WO2025137366A2 - Formes solides d'inhibiteurs de stat3 et leurs méthodes d'utilisation - Google Patents

Formes solides d'inhibiteurs de stat3 et leurs méthodes d'utilisation Download PDF

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Publication number
WO2025137366A2
WO2025137366A2 PCT/US2024/061149 US2024061149W WO2025137366A2 WO 2025137366 A2 WO2025137366 A2 WO 2025137366A2 US 2024061149 W US2024061149 W US 2024061149W WO 2025137366 A2 WO2025137366 A2 WO 2025137366A2
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crystalline form
formula
compound represented
mixture
solid
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WO2025137366A3 (fr
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Imran ALIBHAI
Sofia De Achaval
Yixin Chen
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Tvardi Therapeutics Inc
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Tvardi Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus
    • C07F9/65744—Esters of oxyacids of phosphorus condensed with carbocyclic or heterocyclic rings or ring systems

Definitions

  • compositions comprising one or more solid-state forms of the compound represented by Formula (I), as free acid or base, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • provided herein are methods that involve the use of (e.g., comprise the administration of) a solid-state form of the compound represented by Formula (I), a STAT3 inhibitor, optionally wherein the solid-state form of the compound represented by Formula (I), as free acid or base, or a pharmaceutically acceptable salt or solvate thereof, is formulated in a manner described herein (e.g., is present in a composition as described herein).
  • provided herein are methods of treating, preventing, or reducing the risk or severity of cancer.
  • provided herein are methods of treating, preventing, or reducing the risk or severity of fibrosis.
  • provided herein are methods of treating, preventing, or reducing the risk or severity of an inflammatory disease or disorder.
  • FIG. 1 shows a comparison of X-ray powder diffraction (“XRPD”) diffractograms for the amorphous solid of the compound represented by Formula (I) and Form 1 of the compound represented by Formula (I).
  • XRPD X-ray powder diffraction
  • FIG. 2 A shows an XRPD diffractogram of Form 1 of the compound represented by Formula (I).
  • FIG. 2B shows an XRPD diffractogram of Form 21 of the compound represented by Formula (I).
  • FIG. 3 shows a 'HNMR spectrum of Form 1 of the compound represented by Formula (I).
  • FIG. 4 shows a 31 P NMR spectrum of Form 1 of the compound represented by Formula (I).
  • FIG. 5 shows thermogravimetric analysis (“TGA”) and differential scanning calorimetry (“DSC”) thermogram traces for Form 1 of the compound represented by Formula (I).
  • FIG. 6 shows a DSC thermogram trace for the first heating cycle for Form 1 of the compound represented by Formula (I).
  • FIG. 7 shows a dynamic vapor sorption (“DVS”) kinetic plot of Form 1 of the compound represented by Formula (I).
  • FIG. 8 shows a comparison of XRPD diffractograms of Form 1 of the compound represented by Formula (I) before and after DVS.
  • FIG. 9 shows a variable temperature XRPD diffractogram of Form 1 of the compound represented by Formula (I).
  • FIG. 10 shows XPRD diffractograms of Form 1 subjected to a seven-day stability test.
  • FIG. 11 shows XPRD diffractograms of the compound represented by Formula (I) subjected to maturation cycling and hydration.
  • FIG. 12 shows XRPD diffractograms of the compound represented by Formula (I) subjected to temperature cycling.
  • FIG. 13 shows XRPD diffractograms of the compound represented by Formula (I) subjected to solvent drop grinding.
  • FIG. 14 shows XRPD diffractograms of the compound represented by Formula (I) subjected to vapor diffusion into solids.
  • FIG. 15 shows XRPD diffractograms of the compound represented by Formula (I) subjected to vapor diffusion into saturated solutions.
  • FIG. 16 shows XPRD diffractograms of the compound represented by Formula (I) subjected to antisolvent additions.
  • FIG. 17 shows XRPD diffractograms of the compound represented by Formula (I) subjected to slow solvent evaporation.
  • FIGS. 18 A, 18B, and 18C show an XPRD diffractogram, TGA/DSC plot, and 'H NMR spectrum, respectively, of Form 2 of the compound represented by Formula (I).
  • FIGS. 19A and 19B show an XRPD diffractogram and TGA/DSC plot, respectively, of Form 3 of the compound represented by Formula (I).
  • FIG. 20 shows an XRPD diffractogram of Form 4 of the compound represented by Formula (I).
  • FIGS. 21A and 21B show an XRPD diffractogram and TGA/DSC plot, respectively, of Form 5 of the compound represented by Formula (I).
  • FIGS. 22A and 22B show an XRPD diffractogram and TGA/DSC plot, respectively, of Form 6 of the compound represented by Formula (I).
  • FIG. 23 shows an XRPD diffractogram of Form 7 of the compound represented by Formula (I).
  • FIGS. 24A and 24B show an XRPD diffractogram and TGA/DSC plot, respectively, of Form 8 of the compound represented by Formula (I).
  • FIGS. 25A and 25B show an XRPD diffractogram and TGA/DSC plot, respectively, of Form 9 of the compound represented by Formula (I).
  • FIGS. 26A and 26B show an XRPD diffractogram and TGA/DSC plot, respectively, of Form 10 of the compound represented by Formula (I).
  • FIGS. 27A and 27B show an XRPD diffractogram and TGA/DSC plot, respectively, of Form 11 of the compound represented by Formula (I).
  • FIGS. 28A and 28B show an XRPD diffractogram and TGA/DSC plot, respectively, of Form 12 of the compound represented by Formula (I).
  • FIG. 29 shows an XRPD diffractogram of Form 13 of the compound represented by Formula (I).
  • FIG. 30 shows an XRPD diffractogram of Form 14 of the compound represented by Formula (I).
  • FIG. 31 shows an XRPD diffractogram of Form 15 of the compound represented by Formula (I).
  • FIG. 32 shows an A J H NMR spectrum of Compound 2 as described in Example 2D.
  • FIG. 33 shows Liquid chromatography-mass spectrometry (LCMS) data for Compound 2 as described in Example 2D.
  • FIG. 34 shows an A J H NMR spectrum of Compound 3 as described in Example 2D.
  • FIG. 35 shows Liquid chromatography-mass spectrometry (LCMS) data for Compound 3 as described in Example 2D.
  • FIG. 36 shows an A J H NMR spectrum of Compound 4 (compound represented by Formula (I)) as described in Example 2D.
  • FIG. 37 shows Liquid chromatography-mass spectrometry (LCMS) data for Compound 4 (compound represented by Formula (I)) as described in Example 2D.
  • Formula (I), as free acid or base, or pharmaceutically acceptable salts or solvates thereof pharmaceutical compositions comprising one or more solid-state forms of the compound represented by Formula (I), as free acid or base, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. Also provided herein, in some embodiments, are methods of preparing solid-state forms of the compound represented by Formula (I), as free acid or base, or a pharmaceutically acceptable salt or solvate thereof.
  • the solid-state forms of the compound represented by Formula (I) and compositions disclosed herein are effective at inhibiting signal transducer and activator of transcription 3 (STAT3) and thus are useful in methods of treating, preventing, or reducing the risk or severity of certain diseases or disorders such as cancer, fibrosis, and inflammatory diseases or disorders.
  • STAT3 signal transducer and activator of transcription 3
  • provided herein are pharmaceutical compositions comprising one or more solid-state forms of the compound represented by Formula (I), as free acid or base, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • provided herein are methods that involve the use of (e.g., comprise the administration of) a solid-state form of the compound represented by Formula (I), a STAT3 inhibitor, optionally wherein the solid-state form of the compound represented by Formula (I), as free acid or base, or a pharmaceutically acceptable salt or solvate thereof, is formulated in a manner described herein (e.g., is present in a composition as described herein).
  • provided herein are methods of treating, preventing, or reducing the risk or severity of cancer.
  • provided herein are methods of treating, preventing, or reducing the risk or severity of fibrosis.
  • provided herein are methods of treating, preventing, or reducing the risk or severity of an inflammatory disease or disorder.
  • a” or “an” may mean one or more.
  • the words “a” or “an” when used in conjunction with the word “comprising”, the words “a” or “an” may mean one or more than one.
  • “another” may mean at least a second or more.
  • the terms “having”, “including”, “containing” and “comprising” are interchangeable and one of skill in the art is cognizant that these terms are open ended terms.
  • Some embodiments of the disclosure may consist of or consist essentially of one or more elements, method steps, and/or methods of the disclosure. It is contemplated that any method, compound, or composition described herein can be implemented with respect to any other method, compound, or composition described herein.
  • About” and “approximately” shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values.
  • “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et cd.. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19.
  • Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, di gluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec
  • Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (Ci-4alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • solvate refers to a physical association of a compound with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding and non-hydrogen binding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • the solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules. For example, a solvate with a nonstoichiometric amount of solvent molecules may result from partial loss of solvent from the solvate.
  • Solvate encompasses both solution-phase and isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, isopropanolates, and the like.
  • pharmaceutically acceptable excipient refers to any substance in a pharmaceutical formulation other than the active pharmaceutical ingredient(s).
  • exemplary pharmaceutical excipients include those that aid the manufacturing process; protect, support or enhance stability; increase bioavailability; or increase patient acceptability. They may also assist in product identification or enhance the overall safety or function of the product during storage or use.
  • excipient and carrier are used interchangeably herein.
  • a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs.
  • the subject is a human.
  • the subject is a non- human animal.
  • the terms “human,” “patient,” “subject,” and “individual” are used interchangeably herein. None of these terms require the active supervision of medical personnel.
  • the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or reverses or slows the progression of the disease, disorder or condition (also “therapeutic treatment”).
  • the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response.
  • the effective amount of a compound of the disclosure may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject.
  • a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit (e.g., treating, preventing, and/or ameliorating cancer in a subject, or inhibiting protein-protein interactions mediated by an SH2 domain in a subject, at a reasonable benefit/risk ratio applicable to any medical treatment) in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition.
  • the term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder or condition.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • a “prophylactic treatment” contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition.
  • STAT3 inhibitor or a compound that “inhibits STAT3” refers to a compound that interferes with the activity of STAT3 to perform one or more activities, including the ability of STAT3 to bind to a molecule such as pY-peptide ligand and/or the ability to be phosphorylated.
  • the terms “isolated”, “isolating”, and “isolation”, and the like in reference to solid-state forms of the compound represented by Formula (I) correspond to a solid-state form of the compound represented by Formula (I) that is physically separated from a reaction mixture or a slurry comprising the solid-state form of the compound represented by Formula (I).
  • Ambient conditions of temperature as used herein refer to temperatures of between about 15 to about 30°C, or about 20 to about 30°C, for example, between about 20 to about 25°C.
  • Solid-state forms of the present disclosure include crystalline and amorphous forms of the compounds, including, for example, solvates, hydrates, co-crystals, unsolvated forms (including anhydrates), conformational forms, tautomeric forms, or disordered crystalline forms thereof, as well as mixtures thereof.
  • crystalline when used to describe a form, solid, or substance means that the form, solid, or substance is substantially crystalline as determined, for example, by X-ray diffraction. The crystalline form, solid, or substance has a highly regular physical arrangement of molecules.
  • a crystalline form of a compound is substantially free of amorphous forms or other crystalline forms of the compound, or a salt or a solvate thereof.
  • Crystalline forms of a compound are obtained by a number of methods, such as, without limitation, temperature cycling, melt recrystallization, melt cooling, solvent recrystallization, anti-solvent addition, recrystallization in confined spaces, such as, e.g., in nanopores or capillaries, recrystallization on surfaces or templates, such as, e.g., on polymers, recrystallization in the presence of additives, such as, e.g., cocrystal counter-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, grinding, solvent-drop grinding, microwave-induced precipitation, sonication-induced precipitation, laser-induced precipitation, or precipitation from a supercritical fluid, or a combination thereof.
