Polymorphs of NEK7 inhibitors

Abstract

This disclosure relates to a solid compound having structure (I) or a tautomer thereof. This disclosure also relates to a method for producing and using a solid compound of structure (I). TIFF2026518262000033.tif134164

Description

[Technical Field]

[0001] Embodiments of this disclosure generally relate to compounds used, for example, as therapeutic or prophylactic agents for treating inflammation, as well as methods for producing and using the same. [Background technology]

[0002] Inflammasomes are multiprotein complexes whose activation plays a central role in innate immunity and inflammation. To date, four inflammasomes have been reported: NLRP1, NLRC4, NLRP3, and AIM2. The NLRP3 inflammasome consists of NLRP3, ASC, and caspase-1. Its activation promotes the secretion of IL-1β and IL-18, which are inflammation-mediating cytokines, in animal disease models of some autoimmune diseases, myocardial infarction, metabolic syndrome, inflammatory bowel disease, and macrophage activation syndrome.

[0003] NEK7 is a member of the NIMA-associated kinase (NEK) family and acts as an NLRP3-binding protein to regulate NLRP3 oligomerization and activation. NEK7 is a serine / threonine kinase essential for mitotic initiation, cell cycle progression, cell division, and mitotic progression, and is expressed in various tissues including the brain, heart, lungs, liver, and spleen. Overexpression of NEK7 induces the production of abnormal cells closely associated with tumors (e.g., retinoblastoma, gallbladder cancer, and head and neck cancer).

[0004] Numerous inhibitors have been widely used to inhibit effector signaling pathways involving IL-1β or IL-18, without eliminating the inflammatory response itself. Inhibitors that block NLRP3 inflammasome activation by inhibiting the NLRP3-NEK7 interaction may have therapeutic or prophylactic effects in several human diseases, including type 2 diabetes (T2D), atherosclerosis, gout, and neurodegenerative diseases. However, the precise mechanism of the NLRP3-NEK7 interaction is still not fully understood.

[0005] Therefore, in several pathological diseases such as gout, atherosclerosis, type 2 diabetes, metabolic syndrome, macular degeneration, Alzheimer's disease, multiple sclerosis, and inflammatory bowel disease, there is a need to develop solid-state inhibitors that directly target NEK7 and influence the inflammatory response by modulating the NLRP3 inflammasome. Embodiments of this disclosure satisfy this need and also provide further relevant advantages. [Overview of the Initiative]

[0006] In other words, embodiments of the present disclosure provide compounds that inhibit NEK7 and / or modulate the activity of the NLRP3 inflammasome, pharmaceutically acceptable salts, solvates, cocrystals, polymorphs, and other solids thereof.

[0007] In one embodiment, this disclosure has the following structure (I): [ka] The present invention provides a solid of a compound having the same properties or a tautomer thereof, exhibiting a powder X-ray diffraction pattern having at least two peaks, where 2θ is selected from 7.33±0.2°, 10.51±0.2°, 15.93±0.2°, and 18.92±0.2°.

[0008] Other embodiments have the following structure (I): [ka] The present invention provides a solid of a compound having the same properties or a tautomer thereof, exhibiting a powder X-ray diffraction pattern having at least two peaks where 2θ is selected from 4.67±0.2°, 9.35±0.2°, 25.49±0.2°, and 26.93±0.2°.

[0009] In another embodiment, pharmaceutical compositions comprising the solids of the present disclosure and methods of using them, for example, for the treatment of inflammation, are also provided. [Brief explanation of the drawing]

