphate of compound 1 (form 20). Free base (30 mg) of amorphous compound 1 was dissolved in ACN / H2O (19 / 1, 0.5 mL) and treated with H3PO4 (1-1.1 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 high pressure at 40°C for 4 hours. Analytical data are provided (XRPD, Figure 41; DSC / TGA, Figure 42). 1 1HNMR (Bruker, 400 MHz, DMSO-d6) showed 0.1% residual ACN.

[0630] 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,2 H),7.23(d,J=7.5Hz,2H),7.08(dd,J=8.1,2.4Hz,1H),6.34(s,2H),5.49(d,J=12.7Hz,5H).

[0631] DSC: The product exhibited 2-3 endothermic peaks, including an endothermic peak with an onset temperature of approximately 34°C and a peak temperature of approximately 74°C. TGA: The product showed a weight loss of approximately 4.5% when heated from 25°C to approximately 110°C. The data indicated that its form could be a hydrate. Analysis by ion chro...

Claims

1. Compound 1: 【Chemistry 1】 A solid form comprising the same or a pharmaceutically acceptable salt and / or solvate thereof.

2. The solid form according to claim 1, wherein the solid form is crystalline.

3. The solid form according to claim 1 or 2, wherein the solid form contains the free base of the compound 1.

4. The solid form according to any one of claims 1 to 3, wherein the solid form is a nonsolvate of the compound 1 or a pharmaceutically acceptable salt thereof.

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

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

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

8. The solid form according to claim 7, wherein the compound 1 and a pharmaceutically acceptable solvent are present in a molar ratio in the range of about 2:1 to about 1:

2.

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

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

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

12. The solid form according to claim 11, wherein the solid form is compound 1 (form 1).

13. The solid form according to claim 11 or 12, characterized by an XRPD pattern including peaks at approximately 9.0, 12.8, 16.6, and 18.4°²θ when measured using CuKα radiation.

14. The solid form according to claim 13, wherein the XRPD pattern further includes peaks at approximately 8.6, 12.0, 18.1, and 23.2°²θ.

15. The solid form according to claim 14, wherein the XRPD pattern further includes peaks at approximately 16.1, 17.1, 24.1, and 25.6°²θ.

16. It features an XRPD pattern that substantially matches the XRPD pattern shown in Figure 3, and is optionally, [Math 1] Approximate unit cell dimensions, and P2 １ A solid form according to any one of claims 11 to 15, characterized by having a unit cell of a space group.

17. The solid form according to any one of claims 11 to 16, characterized by a thermal (endothermal) event with an onset temperature of approximately 83°C, a thermal (endothermal, melting) event with an onset temperature of approximately 212°C, and / or endothermal peaks at approximately 137°C and approximately 221°C, when characterized by DSC using a temperature gradient of approximately 10°C / min.

18. The solid form according to any one of claims 11 to 17, characterized by a differential scanning calorimetry plot that substantially matches the DSC plot shown in Figure 4.

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

20. The solid form according to any one of claims 11 to 19, characterized by a thermogravimetric analysis plot substantially consistent with the TGA plot shown in Figure 4.

21. The aforementioned solid form is (a) Purity of at least 98%, 98.5%, 99%, or 99.5%, (b) Solubility of approximately 4.69, 5.04, and 3.67 mg / mL in the SGF medium at 0.5 hours, 2 hours, and 24 hours, respectively, or (c) Solubility of approximately 0.29, 0.31, and 0.33 mg / mL in FeSSIF medium at 0.5 hours, 2 hours, and 24 hours, respectively, or A solid form according to any one of claims 11 to 20, having any combination of (d)(a) to (c).

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

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

24. The solid form according to claim 23, wherein the solid form has a compound 1 / conjugate acid molar ratio in the range of about 2:1 to about 1:

2.

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

26. The solid form according to claim 25, wherein the solid form has a compound molar ratio of approximately 1:1 (1 / benzoic acid molar ratio).

27. The solid form according to claim 25 or 26, wherein the solid form is compound 1 (form 2).

28. The solid form according to any one of claims 25 to 27, characterized by an XRPD pattern including peaks at approximately 4.7, 17.0, and 19.4°²θ when measured using CuKα radiation.

29. The solid form according to claim 28, wherein the XRPD pattern further includes peaks at approximately 12.7, 16.6, 17.8, 18.9, and 21.4°2θ, and optionally further includes peaks at approximately 13.5, 13.7, 14.3, 23.0, 23.9, and 24.6°2θ.

30. A solid form according to any one of claims 25 to 29, characterized by an XRPD pattern substantially consistent with the XRPD pattern shown in Figure 5.

31. The solid form according to any one of claims 25 to 30, characterized by a thermal (endothermic, melting / decomposition) event having an onset temperature of approximately 209°C and / or exhibiting an endothermic peak at approximately 216°C, when characterized by DSC using a temperature gradient of approximately 10°C / min.

32. The solid form according to any one of claims 25 to 31, characterized by a differential scanning calorimetry plot substantially consistent with the DSC plot shown in Figure 6.

33. The solid form according to any one of claims 25 to 32, characterized by TGA, which does not exhibit weight loss when heated to below approximately 180°C.

34. The solid form according to any one of claims 25 to 33, characterized by a thermogravimetric analysis plot substantially consistent with the TGA plot shown in Figure 6.

35. The aforementioned solid form is (a) Purity of at least 98%, 98.5%, 99%, or 99.5%, (b) Solubility in SGF medium of approximately 4.17, 4.47, and 4.49 mg / mL at 0.5 hours, 2 hours, and 24 hours, respectively. (c) Solubility in FeSSIF medium of approximately 0.72, 0.68, and 0.54 mg / mL at 0.5 hours, 2 hours, and 24 hours, respectively, or A solid form according to any one of claims 25 to 34, having any combination of (d)(a) to (c).

36. The solid form according to claim 23 or 24, wherein the pharmaceutically acceptable salt is a benzenesulfonic acid (besylic acid) salt of compound 1.

37. The solid form according to claim 36, wherein the solid form has a compound 1 / benzenesulfonic acid molar ratio of about 1:0.

9.

38. The solid form according to claim 36 or 37, wherein the solid form is compound 1 (form 3).

39. (a) When measured using CuKα radiation, the XRPD pattern is characterized by peaks at approximately 7.6, 8.9, and 14.3°2θ, and optionally further includes peaks at approximately 17.9 and 19.7°2θ, and optionally further includes peaks at approximately 21.0 and 24.8°2θ. (b) Features an XRPD pattern that substantially matches the XRPD pattern shown in Figure 7, (c) (i) When characterized by DSC using a temperature gradient of approximately 10°C / min, it shows a thermal (endothermic) event with an onset temperature of approximately 186°C and / or an endothermic peak at approximately 206°C, or (ii) it is characterized by a differential scanning calorimetry plot that substantially matches the DSC plot shown in Figure 8. (d) (i) When characterized by TGA, when heated over a range of about 95 to about 230°C, it exhibits a weight loss of about 5.7%, or (ii) it features a thermogravimetric analysis plot that substantially matches the TGA plot shown in Figure 8, or (e) A solid form according to any one of claims 36 to 38, which is a combination of any one of (a) to (d).

40. The solid form according to claim 23 or 24, wherein the pharmaceutically acceptable salt is the hydrochloride salt of compound 1.

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

42. The solid form according to claim 40 or 41, wherein the solid form is compound 1 (form 4).

43. (a) When measured using CuKα radiation, the XRPD pattern is characterized by peaks at approximately 5.3, 16.7, 19.1, and 26.0°2θ, and optionally further includes peaks at approximately 8.6, 11.2, 12.6, and 15.3°2θ, and optionally further includes peaks at approximately 15.9, 17.8, 24.3, and 28.2°2θ, (b) Features an XRPD pattern that substantially matches the XRPD pattern shown in Figure 9, (c) (i) When characterized by DSC using a temperature gradient of approximately 10°C / min, showing thermal (endothermic) events with starting temperatures of approximately 28°C, 98°C, and 242°C, and / or endothermic peak temperatures of approximately 64°C and 116°C (loss of water and residual solvent) and 258°C (two overlapping peaks, melting, decomposition), respectively, or (ii) characterized by differential scanning calorimetry plots substantially consistent with the DSC plot shown in Figure 10, (d) (i) When characterized by TGA, when heated from room temperature to about 90°C, it shows a weight loss of about 3.2%, and when heated from about 90°C to 140°C, it shows a weight loss of about 2.7%, or (ii) it is characterized by a thermogravimetric analysis plot that substantially matches the TGA plot shown in Figure 10, or (e) A solid form according to any one of claims 40 to 42, which is a combination of any one of (a) to (d).

44. The solid form according to claim 40 or 41, wherein the solid form is compound 1 (form 5).

45. (a) When measured using CuKα radiation, the XRPD pattern is characterized by peaks at approximately 6.3, 8.4, 15.1, and 23.5°2θ, and optionally further includes peaks at approximately 10.7 and 17.9°2θ, and optionally further includes peaks at approximately 20.8 and 21.6°2θ, (b) Features an XRPD pattern that substantially matches the XRPD pattern shown in Figure 11, (c) (i) when characterized by DSC using a temperature gradient of approximately 10°C / min, showing a thermal (endothermic) event with an onset temperature of approximately 244°C and / or an endothermic peak temperature (loss of water and residual solvent) at approximately 247°C, or (ii) characterized by a differential scanning calorimetry plot substantially consistent with the DSC plot shown in Figure 12, (d) (i) When characterized by TGA, it shows a weight loss of about 5.3% before reaching about 130°C and a weight loss of about 12% over the range of about 175 to about 300°C, or (ii) it is characterized by a thermogravimetric analysis plot that substantially matches the TGA plot shown in Figure 12, or (e) A solid form according to any one of claims 40, 41, or 44, which is a combination of any one of (a) to (d).

46. The solid form according to claim 23 or 24, wherein the pharmaceutically acceptable salt is the citrate of compound 1.