  • additives such as, e.g., cocrystal counter-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, grinding, solvent-drop grinding, microwave
  • amorphous when used to describe a form, solid, or substance means that the form, solid, or substance in question is not substantially crystalline as determined, for example, by X-ray diffraction or Differential Scanning Calorimetry (DSC).
  • DSC Differential Scanning Calorimetry
  • an amorphous form of a compound is substantially free of crystalline forms of the compound, or a salt or a solvate thereof.
  • Amorphous forms of a compound are obtained by several methods, as known in the art. Such methods include, but are not limited to, heating, melt cooling, rapid melt cooling, solvent evaporation, rapid solvent evaporation, desolvation, sublimation, grinding, cryo-grinding, spray drying, and freeze drying.
  • a solid-state form of a compound described herein that is "substantially free" of a substance means that the solid-state form comprises less than about 20 percent by weight, less than about 10 percent by weight, less than about 5 percent by weight, less than about 4 percent by weight, less than about 3 percent by weight, less than about 2 percent by weight, less than about 1 percent by weight, less than about 0.5% by weight, or less than about 0.1 percent by weight of the substance (e.g., other form(s) of the compound, or a salt or a solvate thereof).
  • the term "substantially pure" when used to describe a solid-state form of a compound described herein means a solid-state form of the compound that comprises a particular solid-state form the compound and is substantially free of other solid form(s) of the compound, or a salt or a solvate thereof, or other compound(s).
  • a representative substantially pure solid-state form comprises greater than about 80% by weight of one solid-state form of the compound and less than about 20% by weight of other solid forms of the compound or other compounds; greater than about 90% by weight of one solid-state form of the compound and less than about 10% by weight of other solid forms of the compound or other compounds; greater than about 95% by weight of one solid-state form of the compound and less than about 5% by weight of other solid forms of the compound or other compounds; greater than about 97% by weight of one solid-state form of the compound and less than about 3% by weight of other solid forms of the compound or other compounds; or greater than about 99% by weight of one solid-state form of the compound and less than about 1 % by weight of other solid forms of the compound or other compounds.
  • Techniques for characterizing crystalline forms and amorphous forms include, but are not limited to, thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), single crystal X-ray diffractometry, vibrational spectroscopy, e.g., infrared (IR) and Raman spectroscopy, solid-state nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies, and dissolution studies.
  • TGA thermal gravimetric analysis
  • DSC differential scanning calorimetry
  • XRPD X-ray powder diffractometry
  • IR infrared
  • Raman spectroscopy solid-state nuclear magnetic resonance (NMR) spectroscopy
  • optical microscopy hot stage optical microscopy
  • SEM scanning electron microscopy
  • PSA particle size analysis
  • a diffraction angle (29, “2 theta”) in X-ray powder diffractometry has a variation, for example, in the range of ⁇ 0.5°, ⁇ 0.3°, or ⁇ 0.2°. Accordingly, the diffraction angle values should be understood as including values in the range of about ⁇ 0.5°, ⁇ 0.3°, or ⁇ 0.2°.
  • a solid-state form of a compound described herein, in some embodiments, is described by reference to patterns, spectra, or other graphical data as “substantially” shown or “depicted” in a figure, or by one or more data points. It will be appreciated that patterns, spectra, and other graphical data can be shifted in their positions, relative intensities, or other values due to a number of factors known to those of skill in the art. For example, in the crystallographic and powder X-ray diffraction arts, shifts in peak positions or the relative intensities of one or more peaks of a pattern can occur because of, without limitation, the equipment used, the sample preparation protocol, preferred packing and orientations, the radiation source, operator error, method and length of data collection, or the like.
  • peak when used in connection with the spectra or data presented in graphical form (e.g., XRPD, IR, Raman, and NMR spectra), refers to a peak or other special feature that one skilled in the art would recognize as not attributable to background noise.
  • polymorphic forms for a given compound are not predictable. Different polymorphic forms of the same compound can exhibit different physical, chemical and/or spectroscopic properties. For example, different forms of the compound can have differences in bioavailability, solubility, stability, and/or compressibility that impact the processability of the compound.
  • a particular form of a compound can have improved properties over other forms of the compound such as, but not limited to, ease of handling, ease of processing, ease of purification, improved dissolution profiles, dissolution rates, storage stability, chemical stability, physical stability, bioavailability, storage conditions, shelf-life, purity, process reproducibility, and/or formulation properties.
  • Form 1 [00050] Provided herein, in some embodiments, is crystalline Form 1 of a compound represented by Formula (I).
  • the crystalline form has an XRPD pattern substantially as shown in FIG. 2A. In some embodiments, the crystalline form has an XRPD pattern substantially as shown in Table 1 A.
  • the crystalline form has an XRPD pattern comprising peaks, in terms of 2-theta, at about 18.8°. In some embodiments, the crystalline form has an XRPD pattern comprising peaks, in terms of 2-theta, at about 4.2°. In some embodiments, the crystalline form has an XRPD pattern comprising peaks, in terms of 2-theta, at about 16.7°. In some embodiments, the crystalline form has an XRPD pattern comprising peaks, in terms of 2-theta, at about 16.9°.
  • the crystalline form has an XRPD pattern comprising peaks, in terms of 2-theta, at 18.8° ⁇ 0.2°. In some embodiments, the crystalline form has an XRPD pattern comprising peaks, in terms of 2-theta, at 4.2° ⁇ 0.2°. In some embodiments, the crystalline form has an XRPD pattern comprising peaks, in terms of 2-theta, at 16.7° ⁇ 0.2°. In some embodiments, the crystalline form has an XRPD pattern comprising peaks, in terms of 2-theta, at 16.9° ⁇ 0.2°.
  • the crystalline form has an XRPD pattern comprising peaks, in terms of 2-theta, at about 18.8°.
  • the XRPD pattern further comprises one or more peaks at about 4.2°, 16.7°, or 16.9°.
  • the XRPD pattern further comprises one or more peaks at about 8.4°, 11.6°, 12.0°, 14.6°, or 19.9°.
  • the XRPD pattern further comprises one or more peaks at about 7.3°, 8.3°, 11.1°, 13.0°, 15.5°, 19.4°, 20.4°, or 21.5°.
  • the crystalline form has an XRPD pattern comprising peaks, in terms of 2-theta, at 18.8° ⁇ 0.2°.
  • the XRPD pattern further comprises one or more peaks at 4.2° ⁇ 0.2°, 16.7° ⁇ 0.2°, or 16.9° ⁇ 0.2°.
  • the XRPD pattern further comprises one or more peaks at 8.4° ⁇ 0.2°, 11.6° ⁇ 0.2°, 12.0° ⁇ 0.2°, 14.6° ⁇ 0.2°, or 19.9° ⁇ 0.2°.
  • the XRPD pattern further comprises one or more peaks at 7.3° ⁇ 0.2°, 8.3° ⁇ 0.2°, l l.l° ⁇ 0.2°, 13.0° ⁇ 0.2°, 15.5° ⁇ 0.2°, 19.4° ⁇ 0.2°, 20.4° ⁇ 0.2°, or 21.5° ⁇ 0.2°.
  • the crystalline form has an XRPD pattern comprising peaks, in terms of 2-theta, at about 4.2°.
  • the XRPD pattern further comprises one or more peaks at about 18.8°, 16.7°, or 16.9°.
  • the XRPD pattern further comprises one or more peaks at about 8.4°, 11.6°, 12.0°, 14.6°, or 19.9°.
  • the XRPD pattern further comprises one or more peaks at about 7.3°, 8.3°, 11.1°, 13.0°, 15.5°, 19.4°, 20.4°, or 21.5°.
  • the crystalline form has an XRPD pattern comprising peaks, in terms of 2-theta, at 4.2° ⁇ 0.2°.
  • the XRPD pattern further comprises one or more peaks at 18.8° ⁇ 0.2°, 16.7° ⁇ 0.2°, or 16.9° ⁇ 0.2°.
  • the XRPD pattern further comprises one or more peaks at 8.4° ⁇ 0.2°, 11.6° ⁇ 0.2°, 12.0° ⁇ 0.2°, 14.6° ⁇ 0.2°, or 19.9° ⁇ 0.2°.
  • the XRPD pattern further comprises one or more peaks at 7.3° ⁇ 0.2°, 8.3° ⁇ 0.2°, l l.l° ⁇ 0.2°, 13.0° ⁇ 0.2°, 15.5° ⁇ 0.2°, 19.4° ⁇ 0.2°, 20.4° ⁇ 0.2°, or 21.5° ⁇ 0.2°.
  • the crystalline form has an XRPD pattern comprising peaks, in terms of 2-theta, at about 4.2°, 18.8°, 16.7°, and 16.9°.
  • the XRPD pattern further comprises one or more peaks at about 8.4°, 11.6°, 12.0°, 14.6°, or 19.9°.
  • the XRPD pattern further comprises one or more peaks at about 7.3°, 8.3°, 11.1°, 13.0°, 15.5°, 19.4°, 20.4°, or 21.5°.
  • the crystalline form has an XRPD pattern comprising peaks, in terms of 2-theta, at 4.2° ⁇ 0.2°, 18.8° ⁇ 0.2°, 16.7° ⁇ 0.2°, and 16.9° ⁇ 0.2°.
  • the XRPD pattern further comprises one or more peaks at 8.4° ⁇ 0.2°, 11.6° ⁇ 0.2°, 12.0° ⁇ 0.2°, 14.6° ⁇ 0.2°, or 19.9° ⁇ 0.2°.
  • the XRPD pattern further comprises one or more peaks at 7.3° ⁇ 0.2°, 8.3° ⁇ 0.2°, l l. l° ⁇ 0.2°, 13.0° ⁇ 0.2°, 15.5° ⁇ 0.2°, 19.4° ⁇ 0.2°, 20.4° ⁇ 0.2°, or 21.5° ⁇ 0.2°.
  • the crystalline form has an XRPD pattern comprising peaks, in terms of 2-theta, at about 4.2°, 18.8°, 16.7°, and 16.9°. In some embodiments, the XRPD pattern further comprises peaks at about 8.4°, 11.6°, 12.0°, 14.6°, and 19.9°. In some embodiments, the XRPD pattern further comprises peaks at about 7.3°, 8.3°, 11.1°, 13.0°, 15.5°, 19.4°, 20.4°, and 21.5°.
  • the crystalline form has an XRPD pattern comprising peaks, in terms of 2-theta, at 4.2° ⁇ 0.2°, 18.8° ⁇ 0.2°, 16.7° ⁇ 0.2°, and 16.9° ⁇ 0.2°.
  • the XRPD pattern further comprises peaks at 8.4° ⁇ 0.2°, 11.6° ⁇ 0.2°, 12.0° ⁇ 0.2°, 14.6° ⁇ 0.2°, and 19.9° ⁇ 0.2°.
  • the XRPD pattern further comprises peaks at 7.3° ⁇ 0.2°, 8.3° ⁇ 0.2°, l l.l° ⁇ 0.2°, 13.0° ⁇ 0.2°, 15.5° ⁇ 0.2°, 19.4° ⁇ 0.2°, 20.4° ⁇ 0.2°, and 21.5° ⁇ 0.2°.
  • the crystalline form has a DSC thermogram comprising an endothermic event with onset between about 194 °C to 200 °C. In some embodiments, the crystalline form has a DSC thermogram comprising an endothermic peak at about 205 °C. In some embodiments, the crystalline form has a DSC thermogram substantially as shown in FIG. 5. In some embodiments, the crystalline form has a DSC thermogram comprising an endothermic event with onset between about 190 °C to 196 °C. In some embodiments, the crystalline form has a DSC thermogram comprising an endothermic peak at about 204 °C. In some embodiments, the crystalline form has a DSC thermogram substantially as shown in FIG. 6. In some embodiments, the crystalline form has a DVS kinetic plot substantially as shown in FIG. 7.
