Solid crystalline forms of compounds for treating or preventing hyperuricemia or gout

Abstract

The present invention provides solid crystalline forms of a compound for treating or preventing hyperuricemia or gout, and further provides methods of using said crystalline forms for the preparation and characterization of said crystalline forms of Compound I having activity against URAT1. [Formula 1] TIFF2025530060000020.tif38170

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of International Patent Application No. PCT / CN2022 / 094043, filed May 20, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates generally to crystalline forms of Compound I, designated 3-bromo-5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile, or pharmaceutically acceptable salts or solvates thereof, methods of preparing said crystalline forms, and methods of treatment therewith. [Background technology]

[0003] There remains a need to develop effective treatments for patients suffering from or at risk of hyperuricemia or gout. Compounds suitable for treating such diseases and disorders, including Compound I, are disclosed in U.S. Patent Application Publication No. 2007 / 0129994, the entire disclosure of which is incorporated herein by reference. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] U.S. Patent No. 10,399,971 Summary of the Invention [Problem to be solved by the invention]

[0005] [Means for solving the problem]

[0006] The present invention provides solid crystalline forms of Compound I or a pharmaceutically acceptable salt or solvate thereof. [ka]

[0007] The present invention also provides pharmaceutical compositions comprising the solid crystalline forms of Compound 1. The present invention also provides methods for preparing the solid crystalline forms, and methods for treating hyperuricemia or gout. [Brief explanation of the drawings]

[0008] [Figure 1] 1 is a powder X-ray diffraction pattern (XRPD) of crystalline Form 1 of Compound I. [Figure 2] 1 is a thermogravimetric analysis (TGA) of crystalline Form 1 of Compound I. [Figure 3] 1 is a differential scanning calorimetry heat map (DSC) of crystalline Form 1 of Compound I. [Figure 4] 1 is an XRPD of crystalline form 2 of Compound I. [Figure 5] 1 is a TGA of crystalline Form 2 of Compound I. [Figure 6] 1 is a DSC of crystalline form 2 of Compound I. [Figure 7] 1 is an XRPD of crystalline form 3 of Compound I. [Figure 8] 1 is a TGA of crystalline form 3 of Compound I. [Figure 9] 1 is a DSC of crystalline form 3 of Compound I. [Figure 10] 1 is an XRPD of crystalline form 4 of Compound I. [Figure 11] 1 is a TGA of crystalline form 4 of Compound I. [Figure 12] 1 is a DSC of crystalline form 4 of Compound I. [Figure 13] A, B, C, and D are XRPDs of crystalline form 5A, crystalline form 5B, crystalline form 5C, and crystalline form 5D of Compound I, respectively. [Figure 14] A, B, C, and D are TGAs of crystalline form 5A, crystalline form 5B, crystalline form 5C, and crystalline form 5D of Compound I, respectively. [Figure 15] A, B, C, and D are DSCs of crystalline form 5A, crystalline form 5B, crystalline form 5C, and crystalline form 5D of Compound I, respectively. [Figure 16] 1 is an XRPD of crystalline form 6 of Compound I. [Figure 17] 1 is a TGA of crystalline form 6 of Compound I. [Figure 18] 1 is a DSC of crystalline form 6 of Compound I. [Figure 19] 1 is an XRPD of crystalline form 7 of Compound I. [Figure 20] 1 is a TGA of crystalline form 7 of Compound I. [Figure 21] 1 is a DSC of crystalline form 7 of Compound I. [Figure 22] 1 is an XRPD of crystalline form 8 of Compound I. [Figure 23] 1 is a TGA of crystalline form 8 of Compound I. [Figure 24] 1 is a DSC of crystalline form 8 of Compound I. [Figure 25] 1 is an XRPD of crystalline form 9 of Compound I. [Figure 26] 1 is a TGA of crystalline form 9 of Compound I. [Figure 27] 1 is a DSC of crystalline form 9 of Compound I. [Figure 28] 1 is an XRPD of crystalline form 10 of Compound I. [Figure 29] 1 is a TGA of crystalline form 10 of Compound I. [Figure 30] 1 is a DSC of crystalline form 10 of Compound I. [Figure 31] 1 is an XRPD of crystalline form 11 of Compound I. [Figure 32] 1 is a TGA of crystalline form 11 of Compound I. [Figure 33] 1 is a DSC of crystalline form 11 of Compound I. [Figure 34] 1 is an XRPD of crystalline form 12 of Compound I. [Figure 35] 1 is a TGA of crystalline form 12 of Compound I. [Figure 36] 1 is a DSC of crystalline form 12 of Compound I. [Figure 37] 1 shows the XRPD evolution of crystalline Form 6 of Compound I upon desorption and resorption with solvent. [Figure 38]1 shows the blood concentration-time curve in SD rats after a single intravenous administration of 1 mg / kg of crystalline Form 1 of Compound I. [Figure 39] 1 shows the blood concentration-time curve in SD rats after a single intravenous administration of crystalline Form 1 of Compound I at 5 mg / kg. [Figure 40] 1 shows the blood concentration-time curve in SD rats after a single oral administration of 10 mg / kg of crystalline form 1 of Compound I. [Figure 41] 1 shows the blood concentration-time curve in SD rats after a single oral administration of 10 mg / kg of crystalline Form 2 of Compound I. [Figure 42] 1 shows the blood concentration-time curve in SD rats after a single oral administration of 10 mg / kg of crystalline form 5D of Compound I. [Figure 43] 1 shows the X-ray powder diffraction (XRPD) patterns of a sample of crystalline Form 2 of Compound I aged at 25°C ± 2°C / 60% RH ± 5% RH for 12 months (SPL), a sample of crystalline Form 2 of Compound I aged for 0 days (initial), and a reference standard (STD) of crystalline Form 2 of Compound I. [Figure 44] 1 shows XRPD patterns comparing a sample of crystalline Form 2 of Compound I aged at 40°C ± 2°C / 75% RH ± 5% RH for 6 months (SPL), a sample of crystalline Form 2 of Compound I aged for 0 days (initial), and a reference standard (STD) of crystalline Form 2 of Compound I. [Figure 45] 1 shows the XRPD patterns of a sample of crystalline Form 2 of Compound I (top curve) aged at 40°C ± 2°C / 75% RH ± 5% RH for 6 months compared to a reference standard of crystalline Form 2 of Compound I (bottom curve). [Figure 46] 1 shows XRPD patterns of samples of crystalline Form 2 of Compound I stored at 25°C ± 2°C / 60% RH ± 5% RH for 12 months, 24 months, 36 months, 48 ​​months, and 0 days, compared with a reference standard (STD) of crystalline Form 2 of Compound I. DETAILED DESCRIPTION OF THE INVENTION

[0009] The compound designated 3-bromo-5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile (Compound I), or a pharmaceutically acceptable salt or solvate thereof, is useful for promoting uric acid excretion or for treating or preventing hyperuricemia and gout. The structure of Compound I is as follows: [ka]

[0010] The present invention relates to crystalline forms of Compound I, or a pharmaceutically acceptable salt or solvate thereof, which crystalline forms of Compound I, or a pharmaceutically acceptable salt or solvate thereof, are referred to herein as "Crystalline Form 1 of Compound I," "Crystalline Form 2 of Compound I," "Crystalline Form 3 of Compound I," "Crystalline Form 4 of Compound I," "Crystalline Form 5A of Compound I," "Crystalline Form 5B of Compound I," "Crystalline Form 5C of Compound I," "Crystalline Form 5D of Compound I," "Crystalline Form 6 of Compound I," "Crystalline Form 7 of Compound I," "Crystalline Form 8 of Compound I," "Crystalline Form 9 of Compound I," "Crystalline Form 10 of Compound I," "Crystalline Form 11 of Compound I," and "Crystalline Form 12 of Compound I."

[0011] definition Unless otherwise stated, the following definitions apply:

[0012] All atoms specified in the formulas described herein, whether in the structure provided or in the definition of variables related to that structure, are intended to include all isotopes thereof unless otherwise specified.It is understood that for any given atom, isotopes can be present in substantial proportion to their natural occurrence, or using synthetic methods known to those skilled in the art, one or more specific atoms can be enriched with one or more isotopes.Thus, in the case of hydrogen, for example, 1 H, 2 H, 3 In the case of H, carbon, e.g. 11 C. 12 C. 13 C. 14 C, in the case of oxygen, e.g.16 O. 17 O. 18 In the case of O, nitrogen, e.g. 13 N, 14 N, 15 In the case of N and sulfur, for example, 32 S, 33 S, 34 S, 35 S, 36 S, 37 S, 38 In the case of S, fluorine, e.g. 17 F, 18 F, 19 F, in the case of chlorine, 35 Cl, 36 Cl, 37 Cl, 38 Cl, 39 Cl and others are included.

[0013] Certain compounds contemplated for use in accordance with the present invention may exist in unsolvated or solvated crystalline forms, including hydrated crystalline forms. "Hydrate" refers to a complex formed by combining water molecules with solute molecules or ions. "Solvate" refers to a complex formed by combining solvent molecules with solute molecules or ions. The solvent can be an organic compound, an inorganic compound, or a mixture of both. Solvates include hydrates, hemihydrates, channel hydrates, and the like. Some examples of solvents include, but are not limited to, methanol, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, and water. Generally, solvated crystalline forms are equivalent to unsolvated crystalline forms and are within the scope of the present invention. Certain compounds contemplated for use in accordance with the present invention may exist in various crystalline or amorphous forms. In general, all physical crystalline forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0014] As used herein, the term "solid crystalline form" refers to a solid material including amorphous forms as well as crystalline forms. The term "crystalline form" refers to polymorphs, solvates, hydrates, etc. The term "polymorph" refers to a particular crystalline structure with particular physical properties such as X-ray diffraction, melting point, etc.

[0015] As used herein, the terms "treat," "treating," "therapy," "therapies," and similar terms refer to the administration of a substance, such as any one or more solid, crystalline, or polymorphic forms of Compound I described herein, in an amount that effectively prevents, reduces, or ameliorates one or more symptoms, i.e., indications, of a disease or disorder and / or prolongs the survival of the patient being treated.

[0016] As used herein, the terms "modulating" or "modulate" refer to the effect of changing a biological activity, particularly a biological activity associated with a particular biomolecule, such as human urate transporter 1 (hURAT1). For example, certain molecules described herein modulate the activity of a biomolecule by either increasing or decreasing its activity. This activity is typically measured, for example, in the case of an enzyme, by the inhibitory concentration (IC) of the compound as an inhibitor or activator, respectively. 50 ) or activation concentration (EC 50 )

[0017] As used herein, the terms "promoting" or "promote" refer to the effect of improving a biological activity associated with a particular molecule, such as uric acid. For example, certain molecules described herein promote the excretion (e.g., excretion as a waste product) of a molecule, such as uric acid.

[0018] As used herein, the term "URAT1-mediated disease or disorder" refers to a disease or disorder in which the biological function of URAT1, including any mutations thereof, affects the onset, course, and / or symptoms of the disease or disorder, and / or modulation of URAT1 alters the onset, course, and / or symptoms of the disease or disorder. URAT1-mediated diseases or disorders include diseases or disorders in which inhibition provides a therapeutic effect, for example, treatment with a URAT1 inhibitor (including one or more solid, crystalline, or polymorphic forms of Compound 1 described herein) provides a therapeutic benefit to a subject suffering from or at risk of the disease or disorder.

[0019] As used herein, the term "composition" refers to a pharmaceutical preparation containing at least one pharmaceutically active compound, including any solid crystalline form thereof, suitable for administration to a given individual for therapeutic purposes. The composition may include at least one pharmaceutically acceptable component, such as a suitable carrier or excipient, to provide an improved formulation of the compound.

[0020] As used herein, the term "subject" refers to a living organism treated with the compounds described herein, including, but not limited to, any mammal, such as humans, other primates, sport animals, commercially valuable animals such as cattle, farm animals such as horses, and pets such as dogs and cats.

[0021] The term "pharmaceutically acceptable" means that a substance does not possess properties that would prevent a reasonably prudent physician from administering it to a patient, taking into account the disease or disorder being treated and the respective route of administration. For example, such substances are often required to be essentially sterile, such as when used in injections. The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is biologically or otherwise necessary. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts containing inorganic acids and organic acids. Furthermore, when the compounds described herein are obtained in the crystalline form of an acid addition salt, the free base can be obtained by alkalizing a solution of the acid salt. Alternatively, when the product is a free base, addition salts, particularly pharmaceutically acceptable addition salts, can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional methods for preparing acid addition salts from base compounds. Various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts are known to those skilled in the art. Pharmaceutically acceptable acid addition salts can be prepared with inorganic and organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Salts derived from organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Similarly, pharmaceutically acceptable base addition salts can be prepared with inorganic and organic bases. For example, salts derived from inorganic bases include sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts.Salts derived from organic bases include salts of primary, secondary, and tertiary amines, such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tris(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(substituted alkyl)), dialkenylamines (i.e., NH2(substituted alkyl)3 ... Examples of suitable amines include, but are not limited to, cycloalkylamines (i.e., N(alkenyl)), substituted alkenylamines (i.e., NH(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)), tris(substituted alkenyl)amines (i.e., N(substituted alkenyl)), mono-, di-, or tricycloalkylamines (i.e., NH(cycloalkyl), HN(cycloalkyl), N(cycloalkyl)), mono-, di-, or triarylamines (i.e., NH(aryl), HN(aryl), N(aryl)), or mixed amines. Specific examples of suitable amines include, by way of example, isopropylamine, trimethylamine, diethylamine, tris(isopropyl)amine, tris(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylamine piperidine, and the like.

[0022] As used herein, the terms "therapeutically effective" or "effective amount" refer to a substance or amount of a substance effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or medical disorder and / or prolong the survival of the treated subject. The therapeutically effective amount will vary depending on the compound, the disease or disorder and its severity, as well as the age, weight, etc., of the mammal being treated. For example, an effective amount is an amount sufficient to achieve a beneficial or desired clinical result. An effective dose may be provided entirely in one administration, or a fraction of the effective dose may be provided in several administrations. The precise determination of what constitutes an effective amount may depend on individual factors for each subject, including the subject's size, age, injury, and / or disease or injury being treated, and the time since the injury occurred or the disease began. Those skilled in the art will be able to determine the effective amount for a given subject based on routine considerations in the art.

