Solid crystal form of compound for treating or preventing hyperuricemia or gout

Abstract

The invention provides a solid crystal form of a compound for treating or preventing hyperuricemia or gout, which is the preparation and characterization of the crystal form of a compound I having activity on URAT1, and also provides a method of using the crystal form. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of International Patent Application No. PCT / CN2022 / 094043 filed on May 20, 2022, which is incorporated herein by reference in its entirety. Technical Field

[0003] The present invention generally relates to a crystalline form of Compound I named 3-bromo-5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile, or a pharmaceutically acceptable salt or solvate thereof; a method for preparing the crystalline form; and methods of treatment using the same.

[0004] background

[0005] For patients suffering from hyperuricemia and gout or patients at risk of hyperuricemia and gout, there is still a need to develop effective treatment methods. Suitable compounds for treating such diseases and conditions, including Compound I, are disclosed in U.S. Pat. No. 10,399,971, the disclosure of which is incorporated herein by reference in its entirety.

[0006] Overview

[0007] The present invention provides a solid crystalline form of Compound 1 or a pharmaceutically acceptable salt or solvate thereof:

[0008]

[0009] The present invention also provides a pharmaceutical composition comprising a solid crystal form of Compound 1. The present invention also provides a method for preparing the solid crystal form and a method for treating hyperuricemia or gout. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 This is the X-ray powder diffraction pattern (XRPD) of Compound 1 Form 1.

[0011] Figure 2 This is the thermogravimetric analysis (TGA) of Compound 1 Form 1.

[0012] Figure 3 This is the differential scanning calorimetry (DSC) diagram of Compound 1 Form 1.

[0013] Figure 4 This is the XRPD of Compound 1 Form 2.

[0014] Figure 5 This is the TGA of Compound 1 Form 2.

[0015] Figure 6 This is the DSC of Compound 1 Form 2.

[0016] Figure 7 This is the XRPD of Compound 1 Form 3.

[0017] Figure 8 This is the TGA of Compound 1 Form 3.

[0018] Fig. 9 This is the DSC of Compound 1 Form 3.

[0019] Fig.10 This is the XRPD of Compound 1 Form 4.

[0020] Fig.11 This is the TGA of Compound 1 Form 4.

[0021] Fig.12 This is the DSC of Compound 1 Form 4.

[0022] Fig.13A , 13B , 13C, and 13D are the XRPDs of Compound 1 Form 5A, Form 5B, Form 5C, and Form 5D, respectively.

[0023] Fig.14A , 14B , 14C, and 14D are the TGA of Compound I Form 5A, Form 5B, Form 5C, and Form 5D, respectively.

[0024] Fig.15A , 15B , 15C, and 15D are the DSC of Form 5A, Form 5B, Form 5C, and Form 5D of Compound 1, respectively.

[0025] Fig.16 This is the XRPD of Compound 1 Form 6.

[0026] Fig.17 This is the TGA of Compound 1 Form 6.

[0027] Fig.18 This is the DSC of Compound 1 Form 6.

[0028] Fig.19 This is the XRPD of Compound 1 Form 7.

[0029] Fig. 20 This is the TGA of Compound 1 Form 7.

[0030] Fig.21 This is the DSC of Compound 1 Form 7.

[0031] Fig. 22 This is the XRPD of Compound 1 Form 8.

[0032] Fig.23 This is the TGA of Compound I Form 8.

[0033] Fig.24 This is the DSC of Compound I Form 8.

[0034] Fig.25 This is the XRPD of Compound 1 Form 9.

[0035] Fig.26 This is the TGA of Compound 1 Form 9.

[0036] Fig. 27 This is the DSC of Compound I Form 9.

[0037] Fig.28 This is the XRPD of Compound 1 Form 10.

[0038] Fig.29 This is the TGA of Compound I Form 10.

[0039] Fig.30 This is the DSC of Compound I Form 10.

[0040] Fig.31 This is the XRPD of Compound 1 Form 11.

[0041] Fig.32 This is the TGA of Compound 1 Form 11.

[0042] Fig.33 This is the DSC of Compound I Form 11.

[0043] Fig.34 This is the XRPD of Compound 1 Form 12.

[0044] Fig.35 This is the TGA of Compound 1 Form 12.

[0045] Fig.36 This is the DSC of Compound 1 Form 12.

[0046] Fig.37 Shows the XRPD changes of Compound I Form 6 after solvent desorption and reabsorption.

[0047] Fig.38 The blood concentration-time curve of Compound I Form 1 in SD rats after a single intravenous administration of 1 mg / kg is shown.

[0048] Fig.39 The graph shows the blood concentration-time curve of Compound I Form 1 in SD rats after a single intravenous administration of 5 mg / kg.

[0049] Fig.40 The blood concentration-time curve of Compound I Form 1 after a single oral administration of 10 mg / kg in SD rats is shown.

[0050] Fig.41 The blood concentration-time curve of Compound 1 Form 2 after a single oral administration of 10 mg / kg in SD rats is shown.

[0051] Fig.42 The blood concentration-time curve of Compound I Form 5D in SD rats after a single oral administration of 10 mg / kg is shown.

[0052] Fig.43 A comparative X-ray powder diffraction (XRPD) pattern of a Compound I Form 2 sample stored at 25°C ± 2°C / 60% RH ± 5% RH for 12 months (SPL), a Compound I Form 2 sample stored for 0 days (initial), and a Compound I Form 2 reference standard (STD) is shown.

[0053] Fig.44 Comparative XRPD patterns of a Compound I Form 2 sample stored at 40°C ± 2°C / 75% RH ± 5% RH for 6 months (SPL), a Compound I Form 2 sample stored for 0 days (initial), and a Compound I Form 2 reference standard (STD) are given.

[0054] Fig.45 A comparative XRPD pattern of a Compound I Form 2 sample (upper curve) placed under 40°C ± 2°C / 75% RH ± 5% RH conditions for 6 months and a Compound I Form 2 reference standard (lower curve) is shown.

[0055] Fig.46 The comparative XRPD patterns of the Compound I Form 2 sample placed under 25°C±2°C / 60%RH±5%RH conditions for 12 months, 24 months, 36 months, 48 ​​months, and 0 day with the Compound I Form 2 reference standard (STD) are given.

[0056] Details

[0057] A compound named 3-bromo-5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile (Compound I), or a pharmaceutically acceptable salt or solvate thereof, can be used to promote uric acid excretion or treat or prevent hyperuricemia and gout. The structure of Compound I is as follows:

[0058]

[0059] The present invention relates to a crystalline form of Compound 1 or a pharmaceutically acceptable salt or solvate thereof. The crystalline forms of Compound 1 or a pharmaceutically acceptable salt or solvate thereof are described herein as "Compound 1 Crystalline Form 1", "Compound 1 Crystalline Form 2", "Compound 1 Crystalline Form 3", "Compound 1 Crystalline Form 4", "Compound 1 Crystalline Form 5A", "Compound 1 Crystalline Form 5B", "Compound 1 Crystalline Form 5C", "Compound 1 Crystalline Form 5D", "Compound 1 Crystalline Form 6", "Compound 1 Crystalline Form 7", "Compound 1 Crystalline Form 8", "Compound 1 Crystalline Form 9", "Compound 1 Crystalline Form 10", "Compound 1 Crystalline Form 11", and "Compound 1 Crystalline Form 12".

[0060] definition

[0061] Unless expressly stated otherwise, the following definitions apply:

[0062] All atoms specified in the formulae described herein, whether in a provided structure or in the definition of a variable related to that structure, are intended to include any isotopes thereof unless expressly stated to the contrary. It is understood that for any given atom, the isotopes may be present in substantially the same proportion as they occur naturally, or one or more specific atoms may be enhanced relative to one or more isotopes using synthetic methods known to those skilled in the art. Thus, hydrogen includes, for example, 1 H. 2 H. 3 H; carbon includes for example 11 C. 12 C. 13 C. 14 C; oxygen includes for example 16 O. 17 O. 18 O; nitrogen includes for example 13 N. 14 N. 15 N; sulfur includes for example 32 S. 33 S. 34 S. 35 S. 36 S. 37 S. 38 S; fluorine includes for example 17 F. 18 F. 19 F; Chlorine includes 35 Cl, 36 Cl, 37 Cl, 38 Cl, 39 Cl et al.

[0063] Certain compounds considered for use according to the present invention may exist in non-solvated crystalline forms or in solvated crystalline forms, including hydrate crystalline forms. "Hydrate" refers to a complex formed by the combination of water molecules with solute molecules or ions. "Solvate" refers to a complex formed by the combination of solvent molecules with solute molecules or ions. The solvent can be an organic compound, an inorganic compound, or a mixture of the two. Solvates include hydrates, hemihydrates, channel hydrates, etc. 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 non-solvated crystalline forms and are included within the scope of the present invention. Certain compounds considered for use according to the present invention may exist in a variety of crystals 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.

[0064] As used herein, the term "solid crystalline form" refers to a class of solid substances, which includes amorphous forms and crystalline forms. The term "crystalline form" refers to polymorphs, solvates, hydrates, etc. The term "polymorph" refers to a specific crystal structure with specific physical properties, such as X-ray diffraction, melting point, etc.

[0065] 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, crystals or polymorphs of Compound I described herein, in an amount effective to prevent, alleviate or ameliorate one or more symptoms of a disease or condition, i.e., an indication, and / or prolong the survival of the patient being treated.

[0066] As used herein, the term "modulating" or "modulate" refers to the effect of changing a biological activity, particularly a biological activity associated with a particular biomolecule such as human uric acid transporter 1 (hURAT1). For example, certain molecules described herein modulate the activity of a biomolecule by increasing or decreasing the activity of the biomolecule. This activity is typically measured as an inhibitory concentration (IC) of a compound for an inhibitor or activator, respectively. 50 ) or stimulatory concentration (EC 50 ) means, for example, with respect to an enzyme.

[0067] As used herein, the term "promoting" or "promote" refers to an effect of increasing 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 waste) of the molecule, such as uric acid.

[0068] As used herein, the term "URAT1-mediated disease or condition" refers to a biological function of URAT1, including any mutation thereof, that affects the development, course and / or symptoms of a disease or condition, and / or a disease or condition in which modulation of URAT1 alters the development, course and / or symptoms of a disease or condition. URAT1-mediated diseases or conditions include diseases or conditions for which inhibition provides a therapeutic benefit, e.g., wherein treatment with a URAT1 inhibitor (including one or more solid, crystalline or polymorphic forms of Compound I described herein) provides a therapeutic benefit to a subject suffering from or at risk of a disease or condition.

[0069] As used herein, the term "composition" refers to a pharmaceutical preparation suitable for administration to a predetermined subject for therapeutic purposes, which contains at least one pharmaceutically active compound, including any solid crystalline form thereof. The composition may include at least one pharmaceutically acceptable component to provide an improved formulation of the compound, such as a suitable carrier or excipient.

[0070] As used herein, the term "subject" refers to a living organism treated with a compound described herein, including but not limited to any mammal, such as humans, other primates, sport animals, animals of commercial interest, such as cattle, farm animals, such as horses, or pets, such as dogs and cats.

[0071] The term "pharmaceutically acceptable" means that the substance does not have properties that would cause a reasonably prudent physician to avoid administering the substance to a patient, taking into account the disease or condition to be treated and the respective route of administration. For example, such substances are generally required to be sterile in nature, such as for 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 not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts containing inorganic acids and salts containing organic acids. In addition, if the compounds described herein are obtained in the form of acid addition salts, the free base can be obtained by alkalizing a solution of the acid salt. In contrast, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, following conventional methods for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic acids 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 from inorganic and organic bases. By way of example only, salts derived from inorganic bases include sodium, potassium, lithium, aluminum, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkylamines (i.e., NH 2 (alkyl)), dialkylamine (i.e. HN(alkyl) 2 ), trialkylamine (ie N (alkyl) 3 ), substituted alkylamines (i.e. NH 2 (substituted alkyl)), di(substituted alkyl)amine (i.e. HN(substituted alkyl) 2 ), tri(substituted alkyl)amine (i.e. N(substituted alkyl) 3 ), alkenylamine (i.e. NH 2 (substituted alkyl)), dienylamine (i.e. NH 2 (Substituted Alkyl) 3 ), trialkenylamine (i.e. N(alkenyl)3), substituted alkenylamine (i.e. NH 2 (substituted alkenyl)), di(substituted alkenyl)amine (i.e. HN(substituted alkenyl) 2 ), tri(substituted alkenyl)amine (i.e. N(substituted alkenyl) 3 ), mono-, di- or tri-cycloalkylamines (i.e. NH 2 (cycloalkyl), HN(cycloalkyl) 2 、N(cycloalkyl)3 ), mono-, di- or tri-arylamines (i.e. NH 2 (aryl), HN(aryl) 2 、N(aryl) 3 ) or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0072] As used herein, the term "therapeutically effective" or "effective amount" means that a substance or amount of a substance effectively prevents, alleviates or ameliorates one or more symptoms of a disease or medical condition, and / or prolongs the survival of the subject being treated. The therapeutically effective amount will vary depending on the compound, disease or condition and its severity, as well as age, weight, etc. of the mammal to be treated. For example, an effective amount is an amount sufficient to achieve a beneficial or desired clinical outcome. The effective dose may be provided in its entirety in a single administration, or in portions thereof in several administrations. Exactly how much can be considered an effective dose may be based on individual factors for each subject, including their size, age, injury, and / or disease or injury being treated, and the time since the injury occurred or the disease began. One skilled in the art will be able to determine the effective amount for a given subject based on these considerations routine in the art.