  • the crystalline form is substantially pure. In some embodiments, the crystalline form has a chemical purity of greater than 80% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 90% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 95% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 99% by weight. In some embodiments, the crystalline form has no more than about 10 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 5 mol% of other solid-state forms of the compound represented by Formula (I).
  • the crystalline form has no more than about 3 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 1 mol% of other solid- state forms of the compound represented by Formula (I).
  • the crystalline Form 1 is an anhydrate.
  • the process for preparing crystalline Form 1 of a compound represented by Formula (I) comprises:
  • the compound represented by Formula (I) in step (i) comprises solid-state forms of the compound represented by Formula (I) other than Form 1 of the compound represented by Formula (I).
  • the compound represented by Formula (I) in step (i) comprises less than about 30% w/w of Form 1 of the compound represented by Formula (I). In some embodiments, the compound represented by Formula (I) in step (i) comprises less than about 25% w/w of Form 1 of the compound represented by Formula (I). In some embodiments, the compound represented by Formula (I) in step (i) comprises less than about 20% w/w of Form 1 of the compound represented by Formula (I). In some embodiments, the compound represented by Formula (I) in step (i) comprises less than about 15% w/w of Form 1 of the compound represented by Formula (I).
  • the compound represented by Formula (I) in step (i) comprises less than about 10% w/w of Form 1 of the compound represented by Formula (I). In some embodiments, the compound represented by Formula (I) in step (i) comprises less than about 5% w/w of Form 1 of the compound represented by Formula (I).
  • the first solvent is a mixture of ethanol and water or acetic acid and water. In some embodiments, the first solvent is a mixture of ethanol and water. In some embodiments, the first solvent is a mixture of acetic acid and water.
  • the process further comprises cooling the charged mixture to about 0 °C to about 10 °C. In some embodiments, after step (ii), the process further comprises cooling the charged mixture to about 0 °C. In some embodiments, after step (ii), the process further comprises cooling the charged mixture to about 5 °C. In some embodiments, after step (ii), the process further comprises cooling the charged mixture to about 10 °C.
  • the second solvent is water.
  • the process further comprises washing the isolated solid precipitate with a first solvent, a second solvent, or a mixture thereof, and drying the washed solid precipitate.
  • step (v) slurrying the solid precipitate in the third solvent occurs at about 80 °C to about 100 °C. In some embodiments, the slurrying is at about 85 °C to about 95 °C. In some embodiments, the slurrying is at about 80 °C. In some embodiments, the slurrying is at about 85 °C. In some embodiments, the slurrying is at about 90 °C. In some embodiments, the slurrying is at about 95 °C. In some embodiments, the slurrying is at about 100 °C. [00074] In some embodiments, the third solvent is n-heptane.
  • the process further comprises isolating the slurried solid precipitate from the third solvent, and optionally drying the solid precipitate.
  • the process further comprises:
  • the acid is hydrochloric acid.
  • the contacting comprises agitating the compound represented by Formula (C) in the aqueous solution comprising the acid at about 10 °C to about 50 °C. In some embodiments, in step (i), the contacting comprises agitating the compound represented by Formula (C) in the aqueous solution comprising the acid at about 10 °C to about 30 °C. In some embodiments, in step (i), the contacting comprises agitating the compound represented by Formula (C) in the aqueous solution comprising the acid at about 30 °C to about 50 °C.
  • the contacting comprises agitating the compound represented by Formula (C) in the aqueous solution comprising the acid at about 10 °C. In some embodiments, in step (i), the contacting comprises agitating the compound represented by Formula (C) in the aqueous solution comprising the acid at about 15 °C. In some embodiments, in step (i), the contacting comprises agitating the compound represented by Formula (C) in the aqueous solution comprising the acid at about 20 °C. In some embodiments, in step (i), the contacting comprises agitating the compound represented by Formula (C) in the aqueous solution comprising the acid at about 25 °C.
  • the contacting comprises agitating the compound represented by Formula (C) in the aqueous solution comprising the acid at about 30 °C. In some embodiments, in step (i), the contacting comprises agitating the compound represented by Formula (C) in the aqueous solution comprising the acid at about 35 °C. In some embodiments, in step (i), the contacting comprises agitating the compound represented by Formula (C) in the aqueous solution comprising the acid at about 40 °C. In some embodiments, in step (i), the contacting comprises agitating the compound represented by Formula (C) in the aqueous solution comprising the acid at about 45 °C. In some embodiments, in step (i), the contacting comprises agitating the compound represented by Formula (C) in the aqueous solution comprising the acid at about 50 °C.
  • step (ii) the process further comprises washing the first solid precipitate with water.
  • the first solvent is 2-methyltetrahydrofuran.
  • the acid in step (iv) is hydrochloric acid.
  • the second mixture comprises an organic layer and an aqueous layer
  • the process further comprises separating the organic layer from the aqueous layer, and optionally adding aqueous hydrochloric acid to the separated organic layer, separating the resulting organic layer from the aqueous layer, and reducing the volume of said organic layer.
  • the second solvent is ethanol
  • the third solvent is n-heptane.
  • the contacting comprises agitating the third mixture and third solvent at about 20 °C to about 50 °C. In some embodiments, in step (vi), the contacting comprises agitating the third mixture and third solvent at about 20 °C to about 30 °C. In some embodiments, in step (vi), the contacting comprises agitating the third mixture and third solvent at about 40 °C to about 50 °C. In some embodiments, in step (vi), the contacting comprises agitating the third mixture and third solvent at about 20 °C. In some embodiments, in step (vi), the contacting comprises agitating the third mixture and third solvent at about 25 °C.
  • the contacting comprises agitating the third mixture and third solvent at about 30 °C. In some embodiments, in step (vi), the contacting comprises agitating the third mixture and third solvent at about 35 °C. In some embodiments, in step (vi), the contacting comprises agitating the third mixture and third solvent at about 40 °C. In some embodiments, in step (vi), the contacting comprises agitating the third mixture and third solvent at about 45 °C. In some embodiments, in step (vi), the contacting comprises agitating the third mixture and third solvent at about 50 °C.
  • the process further comprises washing the second solid precipitate with a second solvent, third solvent, or a mixture thereof, and optionally further comprising washing the second solid precipitate with a third solvent.
  • the process further comprises drying the washed second solid precipitate.
  • the process further comprises slurrying the dried second solid precipitate in a solvent, optionally at about 80 °C to about 100 °C. In some embodiments, the process further comprises slurrying the dried second solid precipitate in a solvent, optionally at about 85 °C to about 95 °C. In some embodiments, the process further comprises slurrying the dried second solid precipitate in a solvent at about 80 °C. In some embodiments, the process further comprises slurrying the dried second solid precipitate in a solvent at about 85 °C. In some embodiments, the process further comprises slurrying the dried second solid precipitate in a solvent at about 90 °C. In some embodiments, the process further comprises slurrying the dried second solid precipitate in a solvent at about 95 °C. In some embodiments, the process further comprises slurrying the dried second solid precipitate in a solvent at about 100 °C.
  • the solvent is n-heptane.
  • the process further comprises isolating the slurried solid precipitate from the solvent.
  • the process further comprises:
  • the base is lithium hydroxide.
  • the contacting in step (i) comprises agitating the compound represented by Formula (B) in the aqueous solution comprising the base at about 65 °C to about 85 °C. In some embodiments, the contacting in step (i) comprises agitating the compound represented by Formula (B) in the aqueous solution comprising the base at about 70 °C to about 80 °C. In some embodiments, the contacting in step (i) comprises agitating the compound represented by Formula (B) in the aqueous solution comprising the base at about 65 °C. In some embodiments, the contacting in step (i) comprises agitating the compound represented by Formula (B) in the aqueous solution comprising the base at about 70 °C.
  • the contacting in step (i) comprises agitating the compound represented by Formula (B) in the aqueous solution comprising the base at about 75 °C. In some embodiments, the contacting in step (i) comprises agitating the compound represented by Formula (B) in the aqueous solution comprising the base at about 80 °C. In some embodiments, the contacting in step (i) comprises agitating the compound represented by Formula (B) in the aqueous solution comprising the base at about 85 °C.
  • the acid is hydrochloric acid.
  • the solvent is 2-methyltetrahydrofuran.
  • the second mixture comprises an organic layer and an aqueous layer
  • the process further comprises separating the organic layer from the aqueous layer, and reducing the volume of said organic layer.
  • the contacting in step (iii) comprises agitating the second mixture and pyridine at about 60 °C to about 80 °C. In some embodiments, the contacting in step (iii) comprises agitating the second mixture and pyridine at about 65 °C to about 75 °C. In some embodiments, the contacting in step (iii) comprises agitating the second mixture and pyridine at about 60 °C. In some embodiments, the contacting in step (iii) comprises agitating the second mixture and pyridine at about 65 °C. In some embodiments, the contacting in step (iii) comprises agitating the second mixture and pyridine at about 70 °C.
  • the contacting in step (iii) comprises agitating the second mixture and pyridine at about 75 °C. In some embodiments, the contacting in step (iii) comprises agitating the second mixture and pyridine at about 80 °C.
  • the process further comprises:
  • the contacting in step (i) comprises agitating the compound represented by Formula (A) in the solvent with phosphorous oxychloride at about -5 °C to about 35 °C. In some embodiments, the contacting in step (i) comprises agitating the compound represented by Formula (A) in the solvent with phosphorous oxychloride at about 0 °C to about 25 °C. In some embodiments, the contacting in step (i) comprises agitating the compound represented by Formula (A) in the solvent with phosphorous oxychloride at about 0 °C.
  • the contacting in step (i) comprises agitating the compound represented by Formula (A) in the solvent with phosphorous oxychloride at about 5 °C. In some embodiments, the contacting in step (i) comprises agitating the compound represented by Formula (A) in the solvent with phosphorous oxychloride at about 10 °C. In some embodiments, the contacting in step (i) comprises agitating the compound represented by Formula (A) in the solvent with phosphorous oxychloride at about 15 °C. In some embodiments, the contacting in step (i) comprises agitating the compound represented by Formula (A) in the solvent with phosphorous oxychloride at about 20 °C. In some embodiments, the contacting in step (i) comprises agitating the compound represented by Formula (A) in the solvent with phosphorous oxychloride at about 25 °C.
  • the solvent is pyridine.
  • the contacting step (ii) comprises agitating the first mixture with water and an acid at about 15 °C to about 75 °C. In some embodiments, the contacting step (ii) comprises agitating the first mixture with water and an acid at about 25 °C to about 65 °C. In some embodiments, the contacting step (ii) comprises agitating the first mixture with water and an acid at about 20 °C. In some embodiments, the contacting step (ii) comprises agitating the first mixture with water and an acid at about 25 °C. In some embodiments, the contacting step (ii) comprises agitating the first mixture with water and an acid at about 35 °C.
  • the contacting step (ii) comprises agitating the first mixture with water and an acid at about 40 °C. In some embodiments, the contacting step (ii) comprises agitating the first mixture with water and an acid at about 45 °C. In some embodiments, the contacting step (ii) comprises agitating the first mixture with water and an acid at about 50 °C. In some embodiments, the contacting step (ii) comprises agitating the first mixture with water and an acid at about 55 °C. In some embodiments, the contacting step (ii) comprises agitating the first mixture with water and an acid at about 60 °C. In some embodiments, the contacting step (ii) comprises agitating the first mixture with water and an acid at about 65 °C. In some embodiments, the contacting step (ii) comprises agitating the first mixture with water and an acid at about 70 °C.
  • the acid is hydrochloric acid.
  • the process for preparing crystalline Form 1 of a compound represented by Formula (I) comprises:
  • step (ii) isolating the solid precipitate, thereby preparing the crystalline Form 1 of the compound represented by Formula (I).