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

48. The solid form according to claim 46 or 47, wherein the solid form is compound 1 (form 6).

49. (a) When measured using CuKα radiation, the XRPD pattern is characterized by peaks at approximately 12.0, 16.6, and 18.1°²θ, and optionally further includes peaks at approximately 12.9, 19.5, and 23.3°²θ, and optionally further includes peaks at approximately 24.2, 25.6, and 26.1°²θ, (b) Features an XRPD pattern that substantially matches the XRPD pattern shown in Figure 13, (c) (i) When characterized by DSC using a temperature gradient of approximately 10°C / min, it shows thermal (endothermic) events with starting temperatures of approximately 92°C and 144°C, and / or endothermic peak temperatures of approximately 102°C and 177°C, respectively, or (ii) it features a differential scanning calorimetry plot that substantially matches the DSC plot shown in Figure 14. (d) (i) When characterized by TGA, when heated from about 26°C to about 150°C, it exhibits a weight loss of about 5.1%, or (ii) it features a thermogravimetric analysis plot that substantially matches the TGA plot shown in Figure 14, or (e) A solid form according to any one of claims 46 to 48, which is a combination of any one of (a) to (d).

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

51. The solid form according to claim 46 or 50, wherein the solid form is compound 1 (form 7).

52. (a) When measured using CuKα radiation, the XRPD pattern is characterized by peaks at approximately 11.0, 15.0, 19.0, 22.1, 27.7, and 29.8°2θ, and optionally further includes peaks at approximately 22.1, 24.2, 24.6, 25.2, 25.8, and 26.5°2θ, and optionally further includes peaks at approximately 8.5, 8.8, 12.7, 13.3, 13.8, 16.7, 17.1, 17.5, and 17.9°2θ, (b) Features an XRPD pattern that substantially matches the XRPD pattern shown in Figure 15, (c) (i) when characterized by DSC using a temperature gradient of approximately 10°C / min, showing thermal (endothermic) events with starting 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, respectively, or (ii) characterized by differential scanning calorimetry plots substantially consistent with the DSC plot shown in Figure 16, (d) (i) When characterized by TGA, when heated from about 25°C to about 100°C, it exhibits a weight loss of about 2.8%, or (ii) it features a thermogravimetric analysis plot that substantially matches the TGA plot shown in Figure 16, or (e) A solid form according to any one of claims 46, 50, or 51, which is a combination of any one of (a) to (d).

53. The solid form according to claim 23 or 24, wherein the pharmaceutically acceptable salt is the fumarate of compound 1.

54. The solid form according to claim 53, wherein the solid form has a compound 1 / fumarate molar ratio of about 1:1, and optionally the solid form is a solvate, and optionally the solvate is a hydrate.

55. The solid form according to claim 53 or 54, wherein the solid form is compound 1 (form 8).

56. The solid form according to any one of claims 53 to 55, characterized by an XRPD pattern including peaks at approximately 8.6, 10.9, 16.7, and 23.3°²θ when measured using CuKα radiation.

57. The solid form according to claim 56, wherein the XRPD pattern further includes peaks at approximately 4.9, 11.4, and 17.6°2θ, and optionally further includes peaks at approximately 12.7, 14.6, and 26.0°2θ.

58. A solid form according to any one of claims 53 to 57, characterized by an XRPD pattern substantially consistent with the XRPD pattern shown in Figure 17.

59. The solid form according to any one of claims 53 to 58, characterized by a thermal (endothermic, dehydration) event with an onset temperature of approximately 28°C and / or an endothermic peak at approximately 100°C, and a thermal (endothermic, melting / decomposition) event with an onset temperature of approximately 206°C and / or a peak temperature at approximately 214°C, when characterized by DSC using a temperature gradient of approximately 10°C / min.

60. The solid form according to any one of claims 53 to 59, characterized by a differential scanning calorimetry plot substantially consistent with the DSC plot shown in Figure 18.

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

62. The solid form according to any one of claims 53 to 61, characterized by a thermogravimetric analysis plot substantially consistent with the TGA plot shown in Figure 18.

63. The aforementioned solid form is (a) Purity of at least 98%, 98.5%, 99%, or 99.5%, (b) Solubility of approximately 5 mg / mL or more, 5 mg / mL or more, and 5 mg / mL or more in the SGF medium at 0.5 hours, 2 hours, and 24 hours, respectively. (c) Solubility of approximately 1.27, 1.26, and 1.15 mg / mL in FeSSIF medium at 0.5 hours, 2 hours, and 24 hours, respectively, or A solid form according to any one of claims 53 to 62, having any combination of (d)(a) to (c).

64. The solid form according to claim 23 or 24, wherein the pharmaceutically acceptable salt is gentisinate of compound 1.

65. The solid form according to claim 64, wherein the solid form has a compound 1 / gentisinate molar ratio of about 1:1, and optionally the solid form is a solvate.

66. The solid form according to claim 64 or 65, wherein the solid form is compound 1 (form 9).

67. (a) When measured using CuKα radiation, the XRPD pattern is characterized by peaks at approximately 8.0, 9.6, 16.5, 17.6, 18.7 and 24.6°2θ, and optionally further includes peaks at approximately 11.7, 12.2, 19.9 and 26.5°2θ, and optionally further includes peaks at approximately 13.8, 15.4, 16.1, 20.8 and 21.7°2θ, (b) Features an XRPD pattern that substantially matches the XRPD pattern shown in Figure 19, (c) (i) When characterized by DSC using a temperature gradient of approximately 10°C / min, it shows thermal (endothermic) events with starting temperatures of approximately 56°C and approximately 256°C, and / or endothermic peak temperatures of approximately 81°C and approximately 263°C, respectively, or (ii) it features a differential scanning calorimetry plot that substantially matches the DSC plot shown in Figure 20. (d) (i) When characterized by TGA, when heated from about 26.5°C to about 100°C, it exhibits a weight loss of about 2.2%, or (ii) it features a thermogravimetric analysis plot that substantially matches the TGA plot shown in Figure 20, or (e) A solid form according to any one of claims 64 to 66, which is any one combination of (a) to (d).

68. The solid form according to claim 64, wherein the solid form has a compound molar ratio of approximately 1:1 (1 / gentisinate molar ratio), and the solid form is an anhydrous.

69. The solid form according to claim 64 or 68, wherein the solid form is compound 1 (form 10).

70. (a) When measured using CuKα radiation, the XRPD pattern is characterized by peaks at approximately 4.7, 13.2, and 16.9°2θ, and optionally further includes peaks at approximately 8.39, 17.5, 18.6, 21.8, and 25.3°2θ, and optionally further includes peaks at approximately 11.8, 12.6, 19.0, 19.4, and 23.8°2θ, (b) Features an XRPD pattern that substantially matches the XRPD pattern shown in Figure 21, (c) (i) when characterized by DSC using a temperature gradient of approximately 10°C / min, it shows a thermal (endothermal) event with an onset temperature of approximately 240°C and / or an endothermal peak temperature of approximately 245°C, or (ii) it features a differential scanning calorimetry plot that substantially matches the DSC plot shown in Figure 22. (d) (i) When characterized by TGA, when heated from about 120°C to about 200°C, it exhibits a weight loss of about 0.4%, or (ii) it features a thermogravimetric analysis plot that substantially matches the TGA plot shown in Figure 22, or (e) A solid form according to any one of claims 64, 68, or 69, which is a combination of any one of (a) to (d).

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

72. The solid form according to claim 71, wherein the solid form has a compound molar ratio of approximately 1:1 (1 / glycolic acid molar ratio), and optionally, the solid form is a hydrate.

73. The solid form according to claim 71 or 72, wherein the solid form is compound 1 (form 11).

74. (a) When measured using CuKα radiation, the XRPD pattern is characterized by peaks at approximately 7.4, 12.6, 16.7, and 23.8°2θ, and optionally further includes peaks at approximately 16.2, 23.4, 25.7, and 28.9°2θ, and optionally further includes peaks at approximately 19.0, 20.3, and 26.1°2θ, (b) Features an XRPD pattern that substantially matches the XRPD pattern shown in Figure 23, (c) (i) When characterized by DSC using a temperature gradient of approximately 10°C / min, showing thermal (endothermic) events with starting temperatures of approximately 35°C, approximately 116°C, and approximately 152°C, and / or endothermic peak temperatures of approximately 59°C, approximately 94°C, and approximately 170°C, respectively, or (ii) characterized by differential scanning calorimetry plots substantially consistent with the DSC plot shown in Figure 24, (d) (i) When characterized by TGA, it exhibits a weight loss of approximately 1.7% when heated from approximately 27°C to approximately 80°C and a weight loss of approximately 3.2% when heated from approximately 110°C to approximately 200°C, or (ii) it is characterized by a thermogravimetric analysis plot that substantially matches the TGA plot shown in Figure 24, or (e) A solid form according to any one of claims 71 to 73, which is a combination of any one of (a) to (d).

75. The solid form according to claim 23 or 24, wherein the pharmaceutically acceptable salt is 1-hydroxy-2-naphthoate of compound 1.

76. The solid form according to claim 75, wherein the solid form has a compound molar ratio of approximately 1:1 (1 / 1-hydroxy-2-naphthoate), and optionally the solid form is a solvate.

77. The solid form according to claim 75 or 76, wherein the solid form is compound 1 (form 12).

78. (a) When measured using CuKα radiation, the XRPD pattern is characterized by peaks at approximately 6.2, 11.2, 14.4, and 22.3°2θ, and optionally further includes peaks at approximately 5.1, 14.9, and 18.3°2θ, and optionally further includes peaks at approximately 5.6 and 25.3°2θ, (b) Features an XRPD pattern that substantially matches the XRPD pattern shown in Figure 25, (c) (i) When characterized by DSC using a temperature gradient of approximately 10°C / min, it shows thermal (endothermic) events with starting temperatures of approximately 25°C and approximately 178°C, and / or endothermic peak temperatures of approximately 32°C and approximately 186°C, respectively, or (ii) it features a differential scanning calorimetry plot that substantially matches the DSC plot shown in Figure 26. (d) (i) When characterized by TGA, it exhibits a weight loss of approximately 0.5% when heated from approximately 25°C to approximately 80°C and a weight loss of approximately 7.4% when heated from approximately 100°C to approximately 190°C, or (ii) it is characterized by a thermogravimetric analysis plot that substantially matches the TGA plot shown in Figure 26, or (e) A solid form according to any one of claims 75 to 77, which is any one combination of (a) to (e).