[0073] As used herein, the term "substantially as shown" as applied to a DSC thermogram is meant to include variations of ±3°C, while the term as applied to a TGA is meant to include variations of ±2% weight loss.

[0074] In the context of the use, testing, or screening of compounds that are or may be modulators, the term "contacting" means that the compound is brought into close enough proximity to a specific molecule, complex, cell, tissue, organism, or other designated substance so that a potential binding interaction and / or chemical reaction between the compound and the other designated substance may occur.

[0075] Crystalline form of compound I

[0076] As described above, the present invention provides a crystalline form of Compound I. In some embodiments, the crystalline form of Compound I is a free base compound or a solvate of a free base compound. For example, Compound I crystalline form 1, crystalline form 2, crystalline form 3, and crystalline form 4 described below are crystalline forms of Compound I as a free base compound or a solvate of a free base compound.

[0077] Compound I Crystalline Form 1

[0078] On a diffractometer using Cu-Kα radiation, the XRPD of Compound I Form 1 is characterized by peaks (±0.2°) at 15.0, 22.6, 25.8, 32.0, 41.3° 2θ. In some embodiments, the diffraction pattern includes one, two, three, or four more peaks selected from (±0.2°) 25.5, 27.1, 27.5, and 28.3° 2θ. In some embodiments, the diffraction pattern further includes one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve additional peaks selected from (±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° 2θ. Substantially as Figure 1 Form 1 is also characterized by XRPD as shown. In one embodiment, the invention provides Compound I Form 1 comprising two or more peaks listed herein as measured on a diffractometer using Cu-Kα radiation (±0.2°).

[0079] In some embodiments, Form 1 is further characterized by TGA, which comprises primarily: Figure 2 As shown in the figure, Table 1 gives 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, and the weight loss is about 3.8%.

[0080] In some embodiments, Form 1 is further characterized by a DSC curve substantially as follows Figure 3 As shown. As shown in the figure, Form 1 has two endothermic peaks and one exothermic peak. The first endothermic peak starts at around 93°C, reaches a peak at around 102°C, and ends at around 107°C. This is due to the escape of water or residual solvent from the crystal. The second endothermic peak starts at around 138°C, reaches a peak at around 158°C, and ends at around 167°C. This is due to the evaporation of crystal water causing it to melt. The exothermic peak starts at around 253°C, reaches a peak at around 274°C, and ends at around 290°C. This is caused by the decomposition of the compound.

[0081] In some embodiments, Form 1 is further characterized by a 1H NMR spectrum comprising 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.

[0082] In some embodiments, Form 1 is a hydrate of Compound 1, such as a dihydrate of Compound 1.

[0083] Compound I Crystalline Form 2

[0084] Form 2 of Compound I is characterized by an x-ray powder diffraction pattern. The x-ray powder diffraction pattern includes peaks (± 0.2°) at 6.7, 10.5, 17.0, 23.4, and 26.9°2θ, measured on a diffractometer using Cu-Kα radiation. In some embodiments, the diffraction pattern includes one, two, three, or four more peaks selected from (± 0.2°) 14.8, 21.3, 28.4, and 29.8°2θ. In some embodiments, the diffraction pattern includes one, two, three, three, or eleven additional peaks selected from (± 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°2θ. Figure 4 As shown, Form 2 also has the basic characteristics of XRPD. In one embodiment, the present invention provides Compound I Form 2, which comprises two or more peaks (±0.2°) listed herein as measured on a diffractometer using Cu-Kα radiation.

[0085] In some embodiments, Form 2 is further characterized by TGA, which comprises primarily: Figure 5 As shown in the figure, Table 2 has no obvious weight loss below 250°C. For example, from room temperature to about 120°C, the weight loss is only about 0.03%.

[0086] In some embodiments, Form 2 is further characterized by a DSC curve, mainly as follows Figure 6 As shown in the figure, Table 2 has an endothermic peak and an exothermic peak. The endothermic peak starts at about 253°C, reaches a peak at about 256°C, and ends at about 260°C. The endothermic peak is caused by the melting of Form 2.

[0087] In some embodiments, Form 2 is an anhydrous crystalline form of Compound 1.

[0088] Compound I Crystalline Form 3

[0089] The x-ray powder diffraction pattern of Compound I Form 3 is characterized by peaks (±0.2°) at 16.2, 23.1, 28.0 and 31.8° 2θ, as determined on 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. Mainly as Figure 7 Form 3 is also characterized by XRPD as shown. In one embodiment, the present invention provides Compound I Form 3 comprising two or more peaks listed herein as measured on a diffractometer using Cu-Kα radiation (±0.2°).

[0090] In some embodiments, Form 3 is also characterized by a TGA comprising a thermal map substantially as shown in Figure 8 As shown in the figure, from about 120.0°C to about 214°C, Form 3 loses about 4.5% of its weight.

[0091] In some embodiments, Form 3 is further characterized by a DSC curve substantially as follows Fig. 9 As shown. As shown in the figure, Form 3 has two endothermic peaks. The first endothermic peak starts at about 163°C, reaches a peak at about 171°C, and ends at about 175°C. This peak is due to the escape of the solvent from the crystal. The second endothermic peak starts at about 248°C, reaches a peak at about 251°C, and ends at about 258°C. This peak is due to the melting of Form 3. There is also an exothermic peak after the first endothermic peak. This can be attributed to crystal transformation. In some embodiments, Form 3 is a solvate. In some embodiments, Form 3 is a monohydrate.

[0092] Compound I Crystalline Form 4

[0093] The XRPD characteristics of Compound I Form 4, measured on a diffractometer using Cu-Kα radiation, include peaks at 11.2, 22.4, 25.0, 27.4, and 29.1° 2θ (± 0.2°). In some embodiments, the diffraction pattern includes one, two, three, four, five, or more than six peaks selected from (± 0.2°) 17.2, 22.2, 23.7, 24.1, 27.1, and 30.7° 2θ. In some embodiments, the diffraction pattern includes one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve additional peaks (± 0.2°) selected from 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° 2θ. Predominantly as Fig.10 As shown in Table 4, it is also characterized by XRPD. In one embodiment, the present invention provides Compound I Form 4, which comprises two or more peaks (±0.2°) listed herein measured on a diffractometer using Cu-Kα radiation.

[0094] In some embodiments, Form 4 also has the characteristics of TGA, which mainly includes: Fig.11 The heat map shown. Figure 4 As shown, there are two weight loss steps given in Table 4. The first weight loss stage is from room temperature to about 120°C, with a weight loss of about 2.4%. The second weight loss is from about 120°C to about 172°C, with a weight loss of about 5.8%.

[0095] In some embodiments, Form 4 is further characterized by a DSC curve, substantially as follows Fig.12 As shown. As shown in the figure, Table 4 has three endothermic peaks. The first endothermic peak starts at about 85°C, reaches a peak at about 102°C, and ends at about 110°C. The second endothermic peak starts at about 125°C, peaks at about 149°C, and ends at about 163°C. Both endothermic peaks are attributed to the escape of solvent from the crystal. The third endothermic peak starts at about 253°C, peaks at about 256°C, and ends at about 260°C. This is due to the melting of Form 4. There are two exothermic peaks. The first exothermic peak starts at about 173°C, peaks at about 178°C, and ends at about 182°C. This is attributed to crystal transformation. The second exothermic peak starts at about 267°C, peaks at about 278°C, and ends at about 289°C. This is due to the decomposition of Form 4. In some embodiments, Form 4 is an unstable solvate.

[0096] Crystalline form of salt of compound I

[0097] Compound I can form a salt with a suitable acid. For example, Compound I can form a salt with hydrochloric acid (referred to as hydrochloride), methanesulfonic acid (referred to as mesylate), benzenesulfonic acid (referred to as mesylate), sulfuric acid (referred to as sulfate salt), nitric acid (referred to as nitrate) or maleic acid (referred to as maleate). In addition, Compound I can form a salt with a suitable base. For example, Compound I can form a salt with potassium hydroxide (referred to as potassium salt) or sodium hydroxide (referred to as sodium salt). In some embodiments, solid crystalline forms or crystalline forms of such salts of Compound I are provided herein.

[0098] Compound I Crystalline Form 5A

[0099] Form 5A of Compound 1 is a crystalline form of a tetrahydrofuran solvate of the hydrochloride salt of Compound 1. Form 5A is characterized by XRPD including peaks (± 0.2°) at 13.5, 19.3, 20.2, 21.9, 25.0, 26.4, and 27.4° 2θ as measured by a diffractometer using Cu-Kα radiation. In some embodiments, the diffraction pattern includes one, two, three, four, five, six, seven, eight, nine, or more than ten peaks selected from (± 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 includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 additional peaks selected from (±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° 2θ. Fig.13AForm 5A is also characterized by XRPD as shown. In one embodiment, the present invention provides Compound I Form 5A comprising two or more peaks (±0.2°) listed herein as measured on a diffractometer using Cu-Kα radiation.

[0100] In some embodiments, Form 5A is further characterized by TGA, which comprises approximately Fig.14A Thermogram shown. As shown in the figure, Form 5 exhibits two weight loss steps. The first step is from room temperature to about 120°C, with a weight loss of about 1.3%. The second weight loss occurs at 120°C to 190°C, with a weight loss of about 14.2%.

[0101] In some embodiments, Form 5A is further characterized by a DSC curve, substantially as Fig.15A As shown. As shown in the figure, Form 5A has two endothermic peaks and one exothermic peak. The first endothermic peak starts at around 126°C, reaches a peak at around 140°C, and ends at around 164°C. The second endothermic peak starts at around 222°C, has a peak at around 246°C, and ends at around 252°C. This is attributed to melting. The exothermic peak starts at around 258°C, has a peak at around 266°C, and ends at around 282°C. This is caused by the decomposition of the compound.

[0102] In some embodiments, further use of Form 5A 1 HNMR spectrum characterization, including peaks at 9.1ppm, 8.2ppm, 8.1ppm, 8.0ppm, 7.5ppm, 3.6ppm, 2.6ppm, 2.5ppm, 1.8ppm, and 1.2ppm.

[0103] Compound I Crystalline Form 5B

[0104] Compound 1 Form 5B is a crystalline form of an acetone solvate of the hydrochloride salt of Compound 1. Form 5B is characterized by XRPD, including peaks at (±0.2°) 10.94, 17.62, 25.32, 26.46, and 27.30° 2θ, as determined by a diffractometer using Cu-Kα radiation. In some embodiments, the diffraction pattern includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 more peaks selected from (±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° 2θ. In some embodiments, the diffraction pattern includes one, two, three, four, five, six, seven, eight, or nine additional peaks selected from (±0.2°) 14.9, 23.3, 23.7, 24.7, 27.7, 29.0, 29.5, 31.7, and 35.0° 2θ. Fig. 13BForm 5B is also characterized by XRPD as shown. In one embodiment, the present invention provides Compound I Form 5B comprising two or more peaks listed herein as measured on a diffractometer using Cu-Kα radiation (± 0.2°).

[0105] In some embodiments, Form 5B is further characterized by TGA comprising approximately Fig. 14B The heat map shown. Fig. 14B As shown, there is one weight loss step from room temperature to about 180°C, and the weight loss amplitude is about 15%.

[0106] In some embodiments, Form 5B is further characterized by a DSC curve, substantially as Fig. 15B As shown. As shown in the figure, Form 5B has two endothermic peaks and one exothermic peak. The first endothermic peak starts at around 102°C, reaches a peak at around 113°C, and ends at around 121°C. The second endothermic peak starts at around 233°C, reaches a peak at around 249°C, and ends at around 254°C. This is caused by melting. The exothermic peak starts at around 258°C, reaches a peak at around 267°C, and ends at around 283°C. This is caused by the decomposition of the compound.

[0107] In some embodiments, Form 5B is also used 1 The HNMR spectrum was further characterized and included 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.

[0108] Compound I Form 5C

[0109] Form 5C of Compound I is a crystalline form of a methanol solvate of the hydrochloride salt of Compound I. Form 5C is characterized by XRPD including peaks at (±0.2°) 14.6, 15.9, 19.3, 27.9 and 29.2° 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 (±0.2°) 11.4, 12.7, 17.1, 22.2, 25.5, 25.9 and 27.2° 2θ. In some embodiments, the diffraction pattern includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 additional peaks selected from (±0.2°) 32.1, 33.5, 34.1, 36.7, 37.5 and 37.9° 2θ. Form 5C was also characterized by XRPD, essentially as Fig. 13C In one embodiment, the present invention provides Compound I Form 5C comprising two or more peaks (±0.2°) listed herein as measured on a diffractometer using Cu-Kα radiation.