  • the slurrying occurs at about 80 °C to about 100 °C. In some embodiments, the slurrying is at about 85 °C to about 95 °C. In some embodiments, the slurrying is at about 80 °C. In some embodiments, the slurrying is at about 85 °C. In some embodiments, the slurrying is at about 90 °C. In some embodiments, the slurrying is at about 95 °C. In some embodiments, the slurrying is at about 100 °C. [000105] In some embodiments, the solvent is n-heptane.
  • step (ii) after step (ii), the process further comprises drying the solid precipitate.
  • the compound represented by Formula (I) in step (i) comprises solid-state forms of the compound represented by Formula (I) other than Form 1 of the compound represented by Formula (I).
  • the compound represented by Formula (I) in step (i) comprises less than about 30% w/w of Form 1 of the compound represented by Formula (I). In some embodiments, the compound represented by Formula (I) in step (i) comprises less than about 25% w/w of Form 1 of the compound represented by Formula (I). In some embodiments, the compound represented by Formula (I) in step (i) comprises less than about 20% w/w of Form 1 of the compound represented by Formula (I). In some embodiments, the compound represented by Formula (I) in step (i) comprises less than about 15% w/w of Form 1 of the compound represented by Formula (I).
  • the compound represented by Formula (I) in step (i) comprises less than about 10% w/w of Form 1 of the compound represented by Formula (I). In some embodiments, the compound represented by Formula (I) in step (i) comprises less than about 5% w/w of Form 1 of the compound represented by Formula (I).
  • the process further comprises:
  • the acid is hydrochloric acid.
  • the contacting comprises agitating the compound represented by Formula (C) in the aqueous solution comprising the acid at about 5 °C to about 55 °C. In some embodiments, in step (i), the contacting comprises agitating the compound represented by Formula (C) in the aqueous solution comprising the acid at about 10 °C to about 50 °C. In some embodiments, in step (i), the contacting comprises agitating the compound represented by Formula (C) in the aqueous solution comprising the acid at about 5 °C to about 25 °C.
  • the contacting comprises agitating the compound represented by Formula (C) in the aqueous solution comprising the acid at about 35 °C to about 55 °C. In some embodiments, in step (i), the contacting comprises agitating the compound represented by Formula (C) in the aqueous solution comprising the acid at about 15 °C to about 35 °C. In some embodiments, in step (i), the contacting comprises agitating the compound represented by Formula (C) in the aqueous solution comprising the acid at about 10 °C. In some embodiments, in step (i), the contacting comprises agitating the compound represented by Formula (C) in the aqueous solution comprising the acid at about 15 °C.
  • the contacting comprises agitating the compound represented by Formula (C) in the aqueous solution comprising the acid at about 20 °C. In some embodiments, in step (i), the contacting comprises agitating the compound represented by Formula (C) in the aqueous solution comprising the acid at about 25 °C. In some embodiments, in step (i), the contacting comprises agitating the compound represented by Formula (C) in the aqueous solution comprising the acid at about 30 °C. In some embodiments, in step (i), the contacting comprises agitating the compound represented by Formula (C) in the aqueous solution comprising the acid at about 35 °C.
  • the contacting comprises agitating the compound represented by Formula (C) in the aqueous solution comprising the acid at about 40 °C. In some embodiments, in step (i), the contacting comprises agitating the compound represented by Formula (C) in the aqueous solution comprising the acid at about 45 °C. In some embodiments, in step (i), the contacting comprises agitating the compound represented by Formula (C) in the aqueous solution comprising the acid at about 50 °C.
  • the contacting comprises agitating the compound represented by Formula (C) in the aqueous solution comprising the acid at about 5 °C to about 35 °C, then at about 35 °C to about 55 °C; then about 15 °C to about 35 °C. In some embodiments, in step (i), the contacting comprises agitating the compound represented by Formula (C) in the aqueous solution comprising the acid at about 10 °C to about 30 °C, then at about 40 °C to about 50 °C; then about 20 °C to about 30 °C.
  • step (ii) the process further comprises washing the first solid precipitate with water.
  • the first solvent is 2-methyltetrahydrofuran.
  • step (iv) wherein the acid in step (iv) is hydrochloric acid.
  • step (iv) wherein the second mixture comprises an organic layer and an aqueous layer
  • the process further comprises separating the organic layer from the aqueous layer, and optionally adding aqueous hydrochloric acid to the separated organic layer, separating the resulting organic layer from the aqueous layer, and reducing the volume of said organic layer.
  • the second solvent is ethanol
  • the third solvent is water.
  • step (viii) wherein the contacting comprises agitating the filtrate and the third solvent at about 15 °C to about 70 °C. In some embodiments, in step (viii), wherein the contacting comprises agitating the filtrate and the third solvent at about 25 °C to about 60 °C. In some embodiments, in step (viii), wherein the contacting comprises agitating the filtrate and the third solvent at about 15 °C to about 35 °C. In some embodiments, in step (viii), wherein the contacting comprises agitating the filtrate and the third solvent at about 50 °C to about 70 °C.
  • step (viii) wherein the contacting comprises agitating the filtrate and the third solvent at about 15 °C to about 35 °C then at about 50 °C to about 70 °C. In some embodiments, in step (viii), wherein the contacting comprises agitating the filtrate and the third solvent at about 20 °C to about 30 °C then at about 55 °C to about 65 °C. In some embodiments, in step (viii), wherein the contacting comprises agitating the filtrate and the third solvent at about 20 °C. In some embodiments, in step (viii), wherein the contacting comprises agitating the filtrate and the third solvent at about 25 °C.
  • step (viii) wherein the contacting comprises agitating the filtrate and the third solvent at about 30 °C. In some embodiments, in step (viii), wherein the contacting comprises agitating the filtrate and the third solvent at about 35 °C. In some embodiments, in step (viii), wherein the contacting comprises agitating the filtrate and the third solvent at about 40 °C. In some embodiments, in step (viii), wherein the contacting comprises agitating the filtrate and the third solvent at about 45 °C. In some embodiments, in step (viii), wherein the contacting comprises agitating the filtrate and the third solvent at about 50 °C.
  • step (viii) wherein the contacting comprises agitating the filtrate and the third solvent at about 55 °C. In some embodiments, in step (viii), wherein the contacting comprises agitating the filtrate and the third solvent at about 60 °C. In some embodiments, in step (viii), wherein the contacting comprises agitating the filtrate and the third solvent at about 65 °C.
  • the process further comprises adding additional volume of third solvent.
  • the third solvent is water.
  • the fourth solvent is water.
  • step (xi) the process further comprises drying the solid precipitate.
  • the solid precipitate is crystalline Form 21 of the compound represented by Formula (I).
  • the process further comprises:
  • the base is lithium hydroxide.
  • the contacting in step (i) comprises agitating the compound represented by Formula (B) in the aqueous solution comprising the base at about 65 °C to about 85 °C. In some embodiments, the contacting in step (i) comprises agitating the compound represented by Formula (B) in the aqueous solution comprising the base at about 70 °C to about 80 °C. In some embodiments, the contacting in step (i) comprises agitating the compound represented by Formula (B) in the aqueous solution comprising the base at about 65 °C. In some embodiments, the contacting in step (i) comprises agitating the compound represented by Formula (B) in the aqueous solution comprising the base at about 70 °C.
  • the contacting in step (i) comprises agitating the compound represented by Formula (B) in the aqueous solution comprising the base at about 75 °C. In some embodiments, the contacting in step (i) comprises agitating the compound represented by Formula (B) in the aqueous solution comprising the base at about 80 °C. In some embodiments, the contacting in step (i) comprises agitating the compound represented by Formula (B) in the aqueous solution comprising the base at about 85 °C. [000127] In some embodiments, the acid is hydrochloric acid.
  • the solvent is 2-methyltetrahydrofuran.
  • the second mixture comprises an organic layer and an aqueous layer
  • the process further comprises separating the organic layer from the aqueous layer, and reducing the volume of said organic layer.
  • the contacting in step (iii) comprises agitating the second mixture and pyridine at about 60 °C to about 80 °C. In some embodiments, the contacting in step (iii) comprises agitating the second mixture and pyridine at about 65 °C to about 75 °C. In some embodiments, the contacting in step (iii) comprises agitating the second mixture and pyridine at about 60 °C. In some embodiments, the contacting in step (iii) comprises agitating the second mixture and pyridine at about 65 °C. In some embodiments, the contacting in step (iii) comprises agitating the second mixture and pyridine at about 70 °C.
  • the contacting in step (iii) comprises agitating the second mixture and pyridine at about 75 °C. In some embodiments, the contacting in step (iii) comprises agitating the second mixture and pyridine at about 80 °C.
  • the process further comprises:
  • the contacting in step (i) comprises agitating the compound represented by Formula (A) in the solvent with phosphorous oxychloride at about -5 °C to about 35 °C. In some embodiments, the contacting in step (i) comprises agitating the compound represented by Formula (A) in the solvent with phosphorous oxychloride at about 0 °C to about 25 °C. In some embodiments, the contacting in step (i) comprises agitating the compound represented by Formula (A) in the solvent with phosphorous oxychloride at about 0 °C.
  • the contacting in step (i) comprises agitating the compound represented by Formula (A) in the solvent with phosphorous oxychloride at about 5 °C. In some embodiments, the contacting in step (i) comprises agitating the compound represented by Formula (A) in the solvent with phosphorous oxychloride at about 10 °C. In some embodiments, the contacting in step (i) comprises agitating the compound represented by Formula (A) in the solvent with phosphorous oxychloride at about 15 °C. In some embodiments, the contacting in step (i) comprises agitating the compound represented by Formula (A) in the solvent with phosphorous oxychloride at about 20 °C. In some embodiments, the contacting in step (i) comprises agitating the compound represented by Formula (A) in the solvent with phosphorous oxychloride at about 25 °C.
  • the solvent is pyridine.
  • the contacting step (ii) comprises agitating the first mixture with water and an acid at about 15 °C to about 75 °C. In some embodiments, the contacting step (ii) comprises agitating the first mixture with water and an acid at about 25 °C to about 65 °C. In some embodiments, the contacting step (ii) comprises agitating the first mixture with water and an acid at about 20 °C. In some embodiments, the contacting step (ii) comprises agitating the first mixture with water and an acid at about 25 °C. In some embodiments, the contacting step (ii) comprises agitating the first mixture with water and an acid at about 35 °C.
  • the contacting step (ii) comprises agitating the first mixture with water and an acid at about 40 °C. In some embodiments, the contacting step (ii) comprises agitating the first mixture with water and an acid at about 45 °C. In some embodiments, the contacting step (ii) comprises agitating the first mixture with water and an acid at about 50 °C. In some embodiments, the contacting step (ii) comprises agitating the first mixture with water and an acid at about 55 °C. In some embodiments, the contacting step (ii) comprises agitating the first mixture with water and an acid at about 60 °C. In some embodiments, the contacting step (ii) comprises agitating the first mixture with water and an acid at about 65 °C. In some embodiments, the contacting step (ii) comprises agitating the first mixture with water and an acid at about 70 °C.
  • the acid is hydrochloric acid.
  • the crystalline form has an XRPD pattern substantially as shown in FIG. 18 A. In some embodiments, the crystalline form has a DSC thermogram substantially as shown in FIG. 18B.
  • the crystalline form is substantially pure. In some embodiments, the crystalline form has a chemical purity of greater than 80% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 90% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 95% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 99% by weight. In some embodiments, the crystalline form has no more than about 10 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 5 mol% of other solid-state forms of the compound represented by Formula (I).
  • the crystalline form has no more than about 3 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 1 mol% of other solid- state forms of the compound represented by Formula (I).
  • the crystalline Form 2 is a solvate. In some embodiments, the crystalline Form 2 is a THF solvate. Form 3
  • the crystalline form has an XRPD pattern substantially as shown in FIG. 19A.
  • the crystalline form has a DSC thermogram substantially as shown in FIG. 19B.