[0010] In the diagram, the same reference number indicates the same or similar element or process. The size and relative position of each element shown in the diagram are not necessarily drawn to actual scale. For example, the shape and angle of each element are not based on actual size, and some elements have been enlarged or adjusted in position to improve the readability of the diagram. Furthermore, the shapes of the illustrated elements are not intended to indicate information about the actual shape of the element, but have been selected solely for the purpose of facilitating identification in the diagram. The patterns below each represent the solid form of the compound of structure (I), and unless otherwise specified, they are in their free form. [Figure 1]Figure 1 shows a diagram of the solid-state interconversion relationships for the polymorphs of Structure (I). Each conversion is indicated by the process numbers shown below. 1. Slurry treatment at room temperature (RT) and 50 °C in multiple solvents. 2. Slurry treatment at RT in 1-pentanol or THF / n-heptane, or slurry treatment at 50 °C in isoamyl alcohol. 3. Slurry treatment at 50 °C in IPA. 4. Slurry treatment at 50 °C in m-xylene. 5. Slurry treatment at RT and 50 °C in DMSO / ACN. 6. Slurry treatment at RT in 2-BuOH. 7. Perform slurry treatment at RT in acetone / cyclohexane or MEK / cyclohexane. 8. Slurry treatment at RT in DCM or ACN. 9. Store under ambient conditions of approximately 45% RH. 10. Heat to 100 °C under N2 atmosphere and then cool to room temperature. 11. Slurry treatment at RT in acetone / H2O (v:v = 6:4). 12. Heat to 150 °C under N2 atmosphere and then cool to room temperature. 13. Slurry competition treatment at 5 °C / room temperature / 50 °C in EtOAc / n-heptane. 14. Heat to 100 °C under N2 atmosphere and then cool to room temperature. [Figure 2A] Figure 2A shows the XRPD diffraction pattern of the solid form of Type A. [Figure 2B] Figure 2B shows the TGA / DSC curves of the solid form of Type A. The upper trace starts at 13.6 °C and shows a weight loss of 8.95% at 150.0 °C. The lower trace shows endothermic peaks at 87.8 °C, 116.6 °C, and 128.1 °C. [Figure 3] Figure 3 shows an overlay of the XRPD diffraction patterns of the solid forms of Types A - F (in order from top). [Figure 4] Figure 4 shows an overlay of the XRPD diffraction patterns of the solid forms of Types G - L (in order from top). [Figure 5] Figure 5 shows an overlay of the XRPD diffraction patterns of the solid forms of Types M - Q (in order from top). [Figure 6] Figure 6 shows an overlay of the XRPD diffraction patterns of the solid form of Type A under various conditions. The conditions are (in order from top) before heating, N2 replacement for 20 minutes at 30 °C, heating to 100 °C, heating to 150 °C, cooling to 30 °C, and leaving under ambient conditions. [Figure 7] Figure 7 shows an overlay of the before (upper) and after (lower) drying of the solid forms of Type B [under ambient conditions]. [Figure 8] Figure 8 shows the TGA / DSC curve of the solid form of Type B which has an endothermic peak at 205.7 °C. The upper trace starts at 23.5 °C and shows a weight loss of 2.53% at 150.0 °C. [Figure 9] Figure 9 shows an overlay of the XRPD diffraction patterns of the solid form of Type B before (upper) and after heating to 150 °C (lower). [Figure 10] Figure 10 shows the DVS plot of the solid form of Type B. [Figure 11] Figure 11 shows an overlay of the XRPD diffraction patterns of the solid form of Type B before (upper) and after (lower) DVS measurement. [Figure 12] Figure 12 shows an overlay of the XRPD diffraction patterns of the solid form of Type C before (upper) and after drying under ambient conditions (lower). [Figure 13] Figure 13 is the TGA / DSC curve of the solid form of Type C which has endothermic peaks at 113.8 °C, 142.8 °C, and 189.6 °C. The upper trace starts at 27.8 °C and shows a weight loss of 4.21% at 115.0 °C and a weight loss of 5.08% at 150.0 °C. [Figure 14] Figure 14 shows an overlay of the XRPD diffraction patterns of the solid form of Type C