79. The solid form according to claim 75, wherein the solid form has a compound molar ratio of approximately 1:1 (1 / 1-hydroxy-2-naphthoate), and the solid form is an anhydride.

80. The solid form according to claim 75 or 79, wherein the solid form is compound 1 (form 13).

81. The solid form according to any one of claims 75, 79, or 80, characterized by an XRPD pattern including peaks at approximately 16.6, 18.1, 19.1, and 24.7°²θ when measured using CuKα radiation.

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

83. A solid form according to any one of claims 75 or 79 to 82, characterized by an XRPD pattern substantially consistent with the XRPD pattern shown in Figure 27.

84. The solid form according to claim 75 or any one of claims 79 to 83, characterized by a thermal (endothermic, melting / decomposition) event having an onset temperature of approximately 187°C and / or exhibiting an endothermic peak at approximately 194°C, when characterized by DSC using a temperature gradient of approximately 10°C / min.

85. The solid form according to claim 75 or any one of claims 79 to 84, characterized by a differential scanning calorimetry plot substantially consistent with the DSC plot shown in Figure 28.

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

87. The solid form according to claim 75 or any one of claims 79 to 86, characterized by a thermogravimetric analysis plot substantially consistent with the TGA plot shown in Figure 28.

88. The aforementioned solid form is (a) Purity of at least 98%, 98.5%, 99%, or 99.5%, (b) Solubility in SGF medium was approximately 3.86, 4.05, and 4.12 at 0.5 hours, 2 hours, and 24 hours, respectively. (c) Solubility in FeSSIF medium of approximately 0.74, 0.82, and 0.78 mg / mL at 0.5 hours, 2 hours, and 24 hours, respectively, or A solid form according to any one of claims 79 to 87, having any combination of (d)(a) to (c).

89. The solid form according to claim 23 or 24, wherein the pharmaceutically acceptable salt is the malate salt of compound 1.

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

91. The solid form according to claim 89 or 90, wherein the solid form is compound 1 (form 14).

92. (a) When measured using CuKα radiation, the XRPD pattern is characterized by peaks at approximately 4.7, 16.9, 17.3, 20.8, and 22.7°2θ, and optionally further 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, and optionally further includes peaks at approximately 10.9, 14.1, 18.4, 24.9, 26.1, 26.7, and 27.1°2θ, (b) Features an XRPD pattern that substantially matches the XRPD pattern shown in Figure 29, (c) (i) When characterized by DSC using a temperature gradient of approximately 10°C / min, it shows thermal (endothermic) events with starting temperatures of approximately 28°C and approximately 178°C, and / or endothermic peak temperatures of approximately 69°C and approximately 216°C, respectively, or (ii) it features a differential scanning calorimetry plot that substantially matches the DSC plot shown in Figure 30. (d) (i) When characterized by TGA, when heated from about 30°C to about 120°C, it exhibits a weight loss of about 3.6%, or (ii) it features a thermogravimetric analysis plot that substantially matches the TGA plot shown in Figure 30, or (e) A solid form according to any one of claims 89 to 91, which is a combination of any one of (a) to (d).

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

94. The solid form according to claim 89 or 93, wherein the solid form is compound 1 (form 15).

95. (a) When measured using CuKα radiation, the XRPD pattern is characterized by peaks at approximately 11.1, 12.5, 16.6, and 17.8°2θ, and optionally further includes peaks at approximately 8.39, 22.0, 23.3, and 25.5°2θ, and optionally further includes peaks at approximately 13.9, 14.7, and 24.1°2θ, (b) Features an XRPD pattern that substantially matches the XRPD pattern shown in Figure 31, (c) (i) When characterized by DSC using a temperature gradient of approximately 10°C / min, it shows thermal (endothermal) events with starting temperatures of approximately 127°C and approximately 159°C, and / or endothermal peak temperatures of approximately 145°C and approximately 182°C, respectively, or (ii) it features a differential scanning calorimetry plot that substantially matches the DSC plot shown in Figure 32. (d) (i) When characterized by TGA, when heated from about 90°C to about 160°C, it shows a weight loss of about 3.1%, and when heated from about 160°C to about 190°C, it shows a weight loss of about 3.6%, or (ii) it is characterized by a thermogravimetric analysis plot that substantially matches the TGA plot shown in Figure 32, or (e) A solid form according to any one of claims 89, 93, or 94, which is a combination of any one of (a) to (d).

96. The solid form according to claim 23 or 24, wherein the pharmaceutically acceptable salt is the maleate of compound 1.

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

98. The solid form according to claim 96 or 97, wherein the solid form is compound 1 (form 16).

99. (a) When measured using CuKα radiation, the XRPD pattern is characterized by peaks at approximately 12.2, 12.6, 26.1, and 29.2°2θ, and optionally further includes peaks at approximately 4.8, 16.7, 24.7, and 25.2°2θ, and optionally further includes peaks at approximately 14.5, 17.3, and 24.3°2θ, (b) Features an XRPD pattern that substantially matches the XRPD pattern shown in Figure 33, (c) (i) When characterized by DSC using a temperature gradient of approximately 10°C / min, it shows thermal (endothermic) events with starting temperatures of approximately 26°C and approximately 198°C, and / or endothermic peak temperatures of approximately 53°C and approximately 206°C, respectively, or (ii) it features a differential scanning calorimetry plot that substantially matches the DSC plot shown in Figure 34. (d) (i) When characterized by TGA, when heated from about 24°C to about 100°C, it exhibits a weight loss of about 1.8%, or (ii) it features a thermogravimetric analysis plot that substantially matches the TGA plot shown in Figure 34, or (e) A solid form according to any one of claims 96 to 98, which is a combination of any one of (a) to (d).

100. The solid form according to claim 96 or 97, wherein the solid form is compound 1 (form 17).

101. (a) When measured using CuKα radiation, the XRPD pattern is characterized by peaks at approximately 9.5, 15.2, and 18.6°2θ, and optionally further includes peaks at approximately 4.8, 8.2, 16.6, 17.3, 20.9, 27.0, and 29.1°2θ, and optionally further includes peaks at approximately 12.8, 14.4, 24.0, 25.2, and 25.7°2θ, (b) Features an XRPD pattern that substantially matches the XRPD pattern shown in Figure 35, (c) (i) When characterized by DSC using a temperature gradient of approximately 10°C / min, it shows thermal (endothermic) events with starting temperatures of approximately 27°C and approximately 195°C, and / or endothermic peak temperatures of approximately 60°C and approximately 205°C, respectively, or (ii) it features a differential scanning calorimetry plot that substantially matches the DSC plot shown in Figure 36. (d) (i) When characterized by TGA, when heated from about 26°C to about 100°C, it exhibits a weight loss of about 1.2%, or (ii) it features a thermogravimetric analysis plot that substantially matches the TGA plot shown in Figure 36, or (e) A solid form according to any one of claims 96, 97, or 100, which is a combination of any one of (a) to (d).

102. The solid form according to claim 23 or 24, wherein the pharmaceutically acceptable salt is a methanesulfonic acid (mesylic acid) salt of compound 1.

103. The solid form according to claim 102, wherein the solid form has a compound 1 / methanesulfonic acid molar ratio of about 1:0.8, and optionally the solid form is a solvate.

104. The solid form according to claim 102 or 103, wherein the solid form is compound 1 (form 18).

105. (a) When measured using CuKα radiation, the XRPD pattern is characterized by peaks at approximately 9.0, 9.2, 18.6, and 19.2°2θ, and optionally further includes peaks at approximately 17.5, 18.1, and 23.1°2θ, and optionally further includes peaks at approximately 20.4, 21.0, and 21.2°2θ, (b) Features an XRPD pattern that substantially matches the XRPD pattern shown in Figure 37, (c) (i) When characterized by DSC using a temperature gradient of approximately 10°C / min, it shows a thermal (endothermal) event with an onset temperature of approximately 142°C and / or an endothermal peak temperature of approximately 146°C, or (ii) it is characterized by a differential scanning calorimetry plot that substantially matches the DSC plot shown in Figure 38, (d) (i) When characterized by TGA, when heated from near room temperature to about 145°C, it shows a weight loss of about 5.6%, and when heated from about 145°C to about 200°C, it shows a weight loss of about 9.5%, or (ii) it is characterized by a thermogravimetric analysis plot that substantially matches the TGA plot shown in Figure 38, or (e) A solid form according to any one of claims 102 to 104, which is a combination of any one of (a) to (d).

106. The solid form according to claim 23 or 24, wherein the pharmaceutically acceptable salt is the oxalate of compound 1.

107. The solid form according to claim 106, wherein the solid form has a compound molar ratio of approximately 1:1 (1 / oxalate molar ratio), and optionally, the solid form is a solvate.

108. The solid form according to claim 106 or 107, wherein the solid form is compound 1 (form 19).

109. (a) When measured using CuKα radiation, the XRPD pattern is characterized by peaks at approximately 4.7, 13.2, 19.8, and 25.0°2θ, and optionally further includes peaks at approximately 8.5, 11.4, 14.2, 15.7, and 17.1°2θ, and optionally further includes peaks at approximately 8.8, 9.7, 20.5, and 25.9°2θ, (b) Features an XRPD pattern that substantially matches the XRPD pattern shown in Figure 39, (c) (i) when characterized by DSC using a temperature gradient of approximately 10°C / min, showing thermal (endothermic) events with starting temperatures of approximately 92°C, approximately 137°C, and approximately 194°C, and / or endothermic peak temperatures of approximately 137°C, approximately 190°C, and approximately 194°C, respectively, or (ii) characterized by differential scanning calorimetry plots substantially consistent with the DSC plot shown in Figure 40, (d) (i) When characterized by TGA, when heated from about 90°C to about 190°C, it shows a weight loss of about 7.4%, and when heated from about 190°C to about 240°C, it shows a weight loss of about 19.0%, or (ii) it is characterized by a thermogravimetric analysis plot that substantially matches the TGA plot shown in Figure 40, or (e) A solid form according to any one of claims 106 to 108, which is a combination of any one of (a) to (d).