  • the crystalline form is substantially pure. In some embodiments, the crystalline form has a chemical purity of greater than 80% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 90% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 95% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 99% by weight. In some embodiments, the crystalline form has no more than about 10 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 5 mol% of other solid-state forms of the compound represented by Formula (I).
  • the crystalline form has no more than about 3 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 1 mol% of other solid- state forms of the compound represented by Formula (I).
  • the crystalline form has an XRPD pattern substantially as shown in FIG. 20. In some embodiments, the crystalline form has an XRPD pattern substantially as shown in Table 1C.
  • the crystalline form has an XRPD pattern comprising peaks, in terms of 2-theta, at about 7.4°.
  • the XRPD pattern further comprises one or more peaks at about 3.7°, 11.5°, 12.0°, 16.7°, or 19.2°.
  • the XRPD pattern further comprises one or more peaks at about 8.3°, 18.6°, 19.5°, 20.1°, 20.7°, 21.8°, 24.4°, 25.2°, or 25.7°.
  • the XRPD pattern further comprises one or more peaks at about 10.5°, 12.3°, 12.7°, 14.9°, 15.9°, or 20.3°.
  • the crystalline form has an XRPD pattern comprising peaks, in terms of 2-theta, at 7.4° ⁇ 0.2°.
  • the XRPD pattern further comprises one or more peaks at 3.7° ⁇ 0.2°, 11.5° ⁇ 0.2°, 12.0° ⁇ 0.2°, 16.7°, or 19.2° ⁇ 0.2°.
  • the XRPD pattern further comprises one or more peaks at 8.3° ⁇ 0.2°, 18.6° ⁇ 0.2°, 19.5° ⁇ 0.2°, 20.1° ⁇ 0.2°, 20.7° ⁇ 0.2°, 21.8° ⁇ 0.2°, 24.4° ⁇ 0.2°, 25.2° ⁇ 0.2°, or 25.7° ⁇ 0.2°.
  • the XRPD pattern further comprises one or more peaks at about 10.5° ⁇ 0.2°, 12.3° ⁇ 0.2°, 12.7° ⁇ 0.2°, 14.9° ⁇ 0.2°, 15.9° ⁇ 0.2°, or 20.3° ⁇ 0.2°.
  • the crystalline form is substantially pure. In some embodiments, the crystalline form has a chemical purity of greater than 80% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 90% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 95% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 99% by weight.
  • the crystalline form has no more than about 10 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 5 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 3 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 1 mol% of other solid- state forms of the compound represented by Formula (I).
  • the crystalline form has an XRPD pattern substantially as shown in FIG. 21 A. In some embodiments, the crystalline form has a DSC thermogram substantially as shown in FIG. 21B.
  • the crystalline form is substantially pure. In some embodiments, the crystalline form has a chemical purity of greater than 80% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 90% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 95% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 99% by weight. In some embodiments, the crystalline form has no more than about 10 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 5 mol% of other solid-state forms of the compound represented by Formula (I).
  • the crystalline form has no more than about 3 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 1 mol% of other solid- state forms of the compound represented by Formula (I).
  • the crystalline form has an XRPD pattern substantially as shown in FIG. 22A.
  • the crystalline form has a DSC thermogram substantially as shown in FIG. 22B.
  • the crystalline form is substantially pure. In some embodiments, the crystalline form has a chemical purity of greater than 80% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 90% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 95% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 99% by weight. In some embodiments, the crystalline form has no more than about 10 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 5 mol% of other solid-state forms of the compound represented by Formula (I).
  • the crystalline form has no more than about 3 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 1 mol% of other solid- state forms of the compound represented by Formula (I).
  • the crystalline form has an XRPD pattern substantially as shown in FIG. 23.
  • the crystalline form is substantially pure. In some embodiments, the crystalline form has a chemical purity of greater than 80% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 90% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 95% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 99% by weight. In some embodiments, the crystalline form has no more than about 10 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 5 mol% of other solid-state forms of the compound represented by Formula (I).
  • the crystalline form has no more than about 3 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 1 mol% of other solid- state forms of the compound represented by Formula (I).
  • Form 8 [000158] Provided herein, in some embodiments, is crystalline Form 8 of a compound represented by Formula (I).
  • the crystalline form has an XRPD pattern substantially as shown in FIG. 24A. In some embodiments, the crystalline form has a DSC thermogram substantially as shown in FIG. 24B.
  • the crystalline form is substantially pure. In some embodiments, the crystalline form has a chemical purity of greater than 80% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 90% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 95% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 99% by weight. In some embodiments, the crystalline form has no more than about 10 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 5 mol% of other solid-state forms of the compound represented by Formula (I).
  • the crystalline form has no more than about 3 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 1 mol% of other solid- state forms of the compound represented by Formula (I).
  • the crystalline form has an XRPD pattern substantially as shown in FIG. 25A. In some embodiments, the crystalline form has a DSC thermogram substantially as shown in FIG. 25B.
  • the crystalline form is substantially pure. In some embodiments, the crystalline form has a chemical purity of greater than 80% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 90% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 95% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 99% by weight. In some embodiments, the crystalline form has no more than about 10 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 5 mol% of other solid-state forms of the compound represented by Formula (I).
  • the crystalline form has no more than about 3 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 1 mol% of other solid- state forms of the compound represented by Formula (I).
  • the crystalline form has an XRPD pattern substantially as shown in FIG. 26A. In some embodiments, the crystalline form has a DSC thermogram substantially as shown in FIG. 26B.
  • the crystalline form is substantially pure. In some embodiments, the crystalline form has a chemical purity of greater than 80% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 90% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 95% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 99% by weight. In some embodiments, the crystalline form has no more than about 10 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 5 mol% of other solid-state forms of the compound represented by Formula (I).
  • the crystalline form has no more than about 3 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 1 mol% of other solid- state forms of the compound represented by Formula (I).
  • the crystalline form has an XRPD pattern substantially as shown in FIG. 27A. In some embodiments, the crystalline form has a DSC thermogram substantially as shown in FIG. 27B.
  • the crystalline form is substantially pure. In some embodiments, the crystalline form has a chemical purity of greater than 80% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 90% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 95% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 99% by weight. In some embodiments, the crystalline form has no more than about 10 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 5 mol% of other solid-state forms of the compound represented by Formula (I).
  • the crystalline form has no more than about 3 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 1 mol% of other solid- state forms of the compound represented by Formula (I).
  • the crystalline form has an XRPD pattern substantially as shown in FIG. 28A. In some embodiments, the crystalline form has a DSC thermogram substantially as shown in FIG. 28B.
  • the crystalline form is substantially pure. In some embodiments, the crystalline form has a chemical purity of greater than 80% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 90% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 95% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 99% by weight. In some embodiments, the crystalline form has no more than about 10 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 5 mol% of other solid-state forms of the compound represented by Formula (I).
  • the crystalline form has no more than about 3 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 1 mol% of other solid- state forms of the compound represented by Formula (I).
  • the crystalline form has an XRPD pattern substantially as shown in FIG. 29.
  • the crystalline form is substantially pure. In some embodiments, the crystalline form has a chemical purity of greater than 80% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 90% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 95% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 99% by weight. In some embodiments, the crystalline form has no more than about 10 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 5 mol% of other solid-state forms of the compound represented by Formula (I).
  • the crystalline form has an XRPD pattern substantially as shown in FIG. 30.
  • the crystalline form is substantially pure. In some embodiments, the crystalline form has a chemical purity of greater than 80% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 90% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 95% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 99% by weight. In some embodiments, the crystalline form has no more than about 10 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 5 mol% of other solid-state forms of the compound represented by Formula (I).
  • the crystalline form has no more than about 3 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 1 mol% of other solid- state forms of the compound represented by Formula (I).
  • the crystalline form is substantially pure. In some embodiments, the crystalline form has a chemical purity of greater than 80% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 90% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 95% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 99% by weight. In some embodiments, the crystalline form has no more than about 10 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 5 mol% of other solid-state forms of the compound represented by Formula (I).
  • the crystalline form has no more than about 3 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 1 mol% of other solid- state forms of the compound represented by Formula (I).
  • the crystalline form has an XRPD pattern substantially as shown in FIG. 2B. In some embodiments, the crystalline form has an XRPD pattern substantially as shown in Table IB.
  • the crystalline form has an XRPD pattern comprising peaks, in terms of 2-theta, at about 9.6°. In some embodiments, the crystalline form has an XRPD pattern comprising peaks, in terms of 2-theta, at about 8.5°. In some embodiments, the crystalline form has an XRPD pattern comprising peaks, in terms of 2-theta, at about 20.8°. In some embodiments, the crystalline form has an XRPD pattern comprising one or more peaks, in terms of 2-theta, at about 8.5°, about 9.6°, or about 20.8°.
  • the XRPD pattern further comprises one or more peaks at about 12.6°, about 14.5°, or about 22.2°. In some embodiments, the XRPD pattern further comprises one or more peaks at about 9.9°, about 14.2°, about 16.4°, about 17.0°, about 17.5°, about 25.0°, or about 27.1°. In some embodiments, the XPRD pattern further comprises one or more peaks at about 11.8°, about 14.9°, about 18.7°, or about 26.9°.
  • the crystalline form has an XRPD pattern comprising peaks, in terms of 2-theta, at 9.6° ⁇ 0.2°. In some embodiments, the crystalline form has an XRPD pattern comprising peaks, in terms of 2-theta, at 8.5° ⁇ 0.2°. In some embodiments, the crystalline form has an XRPD pattern comprising peaks, in terms of 2-theta, at 20.8° ⁇ 0.2°. In some embodiments, the crystalline form has an XRPD pattern comprising one or more peaks, in terms of 2-theta, at 8.5° ⁇ 0.2°, 9.6° ⁇ 0.2°, or 20.8° ⁇ 0.2°.
  • the XRPD pattern further comprises one or more peaks at 12.6° ⁇ 0.2°, 14.5° ⁇ 0.2°, or 22.2° ⁇ 0.2° . In some embodiments, the XRPD pattern further comprises one or more peaks at 9.9° ⁇ 0.2°, 14.2° ⁇ 0.2°, 16.4° ⁇ 0.2°, 17.0° ⁇ 0.2°, 17.5° ⁇ 0.2°, 25.0° ⁇ 0.2°, or 27.1° ⁇ 0.2°. In some embodiments, the XPRD pattern further comprises one or more peaks at 11.8° ⁇ 0.2°, 14.9° ⁇ 0.2°, 18.7° ⁇ 0.2°, or 26.9° ⁇ 0.2°. [000186] In some embodiments, the crystalline form is substantially pure.
  • the crystalline form has a chemical purity of greater than 80% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 90% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 95% by weight. In some embodiments, the crystalline form has a chemical purity of greater than 99% by weight. In some embodiments, the crystalline form has no more than about 10 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 5 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 3 mol% of other solid-state forms of the compound represented by Formula (I). In some embodiments, the crystalline form has no more than about 1 mol% of other solid- state forms of the compound represented by Formula (I).
  • compositions comprising a solid-state form of a compound represented by Formula (I), as free acid or base, or a pharmaceutically acceptable salt or a solvate thereof, and a pharmaceutically acceptable carrier.
  • compositions that contain, as the active ingredient, one or more solid-state forms of the compound represented by Formula (I), as free acid or base, or a pharmaceutically acceptable salt or a solvate thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • the pharmaceutical compositions is administered alone or in combination with other therapeutic agents.
  • Such compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed.
  • compositions are administered in either single or multiple doses by any of the accepted modes of administration of agents, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.
  • agents including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.
  • One mode for administration is parenteral, particularly by injection.
  • Aqueous solutions in saline are also conventionally used for injection, but less preferred in the context of the present disclosure.
  • Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Sterile injectable solutions are prepared by incorporating a solid-state form of a compound according to the present disclosure in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuumdrying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral administration is another route for administration of the solid-state forms of a compound represented by Formula (I) in accordance with the disclosure. Administration may be via capsule or enteric coated tablets, or the like.
  • the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • the solid-state forms of the disclosure can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer- coated reservoirs or drug-polymer matrix formulations.
  • Another formulation for use in the methods of the present disclosure employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present disclosure in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • compositions are preferably formulated in a unit dosage form.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule).
  • suitable pharmaceutical excipient e.g., a tablet, capsule, ampoule.
  • the solid-state forms of the disclosure are generally administered in a pharmaceutically effective amount.
  • each dosage unit contains from 1 mg to 2 g of a solid-state form of a compound described herein, and for parenteral administration, preferably from 0.1 to 1000 mg of a solid-state form of a compound described herein.
  • the amount of the solid-state form of a compound actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present disclosure.
  • a pharmaceutical excipient for preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present disclosure.
  • these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • the tablets or pills of the present disclosure is coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
  • compositions comprising a solid-state form of a compound represented by Formula (I) are administered to the subject as oral dosage forms.
  • the oral dosage form is in the form of a tablet.
  • the oral dosage form is in the form of a capsule.
  • the dosage may vary depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl, et al., 1975, in “The Pharmacological Basis of Therapeutics”). Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular subject will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the subject’s disposition to the disease, condition or symptoms, and the judgment of the treating physician.
  • a course of therapy can comprise one or more separate administrations of a compound as described herein.
  • Solid-state forms and compositions described herein are utilized in methods for treating, preventing, or reducing the risk or severity of a disease or disorder mediated by STAT3, or a disease or disorder that is otherwise treatable with a STAT3 inhibitor.
  • the compounds and compositions are useful for treating, preventing, or reducing the risk or severity of certain diseases or disorders characterized by excessive STAT3 protein expression.
  • diseases and disorders include, for example, certain cancers, fibrosis, and inflammatory diseases or disorders.
  • the methods involve the use of (e.g., comprise the administration of) a solid-state form of a compound of formula (I), a STAT3 inhibitor, wherein the solid-state form of the compound of formula (I), as free acid or base, or a pharmaceutically acceptable salt or solvate thereof, is formulated in a manner described herein (e.g., is present in a composition as described herein).
  • a solid-state form of a compound of formula (I), a STAT3 inhibitor wherein the solid-state form of the compound of formula (I), as free acid or base, or a pharmaceutically acceptable salt or solvate thereof, is formulated in a manner described herein (e.g., is present in a composition as described herein).
  • provided herein are methods of treating, preventing, or reducing the risk or severity of cancer.
  • provided herein are methods of treating, preventing, or reducing the risk or severity of fibrosis.
  • provided herein are methods of treating, preventing, or reducing the risk or severity of
  • STAT3 Signal transducer and activator of transcription 3
  • STAT3 is central in regulating the anti-tumor immune response.
  • STAT3 is broadly hyperactivated both in cancer and non-cancerous cells within the tumor ecosystem and plays important roles in inhibiting the expression of crucial immune activation regulators and promoting the production of immunosuppressive factors.
  • Methods provided herein are contemplated as being useful for the treatment of a cancer, including for example, solid tumors, soft tissue tumors, and metastases thereof.
  • kits for treating, preventing, or reducing the risk or severity of a cancer in an individual in need thereof comprising administering to the individual a solid-state form of a compound or a composition described herein.
  • the cancer treated according to a method provided herein is a liver cancer, lung cancer, head and neck cancer, breast cancer, skin cancer, kidney cancer, testicular cancer, colon cancer, rectal cancer, gastric cancer, skin cancer, metastatic melanoma, prostate cancer, ovarian cancer, cervical cancer, bone cancer, spleen cancer, gall bladder cancer, brain cancer, pancreatic cancer, stomach cancer, anal cancer, prostate cancer, multiple myeloma, post-transplant lymphoproliferative disease, restenosis, myelodysplastic syndrome, leukemia, lymphoma, or acute myelogenous leukemia.
  • a cancer treated according to a method provided herein is a liver cancer, lung cancer, liver carcinoma, hepatocellular carcinoma, head and neck squamous cell carcinoma, non-small cell lung cancer, or estrogen receptor-positive breast cancer.
  • a cancer treated according to a method provided herein is head and neck cancer, lung cancer, liver cancer, breast cancer, ovarian cancer, colon cancer, multiple myeloma, leukemia, or pancreatic cancer.
  • the leukemia is acute myelogenous leukemia.
  • STAT3 is essential for Thl7 lymphocyte development and cytokine production, and its activation has been linked to the development of airway inflammation.
  • STAT3 Upon activation, STAT3 is recruited to cytokine-activated receptor complexes and becomes phosphorylated at Tyr (Y) 705.
  • Phosphotyrosylated (p) STAT3 homodimerizes through reciprocal SH2-pY705 interactions, translocates to the nucleus, and binds to promoters to transcriptionally activate genes that drive Th 17 differentiation and production of multiple cytokines.
  • STAT3 activation also is involved in Th2 cytokine production, making it an attractive target for asthma treatment.
  • IBD inflammatory bowel disease
  • GWAS genome-wide association studies
  • ATG16L NOD2/CARD15
  • IBD5 CTLA4, TNFSF15
  • JAK2, STAT3, IL23R IL23R
  • 0RMDL3 regulatory T cells
  • cytokines tumor necrosis factor, interleukins 17, 23, 12, 22, and IL-6.
  • Many of these cytokines serve as ligands for cell surface receptors that activate STAT3.
  • targeting STAT3 may represent an effective means of treating, preventing, or reducing the risk or severity of inflammatory disease/disorder.
  • the inflammatory disease/disorder treated herein is inflammatory bowel disease (IBD), ulcerative colitis, Crohn’s disease, asthma, anaphylaxis, cancer cachexia, chronic kidney disease cachexia, nonalcoholic steatohepatitis (NASH), psoriasis, uveitis, scleritis, multiple sclerosis, or pancreatitis.
  • inflammation treated herein is inflammatory bowel disease (IBD), ulcerative colitis, Crohn’s disease, asthma, anaphylaxis, cancer cachexia, chronic kidney disease cachexia, or nonalcoholic steatohepatitis (NASH).
  • IBD inflammatory bowel disease
  • Crohn’s disease chronic kidney disease cachexia
  • NASH nonalcoholic steatohepatitis
  • the anaphylaxis comprises anaphylactic shock.
  • Fibrosis is a pathological process involving the accumulation of excessive extra-cellular matrix in tissues, leading to tissue damage and organ dysfunction, which can progress to organ failure and death.
  • the trigger is postulated to be an autoimmune response that leads to tissue injury, production of growth factors, pro-inflammatory and pro-fibrotic cytokines, and accumulation of myofibroblasts.
  • Two potential sources of myofibroblasts are the differentiation of local fibroblasts and the process of epithelial-to-mesenchymal transition (EMT).
  • EMT epithelial-to-mesenchymal transition
  • IL-6 is a proinflammatory and profibrotic cytokine increasingly recognized as an important mediator of fibrosis that may contribute to the accumulation of myofibroblasts. After engaging its receptor, IL-6 signals through the STAT3.
  • STAT3 represents a potentially important protein to target to treat fibrosis.
  • kits for treating, preventing, or reducing the risk or severity of fibrosis in an individual in need thereof comprising administering to the individual a solid-state form of a compound or a composition described herein.
  • the fibrosis is associated with a disorder or disease such as skin fibrosis (or dermal fibrosis), cardiac fibrosis, cirrhosis, pulmonary fibrosis, bone marrow fibrosis, intestine fibrosis, pancreatic fibrosis, joint fibrosis, liver fibrosis, retroperitoneum, renal fibrosis, myelofibrosis, non-alcoholic fatty liver disease, steatohepatitis, systemic sclerosis (including diffuse systemic sclerosis or limited systemic sclerosis), endomyocardial fibrosis, myocardial infarction, atrial fibrosis, mediastinal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, Keloid, arthrofibrosis, adhesive capsulitis, or cystic fibrosis.
  • a disorder or disease such as skin fibrosis (or dermal fibrosis), cardiac fibrosis, cirrhosis,
  • the fibrosis is associated with skin fibrosis (scleroderma), cardiac fibrosis, cirrhosis, pulmonary fibrosis, bone marrow fibrosis, intestine fibrosis, pancreatic fibrosis, joint fibrosis, liver fibrosis, retroperitoneum, myelofibrosis, non-alcoholic fatty liver disease, steatohepatitis, or systemic sclerosis.
  • the fibrosis is associated with skin fibrosis (scleroderma), cardiac fibrosis, cirrhosis, or pulmonary fibrosis.
  • the fibrosis is associated with exposure to certain drugs such as chemotherapy, fibrosis following exposure to environmental or other toxins or allergens, fibrosis occurring after an ischemia/reperfusion injury such as myocardial infarction or hypotension, fibrosis occurring after radiation, fibrosis following hepatitis induced by alcohol, toxins, drugs or infections, primary biliary cirrhosis, fibrosis following viral infections involving the heart, liver, or lung, and/or idiopathic retroperitoneal fibrosis.
  • CKD chronic kidney disease
  • diabetes cancer
  • serious infections CKD
  • kits for treating, preventing, or reducing the risk or severity of a muscle wasting disease/disorder, muscle weakness disease/disorder, or cachexia in an individual in need thereof comprising administering to the individual a solid-state form of a compound or a composition described herein.
  • the muscle weakness and/or muscle wasting and/or cachexia may have an unknown cause or it may be associated with an underlying condition.
  • the underlying condition may be a catabolic condition.
  • the underlying medical condition associated with cachexia is least renal disease or failure, cancer, AIDS, HIV infection, chronic obstructive lung disease (including emphysema), multiple sclerosis, congestive heart failure, tuberculosis, familial amyloid polyneuropathy, acrodynia, hormonal deficiency, metabolic acidosis, infectious disease, chronic pancreatitis, autoimmune disorder, celiac disease, Crohn's disease, electrolyte imbalance, Addison's disease, sepsis, bums, trauma, fever, long bone fracture, hyperthyroidism, prolonged steroid therapy, surgery, bone marrow transplant, atypical pneumonia, brucellosis, endocarditis, Hepatitis B, lung abscess, mastocytosis, paraneoplastic syndrome, polyarteritis nodosa, sarcoidosis, systemic lupus erythematosus, myositis, poly
  • STAT3 signaling has been implicated in gap junction intercellular communication, IL-6- and IL 11 -induced vascular leakage, down-regulation of VE-cadherin concomitant with phosphorylation of STAT3, and the STAT3/mirl7-92/E2Fl dependent regulation of 0-catenin nuclear translocation and transcriptional activity.
  • STAT3 inhibition is useful to reduce vascular permeability in the setting of anaphylaxis.
  • a solid-state form of a compound or a composition described herein is administered to the individual a solid-state form of a compound or a composition described herein.
  • the allergic reaction is induced following an exposure to an allergen.
  • the allergen is a food allergen (such as milk, legumes, shellfish, tree nuts, eggs, fish, soy, and wheat), an environmental allergen or seasonal allergen (such as pollen or mold), a venom allergen (such as from wasp, bee, ant, hornet, yellow jacket, or asp), a medication allergen (such as anesthetics, P-lactam antibiotics, aspirin, non-steroidal anti-inflammatory drug, chemotherapy, vaccine, protamine, or herbal preparations), or latex.
  • a food allergen such as milk, legumes, shellfish, tree nuts, eggs, fish, soy, and wheat
  • an environmental allergen or seasonal allergen such as pollen or mold
  • a venom allergen such as from wasp, bee, ant, hornet, yellow jacket, or asp
  • a medication allergen such as anesthetics, P-lactam antibiotics, aspirin, non-steroidal anti-inflammatory drug, chemotherapy, vaccine, protamine,
  • the allergic reaction is anaphylaxis, anaphylactic shock, allergic rhinitis, urticaria, food allergy, drug allergy, hymenoptera allerga, bronchial constriction, asthma, or eczema.