[0110] In some embodiments, Form 5C is further characterized by TGA comprising approximately Fig. 14C Thermogram shown. As shown in the figure, Form 5C exhibits two weight loss steps. The first step is from room temperature to about 120°C, with a weight loss of about 1.3%. The second weight loss is from 120°C to 236°C, with a weight loss rate of about 4.6%.

[0111] In some embodiments, Form 5C is further characterized by a DSC curve substantially as follows Fig. 15C As shown in the figure, Form 5C has two endothermic peaks and one exothermic peak. The first endothermic peak starts at around 154°C, peaks at around 164°C, and ends at around 172°C. The second endothermic peak starts at around 184°C, peaks at around 202°C, and ends at around 213°C. This is attributed to melting. The exothermic peak starts at around 254°C, peaks at around 272°C, and ends at around 287°C. This is caused by the decomposition of the compound.

[0112] Compound I Form 5D

[0113] Compound I Form 5D is a crystalline form of the anhydrous hydrochloride salt of Compound I. Form 5D is characterized by XRPD including peaks at (±0.2°) 12.6, 14.4, 15.9, 22.0, 23.0, 27.0, 27.7, and 29.6° 2θ as determined by a diffractometer using Cu-Kα radiation. In some embodiments, the diffraction pattern includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 more peaks selected from (±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° 2θ. Substantially as Fig.13D Form 5D is also characterized by XRPD as shown. In one embodiment, the invention provides Compound I Form 5D comprising two or more peaks listed herein as measured on a diffractometer using Cu-Kα radiation (±0.2°).

[0114] In some embodiments, Form 5D is further characterized by TGA, which comprises primarily: Fig.14D Thermogram shown. As shown in the figure, Form 5D gives two weight loss steps. The first step is from room temperature to about 120°C, with a weight loss of about 0.4%. The second weight loss is from 120°C to 210°C, with a weight loss of about 4%.

[0115] In some embodiments, Form 5D is further characterized by a DSC curve substantially as follows Fig.15DAs shown in the figure, Form 5D exhibits an endothermic peak and an exothermic peak. The endothermic peak starts at about 182°C, reaches a peak at about 197°C, and ends at about 210°C. This is attributed to melting. The exothermic peak starts at about 253°C, reaches a peak at about 273°C, and ends at about 289°C. This is caused by the decomposition of the compound.

[0116] In some embodiments, Form 5D is also used 1 The HNMR spectrum was further characterized and included peaks at 9.1 ppm, 8.2 ppm, 8.0 ppm, 7.9 ppm, 7.4 ppm, 2.6 ppm, and 1.2 ppm.

[0117] Compound I Crystalline Form 6

[0118] Compound I Form 6 is a crystalline form of Compound I mesylate. The XRPD characteristics of Form 6 include peaks at 15.9, 20.6, 24.2, 24.5, 25.8, 26.8 and 30.4 ° 2θ (± 0.2 °), 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 selected from (± 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 ° 2θ. Fig.16 Form 6 is also characterized by XRPD as shown. In one embodiment, the present invention provides Compound I Form 6 comprising two or more peaks listed herein as measured on a diffractometer using Cu-Kα radiation (±0.2°).

[0119] In some embodiments, Form 6 is further characterized by a TGA comprising a thermal diagram substantially as follows Fig.17 As shown in Table 6, there is a weight loss step from room temperature to about 128°C, and the weight loss range is about 3.7%.

[0120] In some embodiments, Form 6 is further characterized by a DSC curve, substantially as follows Fig.18 As shown. As shown in the figure, Form 6 has two endothermic peaks. The first endothermic peak starts at about 129°C, reaches a peak at about 151°C, and ends at about 158°C, which is due to the escape of water in the crystal. The second endothermic peak starts at about 257°C and reaches a peak at about 260°C, which is caused by the accompanying melting. The exothermic peak appears at about 264°C, which is caused by the decomposition of the compound. In some embodiments, Form 6 is a hydrate.

[0121] Compound I Crystalline Form 7

[0122] Form 7 of Compound 1 is a crystalline form of a benzoate salt of Compound 1 as determined by a diffractometer using Cu-Kα radiation. Form 7 has XRPD features including peaks (±0.2°) at 7.0, 14.0, 14.6, 16.5, 22.1, 22.5, 22.8, 24.8, 26.1, and 28.5° 2θ. The diffraction pattern includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 additional peaks selected from (±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° 2θ. Fig.19 Form 7 is also characterized by XRPD as shown. In one embodiment, the present invention provides Compound I Form 7 comprising two or more peaks (±0.2°) listed herein as measured on a diffractometer using Cu-Kα radiation.

[0123] In some embodiments, Form 7 is further characterized by a TGA comprising a thermal profile substantially as shown in Fig. 20 As shown in the figure, it is not until about 120°C that Form 7 shows obvious weight loss.

[0124] In some embodiments, Form 7 is further characterized by a DSC curve, generally as follows Fig.21 As shown. Figure 7 As shown in Table 7, there is an endothermic peak with an initial temperature of about 255°C, a peak temperature of about 259°C, and an end temperature of about 263°C. This is due to the melting of Form 7. The exothermic peak appears at about 264°C, which is caused by the decomposition of the compound.

[0125] In some embodiments, Form 7 is an anhydrous crystalline form of Compound 1.

[0126] Compound I Crystalline Form 8

[0127] Compound I Form 8 is a crystalline form of the sulfate salt of Compound I. The XRPD characteristics of Form 8 include peaks (±0.2°) at 14.7, 15.2, 19.0, 20.4, 22.7, 23.3, 24.6, 25.0, 26.9, 30.5°2θ (determined by a diffractometer using Cu-Kα radiation). The diffraction pattern includes one, two, three, four, five or six additional peaks selected from (±0.2°) 16.9, 17.2, 27.9, 28.9 and 30.9,°2θ. Fig. 22 Form 8 is also characterized by XRPD as shown. In one embodiment, the present invention provides Compound I Form 8 comprising two or more peaks (±0.2°) listed herein as measured on a diffractometer using Cu-Kα radiation.

[0128] In some embodiments, Form 8 is further characterized by TGA, which mainly includes Fig.23 As shown in the figure, Form 8 does not show obvious weight loss until about 231°C.

[0129] In some embodiments, Form 8 is further characterized by a DSC curve, substantially as Fig.24 As shown in the figure, Form 8 has an endothermic peak with an initial temperature of about 238°C, a peak value of about 253°C, and an end temperature of about 247°C. This is due to the melting of Form 8.

[0130] In some embodiments, Form 8 is an anhydrous crystalline form of Compound 1.

[0131] Compound I Crystalline Form 9

[0132] Compound I Form 9 is a crystalline form of the nitrate salt of Compound I. Form 9 has an XRPD characteristic comprising peaks (±0.2°) at 14.3, 16.1, 22.7, 23.8, 26.7, 27.4, and 29.7° 2θ, measured using a diffractometer with 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 (±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° 2θ. Fig.25 Form 9 is also characterized by XRPD as shown. In one embodiment, the present invention provides Compound I Form 9 comprising two or more peaks listed herein as measured on a diffractometer using Cu-Kα radiation (±0.2°).

[0133] In some embodiments, Form 9 is also used to comprise Fig.26 The TGA characterization of the heat map shown. Fig. 9 As shown, the first weight loss step is from room temperature to about 120°C, and the weight loss is about 0.3%. Form 9 further shows a second weight loss step from about 120°C to about 216°C, and the weight loss is about 8%.

[0134] In some embodiments, Form 9 is further characterized by a DSC curve, substantially as follows Fig. 27As shown in the figure, Form 9 has an endothermic peak that starts at about 164°C, reaches a peak at about 172°C, and ends at about 178°C. This is due to the melting of Form 9. Table 9 further presents an exothermic peak that starts at about 245°C, reaches a peak at about 271°C, and ends at about 289°C. This is caused by the decomposition of the compound.

[0135] In some embodiments, Form 9 is an anhydrous crystalline form of Compound 1.

[0136] Compound I Crystalline Form 10

[0137] Form 10 is a crystalline form of the maleate salt of Compound I. Form 10 has an XRPD characteristic comprising 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° 2θ (measured using a Cu-K radiation diffractometer). The diffraction pattern includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 additional peaks selected from (±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° 2θ. Fig.28 Form 10 is also characterized by XRPD as shown. In one embodiment, the invention provides Compound I Form 10 comprising two or more peaks listed herein as measured on a diffractometer using Cu-Kα radiation (±0.2°).

[0138] In some embodiments, Form 10 further comprises Fig.29 The TGA characterization of the heat map shown. Fig.10 As shown, there is a first weight loss step from room temperature to about 120°C, with a weight loss of about 0.2%. Table 10 further shows a second weight loss step from about 120°C to about 242°C, with a weight loss of about 18.4%.

[0139] In some embodiments, Form 10 is further characterized by a DSC curve, substantially as follows Fig.30 As shown in the figure, Form 10 has an endothermic peak, which starts at about 167°C, reaches a peak at about 178°C, and ends at about 184°C. This is due to the melting and decomposition of Form 10.

[0140] In some embodiments, Form 10 is an anhydrous crystalline form of Compound 1.

[0141] Compound I Crystalline Form 11

[0142] Compound I Form 11 is a crystalline form of the potassium salt of Compound I. The XRPD characteristics of Form 11, as measured by a diffractometer using Cu-Kα radiation, include peaks at 11.4, 17.1, 19.5, 24.9, 27.0, 27.6, and 29.0° 2θ (±0.2°). 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 (± 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 ° 2θ. Fig.31 As shown, Form 11 also has the basic characteristics of XRPD. In one embodiment, the present invention provides Compound I Form 11, which comprises two or more peaks (±0.2°) listed herein measured on a diffractometer using Cu-Kα radiation.

[0143] In some embodiments, Form 11 is further characterized by a TGA comprising a thermogram substantially as shown in Fig.32 As shown in the figure, Form 11 does not show a substantial weight loss step. For example, the weight loss from room temperature to about 120°C is only about 0.2%.

[0144] In some embodiments, Form 11 is further characterized by a DSC curve, substantially as follows Fig.33 As shown in the figure, Form 11 has an exothermic peak, which starts at about 368°C, reaches a peak at about 373°C, and ends at about 378°C. This is caused by the decomposition of the compound.

[0145] In some embodiments, Form 11 is an anhydrous crystalline form of Compound 1.

[0146] Compound I Crystalline Form 12

[0147] Compound I Form 12 is a crystalline form of the sodium salt of Compound I. The XRPD characteristics of Form 12, as measured by a diffractometer using Cu-Kα radiation, include peaks (±0.2°) at 13.2, 16.0, 16.5, 16.9, 17.9, 20.6, 22.1, 24.4, 25.3, 27.0, and 29.0° 2θ. The diffraction pattern includes 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional peaks selected from (±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° 2θ. Fig.34Form 12 is also characterized by XRPD as shown. In one embodiment, the invention provides Compound I Form 12 comprising two or more peaks listed herein as measured on a diffractometer using Cu-Kα radiation (± 0.2°).

[0148] In some embodiments, Form 1 is further used to comprise Fig.35 A or Fig.35 TGA characterization of the thermogram shown in B. In some embodiments, Form 12 is further characterized by a DSC curve substantially as shown in Fig.36 A or 36B. Fig.35 A and Fig.36 A is the analysis result of Form 12 prepared using THF as solvent; Fig.35 B and Fig.36 B is the analysis result of Form 12 prepared by acetone.

[0149] like Fig.35 As shown in Table 12 (from THF), there is a weight loss step from room temperature to about 150°C, and the weight loss amplitude is about 11.6%. There is another weight loss step from about 150°C to about 227°C. In addition, as Fig.36 As shown in A, Table 12 (from THF) presents two endothermic peaks. The first endothermic peak starts at about 80°C, reaches a peak at about 95°C, and ends at about 108°C. The second endothermic peak starts at about 128°C, reaches a peak at about 142°C, and ends at about 152°C. Both endothermic peaks are due to the loss of solvent in the crystals. Table 12 further presents an exothermic peak, which starts at about 373°C, reaches a peak at about 381°C, and ends at about 387°C. This is caused by the decomposition of the compound.

[0150] like Fig.35 As shown in B, from room temperature to about 150°C, Form 12 (acetone) has a weight loss step, and the weight loss is about 8.8%. Fig.36 As shown in B, Form 12 (from acetone) exhibits two endothermic peaks. The first endothermic peak starts at about 87°C, reaches a peak at about 107°C, and ends at about 114°C. The second endothermic peak starts at about 116°C, reaches a peak at about 137°C, and ends at about 165°C. Both endothermic peaks are due to the loss of solvent in the crystals.

[0151] In some embodiments, Form 12 comprises water in its crystal structure.