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

111. The solid form according to claim 110, wherein the solid form is a monophosphate of compound 1, and optionally, the solid form is a hydrate.

112. The solid form according to claim 110 or 111, wherein the solid form is compound 1 (form 20).

113. (a) When measured using CuKα radiation, the XRPD pattern is characterized by peaks at approximately 9.4, 15.1, 16.6, and 18.2°2θ, and optionally further includes peaks at approximately 8.5, 10.6, 12.3, 14.1, 17.5, 20.1, 22.5, and 23.6°2θ, and optionally further includes peaks at approximately 11.1, 12.8, 22.0, 24.4, 25.3, 26.9, and 31.7°2θ, (b) Features an XRPD pattern that substantially matches the XRPD pattern shown in Figure 41, (c) (i) When characterized by DSC using a temperature gradient of approximately 10°C / min, it shows a thermal (endothermal) event with an onset temperature of approximately 34°C and / or an endothermal peak temperature of approximately 74°C, or (ii) it features a differential scanning calorimetry plot that substantially matches the DSC plot shown in Figure 42, (d) (i) When characterized by TGA, when heated from about 25°C to about 110°C, it exhibits a weight loss of about 4.5%, or (ii) it features a thermogravimetric analysis plot that substantially matches the TGA plot shown in Figure 42, or (e) A solid form according to any one of claims 110 to 112, which is a combination of any one of (a) to (d).

114. The solid form according to claim 23 or 24, wherein the pharmaceutically acceptable salt is the tartrate salt of compound 1.

115. The solid form according to claim 114, wherein the solid form has a compound 1 / tartaric acid molar ratio of about 1:1, and optionally the solid form is a hydrate.

116. The solid form according to claim 114 or 115, wherein the solid form is compound 1 (form 21).

117. (a) When measured using CuKα radiation, the XRPD pattern is characterized by peaks at approximately 13.2, 16.9, 17.2, 17.7, 18.4, and 25.3°2θ, and optionally further includes peaks at approximately 8.3, 12.3, 20.9, and 24.0°2θ, and optionally further includes peaks at approximately 14.5, 19.9, and 22.4°2θ, (b) Features an XRPD pattern that substantially matches the XRPD pattern shown in Figure 43, (c) (i) when characterized by DSC using a temperature gradient of approximately 10°C / min, showing thermal (endothermic) events with starting temperatures of approximately 29°C and approximately 201°C, and / or endothermic peak temperatures of approximately 70°C and approximately 204°C, or (ii) characterized by differential scanning calorimetry plots that substantially coincide with the DSC plot shown in Figure 44, (d) (i) When characterized by TGA, when heated from about 30°C to about 140°C, it exhibits a weight loss of about 6.8%, or (ii) it features a thermogravimetric analysis plot that substantially matches the TGA plot shown in Figure 44, or (e) A solid form according to any one of claims 110 to 112, which is a combination of any one of (a) to (d).

118. The solid form according to claim 114, wherein the solid form has a compound molar ratio of approximately 1:1 (1 / tartaric acid), and the solid form is a solvate.

119. The solid form according to claim 114 or 118, wherein the solid form is compound 1 (form 22).

120. (a) When measured using CuKα radiation, the XRPD pattern is characterized by peaks at approximately 10.6, 11.2, 16.6, 17.6, 18.1 and 22.5°2θ, and optionally further includes peaks at approximately 8.5, 14.6, 22.0, 25.2, 25.6 and 29.9°2θ, and optionally further includes peaks at approximately 12.3, 14.2, 23.7, 23.9 and 27.4°2θ, (b) Features an XRPD pattern that substantially matches the XRPD pattern shown in Figure 45, (c) (i) When characterized by DSC using a temperature gradient of approximately 10°C / min, showing thermal (endothermic) events with starting temperatures of approximately 27°C, approximately 106°C, and approximately 209°C, and / or endothermic peak temperatures of approximately 51°C, approximately 141°C, and approximately 222°C, respectively, or (ii) characterized by differential scanning calorimetry plots substantially consistent with the DSC plot shown in Figure 46, (d) (i) When characterized by TGA, when heated from about 80°C to about 170°C, it exhibits a weight loss of about 2.8%, or (ii) it features a thermogravimetric analysis plot that substantially matches the TGA plot shown in Figure 46, or (e) A solid form according to any one of claims 114, 118, or 119, which is a combination of any one of (a) to (d).

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

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

123. The solid form according to claim 114 or 115, wherein the solid form is compound 1 (form 23).

124. (a) When measured using CuKα radiation, the XRPD pattern is characterized by peaks at approximately 8.5, 14.6, 18.1, and 21.7°²θ, and optionally further includes peaks at approximately 6.8, 17.7, and 23.8°²θ, and optionally further includes peaks at approximately 18.8 and 22.9°²θ. (b) Features an XRPD pattern that substantially matches the XRPD pattern shown in Figure 47, (c) (i) When characterized by DSC using a temperature gradient of approximately 10°C / min, it shows thermal (endothermic) events with starting temperatures of approximately 83°C and approximately 186°C, and / or endothermic peak temperatures of approximately 120°C and approximately 202°C, respectively, or (ii) it features a differential scanning calorimetry plot that substantially matches the DSC plot shown in Figure 48. (d) (i) When characterized by TGA, when heated from near room temperature to about 100°C, it shows a weight loss of about 1.8%, and when heated from about 100°C to about 180°C, it shows a weight loss of about 5.6%, or (ii) it is characterized by a thermogravimetric analysis plot that substantially matches the TGA plot shown in Figure 48, or (e) A solid form according to any one of claims 121 to 123, which is a combination of any one of (a) to (d).

125. The solid form according to claim 3, wherein the solid form is the anhydride of the free base of compound 1.

126. The solid form according to claim 125, wherein the solid form is compound 1 (form 24).

127. (a) When measured using CuKα radiation, the XRPD pattern is characterized by peaks at approximately 9.5, 11.8, 14.6, and 20.9°²θ, and optionally further includes peaks at approximately 14.8, 16.4, 22.3, and 23.8°²θ, and optionally further includes peaks at approximately 16.6, 17.1, 24.2, and 25.1°²θ, (b) Features an XRPD pattern that substantially matches the XRPD pattern shown in Figure 49, (c) (i) When characterized by DSC using a temperature gradient of approximately 10°C / min, it shows a thermal (endothermic) event with an onset temperature of approximately 240°C and / or an endothermic peak at approximately 246°C, or (ii) it is characterized by a differential scanning calorimetry plot that substantially matches the DSC plot shown in Figure 50. (d) (i) If characterized by TGA, it shows no weight loss when heated to about 200°C, or (ii) it features a thermogravimetric analysis plot that substantially matches the TGA plot shown in Figure 50, or (e) A solid form according to any one of claims 5, 125, or 126, which is a combination of any one of (a) to (d).

128. Compound 1: 【Chemistry 2】 Pharmacologically acceptable salts, or its isotopic substitutions, or pharmaceutically acceptable solvates of the pharmaceutically acceptable salt.

129. The compound according to claim 128, wherein the pharmaceutically acceptable salt is a benzoate, besilate, chloride, citrate, fumarate, gentisinate, glutarate, glycolate, hippurate, 1-hydroxy-2-naphthoate, malate, maleate, mesilate, oxalate, phosphate, sulfate, tartrate, or tosilate.

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

2.

131. A pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 ２ ,4 ４ - A compound according to any one of claims 128 to 130, which is a dicarbonitrile benzoate or a pharmaceutically acceptable solvate thereof.

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

1.

133. A pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 ２ ,4 ４ - A compound according to any one of claims 128 to 130, which is a dicarbonitrile besylate or a pharmaceutically acceptable solvate thereof.

134. A pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 ２ ,4 ４ - A compound according to any one of claims 128 to 130, which is a dicarbonitrile chloride salt or a pharmaceutically acceptable solvate thereof.

135. The pharmaceutically acceptable salt of the compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacylcyclohexafane-2 ２ , 4 ４ -dicarbonitrile citrate, or a pharmaceutically acceptable solvate thereof, the compound according to any one of claims 128 to 130.

136. A pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 ２ ,4 ４ - A compound according to any one of claims 128 to 130, which is a dicarbonitrile fumarate or a pharmaceutically acceptable solvate thereof.

137. The compound according to claim 136, wherein the pharmaceutically acceptable salt has a compound-to-fumarate molar ratio of about 1:

1.

138. A pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 ２ ,4 ４ - A compound according to any one of claims 128 to 130, which is dicarbonitrile gentisinate or a pharmaceutically acceptable solvate thereof.

139. A pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 ２ ,4 ４ - A compound according to any one of claims 128 to 130, which is a dicarbonitrile glutarate or a pharmaceutically acceptable solvate thereof.

140. A pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 ２ ,4 ４ - A compound according to any one of claims 128 to 130, which is a dicarbonitrile glycolate or a pharmaceutically acceptable solvate thereof.

141. A pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 ２ ,4 ４ - A compound according to any one of claims 128 to 130, which is dicarbonitrile hippurate or a pharmaceutically acceptable solvate thereof.

142. A pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 ２ ,4 ４ The compound according to any one of claims 128 to 130, which is dicarbonitrile 1-hydroxy-2-naphthoate or a pharmaceutically acceptable solvate thereof.

143. The compound according to claim 142, wherein the pharmaceutically acceptable salt has a compound molar ratio of about 1:1 (1 / 1-hydroxy-2-naphthoate).