before (upper) and after heating to 115 °C (lower). [Figure 15] Figure 15 shows an overlay of the VT-XRPD diffraction patterns of the solid form of Type C at (in order from top) before heating, N2 purging at 30 °C for 20 minutes, heating to 75 °C, heating to 120 °C, heating to 175 °C, heating to 200 °C, and cooling to 30 °C. [Figure 16] Figure 16 shows an overlay of the XRPD diffraction patterns of the solid form of Type D before (upper) and after drying under ambient conditions (lower). [Figure 17]Figure 17 shows the TGA / DSC curve for the solid form of type D, with an endothermic peak at 144.5°C. The upper trace starts at 25.2°C and shows a 13.73% weight loss at 175.0°C. [Figure 18] Figure 18 shows a superposition of XRPD diffraction patterns of the type D solid form before (top) and after (bottom) heating to 175°C (the peak around 2θ = 17.5° in the bottom pattern is PTFE originating from the stirring bar). [Figure 19] Figure 19 shows a superposition of XRPD diffraction patterns of the type E solid form before (top) and after (bottom) drying under ambient conditions. [Figure 20] Figure 20 shows the TGA / DSC curve for the solid form of type E, with endothermic peaks at 163.3°C and 165.9°C. The upper trace starts at 27.6°C and shows a 6.53% weight loss at 175.0°C. [Figure 21] Figure 21 shows a superposition of XRPD diffraction patterns of the type E solid form before (top) and after (bottom) cooling to room temperature after heating to 175°C (the peak around 2θ = 17.5° in the bottom pattern is PTFE originating from the stirring bar). [Figure 22] Figure 22 shows a superposition of XRPD diffraction patterns of the type F solid form before (top) and after (bottom) drying under ambient conditions. [Figure 23] Figure 23 shows the TGA / DSC curve for the solid form of type F, with an endothermic peak at 176.3°C. The upper trace starts at 22.4°C and shows a 10.65% weight loss at 175.0°C. [Figure 24] Figure 24 shows a superposition of XRPD diffraction patterns of type F solid form before heating (top), after heating to 120°C and cooling to room temperature (center), and after superheating to 160°C and cooling to room temperature (bottom). [Figure 25] Figure 25 shows a superposition of XRPD diffraction patterns of the type G solid form before (top) and after (bottom) drying under ambient conditions. [Figure 26]Figure 26 shows the TGA / DSC curve for the solid form of type G, with endothermic peaks at 127.4 and 203.9°C. The upper trace starts at 29.0°C, showing a 5.31% weight loss at 100.0°C and a 12.96% weight loss at 175.0°C. [Figure 27] Figure 27 shows a superposition of XRPD diffraction patterns of the type G solid form before heating (top) and after heating to 175°C and cooling to room temperature (bottom). [Figure 28] Figure 28 shows the superposition of XRPD diffraction patterns for the solid-state form of type H. [Figure 29] Figure 29 shows the TGA / DSC curve for the solid form of type H, with an endothermic peak at 130.8°C. The upper trace starts at 20.1°C and shows a 7.57% weight loss at 150.0°C. [Figure 30] Figure 30 shows a superposition of XRPD diffraction patterns of the type H solid form before heating (top) and after heating to 150°C and cooling to room temperature (bottom). [Figure 31] Figure 31 shows a superposition of XRPD diffraction patterns of the type I solid form before (top) and after (bottom) drying under ambient conditions. [Figure 32] Figure 32 shows the TGA / DSC curve for the solid form of type I, with an endothermic peak at 161.0°C. The upper trace starts at 30.2°C and shows a 4.31% weight loss at 150.0°C. [Figure 33] Figure 33 shows a superposition of XRPD diffraction patterns of the type I solid form before heating (top) and after heating to 100°C and cooling to room temperature (bottom). [Figure 34] Figure 34 shows the superposition of XRPD diffraction patterns for the solid-state form of type J. [Figure 35] Figure 35 shows the TGA / DSC curve for the solid form of type J, with endothermic peaks at 154.6°C and 160.9°C. The upper trace starts at 15.3°C and shows a 1.24% weight loss at 150.0°C. [Figure 