[0023] As used herein, when applied to a DSC heat map, the term "substantially as shown in the figure" is meant to include a variation of ±3°C, while when applied to a TGA, the term "substantially as shown in the figure" is meant to include a variation of ±2% weight loss.

[0024] In the context of using, testing, or screening compounds that are or may be modulators, the term "contacting" means that the compound is in sufficient proximity with a particular molecule, complex, cell, tissue, organism, or other particular substance that a potential binding interaction and / or chemical reaction can occur between the compound and the other particular substance.

[0025] Crystalline form of Compound I As described above, the present invention provides crystalline forms of Compound I. In some embodiments, the crystalline forms of Compound I are the free base compound or solvates of the free base compound. For example, the following crystalline forms 1, 2, 3, and 4 of Compound I are crystalline forms of Compound I as the free base compound or solvates of the free base compound.

[0026] Crystalline Form 1 of Compound I The XRPD of Form 1 of Compound I is characterized by peaks (±0.2°) at the following positions on a Cu-Kα diffractometer: 15.0, 22.6, 25.8, 32.0, and 41.3° 2θ. In some embodiments, the diffraction pattern includes one, two, three, or four or more peaks selected from the peaks at (±0.2°) 25.5, 27.1, 27.5, and 28.3° 2θ. In some embodiments, the diffraction pattern further comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 other peaks selected from the peaks at (±0.2°) 11.3, 15.8, 16.5, 19.5, 21.6, 23.3, 23.6, 28.8, 29.3, 29.7, 34.1, 36.6, and 41.3 degrees 2θ. Crystalline Form 1 is also characterized by XRPD, substantially as shown in Figure 1. In one embodiment, the present invention provides crystalline Form 1 of Compound I comprising two or more peaks (±0.2°) measured by a diffractometer using Cu-Kα radiation as described herein.

[0027] In some embodiments, crystalline Form 1 is also characterized by TGA, which primarily includes the heat map shown in Figure 2. As shown in the figure, Table 1 shows two weight loss steps. The first step is from room temperature to about 120°C, during which the weight loss is about 4.7%. The second weight loss is from about 120°C to about 180°C, during which the weight loss is about 3.8%.

[0028] In some embodiments, crystalline Form 1 is further characterized by a DSC curve, approximately as shown in Figure 3. As shown in the figure, crystalline Form 1 has two endothermic peaks and one exothermic peak. The first endothermic peak begins at about 93°C, peaks at about 102°C, and ends at about 107°C. This is due to the elution of water or residual solvent from the crystals. The second endothermic peak begins at about 138°C, peaks at about 158°C, and ends at about 167°C. This is due to the melting of water of crystallization due to evaporation. The exothermic peak begins at about 253°C, peaks at about 274°C, and ends at about 290°C. This is due to the decomposition of the compound.

[0029] In some embodiments, crystalline Form 1 further comprises: 1 It was characterized by its H NMR spectrum, which contains peaks at 9.2 ppm, 8.2 ppm, 8.0 ppm, 7.8 ppm, 7.3 ppm, 4.3 ppm, 2.5 ppm, and 1.2 ppm.

[0030] In some embodiments, crystalline Form 1 is a hydrate of Compound I, e.g., a dihydrate of Compound I.

[0031] Crystalline Form 2 of Compound I Crystalline Form 2 of Compound I is characterized by a powder X-ray diffraction pattern. The powder X-ray diffraction pattern contains peaks (±0.2°) at 6.7, 10.5, 17.0, 23.4, and 26.9 degrees 2θ as measured by a diffractometer using Cu-Kα radiation. In some embodiments, the diffraction pattern contains one, two, three, or four or more peaks selected from the peaks at (±0.2°) 14.8, 21.3, 28.4, and 29.8 degrees 2θ. In some embodiments, the diffraction pattern contains one, two, three, four, or eleven additional peaks selected from the peaks at (±0.2°) 23.8, 25.1, 25.7, 27.9, 30.4, 40.8, 33.4, 31.6, 28.9, 37.1, and 21.8 degrees 2θ. Crystalline Form 2 also has the basic XRPD characteristics, as shown in Figure 4. In one embodiment, the present invention provides crystalline Form 2 of Compound I, which contains two or more peaks (±0.2°) measured by a diffractometer using Cu-Kα radiation as described herein.

[0032] In some embodiments, crystalline Form 2 is also characterized by TGA, which primarily includes the heat map shown in Figure 5. As shown in Table 2, no significant weight loss was observed below 250°C. For example, from room temperature to about 120°C, the weight loss was only about 0.03%.

[0033] In some embodiments, crystalline Form 2 is further characterized by a DSC curve, primarily shown in Figure 6. As shown in the figure, Form 2 has one endothermic peak and one exothermic peak. The endothermic peak begins at about 253°C, peaks at about 256°C, and ends at about 260°C. The endothermic peak is due to the melting of crystalline Form 2.

[0034] In some embodiments, crystalline Form 2 is an anhydrous crystalline form of Compound I.

[0035] Crystalline Form 3 of Compound I The powder X-ray diffraction pattern of crystalline Form 3 of Compound I is characterized by peaks (±0.2°) at 16.2, 23.1, 28.0, and 31.8° 2θ as determined by a diffractometer using Cu-Kα radiation. The diffraction pattern includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 additional peaks (±0.2°) at 13.0, 14.5, 17.1, 19.6, 22.8, 24.1, 26.5, 26.9, 27.3, 30.1, and 30.5° 2θ. Crystalline Form 3 is also characterized by XRPD, primarily as shown in Figure 7. In one embodiment, the present invention provides crystalline Form 3 of Compound I containing two or more peaks (±0.2°) as measured by a diffractometer using Cu-Kα radiation as described herein.

[0036] In some embodiments, crystalline Form 3 is also characterized by TGA, including a heat map, approximately as shown in Figure 8. As shown in the figure, from about 120.0°C to about 214°C, crystalline Form 3 loses weight by about 4.5%.

[0037] In some embodiments, crystalline Form 3 is further characterized by a DSC curve, approximately as shown in FIG. 9. As shown in the figure, crystalline Form 3 has two endothermic peaks. The first endothermic peak begins at about 163°C, peaks at about 171°C, and ends at about 175°C. This peak is due to solvent escaping from the crystals. The second endothermic peak begins at about 248°C, peaks at about 251°C, and ends at about 258°C. This peak is due to the dissolution of crystalline Form 3. There is another exothermic peak after the first endothermic peak, which is due to a crystalline transition. In some embodiments, crystalline Form 3 is a solvate. In some embodiments, crystalline Form 3 is a monohydrate.

[0038] Crystalline Form 4 of Compound I The XRPD of crystalline Form 4 of Compound I is characterized by peaks at (±0.2°) 11.2, 22.4, 25.0, 27.4, and 29.1 degrees 2θ, as measured by a diffractometer using Cu-Kα radiation. In some embodiments, the diffraction pattern includes one, two, three, four, five, six, or more peaks selected from the peaks at (±0.2°) 17.2, 22.2, 23.7, 24.1, 27.1, and 30.7 degrees 2θ. In some embodiments, the diffraction pattern comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 additional peaks (±0.2°) selected from peaks at 12.8, 14.5, 15.3, 15.8, 16.4, 19.4, 25.8, 29.6, 30.5, 34.8, 36.6, and 41.0 degrees 2θ. Table 4 is also characterized by XRPD, generally as shown in Figure 10. In one embodiment, the present invention provides crystalline Form 4 of Compound I comprising two or more peaks (±0.2°) measured by a diffractometer using Cu-Kα radiation as described herein.

[0039] In some embodiments, crystalline Form 4 is also characterized by TGA, which primarily includes the heat map shown in Figure 11. As shown in Figure 4, Table 4 shows two weight loss steps. The first weight loss step is from room temperature to about 120°C, with a weight loss of about 2.4%. The second weight loss step is from about 120°C to about 172°C, with a weight loss of about 5.8%.

[0040] In some embodiments, crystalline Form 4 is further characterized by a DSC curve, approximately as shown in FIG. 12. As shown in the figure, Form 4 has three endothermic peaks. The first endothermic peak begins at about 85°C, peaks at about 102°C, and ends at about 110°C. The second endothermic peak begins at about 125°C, peaks at about 149°C, and ends at about 163°C. These two endothermic peaks are due to solvent escaping from the crystals. The third endothermic peak begins at about 253°C, peaks at about 256°C, and ends at about 260°C. This is due to the melting of crystalline Form 4. There are two exothermic peaks. The first exothermic peak begins at about 173°C, peaks at about 178°C, and ends at about 182°C. This is due to a crystalline transition. A second exothermic peak begins at about 267° C., peaks at about 278° C., and ends at about 289° C. This is due to decomposition of crystalline Form 4. In some embodiments, crystalline Form 4 is an unstable solvate.

[0041] Crystalline forms of salts of Compound I Compound I can form salts with suitable acids. For example, Compound I can form salts with hydrochloric acid (called hydrochloride), methanesulfonic acid (called mesylate), benzenesulfonic acid (called mesylate), sulfuric acid (called sulfate), nitric acid (called nitrate), or maleic acid (called maleate). Compound I can also form salts with suitable bases. For example, Compound I can form salts with potassium hydroxide (called potassium salt) or sodium hydroxide (called sodium salt). In some embodiments, the present specification provides solid crystalline forms or crystalline forms of salts such as Compound I.

[0042] Crystalline Form 5A of Compound I Crystalline Form 5A of Compound I is a crystalline form of a tetrahydrofuran solvate of the hydrochloride salt of Compound I. Crystalline Form 5A is characterized by an XRPD pattern containing peaks at (±0.2°) 13.5, 19.3, 20.2, 21.9, 25.0, 26.4, and 27.4 degrees 2θ as measured with a Cu-Kα diffractometer. In some embodiments, the diffraction pattern contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more peaks selected from the peaks at (±0.2°) 8.0, 14.0, 22.8, 23.9, 28.4, 28.7, 30.0, 31.7, 35.0, and 36.7. In some embodiments, the diffraction pattern comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 additional peaks selected from the peaks at (±0.2°) 14.9, 15.4, 15.9, 16.8, 17.7, 22.3, 24.2, 30.3, 32.1, 33.1, 34.5, 36.4, and 37.8 degrees 2θ. Crystalline Form 5A is also characterized by XRPD, as shown in Figure 13A. In one embodiment, the present invention provides crystalline Form 5A of Compound I comprising two or more peaks (±0.2°) measured by a diffractometer using Cu-Kα radiation as described herein.

[0043] In some embodiments, crystalline Form 5A is also characterized by TGA, which comprises a heat map substantially similar to that shown in Figure 14A. As shown in the figure, crystalline Form 5A exhibits two weight loss steps. Step 1 is from room temperature to about 120°C, resulting in a weight loss of about 1.3%. A second weight loss occurs between 120°C and 190°C, resulting in a weight loss of about 14.2%.

[0044] In some embodiments, crystalline Form 5A is further characterized by a DSC curve, approximately as shown in Figure 15A. As shown in the figure, crystalline Form 5A has two endothermic peaks and one exothermic peak. The first endothermic peak begins at about 126°C, peaks at about 140°C, and ends at about 164°C. The second endothermic peak begins at about 222°C, has one peak at about 246°C, and ends at about 252°C. This is due to melting. The exothermic peak begins at about 258°C, has one peak at about 266°C, and ends at about 282°C. This is due to decomposition of the compound.

[0045] In some embodiments, crystalline form 5A is further characterized by a H NMR spectrum comprising peaks at 9.1 ppm, 8.2 ppm, 8.1 ppm, 8.0 ppm, 7.5 ppm, 3.6 ppm, 2.6 ppm, 2.5 ppm, 1.8 ppm, 1.2 ppm.

[0046] Crystalline Form 5B of Compound I Crystalline Form 5B of Compound I is a crystalline form of an acetone solvate of the hydrochloride salt of Compound I. Crystalline Form 5B is characterized by an XRPD pattern containing peaks at (±0.2°) 10.94, 17.62, 25.32, 26.46, and 27.30 degrees 2θ as measured with a Cu-Kα diffractometer. In some embodiments, the diffraction pattern further contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 peaks selected from the following peaks at (±0.2°) 6.5, 9.4, 12.3, 12.9, 18.7, 19.3, 19.7, 21.2, 21.8, 33.6, 35.8, 37.0, and 39.1 degrees 2θ. In some embodiments, the diffraction pattern comprises one, two, three, four, five, six, seven, eight, or nine additional peaks selected from those at (±0.2°) 14.9, 23.3, 23.7, 24.7, 27.7, 29.0, 29.5, 31.7, and 35.0 degrees 2θ. Crystalline Form 5B is also characterized by XRPD, as shown in Figure 13B. In one embodiment, the present invention provides crystalline Form 5B of Compound I comprising two or more peaks (±0.2°) measured by a diffractometer using Cu-Kα radiation as described herein.

[0047] In some embodiments, crystalline form 5B is also characterized by TGA, which comprises a heat map approximately as shown in Figure 14B. As shown in Figure 14B, one weight loss step is from room temperature to about 180°C, and the weight loss is about 15%.

[0048] In some embodiments, crystalline form 5B is further characterized by a DSC curve, approximately as shown in Figure 15B. As shown in the figure, crystalline form 5B has two endothermic peaks and one exothermic peak. The first endothermic peak begins at about 102°C, peaks at about 113°C, and ends at about 121°C. The second endothermic peak begins at about 233°C, peaks at about 249°C, and ends at about 254°C. This is due to melting. The exothermic peak begins at about 258°C, peaks at about 267°C, and ends at about 283°C. This is due to decomposition of the compound.

[0049] In some embodiments, crystalline form 5B further comprises: 1 It was characterized by its H NMR spectrum, which contains peaks at 9.2 ppm, 8.2 ppm, 8.1 ppm, 8.0 ppm, 7.5 ppm, 2.6 ppm, 2.5 ppm, and 1.2 ppm.