144. A pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 ２ ,4 ４ - A compound according to any one of claims 128 to 130, which is dicarbonitrile malate or a pharmaceutically acceptable solvate thereof.

145. A pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 ２ ,4 ４ - A compound according to any one of claims 128 to 130, which is a dicarbonitrile maleate or a pharmaceutically acceptable solvate thereof.

146. A pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 ２ ,4 ４ - A compound according to any one of claims 128 to 130, which is a dicarbonitrile mesylate or a pharmaceutically acceptable solvate thereof.

147. A pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 ２ ,4 ４ - A compound according to any one of claims 128 to 130, which is a dicarbonitrile oxalate or a pharmaceutically acceptable solvate thereof.

148. A pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 ２ ,4 ４ - A compound according to any one of claims 128 to 130, which is a dicarbonitrile phosphate or a pharmaceutically acceptable solvate thereof.

149. A pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 ２ ,4 ４ - A compound according to any one of claims 128 to 130, which is a dicarbonitrile sulfate or a pharmaceutically acceptable solvate thereof.

150. A pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 ２ ,4 ４ - A compound according to any one of claims 128 to 130, which is a dicarbonitrile tartrate or a pharmaceutically acceptable solvate thereof.

151. A pharmaceutically acceptable salt of compound 1 is (S)-3-amino-3-(1-methyl-1H-imidazole-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzeneacyclohexaphane-2 ２ ,4 ４ - A compound according to any one of claims 128 to 130, which is a dicarbonitrile tosylate or a pharmaceutically acceptable solvate thereof.

152. The compound according to any one of claims 128 to 151, wherein the pharmaceutically acceptable salt of compound 1 is a nonsolvate of the pharmaceutically acceptable salt of compound 1.

153. The compound according to any one of claims 128 to 151, wherein the pharmaceutically acceptable salt of compound 1 is the anhydrous form of the pharmaceutically acceptable salt of compound 1.

154. The compound according to any one of claims 128 to 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 according to claim 154, wherein the pharmaceutically acceptable solvate is a hydrate, hemihydrate, isobutyl acetate solvate, isopropyl acetate solvate, tetrahydrofuran solvate, acetone solvate, acetonitrile solvate, or a combination thereof.

156. The compound according to claim 154, wherein the pharmaceutically acceptable solvate has a compound-to-solvent molar ratio in the range of about 2:1 to about 1:

2.

157. The compound according to claim 156, wherein the molar ratio of the compound to the solvent is approximately 1:

1.

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

159. A pharmaceutical composition, i) Compound 1 in an amount of approximately 0.1 mg to approximately 200 mg: 【Transformation 3】 or a solid form comprising a pharmaceutically acceptable salt and / or solvate thereof, ii) A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients.

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

161. The pharmaceutical composition according to claim 159 or 160, wherein the amount of compound 1 is approximately 0.2 mg free base equivalent.

162. The pharmaceutical composition according to claim 159 or 160, wherein the amount of compound 1 is approximately 1.0 mg free base equivalent.

163. The pharmaceutical composition according to claim 159 or 160, wherein the amount of compound 1 is approximately 10 mg free base equivalent.

164. The pharmaceutical composition according to claim 159 or 160, wherein the amount of compound 1 is approximately 50 mg free base equivalent.

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

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

167. The pharmaceutical composition according to claim 165, wherein the solid form is compound 1 (form 1).

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

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

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

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

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

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

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

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

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

177. The pharmaceutical composition according to 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 to about 95% (w / w) and about 73 to about 75.4 mg.

178. The pharmaceutical composition according to 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 to about 95% (w / w), and in (a) about 80 to about 380 mg, or (b) about 80 to about 90 mg, or (c) about 370 to about 378 mg.

179. The pharmaceutical composition according to 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 to about 95% (w / w) and about 75 to about 85 mg.

180. The pharmaceutical composition according to 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 to about 50% (w / w) and about 40 to about 50 mg, or the silicified microcrystalline cellulose is present in an amount of about 60 to about 70% (w / w) and about 60 to about 70 mg.

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

182. The pharmaceutical composition according to claim 181, wherein the amount of the flow promoter is colloidal silicon dioxide.

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

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

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

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

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

188. The pharmaceutical composition according to claim 187, wherein the lubricant is magnesium stearate.

189. The pharmaceutical composition according to claim 187 or 188, wherein the lubricant is present in an amount of about 0.5 to about 2.5% (w / w), or about 0.5, about 1.0, about 1.5, or about 2.0% (w / w), or about 1.0% (w / w), or about 1.5% (w / w).

190. The pharmaceutical composition according to any one of claims 159 to 189, wherein the pharmaceutical composition comprises a binder.

191. The pharmaceutical composition according to claim 190, wherein the binder is povidone.

192. The pharmaceutical composition according to claim 190 or 191, wherein the binder is present in an amount of about 3 to about 10% (w / w) and about 3 to about 15 mg.

193. The pharmaceutical composition according to claim 192, comprising (a) a core tablet containing about 0.21 mg of compound 1 (form 1), about 75.4 mg of silicified microcrystalline cellulose, about 0.8 mg of colloidal silicon dioxide, about 2.4 mg of croscarmellose sodium, and about 1.2 mg of magnesium stearate, and (b) a tablet coating.

194. The pharmaceutical composition according to claim 192, comprising (a) a core tablet containing about 1.03 mg of compound 1 (form 1), about 377.0 mg of silicified microcrystalline cellulose, about 4.0 mg of colloidal silicon dioxide, about 12.0 mg of croscarmellose sodium, and about 6.0 mg of magnesium stearate, and (b) a tablet coating.

195. The pharmaceutical composition according to claim 192, comprising (a) a core tablet containing about 10.3 mg of compound 1 (form 1), about 84.2 mg of silicified microcrystalline cellulose, about 1.0 mg of colloidal silicon dioxide, about 3.0 mg of croscarmellose sodium, and about 1.5 mg of magnesium stearate, and (b) a tablet coating.

196. (a) a core tablet containing approximately 51.5 mg of compound 1 (form 1), approximately 43.0 mg of silicified microcrystalline cellulose, approximately 1.0 mg of colloidal silicon dioxide, approximately 3.0 mg of croscarmellose sodium, and approximately 1.5 mg of magnesium stearate, and (b) a tablet coating, or The pharmaceutical composition according to claim 192, comprising (a) a core tablet containing about 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 3.0 mg of croscarmellose sodium, and about 1.5 mg of magnesium stearate, and (b) a tablet coating.

197. The core tablet comprises (a) an internal portion containing 51.5 mg of compound 1 (form 1), about 43.0 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 external portion containing about 1.0 mg of croscarmellose sodium and about 0.5 mg of magnesium stearate, or The pharmaceutical composition according to claim 196, comprising (a) an inner granule portion containing 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 outer granule portion containing about 1.0 mg of croscarmellose sodium and about 0.5 mg of magnesium stearate.

198. The pharmaceutical composition according to claim 192, comprising (a) a core tablet containing 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 according to claim 192, comprising (a) a core tablet containing 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 according to claim 192, comprising (a) a core tablet containing 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 according to claim 200, wherein the core tablet comprises (a) an internal portion containing compound 1 (form 1), silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and povidone, and (b) an external portion containing magnesium stearate.

202. The pharmaceutical composition according to any one of claims 170 to 201, wherein the tablet coating is a spray-dried film coating.

203. The pharmaceutical composition according to any one of claims 170 to 201, wherein the tablet coating comprises a polymer, a plasticizer, and a pigment.

204. The pharmaceutical composition according to any one of claims 170 to 201, wherein the tablet coating comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc.

205. A method for preparing a pharmaceutical composition according to any one of claims 169 to 201, i) Optionally crushing the solid form of compound 1, or a pharmaceutically acceptable salt and / or solvate thereof, ii) Mixing the compound 1, or a pharmaceutically acceptable salt and / or solvate thereof in solid form, with a first portion of a disintegrant, a flow enhancer, and a filler to form a first blend; iii) Crushing the first blend to form the crushed first blend, iv) Crushing the second portion of the filler, v) Blending the crushed first blend and the crushed second portion of the filler to form a second blend, vi) Blending the second blend described above with a lubricant to form a smoothed blend, vii) A method comprising optionally compressing the smoothed blend into tablets using a rotary press.

206. The method according to claim 205, further comprising viiii) coating a compressed tablet.

207. The method according to claim 206, wherein the coating is a spray-dried film coating.

208. The method according to any one of claims 205 to 207, wherein the method optionally further comprises ix) packaging the film-coated tablets in a container.

209. The method according to any one of claims 205 to 208, wherein the amount of compound 1, or a pharmaceutically acceptable salt and / or solvate thereof, in solid form present in the pharmaceutical composition is about 0.2 mg, about 1 mg, or about 10 mg free base equivalent.

210. A method for preparing a pharmaceutical composition according to any one of claims 169 to 201, i) Optionally crushing the solid form of compound 1, or a pharmaceutically acceptable salt and / or solvate thereof, ii) Mixing the compound 1, or a pharmaceutically acceptable salt and / or solvate thereof in solid form, with a first portion of a filler, a flow enhancer, and a disintegrant to form a first blend; iii) Declumping the first blend, then blending it to form a second blend, iv) Blending the second blend with the first portion of the lubricant to form a lubricated granular blend, v) Forming granular material from the aforementioned granular blend, vi) Blending the granular material with the second portion of the disintegrant and the second portion of the lubricant to form a smoothed final blend, vii) A method comprising optionally compressing the smoothed final blend into tablets using a rotary press.

211. The method according to claim 210, further comprising viiii) coating a compressed tablet, wherein optionally, the formation of granules from the granular blend is carried out using a roller compressor and a screen.

212. The method according to claim 211, wherein the coating is a spray-dried film coating.

213. The method according to any one of claims 210 to 212, wherein the method optionally further comprises ix) packaging the film-coated tablets in a container.