  • STAT3 also plays an important role in viral infection and pathogenesis.
  • methods of treating, preventing, or reducing the risk or severity of a viral infection in an individual in need thereof comprising administering to the individual a solid-state form of a compound or a composition described herein.
  • the viral infection is a chronic viral infection.
  • the chronic viral infection is AIDS, HIV infection, Hepatitis B infection, Hepatitis C virus infection, or Epstein-Barr virus infection.
  • astrocytes in neurodegenerative diseases including Alzheimer’s disease are implicated in STAT3 phosphorylation.
  • Pathophysiological roles of astrocytes in the reactive state are thought to have important significance in the pathogenesis of neurodegenerative diseases.
  • Provided in some embodiments herein are methods of treating, preventing, or reducing the risk or severity of a neurodegenerative disease in an individual in need thereof, the method comprising administering to the individual a solid- state form of a compound or a composition described herein.
  • the neurodegenerative disease is chemotherapy-induced peripheral neuropathy, diabetic neuropathy, or chemobrain.
  • kits for treating, preventing, or reducing the risk or severity of pain in an individual in need thereof comprising administering to the individual a solid-state form of a compound or a composition described herein.
  • pain is neuropathic pain.
  • methods of treating, preventing, or reducing the risk or severity of graft-versus-host diseases, pulmonary lymphangioleiomyomatosis, chagasic cardiomyopathy, age-related macular degeneration, amyloidosis, astrogliosis in Alzheimer’s or other neurodegenerative diseases, or familial amyloid polyneuropathy are provided in some embodiments herein.
  • STAT3 is involved in cytokine- and nutrient-induced insulin resistance, and excessive STAT3 signaling is implicated in the development of insulin resistance such as skeletal muscle insulin resistance in type 2 diabetes.
  • Provided in some embodiments herein are methods of treating, preventing, or reducing the risk or severity of insulin resistance in an individual in need thereof, the method comprising administering to the individual a solid- state form of a compound or a composition described herein.
  • the insulin resistance is a result of an underlying condition.
  • the insulin resistance is associated with muscle of the individual being treated.
  • the insulin resistance is caused by any reason for the individual, such as elevated free fatty acids in the blood, obesity, being overweight, having visceral fat, having a high fructose intake, having inflammation, being inactive, dysbiosis of the gut microbiota, and/or being genetically predisposed.
  • any method provided herein is a method of treating, preventing, or reducing the risk or severity of medical conditions associated with insulin resistance or that are complications of insulin resistance at least in part, such as severe high blood sugar; severe low blood sugar; heart attack; stroke; kidney disease (including chronic, for example, chronic kidney disease (CKD)); eye problems; cancer; non-alcoholic fatty liver disease (NAFLD); polycystic ovarian syndrome (PCOS); metabolic syndrome; diabetes; or Alzheimer’s disease, for example.
  • the insulin resistance is a hallmark of metabolic syndrome and type 2 diabetes.
  • Metabolic syndrome is a group of risk factors associated with type 2 diabetes and heart disease. Its symptoms include high blood triglycerides, blood pressure, belly fat, and blood sugar, as well as low HDL (good) cholesterol levels.
  • the methods comprise administering a therapeutically effective amount of a composition disclosed herein to the individual.
  • the method comprises administering at least 1 mg/kg/day of one or more solid-state forms of the compound of formula (I) to the individual.
  • the method comprises administering at least 10 mg/kg/day of one or more solid-state forms of the compound of formula (I) to the individual.
  • the method comprises administering at least 20 mg/kg/day of one or more solid-state forms of the compound of formula (I) to the individual.
  • the method comprises administering at least 25 mg/kg/day of one or more solid-state forms of the compound of formula (I) to the individual.
  • NMR experiments were performed on a Bruker® AVIIIHD spectrometer equipped with a DCH cry oprobe operating at 500.12MHz for protons. Experiments were performed in deuterated dimethyl sulfoxide (DMSO) and each sample was prepared to approximately 10 mM concentration. Spectra were referenced against the solvent peak were analyzed using the Topspin® software package.
  • DMSO deuterated dimethyl sulfoxide
  • Infrared spectroscopy was carried out on a Bruker® ALPHA P spectrometer. Sufficient material was placed onto the center of the plate of the spectrometer and the spectra were obtained using the following parameters: Resolution: 4 cm-1; Background Scan Time: 16 scans; Sample Scan Time: 16 scans; Data Collection: 4000 to 400 cm-1; Result Spectrum: Transmittance; Software: OPUS version 6
  • HPLC-UV conditions were as follows: Column Cortecs® UPLC C18 1.6pm 2.1 x 100 mm; Column Temperature (°C) 40; Flow Rate (mL/min) 0.35; Column Pressure at start of Run (Bar) 660; Injection Volume (pL) 2; Autosampler Temperature (°C) Ambient; Detection parameters 220 nm; Mobile Phase A 0.2% trifluoroacetic acid (TFA) in water; Mobile Phase B 0.2% TFA in acetonitrile (ACN); Diluent 50:50 ACN: Water Variable temperature X-ray powder diffraction (VT-XRPD)
  • the resulting slurry was stirred and heated to 50 °C for 30 minutes, during which time the solid dissolved completely to form a clear solution. The solution was then cooled to 0 °C and stirred for 2 hours, during which time a precipitate formed. The resulting suspension was filtered to collect the solid. The solid was then dried under high vacuum to afford the title compound (160 mg, 22% yield) as a solid.
  • Amorphous form of the compound represented by Formula (I) was also prepared from the fast evaporation of a clear solution of Form 1 (see Example 2) in ethyl acetate. Approximately 400 mg of Form 1 was fully dissolved in about 30 mL of warm ethyl acetate to yield a clear solution. The ethyl acetate was distilled using a rotary evaporator under reduced atmosphere with the bath set at about 30-40 °C. The resulting solid was analyzed by XRPD, which indicated the resulting solid was amorphous (FIG. 1).
  • Example 2A Exemplary process of preparing Form 1 of a compound represented by
  • a mixture of Compound 1 (15 kg) and pyridine (45 L) in a vessel was agitated at about 0 °C.
  • Phosphorus oxychloride (5 kg) was added to the mixture while maintaining a temperature of about 0 °C during the addition.
  • the temperature was adjusted to about 25 °C and the mixture was agitated for at least 1 hour (e.g., at least 2 hours).
  • Water (22.5 L) was added to the mixture and the mixture was agitated at about 25 °C for at least 1 hour (e.g., at least 6 hours).
  • the mixture was transferred to a second vessel containing hydrochloric acid (36%; 135 L).
  • a solution of pyridine (5 L) in acetonitrile (34 L) was added to the mixture and the temperature was adjusted to about 22 °C and agitated for at least 1 hour followed by adjusting the temperature to about 70 °C and agitated at about 70 °C for at least 1 hour (e.g., at least 2 hours).
  • the mixture was cooled to about 25 °C and agitated at about 25 °C for at least 1 hour (e.g., at least 12 hours).
  • the resulting solid was collected by filtration.
  • the vessel was rinsed with acetonitrile and filtered over the collected solid. The rinsing step was repeated.
  • the solid was dried under a nitrogen stream followed by drying in a tray dryer under reduced pressure.
  • a mixture of Compound 3 (13 kg), hydrochloric acid (12M; 130 L) and water (260 L) in a vessel was agitated at about 15 °C for at least 1 hour followed by adjusting the temperature to about 45 °C and agitated for at least 1 hour (e.g., at least 12 hours).
  • the mixture was cooled to about 25 °C and agitated for at least 1 hour (e.g., at least 2 hours).
  • the resulting solid was collected by filtration and the vessel was rinsed with water and filtered over the collected solid.
  • a mixture of the solid in 2-MethylTHF (195 L), hydrochloric acid (12N; 6 L) and water (65 L) was agitated at about 25 °C for at least 1 hour.
  • the phases were allowed to separate, and the volume of the organic layer was reduced then was added ethanol (130 L). The volume of the mixture was reduced then was added ethanol (130 L). The mixture was added to activated charcoal and agitated for at least 1 hour (e.g., at least 4 hours) at about 45 °C. The mixture was filtered over Celite®. The vessel was rinsed with ethanol over the Celite®. The volume of the combined filtrate was reduced then water was added. The temperature of the mixture was adjusted to about 60 °C and agitated then cooled to 25 °C. Water was added through an inline filter (0.45 pm) to the mixture.
  • Seeds of Form 1 of the compound represented by Formula (I) (e.g., as prepared by Example 2B) (0.2 kg) were added to the mixture and the mixture was stirred for at least 1 hour (e.g., at least 2 hours).
  • the mixture was cooled to about 5 °C. Additional water was added through an inline filter then the mixture was agitated for at least 1 hour. The temperature was adjusted to about 25 °C.
  • the resulting solid was collected by filtration.
  • the vessel was rinsed with ethanol/water and filtered over the collected solid.
  • the solid was dried under a nitrogen stream followed by drying in a tray dryer.
  • An exemplary XRPD pattern of the resulting solid showed that the solid was primarily crystalline Form 21 of the compound represented by Formula (I) with a trace amount of Form 4 of the compound represented by Formula (I).
  • Example 2B Exemplary process of preparing Form 1 of a compound represented by Formula (I)
  • a mixture of Compound 3 in hydrochloric acid and water in a vessel was agitated at about 15 °C for at least 1 hour followed by adjusting the temperature to about 45 °C and agitated for at least 1 hour (e.g., at least 20 hours).
  • the mixture was cooled to about 25 °C and agitated for at least 1 hour (e.g., at least 2 hours).
  • the resulting solid was collected by filtration and the vessel was rinsed with water and filtered over the collected solid.
  • a mixture of the solid in 2-MethylTHF was mixed with aqueous hydrochloric acid, phases separated, and the organic layer was transferred to a vessel through a 0.45 pm filter.
  • the solid was dried on the filter for at least 1 hour (e.g., at least 2 hours) followed by drying in a tray dryer for at least 1 hour (e.g., at least 12 hours, at least 24 hours, at least 48 hours).
  • the resulting solid in n-heptane was agitated and the temperature was adjusted to about 90 °C and agitated for at least 1 hour (e.g., at least 12 hours, at least 24 hours, at least 30 hours).
  • the mixture was cooled to about 25 °C and agitated for at least 1 hour (e.g., 12 hours).
  • the solid was collected by filtration.
  • the vessel was rinsed with n-heptane and filtered over the collected solid.
  • the combined solids were dried on the filter followed by drying in a tray dryer.
  • An exemplary XRPD pattern of the resulting solid showed that the solid was crystalline Form 1 of the compound represented by Formula (I).
  • Example 2C Characterization of crystalline Form 1, Form 21, and Form 4 of a compound represented by Formula (I)
  • the XRPD pattern of Form 1 is shown in FIG. 2A.
  • Table 1 A shows the peak listing and relative intensities (%) of Form 1.
  • 'H NMR and 31 P NMR are shown in FIG. 3 and FIG. 4, respectively.
  • the thermal analysis of the compound represented by Formula (I) displayed the following properties by TGA/DSC. From the TGA trace, there was a weight loss of 1.83 wt% (20-120 °C), weight loss of 0.94% wt% (190-210 °C) and decomposition at about 230 °C (FIG. 5). The DSC trace showed two endothermic events at an onset of about 197 °C and peak at about 205 °C; and a second peak at about 231 °C (FIG. 5).
  • Thermal analysis by standalone DSC shows in the first heating (FIG. 6), an endothermic event at an onset of about 193 °C and peak at about 204 °C; an exothermic event at an onset of about 208 °C and peak at about 211 °C; in the first cooling, a possible glass transition at about 141 °C; and in the second heating, a glass transition at about 151 °C.