[0050] Crystalline Form 5C of Compound I Crystalline Form 5C of Compound I is a crystalline form of a methanol solvate of the hydrochloride salt of Compound I. Crystalline Form 5C is characterized by an XRPD pattern containing peaks at (±0.2°) 14.6, 15.9, 19.3, 27.9, and 29.2 degrees 2θ, as measured with a Cu-Kα diffractometer. In some embodiments, the diffraction pattern contains one, two, three, four, five, six, or more peaks selected from the peaks at (±0.2°) 11.4, 12.7, 17.1, 22.2, 25.5, 25.9, and 27.2 degrees 2θ. In some embodiments, the diffraction pattern comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 additional peaks selected from those at (±0.2°) 32.1, 33.5, 34.1, 36.7, 37.5, and 37.9 degrees 2θ. Crystalline Form 5C is also characterized by XRPD, approximately as shown in Figure 13C. In one embodiment, the present invention provides crystalline Form 5C of Compound I comprising two or more peaks (±0.2°) measured by a diffractometer using Cu-Kα radiation as described herein.

[0051] In some embodiments, crystalline Form 5C is also characterized by TGA, which comprises a heat map substantially similar to that shown in Figure 14C. As shown in the figure, crystalline Form 5C exhibits two weight loss steps. Step 1 is from room temperature to about 120°C, resulting in a weight loss of about 1.3%. Step 2 is from 120°C to 236°C, resulting in a weight loss of about 4.6%.

[0052] In some embodiments, crystalline form 5C is further characterized by a DSC curve, approximately as shown in Figure 15C. As shown in the figure, crystalline form 5C has two endothermic peaks and one exothermic peak. The first endothermic peak begins at about 154°C, peaks at about 164°C, and ends at about 172°C. The second endothermic peak begins at about 184°C, peaks at about 202°C, and ends at about 213°C. This is due to melting. The exothermic peak begins at about 254°C, peaks at about 272°C, and ends at about 287°C. This is due to decomposition of the compound.

[0053] Crystalline Form 5D of Compound I Crystalline Form 5D of Compound I is a crystalline form of the anhydrous hydrochloride salt of Compound I. Crystalline Form 5D is characterized by an XRPD pattern containing peaks at (±0.2°) 12.6, 14.4, 15.9, 22.0, 23.0, 27.0, 27.7, and 29.6 degrees 2θ, as measured with a Cu-Kα diffractometer. In some embodiments, the diffraction pattern further contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 peaks selected from the group consisting of peaks at (±0.2°) 9.6, 11.4, 16.7, 18.1, 19.1, 20.3, 24.0, 25.4, 28.6, 30.1, 31.7, 32.4, and 33.5 degrees 2θ. Crystalline Form 5D has also been characterized by XRPD, generally as shown in Figure 13D. In one embodiment, the present invention provides crystalline Form 5D of Compound I, which contains two or more peaks (±0.2°) measured by a diffractometer using Cu-Kα radiation as described herein.

[0054] In some embodiments, crystalline Form 5D is also characterized by TGA, which primarily includes the heat map shown in Figure 14D. As shown in the figure, Form 5D exhibits two weight loss steps. Step 1 is from room temperature to about 120°C, resulting in a weight loss of about 0.4%. Step 2 is from 120°C to 210°C, resulting in a weight loss of about 4%.

[0055] In some embodiments, crystalline form 5D is further characterized by a DSC curve, approximately as shown in Figure 15D. As shown in the figure, crystalline form 5D exhibits one endothermic peak and one exothermic peak. The endothermic peak begins at about 182°C, peaks at about 197°C, and ends at about 210°C, which is attributed to melting. The exothermic peak begins at about 253°C, peaks at about 273°C, and ends at about 289°C, which is attributed to decomposition of the compound.

[0056] In some embodiments, crystalline form 5D further comprises: 1 It was characterized by its H NMR spectrum, which contains peaks at 9.1 ppm, 8.2 ppm, 8.0 ppm, 7.9 ppm, 7.4 ppm, 2.6 ppm, and 1.2 ppm.

[0057] Crystalline Form 6 of Compound I Crystalline Form 6 of Compound I is a crystalline form of the mesylate salt of Compound I. Form 6 is characterized by XRPD peaks at 15.9, 20.6, 24.2, 24.5, 25.8, 26.8, and 30.4 degrees 2θ (±0.2°) measured by a diffractometer using Cu-Kα radiation. The diffraction pattern includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 additional peaks selected from the peaks at (±0.2°) 9.1, 14.8, 15.5, 17.3, 19.8, 23.5, 26.1, 28.0, 28.4, 31.7, and 36.3 degrees 2θ. Form 6 can also be characterized by XRPD, as shown in Figure 16. In one embodiment, the present invention provides crystalline Form 6 of Compound I, which contains two or more peaks (±0.2°) measured by a diffractometer using Cu-Kα radiation as described herein.

[0058] In some embodiments, crystalline Form 6 is also characterized by TGA, including a heat map, approximately as shown in Figure 17. As can be seen from Table 6, there is one weight loss step from room temperature to about 128°C, and the weight loss is about 3.7%.

[0059] In some embodiments, crystalline Form 6 is further characterized by a DSC curve, approximately as shown in Figure 18. As shown in the figure, crystalline Form 6 has two endothermic peaks. The first endothermic peak begins at about 129°C, peaks at about 151°C, and ends at about 158°C and is due to the outflow of water from the crystals. The second endothermic peak begins at about 257°C, peaks at about 260°C, and is due to the accompanying melting. The exothermic peak appears at about 264°C and is due to the decomposition of the compound. In some embodiments, crystalline Form 6 is a hydrate.

[0060] Crystalline Form 7 of Compound I As determined by diffractometry using Cu-Kα radiation, crystalline Form 7 of Compound I is a crystalline form of the benzoate salt of Compound I. The XRPD of Form 7 is characterized by peaks at 7.0, 14.0, 14.6, 16.5, 22.1, 22.5, 22.8, 24.8, 26.1, and 28.5 degrees 2θ (±0.2 degrees). The diffraction pattern comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 additional peaks selected from those at (±0.2°) 15.2, 17.0, 17.9, 20.6, 21.0, 21.5, 23.2, 26.7, 26.9, 28.1, 29.4, 31.3, 35.1, 36.5, 36.9, and 38.0 degrees 2θ. Crystalline Form 7 is also characterized by XRPD, as shown in Figure 19. In one embodiment, the present invention provides crystalline Form 7 of Compound I comprising two or more peaks (±0.2°) measured by a diffractometer using Cu-Kα radiation as described herein.

[0061] In some embodiments, crystalline Form 7 is further characterized by TGA, including a heat map, approximately as shown in Figure 20. As shown in the figure, crystalline Form 7 has no apparent weight loss up to about 120°C.

[0062] In some embodiments, crystalline Form 7 is further characterized by a DSC curve, approximately as shown in Figure 21. As shown in Figure 7, Form 7 has one endothermic peak with an onset temperature of about 255°C, a peak value of about 259°C, and an end temperature of about 263°C, which is due to the melting of crystalline Form 7. An exothermic peak appears at about 264°C, which is due to the decomposition of the compound.

[0063] In some embodiments, crystalline form 7 is an anhydrous crystalline form of compound 1.

[0064] Crystalline Form 8 of Compound I Crystalline Form 8 of Compound I is a crystalline form of the sulfate salt of Compound I. Crystalline Form 8 is characterized by an XRPD pattern containing peaks at 14.7, 15.2, 19.0, 20.4, 22.7, 23.3, 24.6, 25.0, 26.9, and 30.5 degrees 2θ (±0.2°) (measured by a diffractometer using Cu-Kα radiation). The diffraction pattern contains one, two, three, four, five, or six additional peaks selected from the peaks at 16.9, 17.2, 27.9, 28.9, and 30.9 degrees 2θ (±0.2°). As shown in Figure 22, Crystalline Form 8 is also characterized by XRPD. In one embodiment, the present invention provides Crystalline Form 8 of Compound I containing two or more peaks at ±0.2° (measured by a diffractometer using Cu-Kα radiation as described herein).

[0065] In some embodiments, crystalline Form 8 is also characterized by TGA, which primarily comprises the heat map shown in Figure 23. As shown in the figure, there is no apparent weight loss for crystalline Form 8 up to about 231°C.

[0066] In some embodiments, crystalline form 8 is further characterized by a DSC curve, approximately as shown in Figure 24. As shown in the figure, crystalline form 8 has one endothermic peak with an onset temperature of about 238°C, a peak value of about 253°C, and an end temperature of about 247°C, which is due to the melting of crystalline form 8.

[0067] In some embodiments, crystalline form 8 is an anhydrous crystalline form of compound 1.

[0068] Crystalline Form 9 of Compound I Crystalline Form 9 of Compound I is a crystalline form of the nitrate salt of Compound I. The XRPD of Crystalline Form 9 is characterized by peaks at 14.3, 16.1, 22.7, 23.8, 26.7, 27.4, and 29.7 degrees 2θ (±0.2 degrees) measured by a diffractometer using Cu-Kα radiation. The diffraction pattern comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 additional peaks selected from the peaks at (±0.2°) 9.6, 12.4, 12.8, 15.6, 16.7, 19.1, 20.5, 21.7, 24.8, 25.5, 25.9, 28.7, 31.4, 32.6, 33.1, 33.8, 37.1, and 39.2 degrees 2θ. Crystalline Form 9 is also characterized by XRPD, as shown in Figure 25. In one embodiment, the present invention provides crystalline Form 9 of Compound I comprising two or more peaks (±0.2°) measured by a diffractometer using Cu-Kα radiation as described herein.

[0069] In some embodiments, crystalline Form 9 is also characterized by TGA, including the heat map shown in Figure 26. As shown in Figure 9, the first weight loss step is from room temperature to about 120°C, with a weight loss of about 0.3%. Crystalline Form 9 further exhibits a second weight loss step from about 120°C to about 216°C, with a weight loss of about 8%.

[0070] In some embodiments, crystalline form 9 is further characterized by a DSC curve, approximately as shown in Figure 27. As shown in the figure, crystalline form 9 has one endothermic peak that begins at about 164°C, peaks at about 172°C, and ends at about 178°C, which is due to the melting of crystalline form 9. Table 9 also shows one exothermic peak that begins at about 245°C, peaks at about 271°C, and ends at about 289°C, which is due to the decomposition of the compound.

[0071] In some embodiments, crystalline form 9 is an anhydrous crystalline form of compound 1.

[0072] Crystalline Form 10 of Compound I Crystalline Form 10 is a crystalline form of the maleate salt of Compound I. Crystalline Form 10 is characterized by an XRPD pattern containing peaks (±0.2°) at 9.7, 14.8, 16.1, 19.4, 20.9, 23.1, 24.1, 25.4, 27.1, 28.0, 29.4, 30.2, and 30.5 degrees 2θ (measured with a Cu-K diffractometer). The diffraction pattern contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 additional peaks selected from the peaks at (±0.2°) 11.6, 12.2, 14.5, 17.0, 18.2, 20.4, 21.9, 23.6, 26.0, 31.7, 32.4, 33.5, and 39.6 degrees 2θ. Crystalline Form 10 has also been characterized by XRPD, as shown in Figure 28. In one embodiment, the present invention provides crystalline Form 10 of Compound I, which contains two or more peaks (±0.2°) measured by a diffractometer using Cu-Kα radiation as described herein.

[0073] In some embodiments, crystalline form 10 is also characterized by TGA, including the heat map shown in Figure 29. As shown in Figure 10, the first weight loss step is from room temperature to about 120°C, resulting in a weight loss of about 0.2%. Table 10 further shows a second weight loss step from about 120°C to about 242°C, resulting in a weight loss of about 18.4%.

[0074] In some embodiments, crystalline form 10 is further characterized by a DSC curve, approximately as shown in Figure 30. As shown in the figure, crystalline form 10 has one endothermic peak that begins at about 167°C, peaks at about 178°C, and ends at about 184°C. This is due to the melting and decomposition of crystalline form 10.

[0075] In some embodiments, crystalline form 10 is an anhydrous crystalline form of Compound 1.

[0076] Crystalline Form 11 of Compound I Crystalline Form 11 of Compound I is a crystalline form of the potassium salt of Compound I. The XRPD of Crystalline Form 11 is characterized by peaks at 11.4, 17.1, 19.5, 24.9, 27.0, 27.6, and 29.0 degrees 2θ (±0.2 degrees) as measured by a diffractometer using Cu-Kα radiation. The diffraction pattern comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 additional peaks selected from those at (±0.2°) 7.7, 9.1, 14.4, 15.9, 18.1, 22.9, 23.2, 24.1, 25.3, 26.4, 29.8, 30.5, 31.0, 31.6, 32.0, 33.6, 34.2, 36.3, and 38.6 degrees 2θ. As shown in Figure 31, crystalline form 11 also possesses essential XRPD characteristics. In one embodiment, the present invention provides crystalline form 11 of Compound I comprising two or more peaks (±0.2°) measured by a diffractometer using Cu-Kα radiation as described herein.

[0077] In some embodiments, crystalline form 11 is also characterized by TGA, including a heat map, approximately as shown in Figure 32. As shown in the figure, crystalline form 11 does not exhibit a substantial weight loss step, e.g., only about 0.2% weight loss from room temperature to about 120°C.

[0078] In some embodiments, crystalline form 11 is further characterized by a DSC curve, approximately as shown in Figure 33. As shown in the figure, crystalline form 11 has one exothermic peak that begins at about 368°C, peaks at about 373°C, and ends at about 378°C, which is due to decomposition of the compound.

[0079] In some embodiments, crystalline form 11 is an anhydrous crystalline form of compound 1.

[0080] Crystalline Form 12 of Compound I Crystalline Form 12 of Compound I is a crystalline form of the sodium salt of Compound I. The XRPD of Crystalline Form 12 is characterized by peaks at (±0.2°) 13.2, 16.0, 16.5, 16.9, 17.9, 20.6, 22.1, 24.4, 25.3, 27.0, and 29.0 degrees 2θ, as measured by a diffractometer using Cu-Kα radiation. The diffraction pattern includes 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional peaks selected from the peaks at (±0.2°) 7.3, 9.0, 10.0, 11.0, 13.7, 20.1, 24.1, 27.7, 28.1, 30.6, and 32.3 degrees 2θ. Crystalline Form 12 can also be characterized by XRPD, as shown in Figure 34. In one embodiment, the present invention provides crystalline form 12 of Compound I, which contains two or more peaks (±0.2°) measured by a diffractometer using Cu-Kα radiation as described herein.