214. The method according to any one of claims 210 to 213, wherein the amount of compound 1, or a pharmaceutically acceptable salt and / or solvate thereof, in solid form present in the film-coated tablet is 50 mg free base equivalent.

215. A method for preparing a pharmaceutical composition according to any one of claims 169 to 201, i) Optionally crushing the solid form of compound 1, or a pharmaceutically acceptable salt and / or solvate thereof, ii) Granulating the compound 1, or a pharmaceutically acceptable salt and / or solvate thereof, in solid form, as a filler, flow promoter, and disintegrant, together with a binder and water to form wet granules, iii) Drying the wet granular material to form dried granular material, iv) Blending the granular material with a lubricant to form a smoothed final blend, v) A method comprising optionally using a rotary press to compress the smoothed final blend into a tablet.

216. The method according to claim 215, further comprising vii) coating a compressed tablet, wherein optionally, the formation of granules from the intragranular blend is carried out using a high-shear granulator and a screen.

217. The method according to claim 216, wherein the coating is a spray-dried film coating.

218. The method according to any one of claims 215 to 217, wherein the method optionally further comprises (viii) packaging the film-coated tablets in a container.

219. The method according to any one of claims 215 to 218, wherein the amount of compound 1, or a pharmaceutically acceptable salt and / or solvate thereof, in solid form present in the film-coated tablet is 1 mg, 10 mg, or 50 mg free base equivalent.

220. Compound 1: 【Chemistry 4】 or a process for preparing such pharmaceutically acceptable form, (a) Racemic compound 19: 【Transformation 5】 The chiral acid is reacted in a solvent to obtain the diastereomer salt of compound 1 and compound 2: 【Transformation 6】 This involves forming a diastereomer salt of, The formation is such that one of the two diastereomer salts selectively precipitates from the solvent, and the other of the two diastereomer salts is selectively soluble in the solvent. (b) Separating the precipitate from the solvent, (c) To provide compound 1 by reacting the diastereomer salt of compound 1 with a base, (d) A process comprising optionally recrystallizing compound 1 from ACN / water in an optionally 2:1 to approximately 1:5 ratio, and optionally 1:1 to approximately 1:3 ratio.

221. The process according to claim 220, wherein the chiral acid is (R)-crosiphos, (S)-crosiphos, (+)-tartaric acid, (-)-tartaric acid, (+)-camphorsulfonic acid, (-)-camphorsulfonic acid, L-(-)-di-p-anisioyltartaric acid, D-(+)-di-p-anisioyltartaric acid, L-(-)-di-toluoyltartaric acid, D-(+)-di-toluoyltartaric acid, (R)-binap phosphate, (S)-binap phosphate, di-benzoyl-l-tartaric acid, or di-benzoyl-D-tartaric acid.

222. The process according to 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 phosphate or (S)-BINAP phosphate and the solvent is dioxane, acetone, ACN, IPAc, MEK, THF, 2-MeTHF, dioxolane, or glycine, or the solvent is THF or dioxolane.

223. The process according to claim 222, wherein the chiral acid is dibenzoyl-D-tartaric acid, and the diastereomer salt of compound 1 is a diastereomer salt that is selectively soluble in the solvent.

224. The process according to claim 222, wherein the chiral acid is dibenzoyl-L-tartaric acid, and the diastereomer salt of compound 1 is a diastereomer salt that selectively precipitates from the solvent.

225. The aforementioned base is Na ２ CO ３ _K ２ CO ３ , NaOH, or KOH, or the base is Na ２ CO ３ The process according to any one of claims 220 to 224.

226. The process according to any one of claims 222 to 225, wherein the solvent is DCM.

227. Compound 18: 【Transformation 7】 The process according to any one of claims 220 to 226, comprising reacting with an ammonia equivalent to form compound 19.

228. The ammonia equivalent is optionally in an amount of about 15 to about 50 equivalents, or about 40 to 50 equivalents of NH ３ The process according to claim 227, wherein the reaction of compound 18 is carried out in a polar solvent, the polar solvent is optionally selected from IPA, EtOH, MeOH, 1,4-dioxane, DMI, and mixtures thereof, optionally the polar solvent is MeOH, and optionally the reaction of compound 18 is carried out at a temperature of about 0 to about 40°C.

229. Compound 17: 【Transformation 8】 The process according to claim 227 or 228, comprising chlorinating with a chlorinating agent to form compound 18.

230. The chlorinating agent is thionyl chloride, POCl ３ , PCL ３ The process according to claim 229, wherein the chlorinating agent is , or oxalyl chloride, optionally, thionyl chloride, optionally used in an amount of about 2 to about 3.5 equivalents, optionally, the chlorination of compound 17 is carried out in a polar aprotic solvent, optionally, the polar aprotic solvent is DMI, optionally, the chlorination of compound 17 is carried out at a temperature of about 10 to about 60°C.

231. Compound 16: 【Chemistry 9】 The process according to claim 229 or 230, comprising reacting a cyanide equivalent and a palladium catalyst with a zinc source and / or a phosphine ligand in the presence of optionally selected zinc sources and / or phosphine ligands to provide compound 17.

232. (a) The cyanide source is optionally about 1 to about 1.7 equivalents of Zn(CN) ２ And, (b) The palladium catalyst is [PdCl(allyl)] ２ , Pd ２ (dba) ３ , Pd(OAc) ２ , Pd(PPh ３ ) ４ , Pd(dppf) ２ Cl ２ , PdCl ２ , or a combination thereof, or Pd ２ (dba) ３ and Pd(OAc) ２ And, (c) The phosphine ligand is PPh ３ , R-BINAP, or dppf, or dppf, wherein the phosphine ligand is optionally present in an amount of about 0.02 to about 0.15 equivalents. (d) The zinc source is zinc metal, (e) The reaction of compound 16 is carried out at a temperature of about 60 to about 110°C, or about 90 to about 110°C. (f) The reaction of compound 16 is carried out in a polar solvent, and optionally the polar solvent is DMA or DMF, or The process according to claim 231, which is any combination of (g)(a) to (f).

233. Compound 1: 【Chemistry 10】 or a process for preparing a pharmaceutically acceptable form thereof, wherein compound 18A 【Chemistry 11】 This is reacted with a cyanide equivalent and a palladium catalyst, optionally in the presence of a zinc source and / or a phosphine ligand, to obtain compound 19: 【Chemistry 12】 To provide, A process comprising purifying a racemic compound 19 by chiral separation to provide compound 1.

234. (a) The cyanide source is optionally about 1 to about 1.7 equivalents of Zn(CN) ２ And, (b) The palladium catalyst is [PdCl(allyl)] ２ , Pd ２ (dba) ３ , Pd(OAc) ２ , Pd(PPh ３ ) ４ , Pd(dppf) ２ Cl ２ , PdCl ２ , or a combination thereof, or Pd ２ (dba) ３ and Pd(OAc) ２ And, (c) The phosphine ligand is PPh ３ , R-BINAP, or dppf, or dppf, wherein the phosphine ligand is optionally present in an amount of about 0.02 to about 0.15 equivalents. (d) The zinc source is zinc metal, (e) The reaction of compound 18A is carried out at a temperature of about 60 to about 110°C, or about 90 to about 110°C. (f) The reaction of compound 18A is carried out in a polar solvent, and optionally the polar solvent is DMA or DMF, or The process according to claim 233, which is any combination of (g)(a) to (f).

235. Compound 17A: 【Chemistry 13】 The process according to claim 233 or 234, comprising reacting with an ammonia equivalent to form compound 18A.

236. The ammonia equivalent is optionally in an amount of about 15 to about 50 equivalents, or about 17 to 21 equivalents of NH ３ The process according to claim 235, wherein the reaction of compound 17A is carried out in a polar solvent, the polar solvent is optionally selected from IPA, EtOH, MeOH, 1,4-dioxane, DMI, and mixtures thereof, optionally the polar solvent is IPA, and optionally the reaction of compound 17A is carried out at a temperature of about 0 to about 40°C.

237. Compound 16: 【Chemistry 14】 The process according to claim 235 or 236, comprising chlorinating with a chlorinating agent to form compound 17A.

238. The chlorinating agent is thionyl chloride, POCl ３ , PCL ３ The process according to claim 237, wherein the chlorinating agent is , or oxalyl chloride, optionally the chlorinating agent is thionyl chloride, optionally used in an amount of about 2 to about 3.5 equivalents, optionally the chlorination of compound 16 is carried out in a polar aprotic solvent, optionally the polar aprotic solvent is DMI, optionally the chlorination of compound 16 is carried out at a temperature of about 10 to about 60°C.

239. Compound 15X: 【Chemistry 15】 The process according to any one of claims 231, 232, 237, or 238, comprising cyclizing a salt thereof (wherein X is a leaving group selected from -Cl, -Br, -I, -OTs, or -OMs, and optionally X is -Cl (compound 15)) in the presence of a base to form compound 16.

240. The aforementioned base is Cs ２ CO ３ _K ２ CO ３ , or Li ２ CO ３ And, optionally, the base is Cs ２ CO ３ The process according to claim 239, wherein optionally, (a) compound 15X is used in free base form, and the base is present in an amount of about 1.5 to 4 equivalents, or (b) compound 15X is used in salt form, and the base is present in an amount of about 4 to 12 equivalents, optionally, the reaction of compound 15X is carried out in a polar aprotic solvent, optionally, the polar aprotic solvent is DME, DMF, MTBE, DMAc or diglym, or a mixture thereof, optionally, the polar aprotic solvent is DMF or DMAc, and optionally, the reaction of compound 15X is carried out at a temperature of about 40 to about 80°C.

241. Compound 14: 【Chemistry 16】 The process according to claim 239 or 240, further comprising reacting the salt thereof with a hydroxyl activator to form compound 15X or a salt thereof.