36]Figure 36 shows a superposition of XRPD diffraction patterns of the type K solid form before (top) and after (bottom) drying under ambient conditions. [Figure 37] Figure 37 shows the TGA / DSC curve for the solid form of type K, with an endothermic peak at 104.7°C. The upper trace starts at 31.1°C and shows a weight loss of 6.47% at 150.0°C. [Figure 38] Figure 38 shows a superposition of XRPD diffraction patterns of the type K solid form before heating (top) and after heating to 120°C and cooling to room temperature (bottom). [Figure 39] Figure 39 shows a superposition of XRPD diffraction patterns of the solid form of type L before (top) and after (bottom) drying under ambient conditions, as well as the solid form of type J (center) for reference. [Figure 40] Figure 40 shows the TGA / DSC curve for the solid form of type L, with endothermic peaks at 87.6°C and 157.6°C. The upper trace starts at 29.3°C and shows an 8.76% weight loss at 175.0°C. [Figure 41] Figure 41 shows a superposition of XRPD diffraction patterns of the type L solid form before heating (top) and after heating to 100°C and cooling to room temperature (bottom). [Figure 42] Figure 42 shows a superposition of XRPD diffraction patterns of the type M solid morph before (top) and after (bottom) drying under ambient conditions. [Figure 43] Figure 43 shows the TGA / DSC curve for the solid form of type M, with endothermic peaks at 83.2°C, 105.2°C, and 129.3°C. The upper trace starts at 27.6°C and shows an 8.28% weight loss at 150.0°C. [Figure 44] Figure 44 shows the XRPD diffraction pattern of the solid-state form of type N. [Figure 45] Figure 45 shows the XRPD diffraction pattern of the solid form of type O. [Figure 46] Figure 46 shows the XRPD diffraction pattern of the solid-state form of type P. [Figure 47]Figure 47 shows a superposition of the XRPD diffraction patterns of the type Q solid form before (top) and after (center) drying under ambient conditions, as well as the type B solid form for reference (bottom). [Figure 48] Figure 48 shows the TGA / DSC curve for the solid form of type Q, with an endothermic peak at 217.0°C. The upper trace starts at 22.4°C and shows a 4.49% weight loss at 150.0°C. [Figure 49] Figure 49 shows a superposition of XRPD diffraction patterns of the type Q solid form before heating (top) and after heating to 150°C and cooling to room temperature (bottom). [Figure 50] Figure 50 shows the DVS plot of the solid form of type Q. [Figure 51] Figure 51 shows a superposition of XRPD diffraction patterns of the solid-state type Q before (top) and after (bottom) DVS measurement. [Figure 52] Figure 52 shows the superposition of XRPD diffraction patterns of type Q and type B solid forms after performing the Competitive Slurry Conversion method. (From top to bottom) .'' .'' .'' n-heptane (1:1, 5°C), .'' n-heptane (1:1, room temperature), .'' n-heptane (1:1, 50°C), type B solid form (for reference), and type Q solid form (for reference). [Figure 53] Figure 53 shows the superposition of XRPD diffraction patterns of type Q and type B solid morphologies after performing the Competitive Slurry Conversion method. (From top to bottom) ¼:n-heptane (1:2, room temperature), ¼:n-heptane (2:1, room temperature), type B solid morphology (for reference), and type Q solid morphology (for reference). [Figure 54] Figure 54 shows a superposition of XRPD diffraction patterns of the solid form of type B (top) and the reference sample (bottom) re-prepared on a 300 mg scale. [Figure 55]Figure 55 shows the TGA / DSC curve of the re-prepared type B solid form, with an endothermic peak at 209.5°C. The upper trace starts at 28.8°C and shows a 3.95% weight loss at 150.0°C. [Figure 56] Figure 56 shows the XRPD diffraction pattern of the solid-state form of type B, and the XRPD diffraction peak data obtained from this pattern are shown in the table below. [Table 1] [Figure 57] Figure 57 shows the XRPD diffraction pattern of the solid-state form of type Q, and the XRPD diffraction peak data obtained from this pattern are shown in the table below. [Table 2]