[0081] In some embodiments, crystalline Form 1 is also characterized by TGA, including the heat maps shown in Figure 35A or Figure 35B. In some embodiments, crystalline Form 12 is further characterized by a DSC curve, approximately shown in Figure 36A or 36B. Figures 35A and 36A were obtained by analyzing crystalline Form 12 prepared in THF as a solvent, while Figures 35B and 36B are analytical results for crystalline Form 12 prepared in acetone.

[0082] As shown in Figure 35A, Table 12 (derived from THF) shows one weight loss step from room temperature to approximately 150°C, with a weight loss of approximately 11.6%. Another weight loss step appears from approximately 150°C to approximately 227°C. Furthermore, as shown in Figure 36A, Table 12 (derived from THF) shows two endothermic peaks. The first endothermic peak begins at approximately 80°C, peaks at approximately 95°C, and ends at approximately 108°C. The second endothermic peak begins at approximately 128°C, peaks at approximately 142°C, and ends at approximately 152°C. Both endothermic peaks are due to the loss of solvent in the crystals. Table 12 also shows one exothermic peak, which begins at approximately 373°C, peaks at approximately 381°C, and ends at approximately 387°C. This is due to the decomposition of the compound.

[0083] As shown in Figure 35B, from room temperature to about 150°C, crystalline form 12 (acetone) exhibits one weight loss step, with a weight loss of about 8.8%. Furthermore, as shown in Figure 36B, crystalline form 12 (derived from acetone) exhibits two endothermic peaks. The first endothermic peak begins at about 87°C, peaks at about 107°C, and ends at about 114°C. The second endothermic peak begins at about 116°C, peaks at about 137°C, and ends at about 165°C. Both endothermic peaks are due to the loss of solvent during crystallization.

[0084] In some embodiments, crystalline form 12 includes water in its crystalline structure.

[0085] composition In one embodiment, the present invention provides a composition comprising two or more compounds selected from Crystalline Form 1 of Compound I, Crystalline Form 2 of Compound I, Crystalline Form 3 of Compound I, Crystalline Form 4 of Compound I, Crystalline Form 5A of Compound I, Crystalline Form 5B of Compound I, Crystalline Form 5C of Compound I, Crystalline Form 5D of Compound I, Crystalline Form 6 of Compound I, Crystalline Form 7 of Compound I, Crystalline Form 8 of Compound I, Crystalline Form 9 of Compound I, Crystalline Form 10 of Compound I, Crystalline Form 11 of Compound I, and Crystalline Form 12 of Compound I, as described herein.

[0086] In another embodiment, the composition comprises crystalline Form 1 of Compound I, crystalline Form 2 of Compound I, crystalline Form 3 of Compound I, crystalline Form 4 of Compound I, crystalline Form 5A of Compound I, crystalline Form 5B of Compound I, crystalline Form 5C of Compound I, crystalline Form 5D of Compound I, crystalline Form 6 of Compound I, crystalline Form 7 of Compound I, crystalline Form 8 of Compound I, crystalline Form 9 of Compound I, crystalline Form 10 of Compound I, crystalline Form 11 of Compound I, or crystalline Form 12 of Compound I. In another embodiment, the composition comprises Compound I, wherein at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% w / w of Compound I is crystalline Form 1. In another embodiment, the composition comprises Compound I, wherein at least 90%, 95% w / w of Compound I is crystalline Form 1. In another embodiment, the composition comprises Compound I, wherein at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% w / w of Compound I is crystalline Form 2. In another embodiment, the composition comprises Compound I, wherein at least 90%, 95% w / w of Compound I is crystalline Form 2. In another embodiment, the composition comprises Compound I, wherein at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% w / w of Compound I is crystalline Form 3. In another embodiment, the composition comprises Compound I, wherein at least 90%, 95% w / w of Compound I is crystalline Form 3. In another embodiment, the composition comprises Compound I, wherein at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% w / w of Compound I is crystalline Form 4. In another embodiment, the composition comprises Compound I, wherein at least 90%, 95% w / w of Compound I is crystalline Form 4. In another embodiment, the composition comprises Compound I, wherein at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% w / w of Compound I is crystalline Form 5A.In another embodiment, the composition comprises Compound I, wherein at least 90%, 95% w / w of Compound I is crystalline form 5A. In another embodiment, the composition comprises Compound I, wherein at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% w / w of Compound I is crystalline form 5B. In another embodiment, the composition comprises Compound I, wherein at least 90%, 95% w / w of Compound I is crystalline form 5B. In another embodiment, the composition comprises Compound I, wherein at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% w / w of Compound I is crystalline form 5C. In another embodiment, the composition comprises Compound I, wherein at least 90%, 95% w / w of Compound I is crystalline form 5C. In another embodiment, the composition comprises Compound I, wherein at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% w / w of Compound I is crystalline form 5D. In another embodiment, the composition comprises Compound I, wherein at least 90%, 95% w / w of Compound I is crystalline form 5D. In another embodiment, the composition comprises Compound I, wherein at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% w / w of Compound I is crystalline form 6. In another embodiment, the composition comprises Compound I, wherein at least 90%, 95% w / w of Compound I is crystalline Form 6. In another embodiment, the composition comprises Compound I, wherein at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% w / w of Compound I is crystalline Form 7. In another embodiment, the composition comprises Compound I, wherein at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% w / w of Compound I is crystalline Form 8.In another embodiment, the composition comprises Compound I, wherein at least 90%, 95% w / w of Compound I is crystalline form 8. In another embodiment, the composition comprises Compound I, wherein at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% w / w of Compound I is crystalline form 9. In another embodiment, the composition comprises Compound I, wherein at least 90%, 95% w / w of Compound I is crystalline form 9. In another embodiment, the composition comprises Compound I, wherein at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% w / w of Compound I is crystalline form 10. In another embodiment, the composition comprises Compound I, wherein at least 90%, 95% w / w of Compound I is crystalline form 10. In another embodiment, the composition comprises Compound I, wherein at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% w / w of Compound I is crystalline form 11. In another embodiment, the composition comprises Compound I, wherein at least 90%, 95% w / w of Compound I is crystalline form 11. In another embodiment, the composition comprises Compound I, wherein at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% w / w of Compound I is crystalline form 12. In another embodiment, the composition comprises Compound I, wherein at least 90%, 95% w / w of Compound I is in crystalline form 12.

[0087] In another embodiment, there is provided a composition comprising crystalline Form 1 of Compound I and crystalline Form 2 of Compound I. In another embodiment, the composition comprises at least 50% w / w of crystalline Form 2 of Compound I.

[0088] In another embodiment, a composition comprising Compound I is provided, wherein at least 85%, or at least 85%, or at least 90%, or at least 95%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5% of Compound I in the composition is present as crystalline Form 2 of Compound I. In another embodiment, the composition comprising crystalline Form 2 of Compound I is substantially unchanged after at least about 6 months, or 12 months, or 24 months, or 36 months, or 48 months. In another embodiment, the composition comprising crystalline Form 2 of Compound I is substantially unchanged after about 6 months at 40° C.±2° C. (optionally 75% RH±5% RH). In another embodiment, the composition comprising crystalline Form 2 of Compound I is substantially unchanged after 6 months, or 12 months, or 24 months, or 36 months, or 48 months. In another embodiment, at 25°C ± 2°C / 60% RH ± 5% RH, a composition comprising crystalline Form 2 of Compound I is substantially unchanged after 6 months, or 12 months, or 24 months, or 36 months, or 48 months.

[0089] Formulation and Administration In another aspect, the present invention provides pharmaceutical compositions comprising / containing a pharmaceutically acceptable carrier or excipient and a crystalline form of Compound I described herein. In one exemplary embodiment, the present invention provides a pharmaceutical composition (or, interchangeably, a "formulation") comprising crystalline Form 1 of Compound I, crystalline Form 2 of Compound I, crystalline Form 3 of Compound I, crystalline Form 4 of Compound I, crystalline Form 5A of Compound I, crystalline Form 5B of Compound I, crystalline Form 5C of Compound I, crystalline Form 5D of Compound I, crystalline Form 6 of Compound I, crystalline Form 7 of Compound I, crystalline Form 8 of Compound I, crystalline Form 9 of Compound I, crystalline Form 10 of Compound I, crystalline Form 11 of Compound I, or crystalline Form 12 of Compound I described herein.

[0090] These crystalline forms are typically used to treat human subjects. However, they can also be used to treat similar or identical indications in other animal subjects. The solid, crystalline, or polymorphic forms of Compound I described herein can be administered by a variety of routes, including injection (i.e., parenteral, including intravenous, intraperitoneal, subcutaneous, and intramuscular), oral, transdermal, mucosal, rectal, or inhalation. Such dosage forms must allow the compound to reach target cells. Other factors are well known in the art and include considerations such as toxicity and dosage forms that prevent the compound or composition from exerting its effects. Techniques and formulations are generally described in Remington's Pharmaceutical Sciences, 21st Edition. edition, Lippincott, Williams & Wilkins, Philadelphia, PA, 2005 (hereby incorporated by reference).

[0091] In some embodiments, the composition comprises one or more of crystalline Form 1 of Compound I, crystalline Form 2 of Compound I, crystalline Form 3 of Compound I, crystalline Form 4 of Compound I, crystalline Form 5A of Compound I, crystalline Form 5B of Compound I, crystalline Form 5C of Compound I, crystalline Form 5D of Compound I, crystalline Form 6 of Compound I, crystalline Form 7 of Compound I, crystalline Form 8 of Compound I, crystalline Form 9 of Compound I, crystalline Form 10 of Compound I, crystalline Form 11 of Compound I, and crystalline Form 12 of Compound I, each having a particular particle size. In some embodiments, particle size has a significant impact on bioavailability. In some embodiments, the composition comprises a solid crystalline form described herein having a particle size of about 1 nm to about 500 μm. In some embodiments, the composition comprises a solid crystalline form described herein having a particle size of about 1 nm to about 100 μm. In some embodiments, the composition comprises a solid crystalline form described herein having a particle size of about 1 nm to about 75 μm. In some embodiments, the composition comprises a solid crystalline form described herein having a particle size of about 1 nm to about 50 μm. In some embodiments, the composition comprises a solid crystalline form described herein having a particle size of about 1 nm to about 20 μm. In some embodiments, the composition comprises a solid crystalline form described herein having a particle size of about 1 nm to about 10 μm. In some embodiments, the composition comprises a solid crystalline form described herein having a particle size of about 1 nm to about 5 μm. In some embodiments, the composition comprises a solid crystalline form described herein having a particle size of about 1 nm to about 1 μm. In some embodiments, the composition comprises a solid crystalline form described herein having a particle size of about 1 nm to about 100 nm. In some embodiments, the composition comprises a solid crystalline form described herein having a particle size of about 1 nm to about 50 nm. In some embodiments, the composition comprises a solid crystalline form described herein having a particle size of about 1 nm to about 20 nm. In some embodiments, the composition comprises a solid crystalline form described herein having a particle size of about 1 nm to about 10 nm. In some embodiments, the desired particle size is achieved by performing a homogenization step such as milling, sonication, or other similar operations. In some embodiments, the desired particle size is fine-tuned by controlling the wavelength and intensity of the ultrasound.

[0092] In some embodiments, the composition includes a pharmaceutically acceptable carrier or excipient, such as a filler, binder, disintegrant, lubricant, complexing agent, solubilizer, and surfactant, which may be selected to facilitate administration of the compound by a particular route. Examples of carriers include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, starches, cellulose derivatives, gelatin, lipids, liposomes, nanoparticles, and the like. Carriers also include physiologically compatible liquids as solvents or suspensions, including, for example, sterile water for injection (WFI) solution, saline solution, glucose solution, Hank's solution, Ringer's solution, vegetable oils, mineral oils, animal oils, polyethylene glycol, liquid paraffin, and the like.Examples of excipients include colloidal silica, silica gel, talc, magnesium silicate, calcium silicate, sodium aluminum silicate, magnesium trisilicate, powdered cellulose, microcrystalline cellulose, carboxymethylcellulose, croscarmellose sodium, sodium benzoate, calcium carbonate, magnesium carbonate, stearic acid, aluminum stearate, calcium stearate, magnesium stearate, zinc stearate, sodium stearoyl fumarate, gum, stearate C, magnesium oxide, starch, sodium starch glycolate, glyceryl monostearate, glyceryl diphenylcinnamate, glyceryl palmitate, hydrogenated vegetable oil, hydrogenated cottonseed oil, castor oil, mineral oil, polyethylene glycol (PEG4000-8000, etc.), polyoxyethylene glycol, polyoxyamine, povidone, cros ... The composition may further comprise sodium roscosate, alginic acid, casein, methacrylate divinylbenzene copolymer, docusate sodium, cyclodextrin (such as 2-hydroxypropyl-triangular cyclodextrin), polysorbate (such as polysorbate 80), melamine, TPGS (d-α-tocopherol polyethylene glycol 1000 succinate), magnesium lauryl sulfate, sodium lauryl sulfate, polyethylene glycol ether, polyethylene glycol difatty acid ester, or polyoxyalkyl sorbitol fatty acid ester (e.g., Polyoxyethylene Sorbitol Ester Tween®), polyoxyethylene sorbitol fatty acid ester, sorbitol fatty acid ester of fatty acids from oleic acid, stearic acid, or palmitic acid, mannitol, xylitol, sorbitol, maltose, lactose, etc. Lactose monohydrate or spray-dried lactose, sucrose, fructose, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, dextrin, glucose, cellulose acetate, maltodextrin, simethicone, polydextrose, chitosan, gelatin, HPMC (hydroxypropyl methylcellulose), HPC (hydroxypropyl fiber cellulose), hydroxyethyl cellulose, etc.

[0093] Pharmaceutical compositions or formulations may be provided in unit-dose crystalline form, with each unit-dose containing a predetermined amount of the active ingredient. Such units may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, and more preferably 5 mg to 100 mg of the solid, crystalline, or polymorphic form of Compound I of the present invention, depending on the disorder being treated, the route of administration, and the age, weight, and condition of the patient. Preferred unit-dose formulations are those containing a daily dose, weekly dose, monthly dose, single dose, or an appropriate fraction thereof, of the active ingredient. Furthermore, these pharmaceutical compositions or formulations can be prepared by any method well known in the art of pharmacy.