[0152] Composition

[0153] In one embodiment, the present invention provides a composition comprising two or more compounds selected from Compound 1 Crystal Form 1, Compound 1 Crystal Form 2, Compound 1 Crystal Form 3, Compound 1 Crystal Form 4, Compound 1 Crystal Form 5A, Compound 1 Crystal Form 5B, Compound 1 Crystal Form 5C, Compound 1 Crystal Form 5D, Compound 1 Crystal Form 6, Compound 1 Crystal Form 7, Compound 1 Crystal Form 8, Compound 1 Crystal Form 9, Compound 1 Crystal Form 10, Compound 1 Crystal Form 11, and Compound 1 Crystal Form 12 described herein.

[0154] In another embodiment, the composition comprises Compound 1, Form 2, Form 3, Form 4, Form 5A, Form 5B, Form 5C, Form 5D, Form 6, Form 7, Form 8, Form 9, Form 10, Form 11, or Form 12. In another embodiment, the composition comprises Compound 1, wherein at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% w / w of Compound 1 is Form 1. In another embodiment, the composition comprises Compound 1, wherein at least 90%, 95% w / w of Compound 1 is 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 Form 2. In another embodiment, the composition comprises Compound I, wherein at least 90%, 95% w / w of Compound I is 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 Form 3. In another embodiment, the composition comprises Compound I, wherein at least 90%, 95% w / w of Compound I is 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 Form 4. In another embodiment, the composition comprises Compound I, wherein at least 90%, 95% w / w of Compound I is 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 Form 5A. In another embodiment, the composition comprises Compound I, wherein at least 90%, 95% w / w of Compound I is Form 5A. In another embodiment, the composition includes 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 Form 5B.In another embodiment, the composition comprises Compound I, wherein at least 90%, 95% w / w of Compound I is 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 Form 5C. In another embodiment, the composition comprises Compound I, wherein at least 90%, 95% w / w of Compound I is 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 Form 5D. In another embodiment, the composition comprises Compound I, wherein at least 90%, 95% w / w of Compound I is 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 Form 6. In another embodiment, the composition comprises Compound I, wherein at least 90%, 95% w / w of Compound I is Form 6. In another embodiment, the composition comprises Compound I, wherein the w / w of Compound I is at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% w / w of Form 7. In another embodiment, the composition comprises Compound I, wherein at least 90%, 95% w / w of Compound I is 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 Form 8. In another embodiment, the composition comprises Compound I, wherein at least 90%, 95% w / w of Compound I is 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 Form 9. In another embodiment, the composition comprises Compound I, wherein at least 90%, 95% w / w of Compound I is in 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 Form 10. In another embodiment, the composition comprises Compound I, wherein at least 90%, 95% w / w of Compound I is 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 Form 11. In another embodiment, the composition comprises Compound I, wherein at least 90%, 95% w / w of Compound I is 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 Form 12. In another embodiment, the composition comprises Compound I, wherein at least 90%, 95% w / w of Compound I is Form 12.

[0155] In another embodiment, a composition comprising Compound I Form 1 and Compound I Form 2 is provided. In another embodiment, the composition comprises Compound I Form 2 at least 50% w / w.

[0156] 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 Compound I Form 2. In another embodiment, the composition comprising Compound I Form 2 is not substantially changed after at least about 6 months, or 12 months, or 24 months, or 36 months, or 48 months. In another embodiment, the composition comprising Compound I Form 2 is not substantially changed after about 6 months at 40°C ± 2°C (optionally at 75% RH ± 5% RH). In another embodiment, the composition comprising Compound I Form 2 is not substantially changed 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, the composition comprising Compound 1 Form 2 does not substantially change after 6 months, or 12 months, or 24 months, or 36 months, or 48 months.

[0157] Preparation and administration

[0158] In another aspect, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a crystalline form of Compound 1 described herein. In an exemplary embodiment, the present invention provides a pharmaceutical composition (or interchangeably "preparation") comprising Compound 1 Crystal Form 1, Compound 1 Crystal Form 2, Compound 1 Crystal Form 3, Compound 1 Crystal Form 4, Compound 1 Crystal Form 5A, Compound 1 Crystal Form 5B, Compound 1 Crystal Form 5C, Compound 1 Crystal Form 5D, Compound 1 Crystal Form 6, Compound 1 Crystal Form 7, Compound 1 Crystal Form 8, Compound 1 Crystal Form 9, Compound 1 Crystal Form 10, Compound 1 Crystal Form 11, or Compound 1 Crystal Form 12 described herein.

[0159] These crystalline forms are generally used to treat human subjects. However, they can also be used to treat similar or identical indications in other animal subjects. The solid, crystal or polymorphic form of Compound I described herein can be administered by different routes, including injection (i.e., parenteral injection, including intravenous injection, intraperitoneal injection, subcutaneous injection and intramuscular injection), oral, transdermal, transmucosal, rectal or inhalation. Such a dosage form should allow the compound to reach the target cells. Other factors are well known in the art and include considerations such as toxicity and dosage forms that hinder the compound or composition from exerting its effect. Techniques and formulations can generally be found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott, Williams and Wilkins, Philadelphia, PA, 2005 (incorporated herein by reference).

[0160] In some embodiments, the composition comprises one or more of Compound 1 Crystalline Form 1, Compound 1 Crystalline Form 2, Compound 1 Crystalline Form 3, Compound 1 Crystalline Form 4, Compound 1 Crystalline Form 5A, Compound 1 Crystalline Form 5B, Compound 1 Crystalline Form 5C, Compound 1 Crystalline Form 5D, Compound 1 Crystalline Form 6, Compound 1 Crystalline Form 7, Compound 1 Crystalline Form 8, Compound 1 Crystalline Form 9, Compound 1 Crystalline Form 10, Compound 1 Crystalline Form 11, and Compound 1 Crystalline Form 12 having a specific particle size. In some embodiments, particle size significantly affects biological usability. 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 includes a solid crystalline form as described herein, and its particle size is about 1nm to about 20μm. In some embodiments, the composition includes a solid crystalline form as described herein, and its particle size is about 1nm to about 10μm. In some embodiments, the composition includes a solid crystalline form as described herein, and its particle size is about 1nm to about 5μm. In some embodiments, the composition includes a solid crystalline form as described herein, and its particle size is about 1nm to about 1μm. In some embodiments, the composition includes a solid crystalline form with a particle size of about 1nm to about 100nm as described herein. In some embodiments, the composition includes a solid crystalline form as described herein, and its particle size is about 1nm to about 50nm. In some embodiments, the composition includes a solid crystalline form as described herein, and its particle size is about 1nm to about 20nm. In some embodiments, the composition includes a solid crystalline form with a particle size of about 1nm to about 10nm as described herein. In some embodiments, the desired particle size is achieved by implementing a homogenization step, such as grinding, ultrasound or other similar operations. In some embodiments, the length and intensity of ultrasound are controlled to fine-tune the desired particle size.

[0161] In some embodiments, the composition will include a pharmaceutically acceptable carrier or excipient, such as a filler, a binder, a disintegrant, a lubricant, a complexing agent, a solubilizer, and a surfactant, which can 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, starch types, cellulose derivatives, gelatin, lipids, liposomes, nanoparticles, etc. Carriers also include physiologically compatible liquids as solvents or suspensions, including, for example, sterile water for injection (WFI) solutions, physiological saline solutions, glucose solutions, Hank's solutions, Ringer's solutions, vegetable oils, mineral oils, animal oils, polyethylene glycols, liquid paraffin, etc. Excipients can also include, for example, colloidal silicon dioxide, silica gel, talc, magnesium silicate, calcium silicate, sodium aluminum silicate, magnesium trisilicate, powdered cellulose, macrocrystalline cellulose, carboxymethyl cellulose, cross-linked carboxymethyl cellulose sodium, sodium benzoate, calcium carbonate, magnesium carbonate, stearic acid, aluminum stearate, calcium stearate, magnesium stearate, zinc stearate, sodium stearyl fumarate, pectin, stearic acid C, magnesium oxide, starch, sodium starch glycolate, glyceryl monostearate, glyceryl stilbene, glyceryl palmitate, hydrogenated vegetable oil, hydrogenated cottonseed oil, castor seed oil, mineral oil, polyethylene glycol (such as PEG 4000-8000), polyoxyethylene glycol, polyoxyamine, povidone, cross-polyvidone, cross-polystarch sodium, alginic acid, casein, divinylbenzene methacrylate copolymer, docusate sodium, cyclodextrin (such as 2-hydroxypropyl-delta-cyclodextrin), polysorbate (such as polysorbate 80), melamine, TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate), magnesium lauryl sulfate, sodium lauryl sulfate, polyethylene glycol ether, polyethylene glycol difatty acid ester or polyoxyalkyl sorbitan fatty acid ester (such as ), polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters, such as sorbitan fatty acid esters from fatty acids such as oleic acid, stearic acid or palmitic acid, mannitol, xylitol, sorbitol, maltose, lactose, etc. Lactose monohydrate or lactose spray-dried, sucrose, fructose, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, dextrin, dextrin, glucose, cellulose acetate, maltodextrin, simethicone, polydextrose, chitosan, gelatin, HPMC (hydroxypropyl methylcellulose), HPC (hydroxypropyl cellulose), hydroxyethyl cellulose, etc.

[0162] The pharmaceutical composition or preparation can be presented in a unit dose crystal form, each unit dose containing a predetermined amount of active ingredient. Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a solid, crystal or polymorph of Compound I of the present invention, depending on the condition being treated, the route of administration, and the age, weight and condition of the patient. Preferred unit dose formulations are formulations containing daily doses, weekly doses, monthly doses, sub-doses or appropriate portions thereof of the active ingredient. In addition, these pharmaceutical compositions or preparations can be prepared by any well-known method in the pharmaceutical field.

[0163] The pharmaceutical composition or formulation may be suitable for administration by any appropriate route, for example, by oral (including capsules, tablets, liquid-filled capsules, disintegrating tablets, immediate release, sustained release and controlled release tablets, oral strips, solutions, syrups, buccal and sublingual), rectal, nasal, inhalation, topical (including transdermal) or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) routes of administration. Such formulations may be prepared by any method known in the pharmaceutical art, for example, by combining the active ingredient with a carrier, excipient or diluent. Typically, the carrier, excipient or diluent used in the pharmaceutical formulation is "non-toxic", meaning that it / they are considered safe in the amount delivered in the pharmaceutical composition, and is "inert", meaning that it / they do not react significantly with the active ingredient or cause an adverse effect on the therapeutic activity of the active ingredient.

[0164] In some embodiments, oral administration can be used. Pharmaceutical preparations for oral administration can be formulated into conventional oral dosage forms, such as discrete unit capsules, tablets, and liquid preparations, such as syrups, elixirs, and concentrated drops. The compounds described herein can be combined with solid excipients, the resulting mixture is optionally ground, and the granular mixture is processed after adding suitable adjuvants (if necessary) to obtain, for example, tablets, coated tablets, hard capsules, soft capsules, solutions (e.g., aqueous, alcoholic or oily solutions), etc. In particular, suitable excipients are fillers such as sugars, including lactose, glucose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, yellow gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose (CMC) and / or polyvinylpyrrolidone (PVP: povidone); oily excipients, including vegetable oils and animal oils, such as sunflower oil, olive oil or cod liver oil. Oral dosage formulations may also contain disintegrants, such as cross-linked polyvinyl pyridone, agar or alginic acid, or salts 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; flavoring agents: natural or artificial flavoring agents, such as mint, wintergreen oil or cherry flavoring; or dyes or pigments, which can be used to identify or characterize different doses or combinations, such as unit doses. Sand cores with suitable coatings are also provided. For this purpose, concentrated sugar solutions can be used, which optionally contain, for example, gum arabic, talc, polyvinyl pyrrolidone, carbophenol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Oral liquids, such as solutions, syrups and elixirs can be prepared in dosage unit crystalline forms so that a given amount contains a predetermined amount of solid, crystal or polymorph of Compound I.

[0165] Pharmaceutical preparations that can be taken orally include push-fit capsules ("gel caps") made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules may contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.

[0166] The amount of each compound to be administered can be determined by standard procedures, taking into account, for example, the activity of the compound (in vitro, e.g., compound IC 50The importance of these and other factors is well known to those of ordinary skill in the art. In general, dosages may range from about 0.01 to 50 mg / kg, and may also range from about 0.1 to 20 mg / kg of the subject being treated. Multiple doses may be used.

[0167] The solid, crystal or polymorphic form of Compound I as described herein may also be used in combination with other therapies for the treatment of the same disease. Such combined use includes administration of the compound and one or more other therapies at different times, or co-administration of the compound and one or more other therapies. In some embodiments, the dosage may be modified for one or more crystalline forms of Compound I or other therapies used in combination, for example, by methods well known to those of ordinary skill in the art, relative to the compound or therapy used alone.