[0011] All XRPD patterns and superpositions, unless otherwise specified, show the count intensity on the y-axis and the 2θ value (°) on the x-axis.

[0012] Unless otherwise specified, each TGA / DSC curve shows weight % on the left y-axis, heat quantity (W / g) on ​​the right y-axis, and temperature on the x-axis. [Modes for carrying out the invention]

[0013] The matters described herein are illustrative only and are provided solely for the purpose of illustrating embodiments of the disclosure. All examples or illustrative expressions ("for example" or "etc.") provided herein are intended solely to provide a clearer explanation of the disclosure and do not limit the scope of the disclosure as described in the claims. Furthermore, nothing described herein should be construed as indicating that any non-claimed element is essential for carrying out the disclosure. Also, all methods described herein may be carried out in any appropriate order unless otherwise stated herein or if the context clearly contradicts it.

[0014] The use of alternative terms (e.g., "or") should be understood to mean one, both, or any combination thereof of the options indicated by the alternative terms. The various embodiments described above can be combined to provide further embodiments. The grouping of alternative elements or embodiments described herein should not be construed as limiting. Each component within a group may be cited or claimed individually, either alone or in any combination with other components within that group or other elements described herein.

[0015] Each embodiment disclosed herein may include, essentially include, or consist of the elements, processes, components, or constituents specifically described herein. In this specification, the term “includes” means “includes, but not limited to,” and it is permissible to include unspecified elements, processes, components, or constituents, even in a major quantity. In this specification, the phrase “consists of” excludes any unspecified elements, processes, components, or constituents. In this specification, the phrase “essentially includes” means that the scope of the embodiment is limited to specific elements, processes, components, or constituents, as well as elements, processes, components, or constituents that do not substantially affect the claimed basic and novel properties.

[0016] In the context describing the contents of this disclosure (particularly within the scope of the claims), the articles or terms “a,” “an,” “the,” and similar articles or terms used herein shall be interpreted as encompassing both singular and plural forms (i.e., “one or more”), unless otherwise stated herein or if the context clearly contradicts this interpretation. Numerical ranges described herein are abbreviated forms for referring individually to each individual value contained within that range. In this specification, any concentration range, percentage range, ratio range, or integer range shall be understood to include any integer value within that range, and, where appropriate, fractional values ​​(e.g., 1 / 10 or 1 / 100 of an integer), unless otherwise specified. Similarly, any numerical range described herein in relation to physical characteristics such as size or thickness shall be understood to include any integer value within that range, unless otherwise specified. Unless otherwise specified herein, each individual value is incorporated herein as being described individually.

[0017] The term "approximately," when used in conjunction with a specific number or range, has a meaning that can be reasonably understood by an ordinary technician in the relevant field. That is, it indicates that a number or range is slightly larger or slightly smaller than the stated number or range, within ±20%, ±19%, ±18%, ±17%, ±16%, ±15%, ±14%, ±13%, ±12%, ±11%, ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%.

[0018] One embodiment has the following structure (I): [ka] The present invention provides a solid of a compound having the same property or a tautomer thereof, which exhibits a powder X-ray diffraction pattern having at least two peaks at 2θ angles selected from the group consisting of 7.33±0.2°, 10.51±0.2°, 15.93±0.2°, and 18.92±0.2°.

[0019] One embodiment has the following structure (I): [ka] The present invention provides a solid of a compound having the same property or a tautomer thereof, the solid exhibiting a powder X-ray diffraction pattern having peaks at 2θ angles selected from at least two of the following: 7.33±0.2°, 10.51±0.2°, 15.93±0.2°, and 18.92±0.2°.

[0020] In some embodiments, the solid exhibits a powder X-ray diffraction pattern having at least three peaks at two θ angles selected from the group consisting of 7.33±0.2°, 10.51±0.2°, 15.93±0.2°, and 18.92±0.2°.

[0021] In a particular embodiment, the solid exhibits a powder X-ray diffraction pattern with peaks at 2θ angles of 7.33±0.2°, 10.51±0.2°, 15.93±0.2°, and 18.92±0.2°.

[0022] In some embodiments, the solid exhibits a powder X-ray diffraction pattern having at least two peaks at two θ angles selected from the group consisting of 7.33°, 10.51°, 15.93°, and 18.92°. In certain embodiments, the solid exhibits a powder X-ray diffraction pattern having at least three peaks at two θ angles selected from the group consisting of 7.33°, 10.51°, 15.93°, and 18.92°.

[0023] In some embodiments, the solid exhibits a powder X-ray diffraction pattern having peaks at 2θ angles selected from at least two of 7.33°, 10.51°, 15.93°, and 18.92°. In certain embodiments, the solid exhibits a powder X-ray diffraction pattern having peaks at 2θ angles selected from at least three of 7.33°, 10.51°, 15.93°, and 18.92°.

[0024] In certain embodiments, the solid exhibits a powder X-ray diffraction pattern with peaks at 2θ angles of 7.33°, 10.51°, 15.93°, and 18.92°. In some embodiments, the solid exhibits a powder X-ray diffraction pattern with peaks at 2θ angles of 3.87±0.2°, 7.73±0.2°, 10.51±0.2°, 12.71±0.2°, 13.53±0.2°, 13.99±0.2°, 15.93±0.2°, 18.92±0.2°, 21.56±0.2°, 22.74±0.2°, 23.19±0.2°, 24.53±0.2°, 25.63±0.2°, 27.73±0.2°, 31.17±0.2°, and 36.49±0.2°. In certain embodiments, the solid exhibits a powder X-ray diffraction pattern with peaks at 2θ angles of 3.87°, 7.73°, 10.51°, 12.71°, 13.53°, 13.99°, 15.93°, 18.92°, 21.56°, 22.74°, 23.19°, 24.53°, 25.63°, 27.73°, 31.17°, and 36.49°.