242. The hydroxyl activator is thionyl chloride, POCl ３ , PCL ３ The process according to claim 241, wherein the hydroxyl activator is oxalyl chloride (where X is -Cl), NaBr or LiBr (where X is -Br), TsCl (where X is -OTs), or MsCl (where X is -OMs), and optionally the hydroxyl activator is thionyl chloride, where X is -Cl, and optionally the thionyl chloride is used in an amount of about 2 to about 4 equivalents or about 3 equivalents, optionally the reaction of compound 14 is carried out in a polar aprotic solvent optionally selected from THF, 2-MeTHF, DMF, or DMA, and optionally the reaction of compound 14 is carried out at a temperature of about 10 to about 60°C.

243. The process according to any one of claims 231, 232, 237, or 238, comprising reacting compound 14 or a salt thereof under Mitsunobu conditions to form compound 16, wherein the Mitsunobu conditions optionally comprise a dialkyl azodicarboxylate and a trialkyl- or triarylphosphine, wherein the dialkyl azodicarboxylate is DEAD or DIAD, and the trialkyl- or triarylphosphine is triphenylphosphine.

244. Compound 13PG: 【Chemistry 17】 The process according to any one of claims 241 to 243, comprising deprotecting a compound (wherein each PG is independently a hydroxyl protecting group) under appropriate deprotection conditions to form compound 14 or a salt thereof.

245. Both PG groups are silyl protecting groups such as tert-butyldimethylsilyl, tri-isopropylsilyl, triethylsilyl, or tert-butyldiphenylsilyl, and optionally both PG groups are tri-isopropylsilyl or tert-butyldimethylsilyl (compound 13), and optionally the deprotection conditions are TBAF, MSA, MSA / H in a polar solvent. ２ O, or HCl / H ２ The process according to claim 244, comprising O, optionally the solvent being THF, ACN, EtOAc, acetone, toluene, or a mixture thereof, optionally the deprotection condition comprising 3N HCl in THF or THF / toluene (optionally, THF / toluene in a ratio of about 4:1 to about 1:4, or THF / toluene in a ratio of about 2:1 to about 3:1), and optionally the deprotection of compound 13PG carried out at a temperature of about 0 to about 40°C.

246. Compound 12PG: [Chemistry 18] The process according to claim 244 or 245, comprising coupling compound 12PG (wherein each PG is independently a hydroxyl protecting group, optionally both PG groups are silyl protecting groups such as tert-butyldimethylsilyl, tri-isopropylsilyl, triethylsilyl, or tert-butyldiphenylsilyl, optionally both PG groups are tri-isopropylsilyl or tert-butyldimethylsilyl) with 1-methylimidazole to form compound 13PG, optionally the coupling of compound 12PG is carried out at a temperature of about -50 to about -90°C.

247. The reaction comprises metallizing 1-methylimidazole at the 5-position to form a reactive species, and mixing the reactive species with compound 12PG, wherein the reactive species is optionally (1-methyl-2-(protecting group)-1H-imidazole-5-yl)lithium, and optionally the 1-methyl-2-(protecting group)-1H-imidazole-5-yl)lithium is (1-methyl-2-(triethylsilyl)-1H-imi The process according to claim 246, wherein the material is lithium (dazole-5-yl), and optionally the metallation comprises reacting 1-methylimidazole with (i)BuLi, (ii)TESCl, and (iii)BuLi to form lithium (1-methyl-2-(triethylsilyl)-1H-imidazole-5-yl), and optionally the metallation and coupling are carried out at a temperature of about -30 to about -90°C.

248. Compound 11PG: 【Chemistry 19】 Compound 9PG 【Chemistry 20】 The process according to claim 246 or 247, comprising condensing with (wherein each PG is independently a hydroxyl protecting group, optionally both the PG groups in compound 9PG and compound 11PG are silyl protecting groups such as tert-butyldimethylsilyl, tri-isopropylsilyl, triethylsilyl, or tert-butyldiphenylsilyl, optionally both PG groups are tri-isopropylsilyl or tert-butyldimethylsilyl (compound 9 and compound 11)) to form compound 12PG.

249. The process according to claim 248, comprising: reacting compound 9PG with a metallating agent such as BuLi or isopropyl MgCl / LiCl to form a reactive species, wherein optionally the metallating agent is used in an amount of about 1 to about 1.3 equivalents in a polar aprotic solvent, optionally the polar aprotic solvent being THF; and mixing the reactive species with compound 11PG, wherein optionally the reaction of compound 9PG and the mixing with compound 11PG are carried out at a temperature of about -60 to about -85°C.

250. Compound 8: 【Chemistry 21】 The process according to claim 248 or 249, comprising reacting with a hydroxyl protecting group reagent to form compound 9PG.

251. The process according to claim 250, wherein PG is a silyl protecting group, the hydroxyl protecting group reagent is a silyl chloride reagent, optionally PG is tert-butyldimethylsilyl, the hydroxyl protecting group reagent is TBSCl, the reaction of compound 8 is carried out in the presence of a base, optionally the base is optionally imidazole, TEA, TEA / DMAP, DIPEA, or pyridine in a polar aprotic solvent, and optionally the polar aprotic solvent is DCM or THF.

252. Compound 7: 【Chemistry 22】 The process according to claim 250 or 251, comprising reacting with a demethylating agent to form compound 8.

253. The demethylating agent is optionally in an amount of about 1.5 to 2.5 equivalents and optionally in the presence of a phase transfer agent, BCl ３ or BBr ３ and optionally, the phase transfer agent is a tetraalkylammonium salt such as tetrabutylammonium iodide in an optionally polar aprotic solvent, and optionally, the polar aprotic solvent is THF, and optionally, the reaction of the compound 7 is carried out at a temperature of about 0 to about 40 ° C., The process according to claim 252.

254. Compound 6: 【Chemistry 23】 The process according to claim 252 or 253, comprising reacting with a dehydrating reagent to form compound 7.

255. The aforementioned dehydrating reagent is POCl ３ oxalyl chloride, thionyl chloride, PCL ３ , or PCL ５ The dehydrating reagent is optionally used in an amount of approximately 2 to approximately 6 equivalents, and optionally in a polar aprotic solvent, POCl ３ The process according to claim 254, wherein the polar aprotic solvent is optionally ACN, THF, 2-MeTHF, toluene, or DCM, and optionally the reaction of compound 6 is carried out at a temperature of about 40 to about 85°C.

256. Compound 5: 【Chemistry 24】 The process according to claim 254 or 255, comprising reacting (i) a base and (ii) an acid to form compound 6.

257. The base is optionally potassium tert-butoxide or sodium tert-butoxide in an amount of from about 1.5 to about 3 equivalents, and the acid is HCl or H ２ SO ４ and the acid is used in stoichiometric or catalytic amounts, optionally the reaction of the compound 5 is carried out in a polar solvent, optionally the polar solvent is THF or toluene, optionally step (i) is carried out at a temperature of from about 10 to about 40 ° C and step (ii) is carried out at a temperature of from about 10 to about 75 ° C, process according to claim 256.

258. Compound 4: 【Chemistry 25】 The process according to claim 256 or 257, comprising acetylating in the presence of an acetylating agent to form compound 5.

259. The acetylating agent is (a) Ac ２ (b) O or (b) AcCl and a base, optionally the base being TEA or DIPEA, optionally (a) or (b) being carried out in a polar solvent such as DCM or toluene, optionally at a temperature of about 15 to about 110°C, or (c) water and Et ２ The process according to claim 258, wherein the organic solvent is O or AcCl in an organic solvent such as DCM.

260. Compound 3: 【Chemistry 26】 The process according to claim 258 or 259, comprising treating with a reducing agent to form compound 4.

261. The reducing agent is (a) TiCl ３ and a proton source, optionally the proton source being water, optionally the TiCl ３ However, it is optionally used in a polar aprotic solvent in an amount of about 1.5 to about 3 equivalents, and optionally the polar aprotic solvent is either THF or (b) H ２ The process according to claim 260, wherein the hydrogenation catalyst is optionally Pd / C or Pt / C.

262. The process according to claim 260 or 261, comprising reacting 1-bromo-4-nitrobenzene with 2-(3-methoxyphenyl)acetonitrile in the presence of a base to form compound 3.

263. The process according to claim 262, wherein the base is NaOH, KOH, or an alkoxide base, optionally the alkoxide base is optionally sodium methoxide, sodium ethoxide, or potassium tert-butoxide in an optionally polar solvent in an optionally large amount of about 2 to about 10 equivalents, optionally the polar solvent is MeOH, EtOH, MeOH / DCM, or EtOH / DCM, and optionally the temperature is optionally about 0 to about 60°C.

264. Compound 23: 【Chemistry 27】 The process according to any one of claims 248 to 263, comprising reacting with a hydroxyl protecting group reagent to form compound 11PG.

265. The process according to claim 264, wherein PG is a silyl protecting group, the hydroxyl protecting group reagent is a silyl chloride reagent, optionally PG is tert-butyldimethylsilyl, the hydroxyl protecting group reagent is TBSCl in the presence of a base, optionally the base is optionally imidazole, TEA, TEA / DMAP, DIPEA, or pyridine in a polar aprotic solvent, and optionally the polar aprotic solvent is DCM or THF.

266. Compound 22: 【Chemistry 28】 The process according to claim 264 or 265, comprising reacting with morpholine under amide coupling conditions to form compound 23.

267. The amide coupling conditions are (a) comprising a carbodiimide and a base, optionally wherein the carbodiimide is EDC, EDCI, or DCC, and optionally wherein the base is TEA, DIPEA, or TEA / DMAP, or (b) BOP, PyBOP, HOAt, HOBt, or T ３ The process according to claim 266, comprising P.

268. Compound 21: 【Chemistry 29】 The process according to claim 266 or 267, comprising converting compound 21 to compound 22 by treating compound 21 with a base and water.

269. The aforementioned base is optionally in a polar protic solvent, Na ２ CO ３ _K ２ CO ３ The process according to claim 268, wherein the polar protic solvent is NaOH or KOH, optionally the polar protic solvent is water, MeOH, EtOH, IPA, or a mixture thereof, optionally the polar protic solvent is EtOH / water, and optionally the temperature is about 50 to about 110°C.