[0094] Pharmaceutical compositions or formulations can be administered by any suitable route, such as oral administration (capsules, tablets, liquid-filled capsules, disintegrating tablets, immediate-release tablets, sustained-release tablets, and controlled-release tablets, oral strips, solutions, syrups, oral and sublingual), rectal, nasal, inhalation, topical (including transdermal), or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes. Such formulations can be prepared by any method known in the pharmaceutical arts, such as by combining the active ingredient with a carrier, excipient, or diluent. Typically, carriers, excipients, or diluents used in pharmaceutical formulations are "non-toxic," meaning that they are considered safe in the amounts delivered in the pharmaceutical composition and are "inert," meaning that they do not significantly react with or adversely affect the therapeutic activity of the active ingredient.

[0095] In some embodiments, oral administration may be used. Pharmaceutical preparations for oral administration may be formulated into conventional oral dosage forms, such as individual unit capsules, tablets, and liquid preparations such as syrups, elixirs, and concentrated drops. The compounds described herein may be combined with solid excipients, and the resulting mixture may be optionally milled, and the granular mixture may be processed after adding suitable auxiliary agents (if necessary) to obtain, for example, tablets, coated tablets, hard capsules, soft capsules, solutions (e.g., aqueous solutions, alcoholic solutions, oily solutions), etc. Particularly suitable excipients include sugar fillers, such as lactose, glucose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, xanthan, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose (CMC), and / or polyvinylpyrrolidone (PVP: povidone); and oily excipients, including vegetable and animal oils, such as sunflower oil, olive oil, or cod liver oil. Oral dosage formulations may contain disintegrating agents such as cross-linked polyvinylpyridone, agar, or alginic acid or a salt thereof, such as sodium alginate; lubricants such as talc or magnesium stearate; plasticizers such as glycerol or sorbitol; sweeteners such as sucrose, fructose, lactose, or aspartame; flavorings, natural or artificial flavors such as peppermint, wintergreen oil, or cherry flavor; or dyes or pigments that can be used to identify or characterize different doses or combinations, such as unit doses. Cores can also be provided with appropriate coatings. For this purpose, concentrated sugar solutions, optionally containing gum arabic, talc powder, polyvinylpyrrolidone, carpofol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures, can be used. Oral liquids, such as solutions, syrups, and elixirs, can be prepared in crystalline form in dosage units, so that a given amount contains a predetermined amount of solid, crystalline, or polymorphic form of Compound I.

[0096] Pharmaceutical preparations for oral administration include push-fit capsules ("gelcaps") made of gelatin and soft, sealed capsules made of gelatin and a plasticizer (such as glycerol or sorbitol). Push-fit capsules may contain the active ingredient and a mixture of fillers such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate, and optional stabilizers. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol.

[0097] The amount of various compounds to be administered can be determined by standard procedures, taking into account, for example, the activity of the compound (in vitro, e.g., the compound's IC50 and target, or in vivo activity in an animal efficacy model), pharmacokinetic results in the animal model (e.g., biological half-life or bioavailability), the subject's age, size, and weight, and any associated disease in the subject. The importance of these and other factors is well known to those skilled in the art. Typically, the dose may range from about 0.01 to 50 mg / kg or from about 0.1 to 20 mg / kg of the subject being treated. Multiple doses may be used.

[0098] The solid, crystalline, or polymorphic forms of Compound I described herein can also be used in combination with other therapies used to treat the same disease. Such combinations include administering the compound and one or more other therapies at different times, or administering the compound and one or more other therapies simultaneously. In some embodiments, the dosage of one or more crystalline forms of Compound I or other combined therapies can be modified, for example, by reducing the dosage compared to the compound or therapy used alone, by methods known to those skilled in the art.

[0099] It should be understood that combination includes use with other therapies, drugs, medical procedures, etc., where the other therapies or procedures may be administered at different times (e.g., within a short period of time, such as within a few hours (e.g., 1, 2, 3, 4-24 hours) or for a longer period of time (e.g., 1-2 days, 2-4 days, 4-7 days, 1-4 weeks) than the compounds described herein, or are administered simultaneously with the compounds described herein. Combination also includes use with treatments or medical procedures (e.g., surgery) that are administered once or infrequently, as well as with compounds described herein that are administered shortly or long-term before or after the other treatment or procedure. In some embodiments, the present invention provides for the delivery of a crystalline form of Compound I described herein and one or more other drug therapies delivered by a different route of administration or the same route of administration. Combination by any route of administration includes delivery of a compound described herein, in any formulation, together with one or more other drug therapies by the same route of administration, where the two compounds are chemically linked in a manner that retains their therapeutic activity upon administration. In one embodiment, another drug therapy can be co-administered with the compounds described herein. Co-administration includes co-formulation or administration of a formulation of chemically linked compounds, or administration of two or more compounds as separate formulations within a short time of each other (e.g., within 1 hour, 2 hours, 3 hours, up to 24 hours) by the same or different routes. Co-administration of separate formulations includes simultaneous administration delivered by a single device (e.g., the same syringe) or administration from separate devices within a short time of each other. Co-formulation of the compounds described herein with one or more additional drug therapies delivered by the same route includes preparing the substances together for administration by a single device, including separate compounds combined into a single formulation, or compounds modified to be chemically linked but retain biological activity. Such chemically linked compounds can have a bond that is substantially maintained in vivo, or the bond can be broken down in vivo to separate the two active components.

[0100] URAT1 targets and indications Solid crystalline forms of the compound, such as Compound I Form 1, Compound I Form 2, Compound I Form 3, Compound I Form 4, Compound I Form 5A, Compound I Form 5B, Compound I Form 5C, Compound I Form 5D, Compound I Form 6, Compound I Form 7, Compound I Form 8, Compound I Form 9, Compound I Form 10, Compound I Form 11, and Compound I Form 12, can be used alone or in combination with each other to treat or prevent various diseases, such as gout and hyperuricemia. Gout is a metabolic disease caused by chronically elevated serum uric acid (sUA) levels (hyperuricemia) due to impaired purine metabolism and / or insufficient excretion of uric acid by the kidneys. The deposition of needle-shaped urate crystals in joints leads to painful inflammatory arthritis. Hyperuricemia, defined as a sUA concentration of 6.8 mg / dL or higher, can lead to the precipitation of urate in the form of monosodium salt crystals in human soft tissues, peripheral articular cartilage, the ear, and the synovial fluid of the olecranon mucosa of the elbow joint. When these symptoms appear, gout is diagnosed. (Terkeltaub R A. Crystal Deposition Diseases. In: Goldman L, Aus-iello D, eds. The Cecil Textbook of Medicine, 23rd ed. Philadelphia, PA: Saunders Elsevier Co; 2008:2069-2075; Richette P, Bardin T. Gout. Lancet. 2010, 375(9711):318-328). Gout is a common type of inflammatory arthritis with an incidence of approximately 1%-2%. The prevalence is relatively high in developed countries, with a 2007-2008 survey indicating that there are approximately 8.3 million gout patients in the United States. The incidence of gout in China has increased dramatically over the past decade. Reports suggest that the number of gout patients in China exceeds 50 million, with the proportion of men with gout far exceeding the proportion of women.

[0101] Uric acid excretion plays a crucial role in the treatment of hyperuricemia and gout. Human urate anion transporter 1 (human URAT1 or hURAT1) is located at the proximal end of the renal tubular epithelial cell membrane and is encoded by the SLC22A12 gene. Several mutations in its cDNA cause abnormal uric acid metabolism. Meta-analysis showed that this gene accounts for 0.13% of the variability affecting serum uric acid levels. (So A, Thorens B. Uric acid transport and disease. Journal of Clinical Investigation., 2010, 120 (6): 1791-1799). URAT1 controls more than 90% of uric acid reabsorption after glomerular filtration. Therefore, selective inhibition of URAT1 reduces uric acid reabsorption and promotes renal excretion, thereby lowering uric acid levels in the body. (Michael FW, Jutabha P, Quada B. Developing potent human uric acid transporter 1 (hURAT1) inhibitors. Journal of Medicinal Chemistry. 2011, 54:2701-2713). Because currently known treatments for gout and hyperuricemia are highly toxic, ineffective, or have other side effects, developing new drugs with high efficacy and low toxicity is crucial.

[0102] Compound I is a URAT1 inhibitor. In vitro and in vivo tests show that, compared with other treatments, Compound I significantly improves the inhibitory effect on URAT1, significantly increases uric acid excretion in mice, and reduces toxicity to normal hepatocytes. Oral maximum tolerated dose acute toxicity tests in rats show that the toxicity of the compound according to the present invention is much lower than that of other treatments. Research has shown that the compound according to the present invention is highly effective in uric acid excretion and has low toxicity.

[0103] To effectively use Compound I as a therapeutic agent, it is desirable to have a solid crystalline form that is easy to prepare and has acceptable chemical and physical stability. For example, to facilitate material processing and storage, it is highly desirable to have a solid crystalline form that is thermally stable, e.g., not hygroscopic or deliquescent at temperatures above about 240°C. Crystalline solids may be preferred over amorphous solids to improve the purity and stability of the final product. Therefore, there is a need for a stable crystalline Compound 1 that is not hygroscopic or deliquescent and exhibits good thermal stability.

[0104] Methods for treating URAT1-mediated diseases In another aspect, the present invention provides a method for treating a subject suffering from or at risk of a URAT1-mediated disease or disorder. In one embodiment, the present invention provides a method for treating a subject suffering from or at risk of a disease or disorder associated with abnormally high expression of URAT1. In one embodiment, the present invention provides a method for treating a subject suffering from or at risk of a disease or disorder associated with chronically elevated serum uric acid levels. In one embodiment, the present invention provides a method for treating a subject suffering from or at risk of a disease or disorder associated with a purine metabolism disorder. In one embodiment, the present invention provides a method for treating a subject suffering from or at risk of a disease or disorder associated with insufficient excretion of uric acid from the kidney. In one embodiment, the present invention provides a method for treating a subject suffering from or at risk of a hyperuricemia-related disease or disorder. In one embodiment, the present invention provides a method for treating a subject suffering from or at risk of a gout-related disease or disorder. The method comprises administering to the subject an effective amount of crystalline Form 1 of Compound I, crystalline Form 2 of Compound I, crystalline Form 3 of Compound I, crystalline Form 4 of Compound I, crystalline Form 5A of Compound I, crystalline Form 5B of Compound I, crystalline Form 5C of Compound I, crystalline Form 5D of Compound I, crystalline Form 6 of Compound I, crystalline Form 7 of Compound I, crystalline Form 8 of Compound I, crystalline Form 9 of Compound I, crystalline Form 10 of Compound I, crystalline Form 11 of Compound I, or crystalline Form 12 of Compound I, or a composition thereof, as described herein. In some embodiments, the method comprises administering to the subject an effective amount of any one or more solid, crystalline forms, or polymorphs of Compound I described herein in combination with one or more other treatments for the disease or disorder.

[0105] In some embodiments, the present invention provides a method for inhibiting URAT1, comprising contacting crystalline Form 1 of Compound I, crystalline Form 2 of Compound I, crystalline Form 3 of Compound I, crystalline Form 4 of Compound I, crystalline Form 5A of Compound I, crystalline Form 5B of Compound I, crystalline Form 5C of Compound I, crystalline Form 5D of Compound I, crystalline Form 6 of Compound I, crystalline Form 7 of Compound I, crystalline Form 8 of Compound I, crystalline Form 9 of Compound I, crystalline Form 10 of Compound I, crystalline Form 11 of Compound I, or crystalline Form 12 of Compound I, or a composition thereof, described herein, with a cell or URAT1 in vitro or in vivo.

[0106] In one embodiment, the present invention provides use of Crystalline Form 1 of Compound I, Crystalline Form 2 of Compound I, Crystalline Form 3 of Compound I, Crystalline Form 4 of Compound I, Crystalline Form 5A of Compound I, Crystalline Form 5B of Compound I, Crystalline Form 5C of Compound I, Crystalline Form 5D of Compound I, Crystalline Form 6 of Compound I, Crystalline Form 7 of Compound I, Crystalline Form 8 of Compound I, Crystalline Form 9 of Compound I, Crystalline Form 10 of Compound I, Crystalline Form 11 of Compound I, or Crystalline Form 12 of Compound I, or a combination thereof, in the preparation of a medicament for treating a disease or disorder. In another embodiment, the present invention provides use of crystalline Form 1 of Compound I, crystalline Form 2 of Compound I, crystalline Form 3 of Compound I, crystalline Form 4 of Compound I, crystalline Form 5A of Compound I, crystalline Form 5B of Compound I, crystalline Form 5C of Compound I, crystalline Form 5D of Compound I, crystalline Form 6 of Compound I, crystalline Form 7 of Compound I, crystalline Form 8 of Compound I, crystalline Form 9 of Compound I, crystalline Form 10 of Compound I, crystalline Form 11 of Compound I, or crystalline Form 12 of Compound I in the treatment of a disease or disorder described herein.

[0107] In some embodiments, provided compositions comprise a therapeutically effective amount of any one or more solid, crystalline, or polymorphic forms of Compound I described herein and at least one pharmaceutically acceptable carrier, excipient, and / or diluent, including combinations of any one or more solid, crystalline, or polymorphic forms of any two or more of Compound I described herein. In certain embodiments, the compositions comprise any one or more solid, crystalline, or polymorphic forms of Compound I described herein and one or more compounds effective in treating the same disease indication. In one aspect, the compositions comprise any one or more solid, crystalline, or polymorphic forms of Compound I described herein and one or more compounds effective in treating the same disease indication, wherein the compounds have a synergistic effect on the disease indication. In one embodiment, the compositions comprise any one or more solid, crystalline, or polymorphic forms of Compound I described herein and one or more other compounds effective in treating gout or hyperuricemia. Furthermore, the compounds have a synergistic effect in treating gout or hyperuricemia. The compounds can be administered simultaneously or sequentially.

[0108] In one embodiment, the present invention provides a method for treating a URAT1-mediated disease or disorder, the method comprising administering to a subject an effective amount of a composition (comprising any one or more solid, crystalline or polymorphic forms of Compound I described herein) in combination with one or more other suitable therapies for treating the disease described herein.