[0025] In certain embodiments, the solid includes a type B solid form. In certain embodiments, the solid essentially includes a type B solid form. In some embodiments, the solid form is substantially pure.

[0026] In another embodiment, the following structure (I) exhibits a powder X-ray diffraction pattern substantially consistent with that shown in Figure 56: [ka] A solid-state form of a compound having or a tautomer of the compound is provided.

[0027] In some embodiments, the solid form is characterized by a differential scanning calorimetry (DSC) thermogram in which the onset temperature of the endothermic peak is approximately 202°C. In some embodiments, the solid form is characterized by a DSC thermogram having an endothermic peak at 205.7°C ± 0.5°C. In some embodiments, the endothermic peak exceeds 100 J / g. In some embodiments, the endothermic peak exceeds 115 J / g.

[0028] In some embodiments, the solid form is characterized by a DSC thermogram that is substantially consistent with that shown in Figure 8.

[0029] In another embodiment, the following structure (I): [ka] A solid of a compound having the same property or a tautomer is provided, which exhibits a powder X-ray diffraction pattern having at least two peaks at 2θ angles selected from the group consisting of 4.67±0.2°, 9.35±0.2°, 25.49±0.2°, and 26.93±0.2°.

[0030] In another embodiment, the following structure (I): [ka] A solid of a compound having the same or a tautomer is provided, which exhibits a powder X-ray diffraction pattern having peaks at 2θ angles selected from at least two of the following: 4.67±0.2°, 9.35±0.2°, 25.49±0.2°, and 26.93±0.2°.

[0031] In some embodiments, the solid exhibits a powder X-ray diffraction pattern having peaks at two θ angles: 4.67±0.2°, 9.35±0.2°, 25.49±0.2°, and 26.93±0.2°. In certain embodiments, the solid exhibits a powder X-ray diffraction pattern having at least two peaks at two θ angles selected from the group consisting of 4.67°, 9.35°, 25.49°, and 26.93°. In certain embodiments, the solid exhibits a powder X-ray diffraction pattern having peaks at two θ angles selected from at least two of 4.67°, 9.35°, 25.49°, and 26.93°.

[0032] In some embodiments, the solid exhibits a powder X-ray diffraction pattern with peaks at 2θ angles of 4.67°, 9.35°, 25.49°, and 26.93°. In certain embodiments, the solid exhibits a powder X-ray diffraction pattern with peaks at 2θ angles of 4.67±0.2°, 5.41±0.2°, 9.35±0.2°, 11.32±0.2°, 13.49±0.2°, 15.35±0.2°, 17.15±0.2°, 18.73±0.2°, 20.57±0.2°, 22.87±0.2°, 24.27±0.2°, 25.49±0.2°, 26.93±0.2°, and 29.97±0.2°. In some embodiments, the solid exhibits a powder X-ray diffraction pattern with peaks at 2θ angles of 4.67°, 5.41°, 9.35°, 11.32°, 13.49°, 15.35°, 17.15°, 18.73°, 20.57°, 22.87°, 24.27°, 25.49°, 26.93°, and 29.97°.

[0033] In certain embodiments, the solid includes a solid form of type Q. In some embodiments, the solid essentially includes a solid form of type Q. In certain embodiments, the solid form is substantially pure.

[0034] In another embodiment, the following structure (I) exhibits a powder X-ray diffraction pattern substantially consistent with that shown in Figure 57: [ka] A solid form of a compound having the same properties or a tautomer is provided.

[0035] In some embodiments, the solid form is characterized by a DSC thermogram having an endothermic peak at 217.0°C ± 0.5°C. In certain embodiments, the solid form is characterized by a DSC thermogram substantially consistent with that shown in Figure 47.

[0036] In certain embodiments, the solid contains a solid form of type B. In certain embodiments, the solid essentially contains a solid form of type B. In some embodiments, the solid is substantially pure (any other solid forms are present in amounts less than, for example, 1%, 0.5%, or 0.1%).

[0037] In certain embodiments, the solid contains a solid form of type Q. In certain embodiments, the solid essentially contains a solid form of type Q. In some embodiments, the solid is substantially pure (any other solid forms are present in amounts less than, for example, 1%, 0.5%, or 0.1%).