[0168] It should be understood that combined use includes use with other therapies, drugs, medical procedures, etc., where the other therapies or procedures can be administered at a different time (e.g., within a short period of time, such as within a few hours (e.g., 1, 2, 3, 4-24 hours) or within 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 administered simultaneously with the compounds described herein. Combination use also includes use with treatments or medical procedures (e.g., surgery) that are administered once or infrequently, and compounds described herein that are administered shortly before or after other treatments or procedures or longer periods of time. In some embodiments, the present invention provides for the delivery of a crystalline form of Compound I as described herein and one or more other drug therapies delivered by different routes of administration or by the same route of administration. Combination use for any route of administration includes delivery of a compound described herein in any formulation and one or more other drug therapies delivered together by the same route of administration, including the two compounds in such a manner that Chemically linked so that they maintain their therapeutic activity when administered. On the one hand, another drug therapy can be co-administered with the compounds described herein. The combined use by co-administration includes administering a co-formulation or a chemically linked compound preparation, or administering two or more compounds in a separate preparation within a short time of each other (e.g., within 1 hour, 2 hours, 3 hours, up to 24 hours), and administering by the same or different routes. The co-administration of a separate preparation includes co-administration delivered by a device (e.g., the same syringe, etc.), or administration from a separate device within a short time of each other. The co-formulation of the compound described herein and one or more additional drug therapies delivered by the same route includes preparing materials together so that they can be administered by a device, including a separate compound combined in a preparation, or a compound modified to be chemically linked but still maintain its biological activity. This chemically linked compound can have a connection that is substantially maintained in vivo, or the connection can be decomposed in vivo to separate the two active ingredients.

[0169] URAT1 Targets and Indications

[0170] Solid crystalline forms of the compound, such as Compound I Crystal Form 1, Compound I Crystal Form 2, Compound I Crystal Form 3, Compound I Crystal Form 4, Compound I Crystal Form 5A, Compound I Crystal Form 5B, Compound I Crystal Form 5C, Compound I Crystal Form 5D, Compound I Crystal Form 6, Compound I Crystal Form 7, Compound I Crystal Form 8, Compound I Crystal Form 9, Compound I Crystal Form 10, Compound I Crystal Form 11, and Compound I Crystal Form 12, alone or in combination, can be used to treat or prevent various diseases, gout, hyperuricemia, etc. Gout is a metabolic disease caused by chronic elevation of serum uric acid (sUA) levels (hyperuricemia) caused by purine metabolism disorders and / or insufficient renal excretion of uric acid. The deposition of urate needle-shaped crystals in the joints leads to painful inflammatory arthritis. Hyperuricemia is defined as a sUA concentration greater than or equal to 6.8 mg / dL, which can cause urate to precipitate in the form of a monosodium salt in the synovial fluid of human soft tissues, peripheral articular cartilage, auricles, and olecranon bursae of the elbow joint. When these symptoms occur, gout can be diagnosed. (Terkeltaub RA. 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 about 1%-2%. The incidence in developed countries is relatively high. A survey in 2007-2008 showed that there were about 8.3 million gout patients in the United States. In China, the incidence of gout has increased dramatically in the past decade. It is reported that the number of gout patients in China has exceeded 50 million, and the proportion of male gout patients is much higher than that of female patients.

[0171] Uric acid excretion plays a very important role in the treatment of hyperuricemia and gout. Human uric acid anion transporter 1 (Human URAT1 or hURAT1) is located at the proximal end of the tubular epithelial cell membrane and is a member of the superfamily of organic anion transporters (OAT) encoded by the SLC22A12 gene. Its cDNA has several mutations that lead to abnormal uric acid metabolism. Meta-analysis shows that 0.13% of the variables in this gene affect 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 can reduce uric acid reabsorption, promote uric acid excretion in the kidneys, and thus reduce 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). Since the currently known treatments for gout and hyperuricemia are highly toxic, low in efficacy or have other side effects, it is of great importance to develop new drugs with high efficacy and low toxicity.

[0172] Compound I is a URAT1 inhibitor. The results of in vitro and in vivo tests showed that compared with other treatments, Compound I can significantly improve the inhibitory effect on URAT1, significantly increase uric acid excretion in mice, and reduce toxicity to normal hepatocytes. The acute toxicity test of the maximum tolerated dose of oral administration in rats showed that the toxicity of the compound provided by the present invention is much lower than that of other treatments. Studies have shown that the compound provided by the present invention is very effective in uric acid excretion and has low toxicity.

[0173] In order to effectively use Compound 1 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, it is very desirable to have a thermally stable solid crystalline form, such as one that is not hygroscopic or deliquescent at temperatures above about 240° C., thereby facilitating the processing and storage of the material. Crystalline solids are sometimes preferred over amorphous solids to improve the purity and stability of the finished product. Therefore, there is a need for a stable, crystalline Compound 1 that is neither hygroscopic nor deliquescent and exhibits good thermal stability.

[0174] Treatments for URAT1-mediated disorders

[0175] On the other hand, the present invention provides a method for treating a subject suffering from or at risk of a disease or condition mediated by URAT1. In one embodiment, the present invention provides a method for treating a subject suffering from or at risk of a disease or condition 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 condition associated with chronic 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 condition 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 condition associated with insufficient renal elimination of uric acid. In one embodiment, the present invention provides a method for treating a subject suffering from or at risk of a disease or condition associated with hyperuricemia. In one embodiment, the present invention provides a method for treating a subject suffering from or at risk of a disease or condition associated with gout. The method comprises administering to the subject an effective amount of Compound 1 Form 1, Compound 1 Form 2, Compound 1 Form 3, Compound 1 Form 4, Compound 1 Form 5A, Compound 1 Form 5B, Compound 1 Form 5C, Compound 1 Form 5D, Compound 1 Form 6, Compound 1 Form 7, Compound 1 Form 8, Compound 1 Form 9, Compound 1 Form 10, Compound 1 Form 11, or Compound 1 Form 12, as described herein, or a combination thereof. In certain embodiments, the method involves administering to the subject an effective amount of any one or more solid, crystal, or polymorph of Compound 1 described herein in combination with one or more other therapies for the disease or condition.

[0176] In some embodiments, the present invention provides a method for inhibiting URAT1. The method comprises contacting Compound 1 Form 1, Compound 1 Form 2, Compound 1 Form 3, Compound 1 Form 4, Compound 1 Form 5A, Compound 1 Form 5B, Compound 1 Form 5C, Compound 1 Form 5D, Compound 1 Form 6, Compound 1 Form 7, Compound 1 Form 8, Compound 1 Form 9, Compound 1 Form 10, Compound 1 Form 11 or Compound 1 Form 12, or a composition thereof, with a cell or URAT1 in vitro or in vivo.

[0177] In certain embodiments, the present invention provides the use of 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 or Compound I Form 12 as described above, or a combination thereof in the preparation of a medicament for treating a disease or condition. In other embodiments, the present invention provides 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 or Compound I Form 12 for treating a disease or condition described herein.

[0178] In some embodiments, the composition provided includes a therapeutically effective amount of any one or more solids, crystals or polymorphs of Compound I described herein and at least one pharmaceutically acceptable carrier, excipient and / or diluent, including any two or more combinations of any one or more solids, crystals or polymorphs of Compound I described herein. In certain embodiments, the composition may include any one or more solids, crystals or polymorphs of Compound I described herein, and one or more compounds effective for the treatment of the same disease indication. In one aspect, the composition includes any one or more solids, crystals or polymorphs of Compound I described herein, and one or more compounds effective for the treatment of the same disease indication, wherein the compound has a synergistic effect on the disease indication. In one embodiment, the composition includes any one or more solids, crystals or polymorphs of Compound I described herein, and one or more other compounds that are effective for the treatment of gout or hyperuricemia, in addition, wherein the compound has a synergistic effect in the treatment of gout or hyperuricemia. The compounds may be administered simultaneously or sequentially.

[0179] In one embodiment, the invention provides a method for treating a disease or condition mediated by URAT1 by administering to a subject an effective amount of a composition (including any one or more solid, crystal, or polymorphic forms of Compound I described herein) in combination with one or more other suitable therapies described herein for treating the disease.

[0180] Reagent test kit

[0181] In another aspect, the present invention provides a kit or container, which includes any solid, crystal or polymorph of Compound I as described herein, or a pharmaceutically acceptable salt thereof, or a composition thereof. In some embodiments, the solid, crystal or polymorph of Compound I or the composition is packaged in, for example, a vial, bottle, flask, which can be further packaged, for example, in a box, envelope or bag; the solid, crystal or polymorph of Compound I or the composition is approved by the U.S. Food and Drug Administration or similar regulatory agency for use in mammals, such as humans; the solid, crystal or polymorph of Compound I or the composition is approved for administration to mammals, such as humans, to treat URAT1-mediated diseases or conditions; the disclosure kit or container may include written instructions for use and / or other indications indicating that the solid, crystal or polymorph of Compound I or the composition is suitable or approved for use in mammals (e.g., humans) to treat URAT1-mediated diseases or conditions; and the solid, crystal or polymorph of Compound I or the composition can be packaged in unit doses or single-dose crystal forms, for example, single-dose pills, capsules, etc. Example

[0182] Dynamic Vapor Sorption / Desorption (DVS)

[0183] Moisture absorption / desorption data were collected on an SMSDVS intrinsic vapor absorption analyzer under nitrogen purge. DVS experiments generally consist of two steps: moisture absorption and desorption. The experiment is considered to be completed when the sample mass does not change over time. That is, when dm / dt≦0.01%, the sample is considered to have reached moisture absorption and desorption equilibrium at relative humidity. The sample was maintained at a temperature of 25°C and the relative humidity varied from 0% to 95%, with each step returning to 0% in increments of 5% RH.

[0184] Coulomb Karl-Fisher analysis (KF)

[0185] Coulometric Karl Fischer (KF) analysis for water determination was performed using a Metrohm 787KF Karl Fischer titrator.

[0186] Differential Scanning Calorimetry (DSC)

[0187] DSC uses a Mettler Toledo DSC1 differential scanning calorimeter. In a typical experiment, a sample of about 1 to 5 grams is weighed and placed in a closed aluminum crucible with a pinhole on the crucible cover. Under nitrogen protection, the sample is scanned at a speed of 20°C / min in the range of 30°C to 300°C.

[0188] Thermogravimetric analysis (TGA)

[0189] Thermogravimetric analysis was performed using a PerkinElmer Pyris 1TGA thermogravimetric analyzer. In a typical experiment, approximately 5 grams of sample was weighed and placed in a crucible under nitrogen protection. The sample was scanned at a rate of 20°C / min in the temperature range of 30 to 400°C. The results were calibrated based on the blank background curve.

[0190] Nuclear Magnetic Resonance Analysis (NMR)

[0191] Proton NMR was obtained using a Bruker AVANCE III 400 MHz instrument. In a typical experiment, samples were prepared by dissolving about 3 mg of sample in about 0.5 mL of deuterated dimethyl sulfoxide.

[0192] High performance liquid chromatography (HPLC)

[0193] Agilent 1260 high performance liquid chromatograph was used.

[0194] X-ray powder diffraction (XRPD)

[0195] Using a Cu Kα radiation source X-ray powder diffraction patterns of Forms 1-12 were obtained using a Shimadzu XRD-6000 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.

[0196] Peaks identified here and in this article are generally the more intense reflections in the powder pattern to avoid uncertainties due to potential preferred orientation and particle statistics issues. Some peaks can be used to distinguish one crystalline polymorph from another. Some of these peaks may be unique, for example, within ±0.2° 2θ, present in one crystalline polymorph of a compound and absent in other known crystalline polymorphs of the compound. However, not all crystalline polymorphs of a compound necessarily have such unique peaks. In such cases, multiple peaks can be used to make the identification.

[0197] Example 1 Synthesis of Compound I

[0198] The synthesis scheme of compound I is as follows:

[0199]

[0200] Step A: In an ice-water bath, add 4-methoxyacetophenone (44 g, 293 mmol) to a mixture containing 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (104 g, 294 mmol), iodine (38.6 g, 152 mmol) and acetonitrile (440 mL). After the addition, the resulting mixture was stirred at room temperature overnight. Water (1350 mL) was added to the reaction mixture, and a large amount of solid precipitated. Filter and dry to obtain 3-iodo-4-methoxyacetophenone (34) (70 g). The yield was 86.5%.

[0201] Step B: A mixture containing compound 34 (70.0 g, 254 mmol), cuprous cyanide (34.0 g, 380 mmol) and DMF (400 mL) was stirred at 130°C overnight. After cooling to room temperature, the mixture was filtered through diatomaceous earth, and water (1600 mL) was added. 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 obtain 5-acetyl-2-methoxybenzonitrile (35) (50.0 g). The compound was used directly in the next step without further treatment.

[0202] 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, filtered, and dried to obtain 5-(2-bromo-acetyl)-2-hydroxy-3-methylbenzonitrile (36) (41.0 g). The total yield of the two-step reaction of steps B and C was 70.6%.

[0203] 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 value 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 = 1:30-2:1 elution) to obtain 5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-methoxybenzonitrile (37) (25.7 g). The yield was 52.3%.

[0204] Step E: In an ice-water bath, 60% sodium hydride (4.8 g, 120 mmol) was added in batches to a solution of ethanethiol (8.4 mL) in THF (30 mL), stirred for about 5 minutes, and filtered to collect the filter cake. The filter cake was then added to a mixture containing compound 37 (9.0 g, 29.5 mmol) and DMF (25 mL), and 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 value was adjusted to 5-6 with 2M citric acid aqueous solution. After filtering, the filter cake was recrystallized from acetonitrile to obtain 5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile (14) (7.2 g). The yield was 83.8%.