[0109] kit In another aspect, the present invention provides a kit or container containing any solid, crystalline, or polymorphic form of Compound I, or a pharmaceutically acceptable salt thereof, or a composition thereof, as described herein. In some embodiments, the solid, crystalline, or polymorphic form of Compound I or the composition is packaged, for example, in a vial, bottle, or flask, and may further be packaged, for example, in a box, envelope, or bag. The solid, crystalline, or polymorphic form of Compound I or the composition is approved for administration to mammals, such as humans, by the U.S. Food and Drug Administration or a similar regulatory agency. The solid, crystalline, or polymorphic form of Compound I or the composition is approved for administration to mammals, such as humans, for treating a URAT1-mediated disease or disorder. The disclosed kit or container may also include written instructions and / or other labeling indicating that the solid, crystalline, or polymorphic form of Compound I or the composition is suitable or approved for use in mammals (e.g., humans) for the treatment of a URAT1-mediated disease or disorder. The solid, crystalline, or polymorphic form of Compound I or the composition may then be packaged in a unit dose or single-dose crystalline form, for example, a single-dose pill, capsule, or the like. [Example]

[0110] Dynamic Vapor Sorption / Desorption (DVS) Moisture adsorption / desorption data were collected using an SMS DVS intrinsic vapor sorption analyzer under nitrogen purging. Distributed switch experiments typically involve two steps: moisture absorption and desorption. The experiment is considered complete when the sample mass does not change over time. That is, when dm / dt ≤ 0.01%, the sample is considered to have balanced moisture absorption and desorption at relative humidity. The sample was maintained at a temperature of 25°C and a relative humidity range of 0% to 95%, increasing in 5% RH at each step and returning to 0%.

[0111] Coulomb-Karl-Fischer analysis (KF) Coulometric Karl Fischer (KF) analysis for water determination was performed using a Metrohm 787 KF Karl Fischer titrator.

[0112] Differential Scanning Calorimetry (DSC) DSC was performed using a Mettler Toledo DSC1 differential scanning calorimeter. In a typical experiment, approximately 1–5 grams of sample was weighed and placed in a sealed aluminum crucible with a pinhole in the lid. Under nitrogen protection, the sample was scanned at a rate of 20°C / min from 30°C to 300°C.

[0113] Thermogravimetric analysis (TGA) Thermogravimetric analysis was performed using a PerkinElmer Pyris 1 TGA thermogravimetric analyzer. In a typical experiment, approximately 5 grams of sample was weighed into a crucible under nitrogen protection. The sample was scanned at a rate of 20 °C / min over the temperature range of 30–400 °C. Results were calibrated against a blank background curve.

[0114] Nuclear magnetic resonance analysis (NMR) Proton NMR was obtained using a Bruker AVANCE III 400 MHz instrument. In a typical experiment, samples were prepared by dissolving approximately 3 mg of sample in approximately 0.5 mL of deuterated dimethyl sulfoxide.

[0115] High-performance liquid chromatography (HPLC) An Agilent 1260 high performance liquid chromatograph was used.

[0116] X-ray powder diffraction (XRPD) Powder X-ray diffraction patterns of crystalline forms 1–12 were obtained using a Shimadzu XRD-6000 equipped with a Cu Kα source (λ = 1.54056 A) operating at a minimum power of 40 kV and 30 mA. 2-θ data were collected from 5 to 50 degrees at a rate of 5 degrees per minute.

[0117] The peaks determined here and herein are generally the more intense reflections in the powder map to avoid uncertainties due to potential preferred orientation and particle statistics issues. Some peaks can be used to distinguish one polymorph from another. Some of these peaks may be unique, for example, within ±0.2° 2θ, and may be present in one polymorph of a compound but not in other known polymorphs of the compound. However, not all polymorphs of a compound necessarily have such unique peaks. In these cases, multiple peaks can be used to distinguish one polymorph from another.

[0118] Example 1: Synthesis of Compound I

[0119] The synthesis scheme of compound I is as follows: [ka]

[0120] Step A: In an ice-water bath, 4-methoxyacetophenone (44 g, 293 mmol) was added to a mixture containing 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (104 g, 294 mmol), iodine (38.6 g, 152 mmol), and acetonitrile (440 mL). After the addition was complete, the resulting mixture was stirred at room temperature overnight. Water (1350 mL) was added to the reaction mixture to precipitate a large amount of solid. The solid was filtered and dried to give 3-iodo-4-methoxyacetophenone (34) (70 g). The yield was 86.5%.

[0121] Step B: A mixture containing compound 34 (70.0 g, 254 mmol), copper cyanide (34.0 g, 380 mmol), and DMF (400 mL) was stirred at 130 °C overnight. After cooling to room temperature and filtering through diatomaceous earth, water (1600 mL) was added and the mixture was extracted with ethyl acetate (800 mL × 3). The combined organic phase was washed with water (400 mL × 2) and saturated brine (400 mL) in turn and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 5-acetyl-2-methoxybenzonitrile (35) (50.0 g). This compound was used in the next step without further treatment.

[0122] Step C: A solution of bromine (49.0 g, 307 mmol) in methanol (50 mL) was added dropwise to a solution of crude compound 35 (45.0 g) in methanol (250 mL), and the resulting mixture was stirred at room temperature overnight. Water (900 mL) was added, and the mixture was filtered and dried to give 5-(2-bromoacetyl)-2-hydroxy-3-methylbenzonitrile (36) (41.0 g). The overall yield of the two-step reaction, Steps B and C, was 70.6%.

[0123] Step D: A mixture containing compound 36 (41.0 g, 161 mmol), compound 1 (24.0 g, 161 mmol), and toluene (600 mL) was stirred under reflux for 48 hours. After cooling to room temperature, water (400 mL) was added and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (600 mL × 3) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate:petroleum ether = 1:30 to 2:1) to give 5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-methoxybenzonitrile (37) (25.7 g). The yield was 52.3%.

[0124] Step E: In an ice-water bath, 60% sodium hydride (4.8 g, 120 mmol) was added batchwise to a solution of ethyl mercaptan (8.4 mL) in THF (30 mL). After stirring for approximately 5 minutes, the mixture was filtered and the filter cake was collected. This filter cake was added to a mixture containing compound 37 (9.0 g, 29.5 mmol) and DMF (25 mL). The resulting mixture was stirred at 60 °C for 2 hours. After cooling to room temperature and filtering through diatomaceous earth, water (100 mL) was added and the pH was adjusted to 5-6 with 2 M aqueous citric acid. After filtration, the filter cake was recrystallized from acetonitrile to give 5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile (14) (7.2 g). The yield was 83.8%.

[0125] Step F: NBS (5.28 g, 29.7 mmol) was added batchwise to a solution of compound 14 (7.2 g, 24.7 mmol) in DMF (70 mL). After the addition was complete, the resulting mixture was stirred at room temperature for 1 h. Water (210 mL) was added, filtered, and the filter cake was washed with water (100 mL × 3). It was then recrystallized from acetonitrile to give 3-bromo-5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile (38) (7.0 g). The yield was 76.8%.

[0126] 1 H NMR (DMSO-d6,300 MHz) δ 9.01 (d,J = 6.9 Hz,1H),8.02 (s,1H),7.83 (s,1H),7.78-7.75 (m,1H),7.65-7.59 (m,1H),7.22-7.17 (m,1H),2.58-2.50 (m,2H),1.19 (t,J = 7.2 Hz,3H). MS (EI, m / z):368.0 [MH]-.

[0127] Example 2: Crystalline Form 1 of Compound I

[0128] The product prepared in Example 1 was purified and crystallized from acetonitrile. The resulting crystals were characterized by XRPD and designated as crystalline Form 1 of Compound I. The XRPD of crystalline Form 1 of Compound I is described above with reference to Figure 1. Additionally, the TGA and DSC of crystalline Form 1 of Compound I are shown in Figures 2 and 3, respectively.

[0129] A heating study was performed on a fresh sample of Form 1. Using a thermogravimetric analyzer, the sample was heated to 140°C and held for 30 minutes. The XRPD pattern of the treated sample showed no peaks, consistent with an amorphous state. This indicates that the endothermic peak beginning at approximately 140°C in Figure 3 is the melting peak of Form 1.

[0130] The water content of Form 1 was determined to be 8.8% by KF method. This suggests that each mole of Compound I in Form 1 is associated with approximately 2 moles of water. DVS results indicate that Form 1 is a hydrate. When the relative humidity was cycled from 0% RH to 5% RH, it rapidly absorbed approximately 3.4% of its weight of water, after which the moisture absorption slowed.

[0131] Crystalline Form 1 was further characterized by 1H NMR, which showed peaks at 9.2 ppm, 8.2 ppm, 8.0 ppm, 7.8 ppm, 7.3 ppm, 4.3 ppm, 2.5 ppm, and 1.2 ppm.

[0132] In some embodiments, if crystalline Form 1 has satisfactory crystalline quality, it was prepared in wet acetonitrile (eg, acetonitrile with a water content of about 0.5%).

[0133] solubility The solubility of crystalline Form 1 was determined visually. Approximately 5 mg of crystalline Form 1 was accurately weighed and placed in a 5 mL glass vial. Small amounts of solvent were gradually added to the vial until the compound dissolved or the total amount added reached 5 mL, and the cumulative volume of solvent was recorded. The experimentally calculated solubility is shown in Table 1.

[0134] [Table 1]

[0135] As shown in Table 1, crystalline Form 1 is insoluble in water and in organic solvents such as methanol, ethanol, acetone, acetonitrile, ethyl acetate, n-heptane, isopropyl alcohol, methyl ethyl ketone, methylene chloride, and toluene. It is soluble in tetrahydrofuran (THF) at a concentration of approximately 3 mg / mL and highly soluble in dimethyl sulfoxide (DMSO) and dimethylformamide (DMF) at concentrations greater than 25 mg / mL.

[0136] heating research Approximately 150 mg of Form 1 was heated to 110°C and held for approximately 10 minutes. The sample color changed from light yellow to dark yellow. The darker sample was evaluated by XRPD. After the XRPD evaluation was completed, the sample color returned to a light yellow similar to the color before heat treatment. Further TGA evaluation was performed on the same sample, and it was found that the quality of the sample significantly deteriorated between room temperature and 85°C. Another sample of Form 1 was heated in an oven at 100°C for 20 minutes and then analyzed for moisture content by the KF method. After heating, the moisture content of Form 1 was 6.8%. From this, it was concluded that Form 1 may lose moisture when heated. This product is unstable and rapidly absorbs water.

[0137] (Example 3) Screening of Crystal Polymorphism

[0138] Crystalline Form 1 of Compound I was used as the starting material for screening of crystalline polymorphs, several methods of which are described in detail below.

[0139] slurry Approximately 40 mg of crystalline Form 1 was weighed into each 5 mL vial and mixed with approximately 2 mL of various solvents as shown in Table 2. All samples were stirred at room temperature or 50°C (as shown in Table 2) for 24 hours to form a suspension. The wet solid was then centrifuged and further dried in vacuo (40°C, -0.09 MPa). The dried solid was analyzed by XRPD, and the identities of the crystalline forms are shown in Table 2.

[0140] Antisolvent method Approximately 50 mg of crystalline Form 1 was weighed into a 40 mL vial and dissolved in 1 mL of DMF. The antisolvent was then added dropwise until sufficient solid precipitated or until 10 mL of antisolvent had been added. When water was used as the antisolvent, the solution became cloudy after 1 mL of antisolvent was added; however, a total of 3 mL was added. When methanol, acetone, or ethyl acetate were used as antisolvents, no precipitation occurred even after 10 mL of antisolvent was added. All samples were stirred at room temperature for 24 hours. The wet solid precipitate was isolated by centrifugation, dried under vacuum (40 °C, -0.09 MPa), and analyzed by XRPD. The identities of the crystalline forms are shown in Table 2.

[0141] [Table 2]

[0142] Solvent evaporation Approximately 25 mg of Form 1 was weighed into a 40 mL glass vial, dissolved in 8 mL of tetrahydrofuran, and sonicated. The uncapped vial was then placed in a fume hood to allow the solvent to evolve at room temperature. After 24 hours, any remaining solvent in the sample was blown dry with nitrogen. The solid was collected and analyzed by XPRD, which showed a pattern consistent with Form 1, although the crystalline quality was poor.

[0143] Milling Method Approximately 80-100 mg of Form 1 was weighed into an agate mortar and immersed in a small amount of acetone or tetrahydrofuran. The sample was milled until the solvent was gone. The remaining solvent was added and the sample was milled again until the solvent was gone. This procedure was repeated several times until the total milling time reached approximately 5 minutes. The final sample was analyzed by XRPD. Both the tetrahydrofuran- and acetone-treated samples showed XRPD consistent with Form 1.

[0144] Preparation of new crystalline forms As mentioned above, Form 2 can be prepared in acetone, acetonitrile, ethyl acetate, or methyl ethyl ketone. For example, Form 2 can be prepared using the room temperature slurry method and anti-solvent method in an acetone system, the slurry method at 50°C and the anti-solvent method in an ethyl acetate system, or the slurry method at 50°C in a methyl ethyl ketone and acetonitrile system.

[0145] The correlation between the TGA and DSC of Form 2 and Figures 5 and 6 is as described above. KF analysis indicated that the water content of Form 2 obtained from the acetone slurry was approximately 0.4%. DVS analysis indicated that Form 2 has low hygroscopicity at relative humidity below 80%. When the relative humidity reached 85% RH, Form 2 quickly absorbed approximately 3.8% water, and as the relative humidity increased, Form 2 absorbed even more water. When the relative humidity decreased to 0% during desorption, approximately 3.4% water remained in the sample. DSE analysis revealed that the XRPD of the sample showed that it had converted to Form 1, again confirming that Form 1 is a hydrate.

[0146] The XRPD patterns indicated that crystalline Form 3 could be obtained from both an acetonitrile slurry at room temperature and a THF slurry at 50°C. The XRPD patterns are shown in Figure 7 above. TGA and DSC analyses were performed on the sample prepared from the THF slurry at 50°C, as shown in Figures 8 and 9. Form 3 is believed to be a relatively unstable solvate.

[0147] Crystalline Form 4 can be prepared from a DMF solution using methanol as an anti-solvent. The XRPD pattern is shown above in Figure 10. The TGA and DSC of Crystalline Form 4 are described in Figures 11 and 12.