270. Compound 21 is in a mixture with methyl 4-bromo-3-(dibromomethyl)benzoate, and the conversion further comprises mixing the product of the processing step with a reducing agent, optionally the reducing agent being NaBH ４ NaCNBH ３ , or BH ３ The process according to claim 268 or 269, wherein the process is a DMS.

271. Compound 20: 【Transformation 30】 The process according to claim 269 or 270, comprising reacting with a brominating agent and a radical initiator to form compound 21.

272. The aforementioned brominaters are NBS, Br ２ NaBrO ３ The process according to claim 271, wherein the radical initiator is HBr or 1,3-dibromo-5,5-dimethylhydantoin, the radical initiator is light, heat or AIBN, optionally the brominating agent is NBS, the radical initiator is light, optionally the reaction of compound 20 is carried out in a continuous flow reactor equipped with a photodegradation flow cell having a wavelength in the range of about 300 to about 500 nm, optionally the reaction of compound 20 produces a mixture of compound 21 and methyl 4-bromo-3-(dibromomethyl)benzoate.

273. A process for preparing compound 9, wherein compound 7: 【Chemistry 31】 Reacting with a demethylating agent, compound 8: 【Chemistry 32】 To form, A process comprising reacting compound 8 with TBSCl and a base to form compound 9.

274. (a) The demethylating agent is optionally present in an amount of about 1.5 to 2.5 equivalents, optionally in the presence of a phase transfer agent, BCl ３ or BBr ３ The phase transfer agent is optionally a tetraalkylammonium salt such as tetrabutylammonium iodide in a polar aprotic solvent, optionally the polar aprotic solvent is THF, optionally the reaction of compound 7 is carried out at a temperature of about 0 to about 40°C, and / or (b) The process according to claim 273, wherein the base is imidazole, TEA, TEA / DMAP, DIPEA, or pyridine, and optionally the reaction is carried out in a polar aprotic solvent, and optionally the polar aprotic solvent is DCM or THF.

275. Compound 6: 【Transformation 33】 The process according to claim 273 or 274, comprising reacting with a dehydrating reagent to form compound 7.

276. The aforementioned dehydrating reagent is POCl ３ oxalyl chloride, thionyl chloride, PCL ３ , or PCL ５ The dehydrating reagent is optionally used in an amount of approximately 2 to approximately 6 equivalents, and optionally in a polar aprotic solvent, POCl ３ The process according to claim 275, wherein the polar aprotic solvent is optionally ACN, THF, 2-MeTHF, toluene, or DCM, and optionally the reaction of compound 6 is carried out at a temperature of about 40 to about 85°C.

277. Compound 11: 【Transformation 34】 A process for preparing, Compound 23: 【Chemistry 35】 A process comprising reacting with TBSCl in the presence of a base to form compound 11.

278. The process according to claim 277, wherein the base is imidazole, TEA, TEA / DMAP, DIPEA, or pyridine, and optionally the reaction of compound 11 is carried out in a polar aprotic solvent, and optionally the polar aprotic solvent is DCM or THF.

279. Compound 19: 【Transformation 36】 A process for preparing, Compound 17: 【Chemistry 37】 Chlorinated with a chlorinating agent, compound 18: 【Transformation 38】 To form, A process comprising reacting compound 18 with an ammonia equivalent to form compound 19.

280. (a) The chlorinating agent is thionyl chloride, POCl ３ , PCL ３ , or oxalyl chloride, optionally the chlorinating agent is thionyl chloride, optionally used in an amount of about 2 to about 3.5 equivalents, optionally the chlorination is carried out in a polar aprotic solvent, optionally the polar aprotic solvent is DMI, optionally the chlorination of compound 17 is carried out at a temperature of about 10 to about 60°C, and / or (B) The ammonia equivalent is optionally in an amount of about 15 to about 50 equivalents, or about 40 to 50 equivalents of NH ３ The process according to claim 279, wherein the reaction of compound 18 is carried out in a polar solvent, the polar solvent is optionally selected from IPA, EtOH, MeOH, 1,4-dioxane, DMI, and mixtures thereof, optionally the polar solvent is MeOH, and optionally the reaction of compound 18 is carried out at a temperature of about 0 to about 40°C.

281. Compound 14: 【Chemistry 39】 A process for preparing, Compound 13: 【Chemistry 40】 A process comprising reacting under deprotection conditions to form compound 14.

282. The deprotection conditions are optionally TBAF, MSA, MSA / H in a polar solvent. ２ O, or HCl / H ２ The process according to claim 281, comprising O, optionally the solvent being THF, ACN, EtOAc, acetone, toluene, or a mixture thereof, optionally the deprotection condition comprising 3N HCl in THF or THF / toluene (optionally, THF / toluene in a ratio of about 4:1 to about 1:4, or THF / toluene in a ratio of about 2:1 to about 3:1), and optionally the deprotection of compound 14 at a temperature of about 0 to about 40°C.

283. Compound 12: 【Chemistry 41】 A process for preparing, Compound 11: 【Chemistry 42】 Compound 9: 【Chemistry 43】 A process comprising condensing with to form compound 12.

284. The process according to claim 283, comprising reacting compound 9 with a metallating agent such as BuLi or isopropyl MgCl / LiCl to form a reactive species, wherein optionally the metallating agent is used in an amount of about 1 to about 1.3 equivalents in a polar aprotic solvent, and optionally the polar aprotic solvent is THF, the reaction, and the mixing of the reactive species with compound 11, wherein optionally the reaction of compound 9 and the mixing of the reactive species with compound 11 are carried out at a temperature of about -60 to about -85°C.

285. A process for preparing compound 13, comprising coupling compound 12 with 1-methylimidazole to form compound 13.

286. The method comprises metallizing 1-methylimidazole at the 5-position to form a reactive species, and mixing the reactive species with compound 12, wherein the reactive species is optionally (1-methyl-2-(protecting group)-1H-imidazole-5-yl)lithium, and optionally the 1-methyl-2-(protecting group)-1H-imidazole-5-yl)lithium is (1-methyl-2-(triethylsilyl)-1H-imidazole-5-yl)lithium, The process according to claim 285, wherein the metallation optionally comprises reacting 1-methylimidazole with (i)BuLi, (ii)TESCl, and (iii)BuLi to form (1-methyl-2-(triethylsilyl)-1H-imidazole-5-yl)lithium, wherein the metallation is optionally carried out at a temperature of about -30 to about -90°C, and optionally the coupling is optionally carried out at a temperature of about -30 to about -90°C.

287. below 【Chemistry 44】 Compounds selected from, and their salts.

288. Compound 1 or Compound 2: (R)-crosiphos, (S)-crosiphos, (+)-tartaric acid, (-)-tartaric acid, (+)-camphor sulfonic acid, (-)-camphor sulfonic acid, L-(-)-di-p-anisioyltartaric acid, D-(+)-di-p-anisioyltartaric acid, L-(-)-di-toluoyltartaric acid, D-(+)-di-toluoyltartaric acid, (R)-BINAP phosphate, (S)-BINAP phosphate, di-benzoyl-l-tartaric acid, or di-benzoyl-D-tartrate.

289. The salt according to claim 288, wherein the salt is dibenzoyl-l-tartrate or dibenzoyl-D-tartrate of compound 1 or compound 2.

290. The salt according to claim 288, wherein the salt is the L-DBTA salt of compound 1.

291. A method for inhibiting farnesyltransferase, comprising contacting the farnesyltransferase with an effective amount of the solid form described in any one of claims 1 to 127, a pharmaceutically acceptable salt of the compound described in any one of claims 128 to 158, or an isotopic substitution or pharmaceutically acceptable solvate of the pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in any one of claims 159 to 204. Selectively, the farnesyltransferase is present in the cell. Selectively, the contact of the farnesyltransferase occurs intracellularly, selectively, the cell is within the target, selectively, the cell is a mammalian cell, selectively, the cell is a human cell, and A method in which, optionally, the subject is suffering from a farnesylated protein-dependent cancer.

292. A method for treating a farnesylated protein-dependent cancer in a subject, comprising administering to a subject having the farnesylated protein-dependent cancer a therapeutically effective amount of a solid form according to any one of claims 1 to 127, a pharmaceutically acceptable salt of a compound according to any one of claims 128 to 158, or an isotopic substitution or pharmaceutically acceptable solvate of the pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 159 to 204, wherein the subject is optionally human.

293. The cancer dependent on the farnesylated protein is a cancer dependent on the farnesylated H-Ras protein, and optionally, the cancer dependent on the farnesylated protein has an H-Ras protein mutation, and optionally, the H-Ras protein mutation is a modification in a codon encoding an amino acid substitution at a specific position selected from G12, Gl3, Q61, Q22, K117, A146, and any combination thereof in the corresponding mutant H-Ras protein, or includes such modification. The method according to claim 291 or 292, wherein, optionally, the presence or absence of the H-Ras protein mutation is determined by analysis of nucleic acids obtained from a sample derived from the subject, optionally, the sample is a tissue biopsy or a tumor biopsy, and optionally, the H-Ras mutation is 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 according to any one of claims 291 to 293, wherein the cancer dependent on the farnesylated protein is 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.

295. The cancer dependent on the farnesylated protein is a head and neck cancer, and optionally, the head and neck cancer is head and neck squamous cell carcinoma (HNSCC), or The method according to any one of claims 291 to 293, wherein the farnesylated protein-dependent cancer is squamous cell carcinoma (SCC), and optionally, the SCC is head and neck SCC (HNSCC), lung SCC (LSCC), thyroid SCC (TSCC), esophageal SCC (ESCC), bladder SCC (BSCC), or urothelial carcinoma (UC), and optionally, the SCC is HNSCC, and optionally, the HNSCC is tracheal HNSCC, micrognathic HNSCC, or oral cavity HNSCC.

296. The method according to any one of claims 291 to 295, wherein the cancer dependent on the farnesylated protein is a solid tumor.

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