[0205] Step F: NBS (5.28 g, 29.7 mmol) was added in batches to a DMF (70 mL) solution of compound 14 (7.2 g, 24.7 mmol). After the addition was complete, the resulting mixture was stirred at room temperature for 1 hour. Water (210 mL) was added, filtered, and the filter cake was washed with water (100 mL × 3), and then recrystallized from acetonitrile to obtain 3-bromo-5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile (38) (7.0 g). The yield was 76.8%.

[0206] 1 H NMR (DMSO-d6, 300MHz) δ9.01 (d, J=6.9Hz, 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=7.2Hz, 3H). MS(EI, m / z): 368.0[MH] - .

[0207] Example 2 Compound I Crystalline Form 1

[0208] The product prepared in Example 1 was purified and crystallized using acetonitrile. The resulting crystals were characterized by XRPD and named Compound I Form 1. The XRPD of Compound I Form 1 has been prepared according to the above Figure 1 In addition, the TGA and DSC of Compound I Form 1 have been described in Figure 2 and 3 Described above.

[0209] A heating study was performed on a fresh sample of Form 1. The sample was heated to 140°C using a thermogravimetric analyzer and held for 30 minutes. The XRPD pattern of the treated sample did not show any peaks, consistent with amorphous. This indicates that Figure 3 The endothermic peak starting at about 140°C is the melting peak of Form 1.

[0210] The water content of Form 1 was 8.8% as determined by the KF method. Based on this, it was estimated that each mole of Compound I in Form 1 was associated with about 2 moles of water. The DVS results showed that Form 1 was a hydrate. When the relative humidity was cycled from 0% RH to 5% RH, it rapidly absorbed about 3.4% of water by weight, followed by a slower moisture absorption.

[0211] Crystal form 1 1 Further characterization by H NMR 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.

[0212] In some embodiments, if Form 1 has satisfactory crystalline quality, Form 1 is prepared from wet acetonitrile (eg, acetonitrile having a water content of about 0.5%).

[0213] Solubility

[0214] Solubility of Form 1 was visually evaluated. About 5 mg of Form 1 was accurately weighed and placed in a 5 mL glass bottle. A small amount of solvent was gradually added to the bottle until the compound was dissolved or the total amount added reached 5 mL, and the cumulative volume of the solvent was recorded. The experimentally calculated solubility is shown in Table 1.

[0215] Table 1 Visual solubility in common solvents

[0216]

[0217]

[0218] As shown in Table 1, Form 1 is insoluble in water, and insoluble in organic solvents such as methanol, ethanol, acetone, acetonitrile, ethyl acetate, n-heptane, isopropanol, methyl ethyl ketone, dichloromethane, toluene, etc. It is soluble in tetrahydrofuran (THF) at a concentration of about 3 mg / mL, and has a greater solubility in dimethyl sulfoxide (DMSO) and dimethylformamide (DMF) at a concentration of more than 25 mg / mL.

[0219] Heating studies

[0220] About 150 mg of Form 1 was heated to 110°C for about 10 minutes. The color of the sample changed from light yellow to dark yellow. The darker colored sample was evaluated by XRPD. After the XRPD evaluation, the sample color returned to light yellow, similar to the color before the heat treatment. Further TGA evaluation of the same sample showed that the quality of the sample decreased significantly 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. The moisture content of Form 1 after heating was 6.8%. It was concluded that Form 1 may lose water when heated. This product is unstable and will absorb water rapidly.

[0221] Example 3: Polycrystalline Screening

[0222] Compound I Form 1 was used as the starting material for polymorphic screening. Several methods are described in detail below.

[0223] Slurry

[0224] About 40 mg of Form 1 was weighed, placed in respective 5 mL glass bottles, and mixed with about 2 mL of various solvents, as shown in Table 2. All samples were stirred for 24 hours at room temperature or 50°C (as shown in Table 2). A suspension was formed. The wet solid was then centrifuged and further dried in vacuum (40°C, -0.09 MPa). The dried solid was analyzed by XRPD, and the identification of the form is shown in Table 2.

[0225] Antisolvent method

[0226] About 50 mg of Form 1 was weighed, placed in a 40 mL glass bottle, and dissolved with 1 mL of DMF. The antisolvent was then added dropwise until enough solid precipitated out, or until 10 mL of antisolvent was added. When water was used as the antisolvent, the solution became turbid after mL of antisolvent was added. However, a total of 3 mL was added. With methanol, acetone or ethyl acetate as the antisolvent, no precipitation occurred after 10 mL of antisolvent was added. All samples were stirred at room temperature for 24 hours. The wet solid precipitate was separated by centrifugation, dried in vacuo (40°C, -0.09MP), and analyzed by XRPD. The identification of the crystal form is shown in Table 2.

[0227] Table 2 Polymorph screening

[0228]

[0229] Solvents Room temperature slurry 50℃ slurry Antisolvent water Crystal form 1 Crystal form 1 Crystal form 1 Methanol (MeOH) Crystal form 1 Crystal form 1 Crystal form 4 acetone Crystal form 2 Crystal form 2 Crystal form 2 Acetonitrile (ACN) Crystal form 3 Crystal form 2 - Ethyl acetate (EtOAc) Mixed crystal Crystal form 2 Crystal form 2 Methyl Ethyl Ketone (MEK) Crystal form 1 Crystal form 2 - Dichloromethane (DCM) Crystal form 1 - - Toluene Crystal form 1 Crystal form 1 - Heptane Crystal form 1 Crystal form 1 - MeOH:water(3:1) Crystal form 1 Crystal form 1 - Acetone:water (3:1) Crystal form 1 Crystal form 1 - Tetrahydrofuran (THF) Crystal form 1 Crystal form 3 -

[0230] Solvent evaporation

[0231] About 25 mg of Form 1 was weighed into a 40 mL glass bottle and dissolved in 8 mL of tetrahydrofuran by sonication. The bottle was then placed in a fume hood without a lid so that the solvent could escape at room temperature. After 24 hours, nitrogen was used to blow dry any residual solvent on the sample. The solid was collected and analyzed by XPRD and showed a spectrum consistent with Form 1, but the crystal quality was lower.

[0232] Grinding method

[0233] About 80-100 mg of Form 1 was weighed into an agate mortar and soaked with a small amount of acetone or tetrahydrofuran. The sample was ground until the solvent disappeared. Another portion of the same solvent was added and the sample was further ground until the solvent disappeared again. This operation was repeated several times until the total grinding time reached about 5 minutes. The final sample was analyzed by XRPD. The samples treated with tetrahydrofuran and acetone showed XRPD consistent with Form 1.

[0234] Prepare new crystal form

[0235] As described above, Form 2 can be prepared from acetone, acetonitrile, ethyl acetate or methyl ethyl ketone. For example, Form 2 can be prepared in an acetone system by a room temperature slurry method and an anti-solvent method; in an ethyl acetate system by a slurry method at 50°C and an anti-solvent method; or in a methyl ethyl ketone and acetonitrile system by a slurry method at 50°C.

[0236] TGA and DSC of Form 2 Figure 5 and 6 The relationship is as described above. KF analysis shows that the water content of Form 2 obtained from the acetone slurry is about 0.4%. DVS analysis shows that Form 2 has low hygroscopicity when the relative humidity is less than 80%. When the relative humidity reaches 85% RH, Form 2 immediately absorbs about 3.8% of water, and as the relative humidity increases, the moisture absorbed by Form 2 further increases. When the relative humidity drops to 0% during the desorption process, about 3.4% of water remains in the sample. After DVS analysis, the XRPD of the sample shows that the sample has been converted into Form 1. This also confirms that Form 1 is a hydrate.

[0237] From the XRPD diagram, it can be seen that both the acetonitrile slurry at room temperature and the THF slurry at 50°C can obtain Form 3. Figure 7 as shown; Figure 8 and 9 As shown, TGA and DSC analysis were performed on samples prepared as THF slurries at 50° C. Form 3 is considered to be a relatively unstable solvate.

[0238] Form 4 can be prepared from DMF solution using methanol as an anti-solvent. XRPD pattern as above Fig.10As shown; TGA and DSC of Form 4 have been Fig.11 and 12 As described above.

[0239] Other observations and data of the crystal form are shown in Table 3.

[0240] Table 3 Physical characterization results of the new crystal form

[0241]

[0242] Example 4: Salt Screening

[0243] Small scale

[0244] Using tetrahydrofuran or acetone as solvent (as shown in Table 4 below), the solvent is about 1.0 mL per 10 mg of Compound I Form 1, and Compound I Form 1 (80-100 mg) is prepared into 8 samples. The sample forms a uniform suspension. Subsequently, hydrochloric acid, sulfuric acid, nitric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, potassium hydroxide and sodium hydroxide (collectively referred to as counterions) are added to respective glass vials at a molar ratio of 1:1.05 (Compound I: counterions), unless otherwise stated. All samples are further magnetically stirred overnight at room temperature. The salts are collected by centrifugation or solvent evaporation, dried in vacuo at 40°C, and then analyzed by XRPD. The experimental results are summarized in Table 4. Blank control samples were used to confirm that similar treatments did not result in any changes in the crystal form except for the introduction of counterions.

[0245] Table 4 Salt screening

[0246]

[0247]

[0248] a Approximately 50 mg of Compound I was used. b The ratio of compound I to acid is 1:1.1. c Approximately 50 mg of Compound I was used.

[0249] As shown in the figure, in the THF system, compound I forms salts with all acids except benzenesulfonic acid; in the acetone system, it forms salts with all acids except maleic acid. The XRPD results of the corresponding salts obtained from tetrahydrofuran and acetone match, and therefore have the same crystal form. The XRPD pattern of the new crystal form has been described above. Further observations and data of crystal form 1 and salt crystal forms are shown in Table 5.

[0250] Table 5 Characterization of Form 1 and its salt forms

[0251]

[0252]

[0253] Example 5: Scale-up and characterization of salt crystal forms

[0254] The hydrochloride salt (form 5D) was scaled up as follows: About 400 mg of compound I form 1 was weighed into a 40 mL glass bottle and mixed with about 10 mL of ethanol to form a light yellow suspension. Subsequently, a hydrochloric acid solution (2 mol / L methanol) was introduced at a molar ratio of 1:1.05 (compound I: counterion). The color of the suspension deepened after the addition. The sample was placed on a plate and stirred for 24 hours at room temperature. The solid was collected by centrifugation and dried for 4 to 6 hours. The dried solid was analyzed by XRPD. The ion ratios of compound I and counterion in the hydrochloride salt were determined by HPLC-ELSD to be 1:0.50 and 1:0.88, respectively. It can be seen that it is difficult to form a hydrochloride salt with a stable molar ratio.

[0255] Methanesulfonic acid (Form 6) was similarly amplified as methanesulfonic acid (1 mol / L in water), although the color of the suspension changed from pale yellow to white after the addition of the acid. 1 H NMR determined that the ion ratio of compound I to counterion in the mesylate salt was 1:0.96. Therefore, the compound can form a mesylate salt with an approximate molar ratio of 1:1.

[0256] The mesylate prepared from acetone was heated to 160°C using a thermogravimetric analyzer and kept at 160°C for 5 min to remove the solvent, and then analyzed by XRPD. The desolvated mesylate was placed under high humidity conditions (92.5% RH) overnight and analyzed again by XRPD. The results are shown in Table 1. Fig.37 As shown in the figure, the crystal form of the mesylate changes after losing the solvent, but after absorbing moisture again under high humidity conditions, it slowly returns to the initial crystal form. This shows that the mesylate is a hydrate.

[0257] The sulfate salt (form 8) was also enlarged with sulfuric acid (2 mol / L in water), although the pale yellow suspension became a transparent solution after the addition of acid. The ion ratio of compound I to counterion in sulfuric acid was 1:0.52 as determined by the Shanghai Institute of Metrology, i.e., each mole of compound I was associated with approximately 0.5 mole of form 8 sulfuric acid.

[0258] The potassium salt (form 11) was also enlarged with potassium hydroxide (5 mol / L in water), although the light yellow suspension did not undergo any substantial changes after the addition of the base. The ion ratio of compound I to counterion in the potassium salt measured at Shanghai Metrology was 1:0.86, indicating that the salt formation was incomplete.

[0259] The XRPD of each salt after scale-up was consistent with 80 mg to 100 mg of the salt.

[0260] Example 6: Solubility of Form 1, Form 2, Form 5D, Form 6, Form 8 and Form 11

[0261] The solubilities of Form 1, Form 2, Form 5D, Form 6, Form 8 and Form 11 in water, 0.1N HCl aqueous solution, pH 4.5 acetate buffer, pH 6.8 phosphate buffer, simulated gastric fluid (SGF), fasted state simulated intestinal fluid (FaSSIF) and fed state simulated intestinal fluid (FeSSIF) were analyzed.