[0148] Further observations and data on the crystalline forms are shown in Table 3. [Table 3]

[0149] Example 4: Salt screening

[0150] Small scale Eight samples of Compound I crystalline Form 1 (80–100 mg) were prepared using tetrahydrofuran or acetone as solvent (as shown in Table 4 below) at approximately 1.0 mL of solvent per 10 mg of Compound I crystalline Form 1. The samples formed homogeneous suspensions. Subsequently, unless otherwise noted, hydrochloric acid, sulfuric acid, nitric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, potassium hydroxide, and sodium hydroxide (collectively referred to as counterions) were added to each glass vial in a molar ratio of 1:1.05 (Compound I:counterions). All samples were further magnetically stirred overnight at room temperature. The salts were collected by centrifugation or solvent evaporation, dried under vacuum at 40 °C, and then analyzed by XRPD. The experimental results are summarized in Table 4. A blank control sample was used to confirm that similar treatments did not cause any changes in the crystalline form other than the introduction of counterions.

[0151] [Table 4] TIFF2025530060000009.tif229170

[0152] As shown in the figure, in the THF system, Compound I formed salts with all acids except benzenesulfonic acid, and in the acetone system, it formed salts with all acids except maleic acid. The XRPD results for the corresponding salts obtained from tetrahydrofuran and acetone were consistent and therefore had the same crystalline form. The XRPD pattern of the new crystalline form is described above. Further observations and data regarding Form 1 and the salt crystalline forms are presented in Table 5.

[0153] [Table 5] TIFF2025530060000011.tif102170

[0154] Example 5: Scaling up and characterization of salt crystal forms

[0155] The hydrochloride salt (crystalline form 5D) was scaled up as follows: Approximately 400 mg of crystalline form 1 of compound I was weighed into a 40 mL glass bottle and mixed with approximately 10 mL of ethanol to form a pale yellow suspension. Subsequently, a hydrochloric acid solution (2 mol / L methanol) was added at a molar ratio of 1:1.05 (compound I:counter ion). After the addition, the color of the suspension darkened. The sample was placed on a plate at room temperature and stirred for 24 hours. The solid was collected by centrifugation and dried for 4-6 hours. The dried solid was analyzed by XRPD. The ionic ratios of compound I and counter ion in the hydrochloride salt were determined by HPLC-ELSD to be 1:0.50 and 1:0.88, respectively. This indicates the difficulty of forming the hydrochloride salt at a stable molar ratio.

[0156] Methanesulfonic acid (crystalline form 6) was scaled up in the same manner as methanesulfonic acid (1 mol / L in water), but the color of the suspension changed from light yellow to white upon addition of the acid. The ionic ratio of compound I to the counterion in the methanesulfonate salt was determined by 1H NMR to be 1:0.96. Therefore, this compound can form the methanesulfonate salt in an approximately 1:1 molar ratio.

[0157] The mesylate salt prepared in acetone was heated to 160°C in a thermogravimetric analyzer and held at 160°C for 5 minutes to remove the solvent, then analyzed by XRPD. The solvent-removed mesylate salt was left overnight under high humidity conditions (92.5% RH) and analyzed again by XRPD. The results are shown in Figure 37. As shown in the figure, the methanesulfonate salt changed its crystalline form when it lost the solvent, but slowly returned to its original crystalline form when it absorbed moisture again in a high humidity environment. This indicates that the methanesulfonate salt is a hydrate.

[0158] The sulfate salt (crystalline form 8) was also scaled up in sulfuric acid (2 mol / L in water), but the pale yellow suspension turned into a clear solution upon addition of the acid. The ionic ratio of compound I to counterion in sulfuric acid was determined to be 1:0.52 by the Shanghai Metrology Institute. This means that each mole of compound I is associated with approximately 0.5 moles of sulfuric acid of crystalline form 8.

[0159] The potassium salt (crystalline form 11) was scaled up in the same manner as potassium hydroxide (5 mol / L in water), but the pale yellow suspension remained essentially unchanged after the addition of base. The ionic ratio of compound I to counterion in the potassium salt was 1:0.86, as determined by the Shanghai Metrology Institute, indicating incomplete salt formation.

[0160] The XRPD of each salt in the scale-up was consistent with 80 mg to 100 mg of salt.

[0161] Example 6 Solubility of Crystalline Form 1, Crystalline Form 2, Crystalline Form 5D, Crystalline Form 6, Crystalline Form 8, and Crystalline Form 11

[0162] Form 1, Form 2, Form 5D, Form 6, Form 8, and Form 11 were analyzed for solubility in water, 0.1 N aqueous HCl, pH 4.5 acetate buffer, pH 6.8 phosphate buffer, and simulated gastric fluid (SGF), fasted-state simulated intestinal fluid (FaSSIF), and fed-state simulated intestinal fluid (FeSSIF).

[0163] Approximately 5 mg or 10 mg of sample was weighed into each vial and mixed with approximately 5 mL of medium to form a solution. The target concentration of the potassium salt in water was 2 mg / mL, and the target concentrations of all other crystalline forms were 1 mg / mL. All samples were stirred at 37 °C and 200 revolutions per minute (rpm) for 24 hours. After 24 hours of stirring, the pH of these samples was measured. They were then centrifuged at 12,000 rpm for 2 minutes. Where necessary, the supernatant was diluted with methanol and the concentration was measured by high-performance liquid chromatography. When testing the aqueous solubility of the potassium salt, the supernatant was diluted 100-fold; other samples were left undiluted. For HPLC analysis, the Agilent Eclipse XDB-C8 4.6*150 mm, 5 μm column was used at 40 °C, with a mobile phase of 0.1% TFA:ACN = 70:30, an injection volume of 10 μL, a flow rate of 1.0 mL / min, a diluent of methanol, and a detection wavelength of 234 nm.

[0164] After approximately 24 hours of stirring, Forms 1 and 2 formed homogeneous suspensions in all media. Forms 1 and 2 have low solubility in both buffer solutions and biologically relevant media. However, Form 2 showed higher solubility in some media, with a maximum concentration of approximately 40 μg / mL.

[0165] Form 11 formed a nearly clear solution in water, but formed a homogeneous suspension in all other media, similar to Form 1. The increased solubility of the potassium salt (Table 11) in water may be caused by a large increase in pH. Also, Forms 5D, 6, and 8 all became heterogeneous suspensions of small particles after the same treatment, and their solubilities in water were lower than that of the free base form (Form 1).

[0166] Table 6 shows the solubilities of Form 1, Form 2, Form 5D, Form 6, Form 8, and Form 11. [Table 6]

[0167] (Example 7) Stability of Crystal Form

[0168] Slurry stability of Form 1, Form 5D, Form 6, and Form 8. Approximately 30 mg of Form 1, Form 5D, Form 6, and Form 8 were mixed with approximately 2.5 mL of purified water and stirred overnight at room temperature. The wet solid was centrifuged and further dried under vacuum for 2.5 hours, then analyzed by XRPD. The XRPD results show that Form 5D, Form 6, and Form 8 were all converted to Form 1 after the experiment.

[0169] Solid-state stability studies of Form 1, Form 2, Form 6, Form 8, and Form 11 Form 1, Form 2, Form 6, Form 8, and Form 11 were subjected to the following stress conditions: (1) a sealed bottle at a temperature of approximately 60°C, and (2) a sealed bottle at a temperature of approximately 40°C and a humidity of approximately 75% RH. The solids were analyzed by XRPD at one-week and two-week intervals. All of the forms exhibited essentially similar XRPD patterns to those initially obtained, indicating their stability under these stress conditions.

[0170] Furthermore, impurities in all crystalline forms were analyzed by high-performance liquid chromatography at weekly and biweekly intervals. In a typical analysis, approximately 5 mg of crystals were dissolved in 10 mL of diluent for 2 minutes using ultrasound. Tetrahydrofuran was used as the diluent for crystalline Form 1, and methanol was used as the diluent for crystalline Forms 6, 8, and 11. For HPLC analysis, an Agilent Eclipse XDB-C18 4.6*150 mm column, 3.5 μm column, and 30°C were used. The mobile phase gradient was 0.1% H3PO4-acetonitrile (9:1 to 2:8 to 9:1), the injection volume was 10 μL, the flow rate was 1.0 mL / min, and the detection wavelength was 214 nm. The results showed no significant changes compared to the initial HPLC data, confirming the good stability of all crystalline forms under these stress conditions.

[0171] Form 2 underwent stability testing in an open bottle at 40°C and 75% relative humidity. XRPD analysis showed significant changes at the end of the 9th day, indicating that Form 2 should be stored away from moisture.

[0172] Example 8: Suspension for animal formulation

[0173] Approximately 30 mg of each of Form 1, Form 2, and Form 5D was added to a 40 mL vial and mixed with 30 mL of 0.5% CMC-Na solution. Ultrasound was used to uniformly disperse the solids in the solution. The solids were then centrifuged and dried at room temperature. The dried solids were analyzed by XRPD. Analysis revealed that under these conditions, Form 2 transformed into Form 1, while Form 1 and Form 5D remained unchanged.

[0174] Example 9: Pharmacokinetic study of Formsin in rats

[0175] Crystalline Form 1, Crystalline Form 2, and Crystalline Form 5D were evaluated through single-dose pharmacokinetic studies after oral and intravenous administration to SD rats, respectively. The results showed that the average bioavailability of all samples was approximately 50%, which was satisfactory. Crystalline Form 2 exhibits higher dose exposure and bioavailability than Crystalline Form 1, making it an ideal candidate for formulation development. Crystalline Form 1, Crystalline Form 2, and Crystalline Form 5D were evaluated through pharmacokinetic studies in rats.

[0176] Materials and equipment Male SD rats were purchased from Shanghai Sippr B&K Laboratory Animal Co., Ltd., weighing 180g-200g.

[0177] Preparation of test samples 20% HP-β-CD (Sigma) was prepared by dissolving 20 g of HP-β-CD in 100 mL of purified water. 0.5% CMC-Na was prepared by dissolving 1 g of CMC-Na (Aladdin) in 200 mL of purified water. The solution was stored at 2-8°C.

[0178] Group 1: 4.95 mg of crystalline Form 1 (equivalent to 4.50 mg of anhydrous free base) was weighed and placed in a 20 mL bottle. 0.225 mL of dimethyl sulfoxide was used to completely dissolve the solution by ultrasonication. 4.275 mL of 20% HP-β-CD was added and mixed uniformly by ultrasonication. Finally, the pH was adjusted to 7.0 with sodium hydroxide solution. A clear solution with a concentration of 1 mg / mL was obtained.

[0179] Group 2: 10.08 mg of crystalline Form 1 (equivalent to 9.164 mg of anhydrous free base) was weighed and placed in a 20 mL bottle, and 9.164 mL of 0.5% CMC-Na was added. The mixture was sonicated using an ultrasonic cell disrupter to form a white suspension with a concentration of 1 mg / mL.

[0180] Group 3: 9.47 mg of crystalline Form 2 was weighed and placed in a 20 mL bottle, followed by adding 9.470 mL of 0.5% CMC-Na. After ultrasonic treatment, the mixture was homogenized for 2 minutes. Finally, a white suspension with a concentration of 1 mg / mL was formed.

[0181] Group 4: 9.80 mg of crystalline form 5D (equivalent to 8.909 mg of the free base) was weighed and placed in a 20 mL bottle, followed by 8.909 mL of 0.5% CMC-Na. After ultrasonic treatment, the mixture was homogenized for 2 minutes. Finally, a white suspension with a concentration of 1 mg / mL was formed.

[0182] Group 5: 1.94 mg of crystalline Form 1 (equivalent to 1.763 mg of anhydrous free base) was weighed and placed in a 20 mL bottle. 0.088 mL of dimethyl sulfoxide was used to completely dissolve the solution by ultrasonication. 1.675 mL of 20% HP-β-CD was added and mixed uniformly by ultrasonication. Finally, the pH was adjusted to 7.0 with sodium hydroxide solution. A clear solution with a concentration of 0.2 mg / mL was obtained.

[0183] Administration and blood sampling The intravenous doses were 1 mg / kg and 5 mg / kg, respectively. The oral dose was 10 mg / kg. The animals were fasted overnight before administration. After administration, the rats were given food 4 hours later.

[0184] Blood samples (150–200 μL) were collected by jugular venipuncture at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after the initial injection. EDTA-K2 was used as the anticoagulant. Blood samples were centrifuged at 6000 rpm for 8 min within 1 h (placed on wet ice before centrifugation). The supernatant was stored at -20°C and used for LC-MS / MS analysis.

[0185] Data and figures were processed using the computer program Microsoft Office Excel 2007 (Microsoft, USA). Pharmacokinetic parameters were calculated using WinNolin 6.4 software.

[0186] Plasma drug concentrations were collected at various time points after intravenous and oral administration to male SD rats. Figure 38 shows the blood concentration-time curves in SD rats after a single intravenous dose of 1 mg / kg of crystalline Form 1 of Compound I. Figure 39 shows the blood concentration-time curves in SD rats after a single intravenous dose of 5 mg / kg of crystalline Form 1 of Compound I. Figure 40 shows the blood concentration-time curves in SD rats after a single oral dose of 10 mg / kg of crystalline Form 1 of Compound I. Figure 41 shows the blood concentration-time curves in SD rats after a single oral dose of 10 mg / kg of crystalline Form 2 of Compound I. Figure 42 shows the blood concentration-time curves in SD rats after a single oral dose of 10 mg / kg of crystalline Form 5D of Compound I. Pharmacokinetic parameters of the non-compartmental model are shown in Tables 7 to 11.

[0187] [Table 7]

[0188] [Table 8]

[0189] [Table 9]

[0190] [Table 10]

[0191] [Table 11]

[0192] Analysis of pharmacokinetic results in SD rats The pharmacokinetic results showed that Form 2 had a higher exposure (AUC 0-t ) and showed better bioavailability, potentially superior to that of crystalline form 1. After oral administration, the exposure (AUC 0-t ) and bioavailability are nearly identical to those of Form 5D. The exposure of Form 5D is nearly identical to third-party results. When administered intravenously to SD rats at 1 mg / kg and 5 mg / kg, the latter exposure is approximately five times higher than the former. Furthermore, the calculated bioavailability at both dose levels was approximately 50%. Both Form 1 and Form 2 possess sufficiently high bioavailability that they are considered suitable for the development of oral formulations.

[0193] Example 10: Stability Studies

[0194] The stability of crystalline Form 2 of Compound I was analyzed through the following two experiments.

[0195] Experiment A: ChP <0451> / USP / NF <941> The data shown in Figures 43 and 44 were obtained using powder X-ray diffraction analysis in accordance with the requirements of / EP10.6 2.9.33. Standard XRPD patterns were collected using a Bruker D8 Advance diffractometer or equivalent instrument.