  • Karl Fisher titration showed an average water content of 0.70%.
  • DVS analysis (FIG. 7) showed a moisture uptake of about 1.5 wt% at 90% RH.
  • the XRPD of the material post DVS showed that Form 1 was retained after DVS analysis (FIG. 8).
  • Variable temperature XRPD showed that Form 1 was retained from ambient to 190 °C. At 205 °C, the material became amorphous (FIG. 9). The recovered amorphous material was analyzed by HPLC and showed that the compound was degraded. Table 1A. Representative XRPD peaks of Form 1
  • Example 2D Exemplary process of preparing Form 1 of a compound represented by
  • the mixture in reactor A was transferred to reactor B which contained hydrochloric acid (9 vol).
  • Reactor A was rinsed with a mixture of pyridine/water (0.5 vol / 0.5 vol), and the rinse was transferred to reactor B.
  • the mixture in reactor B was agitated at 65 ⁇ 5 °C at least 2 hours. The temperature was adjusted to 25 ⁇ 5 °C over 3 hours, the solids were collected by filtration, and the filter cake was washed with water (2 ⁇ 5 vol). The solids were dried in a vacuum oven at 48 °C for 90 hours. 18.8 Kg of Compound 2 was obtained in 104% yield and 98.6% purity.
  • the material contained ⁇ 0.8 equivalents of pyridine by weight (estimated by J H NMR).
  • a J H NMR spectrum of Compound 2 (DMSO-d6) is shown in FIG. 32.
  • Liquid chromatographymass spectrometry (LCMS) data are shown in FIG. 33.
  • the organic layer was distilled to 3 vol, and acetonitrile (15 vol) was charged followed by distilling to 3 vol. Water (1 vol) was charged followed by acetonitrile (15 vol).
  • a solution of pyridine (2 equivalents) in acetonitrile (2 vol) was charged and the temperature was adjusted to 25 ⁇ 5 °C.
  • the mixture was agitated at 25 ⁇ 5 °C for 4 hours post pyridine addition followed by adjusting the temperature to 70 ⁇ 5 °C over at least 2 hours.
  • the mixture was agitated at 70 ⁇ 5 °C for 2.5 hours followed by adjusting the temperature to 25 ⁇ 5 °C over 2 hours and held for 5 hours.
  • the solids were collected by filtration.
  • the reactor was rinsed with acetonitrile (2x5 vol) sending the rinse through the filter cake.
  • the product was dried on the filter for at least 1 h followed by drying in a tray dryer at 46 °C for 24 hours. 14.5 Kg of Compound 3 was obtained in 65% yield and 98.8% purity.
  • the material contained 0.41% acetonitrile by weight (estimated by J H NMR).
  • a J H NMR spectrum of Compound 3 (DMSO- d6) is shown in FIG. 34.
  • Liquid chromatography-mass spectrometry (LCMS) data are shown in FIG. 35.
  • Ethanol (10 vol) was charged and the mixture was distilled to 2.5 vol.
  • Ethanol (10 vol) was charged to reactor C.
  • the reactor D was cleaned and charged with charcoal (1.44 Kg).
  • the contents of R-302 were transferred to reactor D.
  • the temperature of reactor D was adjusted to 45 ⁇ 5 °C and agitated at 45 ⁇ 5 °C for 13 hours.
  • the contents in reactor D were filtered through a pad of celite, and the filtrate was transferred to the cleaned reactor C through a 0.45 pm polish filter.
  • Reactor D was rinsed with ethanol (2 vol).
  • the celite cake was rinsed with the ethanol rinse, which was directed to reactor C through the 0.45 pm polish filter.
  • the filtrate in reactor C was distilled to 3 vol.
  • the temperature was adjusted to 25 ⁇ 5 °C.
  • the solids were collected by filtration and the filter cake was rinsed with a pre-mixed ethanol solution.
  • the solids were dried in the filter for 16.5 hours followed by drying in tray dryer at 50 °C for at least 24 hours.
  • the loss-on-drying (LOD) was 0.85%.
  • the product was de-lumped using a conical screen mill. A screen size of 024R (600 pm) was used. 11.8 Kg of crude Compound 4 was obtained in 99.9% purity and 93% yield.
  • the residual pyridine was 14 ppm (HSGC).
  • X-ray power diffraction was checked and failed. Processing continued under a deviation.
  • the mixture was cooled to 25 ⁇ 5 °C over 2 hours before the solids were collected by filtration, reactor C was rinsed with heptane (3 vol). The filter cake was rinsed with the rinse.
  • the solids were dried in the filter for 5 h followed by drying in a tray dryer for 36 hours at 54 °C.
  • the loss-on-drying (LOD) was 0.38%.
  • the solids were de-lumped using a conical screen mill and the product was packaged and stored at 5 °C.
  • Compound 4 Form 1 (10.5 kg) was obtained in 98.7% purity and 89% yield.
  • FIG. 36 A J H NMR spectrum of Compound 4 (DMSO-d6) is shown in FIG. 36.
  • Liquid chromatography-mass spectrometry (LCMS) data are shown in FIG. 37.
  • Example 3 Stability study of Form 1 of a compound represented by Formula (I) [000244] A seven-day stability test was performed on Form 1 to evaluate any changes to the physical form or chemical purity when the material was held under different conditions: 40°C/75 % RH, 80°C, and ambient (25°C). After 7 days, XRPD analysis showed that Form 1 was maintained (FIG. 10). HPLC of Form 1 used for the stability testing showed purity of 99.77%. The purities of the material post 7 days at 40°C/75 % RH, 80°C, and ambient (25°C) conditions were 99.46%, 99.59%, and 99.41%, respectively.
  • Example 5 Polymorph screening of a compound represented by Formula (I) Temperature cycling
  • Form 1 and Form 4 were obtained from ethanokwater and acetic acid:water systems. Upon drying Form 4 at 40 °C under vacuum, Form 4 converted to Form 1 : after drying for about 16 hours, Form 4 was still observed by PXRD; longer drying time (additional 48 hours) showed the full conversion to Form 1.
  • Form 5 and Form 6 were obtained from 2-propanol based solvent system. In 2- propanol: water, Form 5 was favored while in 2-propanol: heptane, Form 6 was favored.
  • Amorphous solid of the compound represented by Formula (I) and solvent (Table 4) were milled for 4 cycles of 15 minutes at 5000 rpm.
  • the isolated solids were analyzed by XRPD while the solids were damp.
  • XRPD analysis of the solids after drying at 40 °C under vacuum for 16 hours was also carried out.
  • Table 4 and FIG. 13 summarize the results from solvent drop grinding.
  • Form 4 and Form 1 were obtained from ethanokwater and acetic acid:water solvent systems. Form 4 converted to Form 1 upon drying. Form 5 was obtained from 2- propanol: heptane.
  • Amorphous solid of a compound represented by Formula (I) in a smaller vial was placed in a larger vial containing a solvent (Table 5) such that the solid did not come in direct contact with the solvent.
  • the larger vial was closed and left for 7 days at ambient temperature.
  • the isolated solids were analyzed by XRPD while the solids were damp. XRPD analysis of the solids after drying at 40 °C under vacuum for 16 hours was also carried out.
  • Table 5 and FIG. 14 summarize the results from vapor diffusion into solids.
  • Form 4 and Form 1 were obtained from ethanokwater and acetic acid:water solvent systems. Form 4 converted to Form 1 upon drying.
  • Form 5 was obtained from 2- propanol: water and Form 12 was obtained from 2-propanol:heptane.
  • Form 9 and Form 10 were obtained from acetone: heptane and TBME, respectively.
  • Form 11 was obtained from MeTHF : heptane.
  • Form 4 and Form 1 were obtained from ethanol: water. Form 4 converted to Form 1 upon drying. Form 6 was obtained from 2-propanol:heptane. Form 13 formed from MeTHF : heptane.
  • Form 4 and Form 1 were obtained from ethanokwater and acetic acid:water. Form 4 converted to Form 1 upon drying. Form 5 was obtained from 2-propanol:heptane.
  • Table 9 summarizes exemplary solid-state forms of the compound represented by Formula (I) based at least on the above experiments.
  • TC refers to temperature cycling
  • SE refers to solvent evaporation
  • ASA anti-solvent addition
  • SDG solvent drop grinding
  • VDS vapor diffusion into a solid
  • VDL vapor diffusion into a saturated solution.
  • Form 1 was a nonsolvated crystalline form (anhydrate).
  • FIG. 18 A, 18B, and 18C show an XPRD diffractogram, TGA/DSC plot, and 'HNMR spectrum, respectively, of Form 2 of the compound represented by Formula (I).
  • FIG. 19A and 19B show an XRPD diffractogram and TGA/DSC plot, respectively, of Form 3 of the compound represented by Formula (I).
  • FIG. 20 shows an XRPD diffractogram of Form 4 of the compound represented by Formula (I).
  • FIG. 21 A and 2 IB show an XRPD diffractogram and TGA/DSC plot, respectively, of Form 5 of the compound represented by Formula (I).
  • FIG. 22A and 22B show an XRPD diffractogram and TGA/DSC plot, respectively, of Form 6 of the compound represented by Formula (I).
  • FIG. 23 shows an XRPD diffractogram of Form 7 of the compound represented by Formula (I).
  • FIG. 24A and 24B show an XRPD diffractogram and TGA/DSC plot, respectively, of Form 8 of the compound represented by Formula (I).
  • FIG. 25A and 25B show an XRPD diffractogram and TGA/DSC plot, respectively, of Form 9 of the compound represented by Formula (I).
  • FIG. 26A and 26B show an XRPD diffractogram and TGA/DSC plot, respectively, of Form 10 of the compound represented by Formula (I).
  • FIG. 27A and 27B show an XRPD diffractogram and TGA/DSC plot, respectively, of Form 11 of the compound represented by Formula (I).
  • FIG. 28A and 28B show an XRPD diffractogram and TGA/DSC plot, respectively, of Form 12 of the compound represented by Formula (I).
  • FIG. 29 shows an XRPD diffractogram of Form 13 of the compound represented by Formula (I).
  • FIG. 30 shows an XRPD diffractogram of Form 14 of the compound represented by Formula (I).
  • FIG. 31 shows an XRPD diffractogram of Form 15 of the compound represented by Formula (I).

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Abstract

Selon certains modes de réalisation, l'invention concerne des formes solides d'un composé représenté par la formule (I), en tant qu'acide ou base libre, ou sel ou solvate pharmaceutiquement acceptable de celui-ci, des compositions pharmaceutiques comprenant une ou plusieurs formes solides d'un composé représenté par la formule (I), en tant qu'acide ou base libre, ou sel ou solvate pharmaceutiquement acceptable de celui-ci, et leurs méthodes d'utilisation.
PCT/US2024/061149 2023-12-20 2024-12-19 Formes solides d'inhibiteurs de stat3 et leurs méthodes d'utilisation Pending WO2025137366A2 (fr)

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US12617810B2 (en) 2022-06-15 2026-05-05 Tvardi Operating Company, Inc. Prodrugs of STAT3 inhibitors

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WO2021150912A1 (fr) * 2020-01-24 2021-07-29 Tvardi Therapeutics, Inc. Composés thérapeutiques, formulations et leurs utilisations
EP4539936A1 (fr) * 2022-06-15 2025-04-23 Tvardi Therapeutics, Inc. Promédicaments d'inhibiteurs de stat3

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Title
"Remington's Pharmaceutical Sciences", 1985, MACE PUBLISHING CO.
BERGE ET AL., J. PHARMACEUTICAL SCIENCES, vol. 66, 1977, pages 1 - 19
FINGL ET AL., THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 1975

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US12617810B2 (en) 2022-06-15 2026-05-05 Tvardi Operating Company, Inc. Prodrugs of STAT3 inhibitors

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