[0262] About 5 mg or 10 mg of sample was weighed into each vial and mixed with about 5 mL of medium to form a solution. The target concentration of potassium salt in water was 2 mg / mL; the target concentration of other crystalline forms was 1 mg / mL. All samples were stirred at 200 rpm for 24 hours at 37°C. The pH of these samples was measured after stirring for 24 hours. Subsequently, the samples were centrifuged at 12,000 rpm for 2 minutes. The supernatant was diluted with methanol when necessary and the concentration was determined by HPLC. When testing the solubility of potassium salt in water, the supernatant was diluted 100 times, and other samples were not diluted. HPLC analysis used Agilent Eclipse XDB-C8 4.6*150mm, 5μm column 40°C, mobile phase 0.1% TFA:ACN=70:30, injection volume 10μL, flow rate 1.0mL / min, diluent methanol, detection wavelength 234nm.

[0263] After stirring for about 24 hours, Form 1 and Form 2 became homogeneous suspensions in all media. Form 1 and Form 2 had low solubility in buffer solutions and biorelevant media. However, Form 2 did show higher solubility in several media, with the highest concentration being about 40 μg / mL.

[0264] Form 11 forms an almost clear solution in water, but forms a homogeneous suspension in all other media, similar to Form 1. The increase in the solubility of the potassium salt (Table 11) in water may be caused by the large increase in pH. At the same time, Forms 5D, 6, and 8 all became heterogeneous suspensions of small particles after the same treatment, and their solubility in water was lower than that of the free base form (Form 1).

[0265] Table 6 shows the solubility of Form 1, Form 2, Form 5D, Form 6, Form 8, and Form 11.

[0266] Table 6 Solubility of Form 1, its salts and Form 2 (37°C)

[0267]

[0268]

[0269] Example 7: Stability of Crystalline Form

[0270] Slurry stability of Form 1, Form 5D, Form 6 and Form 8.

[0271] About 30 mg of Form 1, Form 5D, Form 6, and Form 8 were mixed with about 2.5 mL of purified water and stirred overnight at room temperature. The wet solid was centrifuged, further vacuum dried for 2.5 hours, and then analyzed by XRPD. The XRPD results showed that after the experiment, Form 5D, Form 6, and Form 8 were all converted into Form 1.

[0272] Solid-state stability study of Form 1, Form 2, Form 6, Form 8 and Form 11

[0273] Form 1, Form 2, Form 6, Form 8, and Form 11 were placed under the following stress conditions: (1) in a sealed bottle at a temperature of about 60°C; (2) in a sealed bottle at a temperature of about 40°C and a humidity of about 75% RH. The solids were analyzed by XRPD every 1 week and 2 weeks. All forms presented XRPD patterns that were essentially similar to those initially received, indicating their stability under these stress conditions.

[0274] In addition, all crystalline forms were analyzed for impurities by HPLC every 1 and 2 weeks. In a typical analysis, about 5 mg of the crystalline form was dissolved in 10 mL of diluent for 2 minutes with the help of ultrasound. Tetrahydrofuran was used as the diluent for crystalline form 1, and methanol was used as the diluent for crystalline form 6, crystalline form 8 and crystalline form 11. HPLC analysis was performed using agilent Eclipse XDB-C18 4.6*150mm, 3.5μm, 30℃, and the mobile phase gradient was 0.1% H 3 PO 4 -acetonitrile (9:1~2:8~9:1), injection volume of 10μL, flow rate of 1.0mL / min, detection wavelength of 214nm. The results showed no significant changes compared with the HPLC data initially received, confirming that all crystalline forms have good stability under these stress conditions.

[0275] Form 2 was subjected to stability testing in an open bottle at 40°C and 75% RH. XRPD analysis showed significant changes at the end of day 9, indicating that Form 2 should be stored away from moisture.

[0276] Example 8: Suspension for animal preparation

[0277] About 30 mg of each of Form 1, Form 2 and Form 5D were added to 40 mL glass bottles and mixed with 30 mL of 0.5% CMC-Na solution. The solid was evenly dispersed in the solution with the help of ultrasound. The solid was then centrifuged and dried at room temperature, and the dried solid was analyzed by XRPD. The analysis showed that under this condition, Form 2 was transformed into Form 1, while Form 1 and Form 5D did not change.

[0278] Example 9: Formsin Pharmacokinetic Study in Rats

[0279] After oral and intravenous administration to SD rats, Form 1, Form 2 and Form 5D were evaluated by single-dose pharmacokinetic studies. The results showed that the average bioavailability of all samples was around 50%, which was satisfactory. Form 2 showed higher dose exposure and bioavailability than Form 1, making it an ideal candidate for formulation development. Form 1, Form 2 and Form 5D were evaluated by rat pharmacokinetic studies.

[0280] Materials and instruments

[0281] Male SD rats were purchased from Shanghai Sippr B&K Laboratory Animal Co., Ltd. The weight was 180 g to 200 g.

[0282] Preparation of test products

[0283] Dissolve 20g HP-β-CD (from Sigma) in 100mL purified water to prepare 20% HP-β-CD. Dissolve 1g CMC-Na (from Aladdin) in 200mL purified water to prepare 0.5% CMC-Na. Store the solution at 2-8 degrees.

[0284] Group 1: Weigh 4.95 mg of Form 1 (equivalent to 4.50 mg of anhydrous free base) into a 20 mL bottle and dissolve it completely by ultrasonication with 0.225 mL of dimethyl sulfoxide. Add 4.275 mL of 20% HP-β-CD and mix well by ultrasonication. Finally, adjust the pH to 7.0 with sodium hydroxide solution. A clear solution with a concentration of 1 mg / mL is obtained.

[0285] Group 2: Weigh 10.08 mg of Form 1 (equivalent to 9.164 mg of anhydrous free base) into a 20 mL bottle, add 9.164 mL of 0.5% CMC-Na, and form a white suspension with a concentration of 1 mg / mL after ultrasonication using an ultrasonic cell pulverizer.

[0286] Group 3: 9.47 mg of Form 2 was weighed and placed in a 20 mL bottle, and then 9.470 mL of 0.5% CMC-Na was added. After ultrasonic treatment, the mixture was stirred evenly with a homogenizer for 2 minutes. Finally, a white suspension was formed with a concentration of 1 mg / mL.

[0287] Group 4: Weigh 9.80 mg of Form 5D (equivalent to 8.909 mg of free base) into a 20 mL bottle, add 8.909 mL of 0.5% CMC-Na. After ultrasonic treatment, stir evenly with a homogenizer for 2 minutes. Finally, a white suspension is formed with a concentration of 1 mg / mL.

[0288] Group 5: Weigh 1.94 mg of Form 1 (equivalent to 1.763 mg of anhydrous free base) into a 20 mL bottle and dissolve it completely with 0.088 mL of dimethyl sulfoxide by ultrasonic method. Add 1.675 mL of 20% HP-β-CD and mix well by ultrasonic method. Finally, adjust the pH value to 7.0 with sodium hydroxide solution. A clear solution with a concentration of 0.2 mg / mL is obtained.

[0289] Medication and blood draw

[0290] 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 fed 4 hours later.

[0291] Blood samples were collected by jugular vein puncture at the initial time (vein only) and 0.25, 0.5, 1, 2, 4, 6, 8, 24 hours. EDTA-K2 was selected as the anticoagulant. Blood samples were centrifuged at 6000 rpm for 8 minutes within 1 hour (placed on wet ice before centrifugation). The supernatant was stored at -20℃ for LC-MS / MS analysis.

[0292] Data and graphics were processed using the computer program Microsoft Office Excel 2007 (Microsoft, USA). Pharmacokinetic parameters were calculated using WinNolin 6.4 software.

[0293] After intravenous and oral administration to male SD rats, the drug concentrations in plasma were collected at different time points. Fig.38 The blood concentration-time curve of Compound 1 Form 1 after a single intravenous administration of 1 mg / kg to SD rats is shown. Fig.39 Shown is the blood concentration-time curve of SD rats after a single intravenous administration of 5 mg / kg Compound I Form 1. Fig.40 Shown is the blood concentration-time curve of Compound I Form 1 in SD rats after a single oral administration of 10 mg / kg. Fig.41 The figure shows the blood concentration-time curve of Compound I Form 2 in SD rats after a single oral administration of 10 mg / kg. Fig.42 The blood drug concentration-time curve of Compound I Crystal Form 5D in SD rats after a single oral administration of 10 mg / kg. The non-compartmental pharmacokinetic parameters are shown in Tables 7 to 11.

[0294] Table 7 Non-compartmental pharmacokinetic parameters of male SD rats after intravenous administration of 1 mg / kg

[0295] parameter 501 502 503 average SD <![CDATA[HL_Lambda_z(T 1 / 2 ,hr)]]> 3.20 2.61 2.90 2.90 0.29 <![CDATA[C max (ng / mL)]]> 7116.3 11256.4 10356.4 9576.4 2177.5 <![CDATA[AUC last (hr*ng / mL)]]> 18450.5 15448.2 18170.6 17356.4 1658.5 <![CDATA[AUC INF_pred (hr*ng / mL)]]> 18531.5 15467.7 18214.0 17404.4 1684.7 <![CDATA[MRT last (hr)]]> 3.99 3.28 3.68 3.65 0.36 <![CDATA[V z_pred (L / kg)]]> 0.25 0.24 0.23 0.24 0.01 <![CDATA[Cl _pred (L / hr / kg)]]> 0.05 0.06 0.05 0.06 0.01 λz calculation time range (hr) 6-24 4-24 6-24 NA NA

[0296] Table 8 Non-compartmental pharmacokinetic parameters of male SD rats after administration of 5 mg / kg

[0297] parameter 101 102 103 average SD <![CDATA[HL_Lambda_z(T 1 / 2 ,hr)]]> 3.12 3.03 3.10 3.08 0.05 <![CDATA[C max (ng / mL)]]> 55666.4 51717.5 46753.2 51379.0 4466.2 <![CDATA[AUC last (hr*ng / mL)]]> 90790.9 77235.7 72609.9 80212.2 9448.9 <![CDATA[AUC INF_pred (hr*ng / mL)]]> 91117.6 77458.7 72847.5 80474.6 9501.1 <![CDATA[MRT last (hr)]]> 3.65 3.40 3.28 3.44 0.19 <![CDATA[V z_pred (L / kg)]]> 0.25 0.28 0.31 0.28 0.03 <![CDATA[Cl _pred (L / hr / kg)]]> 0.05 0.06 0.07 0.06 0.01 λz calculation time range (hr) 1-24 4-24 2-24 NA NA

[0298] Table 9 Pharmacokinetic parameters of non-compartmental model after oral administration of 10 mg / kg Form 1 to male SD rats

[0299]

[0300]

[0301] Note: F (%) is calculated based on intravenous administration of 1 mg / kg

[0302] Table 10 Pharmacokinetic parameters of non-compartmental model after oral administration of 10 mg / kg Form 2 in male SD rats

[0303] parameter 301 302 303 average SD <![CDATA[HL_Lambda_z(T 1 / 2 ,hr)]]> 2.90 3.32 3.01 3.08 0.22 <![CDATA[T max (hr)]]> 4.00 6.00 2.00 4.00 2.00 <![CDATA[C max (ng / mL)]]> 8489.9 8030.2 7328.5 7949.5 584.9 <![CDATA[AUC last (hr*ng / mL)]]> 91923.1 108067.6 65456.4 88482.4 21513.0 <![CDATA[AUC INF_pred (hr*ng / mL)]]> 92375.2 109095.0 65798.9 89089.7 21834.3 <![CDATA[MRT last (hr)]]> 6.15 6.66 5.56 6.12 0.55 <![CDATA[V z_F_pred (L / kg)]]> 0.45 0.44 0.66 0.52 0.12 <![CDATA[Cl _F_pred (L / hr / kg)]]> 0.11 0.09 0.15 0.12 0.03 λz calculation time range (hr) 6-24 6-24 6-24 NA NA F(％) 52.96 62.26 37.71 50.98 12.39

[0304] Note: F (%) is calculated based on intravenous administration of 1 mg / kg

[0305] Table 11 Non-compartmental pharmacokinetic parameters of male SD rats after oral administration of 10 mg / kg crystalline form 5D

[0306] parameter 401 402 403 average SD <![CDATA[HL_Lambda_z(T 1 / 2 ,hr)]]> 3.55 3.44 3.20 3.40 0.18 <![CDATA[T max (hr)]]> 4.00 2.00 4.00 3.33 1.15 <![CDATA[C max (ng / mL)]]> 8543.5 8879.3 9523.3 8982.0 497.9 <![CDATA[AUC last (hr*ng / mL)]]> 95560.7 84721.7 95462.1 91914.8 6229.6 <![CDATA[AUC INF_pred (hr*ng / mL)]]> 96578.2 85492.7 96111.1 92727.3 6269.7 <![CDATA[MRT last (hr)]]> 6.11 5.81 5.95 5.95 0.15 <![CDATA[V z_F_pred (L / kg)]]> 0.53 0.58 0.48 0.53 0.05 <![CDATA[Cl _F_pred (L / hr / kg)]]> 0.10 0.12 0.10 0.11 0.01 λz calculation time range (hr) 6-24 6-24 6-24 NA NA F(％) 55.06 48.81 55.00 52.96 3.59

[0307] Note: F (%) is calculated based on intravenous administration of 1 mg / kg

[0308] Analysis of pharmacokinetic results in SD rats

[0309] Pharmacokinetic results showed that Form 2 had a higher exposure (AUC 0-t ) and better bioavailability, which may be superior to Form 1. After oral administration, the exposure of Form 2 (AUC 0-t ) and bioavailability are roughly the same as those of Form 5D. The exposure of Form 5D is roughly the same as the results of a third party. When SD rats were intravenously administered at doses of 1 mg / kg and 5 mg / kg, the exposure of the latter was about 5 times that of the former. At the same time, the bioavailability at both dosing levels was calculated to be about 50%. Both Forms 1 and 2 have sufficiently high bioavailability and are considered suitable for development into oral preparations.