[0196] The XRPD collection parameters shown in Figures 43 and 44 are as follows: [Table 12]

[0197] Figure 43 shows powder X-ray diffraction (XRPD) patterns comparing a sample of crystalline Form 2 of Compound I aged at 25°C ± 2°C / 60% RH ± 5% RH for 12 months, a sample of crystalline Form 2 of Compound I on day 0, and a reference standard of crystalline Form 2 of Compound I. In Figure 43, the top curve represents the sample of crystalline Form 2 of Compound I aged at 25°C ± 2°C / 60% RH ± 5% RH for 12 months (SPL), the middle curve represents the sample of crystalline Form 2 of Compound I aged on day 0 (initial), and the bottom curve represents the reference standard of crystalline Form 2 of Compound I (STD).

[0198] Figure 44 shows the XRPD patterns comparing a sample of crystalline Form 2 of Compound I aged at 40°C ± 2°C / 75% RH ± 5% RH for 6 months, a sample of crystalline Form 2 of Compound I aged for 0 days, and a reference standard of crystalline Form 2 of Compound I. In Figure 44, the top curve is the sample of crystalline Form 2 of Compound I aged at 40°C ± 2°C / 75% RH ± 5% RH for 6 months (SPL), the bottom curve is the sample of crystalline Form 2 of Compound I aged for 0 days (initial), and the middle curve is the reference standard (STD) of crystalline Form 2 of Compound I.

[0199] As can be seen from Figures 43 and 44, the XRPD patterns of crystalline Form 2 of Compound I at the time of preparation (day 0), after long-term storage at 25°C ± 2°C / 60% RH ± 5% RH, and after storage at 40°C ± 2°C / 75% RH ± 5% RH are consistent with those of a standard of crystalline Form 2. This indicates that crystalline Form 2 of Compound I is stable for at least 12 months at 25°C and for at least 6 months at 40°C.

[0200] Experiment B: The following was the powder X-ray diffraction analysis method, which resulted in the data shown in Figures 45 and 46. The XRPD patterns shown in Figures 45 and 46 were collected using a Bruker D2 Phase X-ray Diffractometer. Detector: PSD LynxEye, Sample holder: Zero Background Sample Holder or equivalent, Software: DIFFRAC. Measurement center: Version V6.5.0 or equivalent. Diffractometer settings: Diffractometer type: 02 phase controller; Goniometer type: θ / θ; Sample stage: standard rotation stage; Goniometer diameter: 282.2 mm; Divergence slit: 1.0 mm; Main Soller slit: 2.5°; Secondary Soller slit: 2.5°; Airscatter screen module: 1.0 mm; Tube core: copper; Tube parameters: Voltage 30 kv; Current 10 mA; Scan parameters: SSD160: lock coupling; SSD160-2: two coupled θ / θ; Scan type: SSD160: lock coupling; SSD160-2: two coupled θ / θ; Continuous PSD fast scan mode: continuous PSD fast scan; Rotation speed: 20 rpm; Starting: 3°-40° (20); Scan step: 0.02° (20); Scan speed: 0.2 s / step; Detector opening: 4.5°; Sample analysis: Test the sample using the diffractometer settings and scan parameters. Record the powder X-ray diffraction pattern of the sample and perform calculations according to the Bruker D2 phase radiation X-ray diffractometer user manual V6 - X-ray powder diffraction (XRPD) - Bruker D2 phase radiation identification crystalline form.

[0201] Figure 45 shows the XRPD patterns comparing a sample of crystalline Form 2 of Compound I aged at 40°C ± 2°C / 75% RH ± 5% RH for 6 months with a reference standard of crystalline Form 2 of Compound I. In Figure 45, the bottom curve is the standard of crystalline Form 2 of Compound I, and the top curve is the sample of crystalline Form 2 of Compound I aged at 40°C ± 2°C / 75% RH ± 5% RH for 6 months.

[0202] Figure 46 shows the XRPD patterns comparing samples of crystalline Form 2 of Compound I aged under conditions of 25°C ± 2°C / 60% RH ± 5% RH for 12, 24, 36, and 48 months, and a reference standard of crystalline Form 2 of Compound I. Additionally, the lower curve represents the sample of crystalline Form 2 on day 0, and the upper curves represent the reference standard (STD) of crystalline Form 2 of Compound I and samples of crystalline Form 2 of Compound I aged under conditions of 25°C ± 2°C / 60% RH ± 5% RH for 12, 24, 36, and 48 months.

[0203] 45 and 46, the XRPD patterns of crystalline Form 2 of Compound I at the initial stage (day 0), after long-term storage at 40°C ± 2°C / 75% RH ± 5% RH for 6 months, and after long-term storage at 25°C ± 2°C / 60% RH ± 5% RH for 48 months are consistent with those of the standard crystalline Form 2 of Compound I. This indicates that crystalline Form 2 of Compound I is stable at 40°C for at least 6 months and at 25°C for at least 48 months.

[0204] All patents and other references cited herein are indicative of the level of skill of those skilled in the art to which this invention pertains and are incorporated by reference in their entirety, including any tables and figures, to the extent that the entire contents of each reference are individually incorporated by reference.

[0205] Those skilled in the art will readily appreciate that the present invention is well adapted to obtain the objects and advantages set forth above, as well as those inherent therein. The methods, variations, and compositions described herein, which represent presently preferred embodiments, are exemplary and are not intended to limit the scope of the invention. Modifications thereof and other uses which occur to those skilled in the art are within the spirit of the invention as defined by the scope of the claims.

[0206] The subject matter disclosed in the illustrative descriptions herein may suitably be practiced without elements, limitations, or restrictions not specifically disclosed herein. Thus, for example, in each example herein, any of the terms "comprising," "consisting essentially of," and "consisting of" can be replaced with either of the other two terms. Thus, for an embodiment of the invention using one of the terms, the invention also includes another embodiment in which one of the terms is replaced with the other of the terms. In each example, the terms have a specific meaning. Thus, for example, one embodiment includes a method "comprising" a series of steps, another embodiment includes a method "consisting essentially of" the same steps, and a third embodiment includes a method "consisting of" the same steps. The terms and phrases used are intended to be descriptive, not limiting, and their use is not intended to exclude equivalents of the features shown and described, or portions thereof, and it is recognized that various modifications can be made within the scope of the disclosure set forth in the claims. Thus, while the present invention has been specifically disclosed by preferred embodiments and optional features, modifications and variations to the concepts disclosed herein may be made by those skilled in the art, and such modifications and variations are deemed to be within the scope of the present invention as defined in the appended claims.

[0207] Furthermore, where features or aspects of the invention are described according to Markush groups or other alternative subgroups, those skilled in the art will recognize that the invention may therefore also be described according to any individual group or subgroup of members of the Markush group or other groups.

[0208] Furthermore, unless otherwise indicated, when various numerical values ​​are provided for an embodiment, additional embodiments are described by stating any two different numerical values ​​as the endpoints of a range, and these ranges are also within the described invention.

[0209] Accordingly, other embodiments are within the scope of the present invention and the following claims.

Claims

1. A crystalline form of Compound I, or a crystalline form of a pharmaceutically acceptable salt or solvate of Compound I. 【Chemical 1】

2. 2. The crystalline form of claim 1, characterized in that it is crystalline form 1 of Compound I, characterized by a powder X-ray diffraction pattern containing peaks at 2θ of 15.0, 22.6, 25.8, 32.0, and 41.3° (±0.2°) as measured by a diffractometer using Cu-Kα radiation.

3. i) a powder X-ray diffraction pattern containing additional peaks at 25.5, 27.1, 27.5, and 28.3° 2θ±0.2°; ii) a diffraction pattern substantially as shown in Figure 1; iii) Differential Scanning Calorimetry (DSC) with endothermic peaks reaching peak values ​​at about 102°C and about 158°C; or iv) Thermogravimetric analysis (TGA) including a heat map substantially as shown in FIG. 2; 3. The crystalline form of claim 2, characterized by:

4. 2. The crystalline form of claim 1, characterized in that it is crystalline form 2 of Compound I, characterized by a powder X-ray diffraction pattern containing peaks at 2θ of 6.7, 10.5, 17.0, 23.4, and 26.9° (±0.2°) as measured by a diffractometer using Cu-Kα radiation.

5. i) a powder X-ray diffraction pattern containing additional peaks at 14.8, 21.3, 28.4, and 29.8° 2θ±0.2°; ii) a diffraction pattern containing peaks approximately as shown in Figure 4; iii) Differential Scanning Calorimetry (DSC) with an endothermic peak at about 256°C; or iv) Thermogravimetric analysis (TGA) including a heat map substantially as shown in FIG. 5; 5. The crystalline form of claim 4, characterized by:

6. 2. The crystalline form of claim 1, characterized in that it is crystalline form 3 of Compound I, characterized by a powder X-ray diffraction pattern containing peaks at 2θ of 16.2, 23.1, 28.0, and 31.8° (±0.2°) as measured by a diffractometer using Cu-Kα radiation.

7. i) a powder X-ray diffraction pattern comprising peaks at 13.0, 14.5, 17.1, 19.6, 22.8, 24.1, 26.5, 26.9, 27.3, 30.1, and 30.5° 2θ±0.2°, among others; ii) a diffraction pattern approximately as shown in Figure 7; iii) Differential Scanning Calorimetry (DSC) with endothermic peaks reaching peak values ​​at about 171°C and 251°C; or iv) Thermogravimetric analysis (TGA) including a heat map substantially as shown in FIG. 8; 7. The crystalline form of claim 6, characterized by:

8. 2. The crystalline form of claim 1, characterized in that it is crystalline form 4 of Compound I, characterized by a powder X-ray diffraction pattern containing peaks at 2θ of 11.2, 22.4, 25.0, 27.4, and 29.1° (±0.2°) as measured by a diffractometer using Cu-Kα radiation.

9. i) a powder X-ray diffraction pattern containing peaks at 17.2, 22.2, 23.7, 24.1, 27.1, and 30.7° 2θ±0.2°, among others; ii) a diffraction pattern approximately as shown in Figure 10; iii) Differential Scanning Calorimetry (DSC) with endothermic peaks reaching peak values ​​at about 102°C, 149°C, and 256°C; or iv) Thermogravimetric analysis (TGA) including a heat map substantially as shown in FIG. 11; 9. The crystalline form of claim 8, characterized by:

10. 2. The crystalline form of claim 1, characterized in that it is crystalline form 5D of Compound I, characterized by a powder X-ray diffraction pattern containing peaks at 2θ of 12.6, 14.4, 15.9, 22.0, 23.0, 27.0, 27.7, and 29.6° (±0.2°) as measured by a diffractometer using Cu-Kα radiation.

11. i) a powder X-ray diffraction pattern comprising peaks at 9.6, 11.4, 16.7, 18.1, 19.1, 20.3, 24.0, 25.4, 28.6, 30.1, 31.7, 32.4, and 33.5 degrees 2θ±0.2 degrees; ii) a diffraction pattern approximately as shown in FIG. 13D; iii) Differential Scanning Calorimetry (DSC) with an endothermic peak at about 197°C; or iv) Thermogravimetric analysis (TGA) including a heat map substantially as shown in FIG. 14D; 11. The crystalline form of claim 10, characterized by:

12. The crystalline form according to claim 1, which is crystalline form 6 of Compound I, characterized by a powder X-ray diffraction pattern containing peaks at 2θ of 15.9, 20.6, 24.2, 24.5, 25.8, 26.8, and 30.4° (±0.2°) as measured with a diffractometer using Cu-Kα radiation, and which is a crystalline form of a partial acetic acid solvate of Compound I.

13. i) a powder X-ray diffraction pattern comprising peaks at 9.1, 14.8, 15.5, 17.3, 19.8, 23.5, 26.1, 28.0, 28.4, 31.7, and 36.3° 2θ±0.2°, among others; ii) a diffraction pattern containing peaks approximately as shown in Figure 16; iii) Differential Scanning Calorimetry (DSC) with endothermic peaks reaching peak values ​​at about 151°C and 260°C; or iv) Thermogravimetric analysis (TGA) including a heat map substantially as shown in FIG. 17; 13. The crystalline form of claim 12, characterized by:

14. A composition comprising two or more compounds selected from the group consisting of crystalline form 1 of Compound I as defined in claim 2, crystalline form 2 of Compound I as defined in claim 4, crystalline form 3 of Compound I as defined in claim 6, crystalline form 4 of Compound I as defined in claim 8, crystalline form 5D of Compound I as defined in claim 10, and crystalline form 6 of Compound I as defined in claim 12.

15. 15. The composition according to claim 14, characterized in that it comprises crystalline form 1 of compound I according to claim 2 and crystalline form 2 of compound I according to claim 4.

16. 16. The composition according to claim 15, characterized in that it contains at least 50% w / w of crystalline form 2 of compound I.

17. A composition comprising Compound I, A composition characterized in that at least 85%, or at least 85%, or at least 90%, or at least 95%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5% of Compound I in said composition is present in crystalline Form 2 of Compound I.

18. A pharmaceutical composition comprising one or more compounds selected from the group consisting of crystalline form 1 of Compound I as set forth in claim 2, crystalline form 2 of Compound I as set forth in claim 4, crystalline form 3 of Compound I as set forth in claim 6, crystalline form 4 of Compound I as set forth in claim 8, crystalline form 5D of Compound I as set forth in claim 10, and crystalline form 6 of Compound I as set forth in claim 12, and further comprising a pharmaceutically acceptable excipient.

19. 1. A method of treating a subject suffering from or at risk of suffering from a URAT1-mediated disease or disorder, comprising:

17. A method comprising administering to the subject an effective amount of crystalline Form 1 of Compound I described in claim 2, crystalline Form 2 of Compound I described in claim 4, crystalline Form 3 of Compound I described in claim 6, crystalline Form 4 of Compound I described in claim 8, crystalline Form 5D of Compound I described in claim 10, and crystalline Form 6 of Compound I described in claim 12, and a pharmaceutically acceptable excipient, the composition of claim 17, or the pharmaceutical composition of claim 18.

20. 20. The method of claim 19, wherein the disease or disorder is associated with insufficient excretion of uric acid from the kidney.

21. 20. The method of claim 19, wherein the disease or disorder is gout or hyperuricemia.

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