[0038] In some specific embodiments, the solid contains a mixture of solid forms of type B and type Q. In some specific embodiments, the solid contains a mixture of solid forms of type B and type Q essentially. In some embodiments, the solid is substantially pure (any other solid forms are present, for example, less than 1%, less than 0.5%, or less than 0.1%). In some specific embodiments, the solid contains a mixture of solid forms of type B and type Q, with type B present at concentrations greater than 99%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, or 55%. In some embodiments, the solid contains a mixture of solid forms of type B and type Q, with type Q present at concentrations less than 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, or 45%.

[0039] In some embodiments, the solid includes, essentially includes, or consists of a solid form of type A. In some embodiments, the solid includes, essentially includes, or consists of a solid form of type B. In some embodiments, the solid includes, essentially includes, or consists of a type C solid form. In some embodiments, the solid includes, essentially includes, or consists of a solid form of type D. In some embodiments, the solid includes, essentially includes, or consists of a solid form of type E. In some embodiments, the solid includes, essentially includes, or consists of a solid form of type F. In some embodiments, the solid includes, essentially includes, or consists of a solid form of type G. In some embodiments, the solid includes, essentially includes, or consists of a solid form of type H. In some embodiments, the solid includes, essentially includes, or consists of a type I solid form. In some embodiments, the solid includes, essentially includes, or consists of a solid form of type J. In some embodiments, the solid includes, essentially includes, or consists of a solid form of type K. In some embodiments, the solid includes, essentially includes, or consists of a solid form of type L. In some embodiments, the solid includes, essentially includes, or consists of a solid form of type M. In some embodiments, the solid includes, essentially includes, or consists of a solid form of type N. In some embodiments, the solid includes, essentially includes, or consists of a solid form of type O. In some embodiments, the solid includes, essentially includes, or consists of a solid form of type P. In some embodiments, the solid includes, essentially includes, or consists of a solid form of type Q.

[0040] [Pharmaceutical composition] Other embodiments relate to pharmaceutical compositions. A pharmaceutical composition comprises one (or more) of the solid forms described above and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In yet another embodiment, the pharmaceutical composition comprises the compounds of the Disclosure and another therapeutic agent (e.g., an anticancer agent). Examples of such other therapeutic agents are described below, but are not limited to these.

[0041] Appropriate routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, transvaginal, ocular, transnasal, and topical administration. Furthermore, parenteral administration, as just a few examples, includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as subarachnoid, direct intraventricular, intraperitoneal, lymphatic, and intranasal injection.

[0042] In one embodiment, the compounds described herein are administered topically rather than systemically (for example, by direct injection of the compound into an organ, often in the form of a depot or sustained-release formulation). In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Furthermore, in other embodiments, the compounds are delivered by a targeted drug delivery system (e.g., liposomes coated with organ-specific antibodies). In such embodiments, the liposomes are selectively delivered to the organ. In yet another embodiment, the compounds described herein are provided in the form of an immediate-release formulation, a sustained-release formulation, or an intermediate-release formulation. In yet another embodiment, the compounds described herein are administered topically.

[0043] In the therapeutic methods disclosed herein, at least one solid form of structure (I) is administered in an effective dose to a subject suffering from or diagnosed with a disease, disorder, or illness. The effective dose or amount may be determined by methods such as modeling, dose escalation studies, or clinical trials. These methods may take into account, for example, the method or route of administration or drug delivery, the pharmacokinetics of the drug, the severity and course of the disease, disorder, or symptoms, the subject's past or present treatment, the subject's health status and response to the drug, and the judgment of the attending physician.

[0044] The solids described herein are effective over a wide dose range. In some embodiments, doses are 10–5000 mg, 100–5000 mg, and 1000–4000 mg per day, with 1000–3000 mg per day being an example of a dose used in the treatment of adult humans. The exact dose will vary depending on the route of administration, the form of the administered compound, the patient being treated, the patient's body weight, and the physician's preference and experience.

[0045] In some embodiments, the solids of the Disclosure are administered as a single dose. Generally, single doses are administered by injection (e.g., intravenous injection) to rapidly introduce the drug into the body, although other routes may be used as needed. Single doses of the compounds of the Disclosure may also be used to treat acute symptoms.