[0310] Example 10: Stability Study

[0311] The stability of Compound 1 Form 2 was analyzed by the following two experiments.

[0312] Experiment A: According to ChP <0451> / USP / NF <941> / EP10.6 2.9.33, obtained by X-ray powder diffraction analysis Fig.43 and Fig.44 Data shown. Standard XRPD patterns were collected using a Bruker D8 Advance diffractometer or equivalent.

[0313] Fig.43 , Fig.44 The XRPD acquisition parameters shown are as follows:

[0314]

[0315] Fig.43 The X-ray powder diffraction (XRPD) comparison diagram between the Compound I Form 2 sample placed under 25°C ± 2°C / 60% RH ± 5% RH conditions for 12 months, the Compound I Form 2 sample at 0 days, and the Compound I Form 2 reference standard is shown. Fig.43 In the figure, the top curve represents the Compound I Form 2 sample (SPL) placed at 25°C ± 2°C / 60% RH ± 5% RH for 12 months, the middle curve represents the Compound I Form 2 sample (initial) placed for 0 days, and the bottom curve represents the Compound I Form 2 reference standard (STD).

[0316] Fig.44 Comparative XRPD patterns of a Compound I Form 2 sample placed under 40°C ± 2°C / 75% RH ± 5% RH conditions for 6 months, a Compound I Form 2 sample placed for 0 days, and a Compound I Form 2 reference standard are given. Fig.44 In the figure, the top curve is a sample of Compound I Form 2 placed at 40°C ± 2°C / 75% RH ± 5% RH for 6 months (SPL), the bottom curve is a sample of Compound I Form 2 at 0 days (initial), and the middle curve is a reference standard of Compound I Form 2 (STD).

[0317] from Fig.43 and Fig.44 It can be seen that the XRPD patterns of Compound I Form 2 in the initial preparation (0 days) and long-term storage at 25°C ± 2°C / 60% RH ± 5% RH and 40°C ± 2°C / 75% RH ± 5% RH are consistent with the Form 2 standard. This indicates that Compound I Form 2 can remain stable for at least 12 months at 25°C and at least 6 months at 40°C.

[0318] Experiment B: The following is the X-ray powder diffraction analysis method, obtained Fig.45 and Fig.46 Data shown. Fig.45 and Fig.46 The XRPD patterns shown 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: 282.2mm; Slit: 1.0mm; Primary Soller slit: 2.5°; Secondary Soller slit: 2.5°; Airscatter screen module: 1.0mm; Tube core: copper; Tube parameters: Voltage 30kV; Current 10ma; Scan parameters: SSD160: lock coupling; SSD160-2: couple two θ / θ Scan type: SSD160: lock coupling; SSD160-2: couple two θ / θ; Continuous PSD fast scan mode: Continuous PSD fast scan; Rotation speed: 20rpm; Start: 3°~40°(2 0); Scan step: 0.02°(2 0); Scanning speed: 0.2s / step; Detector opening: 4.5°; Sample analysis; Test the sample with the diffractometer settings and scanning parameters. Record the powder X-ray diffraction pattern of the sample and calculate according to the Bruker D2 Phase X-ray Diffractometer User Manual V6-X-ray Powder Diffraction (XRPD)-Bruker D2 Phase X-ray Identification of Crystalline Forms.

[0319] Fig.45 A comparative XRPD pattern of a Compound I Form 2 sample placed under 40°C ± 2°C / 75% RH ± 5% RH conditions for 6 months and a Compound I Form 2 reference standard is shown. Fig.45 In the figure, the bottom curve is the standard of Compound I Form 2, and the top curve is the sample of Compound I Form 2 placed under 40°C ± 2°C / 75% RH ± 5% RH for 6 months.

[0320] Fig.46 A comparative XRPD pattern of a Compound I Form 2 sample placed at 25°C ± 2°C / 60% RH ± 5% RH for 12 months, 24 months, 36 months, and 48 months with a Compound I Form 2 reference standard is given. In addition, the lower curve represents the Form 2 sample at day 0, while the subsequent curves above represent the Compound I Form 2 reference standard (STD), as well as a Compound I Form 2 sample placed at 25°C ± 2°C / 60% RH ± 5% RH for 12 months, 24 months, 36 months, and 48 months.

[0321] from Fig.45 and Fig.46It can be seen that the XRPD patterns of Compound I Form 2 in the initial preparation (0 days) and long-term storage at 40°C ± 2°C / 75%RH ± 5%RH for 6 months and 25°C ± 2°C / 60%RH ± 5%RH for 48 months are consistent with the standards of Compound I Form 2. This indicates that Compound I Form 2 can remain stable for at least 6 months at 40°C and at least 48 months at 25°C.

[0322] All patents and other references cited in this specification are indicative of the levels 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 same extent as if each reference were individually incorporated by reference in its entirety.

[0323] Those skilled in the art will readily appreciate that the present invention is well adapted to obtain the objects and advantages mentioned, as well as those inherent therein. The methods, variations and compositions described herein, which presently represent preferred embodiments, are exemplary and are not intended as limitations on the scope of the invention. Changes therein and other uses that will occur to those skilled in the art are within the spirit of the invention and are defined by the scope of the claims.

[0324] The disclosed contents described illustratively herein can be appropriately implemented without any element or disclosed element, limitation or multiple limitations not specifically disclosed herein. Thus, for example, in each instance herein, any one of the terms "comprising", "consisting essentially of" and "consisting of" can be replaced by any one of the other two terms. Thus, for an embodiment of the present invention using one of the terms, the present invention also includes another embodiment in which one of these terms is replaced by another of these terms. In each example, the terms have their defined meanings. Thus, for example, one embodiment may include a method "comprising" a series of steps, another embodiment will include a method "consisting essentially of" the same steps, and a third embodiment will include a method "consisting of" the same steps. The terms and expressions used are used as descriptive terms rather than limiting terms, and when using these terms and expressions, it is not intended to exclude any equivalents of the features shown and described or parts thereof, but it is recognized that various modifications can be made within the scope of the disclosure required. Therefore, it should be understood that although the present invention is specifically disclosed by preferred embodiments and optional features, those skilled in the art may make modifications and changes to the concepts disclosed herein, and such modifications and changes are considered to be within the scope of the present invention defined by the appended claims.

[0325] In addition, where features or aspects of the invention are described in terms of Markush groups or other groupings of alternatives, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush or other group.

[0326] Furthermore, unless otherwise indicated, where various numerical values ​​are provided for embodiments, additional embodiments are described by including any two different values ​​as endpoints of the range. These ranges are also within the scope of the described invention.

[0327] Accordingly, other implementations are within the scope of the invention and within 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:

2. The crystal form according to claim 1, Features It is Compound I Form 1, characterized by an X-ray powder diffraction pattern including peaks at 15.0, 22.6, 25.8, 32.0 and 41.3° 2θ (±0.2°), as measured by a diffractometer using Cu-Kα radiation.

3. The crystal form according to claim 2, Features It is characterized by: i) an X-ray powder diffraction pattern including 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), including endothermic peaks peaking at about 102°C and about 158°C; or iv) Thermogravimetric analysis (TGA), including a thermogram substantially as shown in Figure 2.

4. The crystal form according to claim 1, Features It is Compound I Form 2, characterized by an X-ray powder diffraction pattern including peaks at 6.7, 10.5, 17.0, 23.4 and 26.9 degrees 2θ (±0.2°), as measured by a diffractometer using Cu-Kα radiation.

5. The crystal form according to claim 4, Features It is characterized by: i) an x-ray powder diffraction pattern including additional peaks at 14.8, 21.3, 28.4 and 29.8° 2θ±0.2°; ii) comprising a peak diffraction pattern substantially as shown in Figure 4; iii) differential scanning calorimetry (DSC), including an endothermic peak peaking at about 256°C; or iv) Thermogravimetric analysis (TGA), including a thermogram substantially as shown in Figure 5.

6. The crystal form according to claim 1, Features It is Compound I Form 3, characterized by an X-ray powder diffraction pattern including peaks at 16.2, 23.1, 28.0 and 31.8° 2θ (±0.2°), as measured by a diffractometer using Cu-Kα radiation.

7. The crystal form according to claim 6, Features It is characterized by: i) an X-ray powder diffraction pattern including additional 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°; ii) a diffraction pattern substantially as shown in Figure 7; iii) differential scanning calorimetry (DSC), including endothermic peaks peaking at about 171°C and 251°C; or iv) Thermogravimetric analysis (TGA), including a thermogram substantially as shown in Figure 8.

8. The crystal form according to claim 1, Features It is Compound I Form 4, characterized by an X-ray powder diffraction pattern including peaks at 11.2, 22.4, 25.0, 27.4 and 29.1° 2θ (±0.2°), as measured by a diffractometer using Cu-Kα radiation.

9. The crystal form according to claim 8, Features It is characterized by: i) an X-ray powder diffraction pattern including additional peaks at 17.2, 22.2, 23.7, 24.1, 27.1 and 30.7° 2θ±0.2°; ii) a diffraction pattern substantially as shown in Figure 10; iii) differential scanning calorimetry (DSC), including endothermic peaks peaking at about 102°C, 149°C, and 256°C; or iv) Thermogravimetric analysis (TGA), including a thermogram substantially as shown in Figure 11.

10. The crystal form according to claim 1, Features It is Compound I Form 5D, characterized by an X-ray powder diffraction pattern including peaks at 12.6, 14.4, 15.9, 22.0, 23.0, 27.0, 27.7 and 29.6° 2θ (±0.2°) as measured by a diffractometer using Cu-Kα radiation.

11. The crystal form according to claim 10, Features It is characterized by: i) an X-ray powder 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° 2θ±0.2°; ii) a diffraction pattern substantially as shown in FIG13D ; iii) Differential Scanning Calorimetry (DSC), including an endothermic peak peaking at about 197°C; or iv) Thermogravimetric analysis (TGA), including a thermogram substantially as shown in Figure 14D.

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

13. The crystal form according to claim 12, Features It is characterized by: i) an X-ray powder diffraction pattern including additional 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°; ii) a diffraction pattern comprising peaks substantially as shown in Figure 16; iii) differential scanning calorimetry (DSC), including endothermic peaks peaking at about 151°C and 260°C; or iv) Thermogravimetric analysis (TGA), including a thermogram substantially as shown in Figure 17.

14. A composition, Features It includes two or more compounds selected from the group consisting of Compound I Crystal Form 1 according to claim 2, Compound I Crystal Form 2 according to claim 4, Compound I Crystal Form 3 according to claim 6, Compound I Crystal Form 4 according to claim 8, Compound I Crystal Form 5D according to claim 10 and Compound I Crystal Form 6 according to claim 12.

15. The composition according to claim 14, Features Wherein the composition comprises Compound I Crystal Form 1 according to claim 2 and Compound I Crystal Form 2 according to claim 4.

16. The composition according to claim 15, Features wherein the composition comprises at least 50% w / w Compound I Form 2.

17. A composition comprising Compound I, Features 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 in Form 2 of Compound I.

18. A pharmaceutical composition, Features Comprising any one or more compounds selected from the group consisting of Compound I Crystal Form 1 according to claim 2, Compound I Crystal Form 2 according to claim 4, Compound I Crystal Form 3 according to claim 6, Compound I Crystal Form 4 according to claim 8, Compound I Crystal Form 5D according to claim 10 and Compound I Crystal Form 6 according to claim 12, and further comprising a pharmaceutically acceptable excipient.

19. A method of treating a subject having or at risk of having a URAT1-mediated disease or condition, the method comprising administering to the subject an effective amount of Compound 1 Crystal Form 1 according to claim 2, Compound 1 Crystal Form 2 according to claim 4, Compound 1 Crystal Form 3 according to claim 6, Compound 1 Crystal Form 4 according to claim 8, Compound 1 Crystal Form 5D according to claim 10, and Compound 1 Crystal Form 6 according to claim 12, and a pharmaceutically acceptable excipient, the composition of claim 17, or the pharmaceutical composition of claim 18.

20. The method according to claim 19, Features Wherein the disease or condition is associated with insufficient renal elimination of uric acid.

21. The method according to claim 19, Features Wherein the disease or condition is gout or hyperuricemia.

Images