[0046] In some embodiments, the solid of the Disclosure is administered multiple times. In some embodiments, it is administered approximately once, twice, three times, four times, five times, six times, or seven times or more per day. In other embodiments, it is administered approximately once a month, approximately once every two weeks, approximately once a week, or approximately once every other day. In yet another embodiment, the solid of the Disclosure and another drug (e.g., an anticancer drug) are administered together approximately once to approximately six times per day. In yet another embodiment, the administration of the solid and drug of the Disclosure continues for less than approximately seven days. In yet another embodiment, the above administration continues for a period of approximately six days, ten days, fourteen days, twenty-eight days, two months, six months, or more than one year. In some cases, continuous administration is maintained for as long as necessary.

[0047] The administration of the solids of this disclosure may be maintained for as long as necessary. In some embodiments, the solids of this disclosure are administered for periods exceeding 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the solids of this disclosure are administered for periods of less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the solids of this disclosure are administered continuously and over a long period of time, for example, to treat chronic conditions.

[0048] In some embodiments, the solid forms of the present disclosure are administered in their respective dosage forms. Because the pharmacokinetics of compounds exhibit intersubjective variability, it is well known in the art that individualization of the administration plan is essential for optimal treatment.

[0049] In some embodiments, the solids described herein are formulated into pharmaceutical compositions. In certain embodiments, the pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers containing excipients and adjuvants that facilitate the preparation of the solid forms disclosed into pharmaceutically usable formulations. The appropriate formulation depends on the selected route of administration. Any pharmaceutically acceptable methods, carriers, and excipients described herein, Remington, The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995), Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975, Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980, and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999) are used as appropriate.

[0050] This specification provides a compound of structure (I) in solid form and a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0051] This specification provides pharmaceutical compositions comprising a solid of the compound of structure (I) and pharmaceutically acceptable diluents, excipients, and carriers. In one embodiment, the described solid form is administered as a combination therapy pharmaceutical composition by mixing the solid of the compound of structure (I) with other active ingredients. This disclosure encompasses all combinations of active ingredients shown in the following combination therapy section and throughout this disclosure.

[0052] In one embodiment, a pharmaceutical composition in solid form of the compound of structure (I) is a modulator of the NLRP3 inflammasome.

[0053] In certain embodiments, a pharmaceutical composition of the compound of structure (I) in solid form inhibits NEK7 when administered to a patient or biological sample.

[0054] As used herein, a pharmaceutical composition refers to a mixture of the solid form of the compound of structure (I) and other chemical components (e.g., carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients). In some embodiments, the pharmaceutical composition facilitates the administration of the compound to a living organism. In some embodiments, a therapeutically effective amount of the solid form of the compound of structure (I) provided herein is administered as a pharmaceutical composition to a mammal having the disease, disorder, or condition to be treated. In certain embodiments, the mammal is a human. In some embodiments, the therapeutically effective amount varies depending on the severity of the disease, the age and relative health status of the subject, the efficacy of the compound used, and other factors. The solids described herein are used individually or as components of a mixture in combination with one or more therapeutic agents.

[0055] In one embodiment, the solid of the compound of structure (I) is formulated in an aqueous solution. In a particular embodiment, the aqueous solution is selected from, but is not limited to, a physiologically compatible buffer such as Hanks' solution, Ringer's solution, or physiological saline. In another embodiment, the solid of the compound of structure (I) is formulated for transmucosal administration. In a particular embodiment, the transmucosal formulation includes a penetrating agent suitable for the barrier to which it must be penetrated. In yet another embodiment, if the solid described herein is formulated for other parenteral injections, the suitable formulation includes an aqueous solution or a non-aqueous solution. In the above embodiments, the solution may include a physiologically compatible buffer and / or excipients.

[0056] In another embodiment, the solid forms described herein are formulated for oral administration. The solid forms described herein are formulated by combining the active solid form with, for example, a pharmaceutically acceptable carrier or excipient. In various embodiments, the solid forms described herein are formulated as oral preparations (e.g., tablets, powders, pills, sugar-coated tablets, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, etc.).

[0057] In some embodiments, the composition is formulated for oral administration. In some embodiments, the composition is in the form of capsules. In some embodiments, the composition is in the form of tablets.

[0058] In one embodiment, an oral pharmaceutical formulation is prepared by mixing one or more solid excipients with one or more solid forms described herein, grinding the resulting mixture, adding appropriate auxiliary agents as needed, and then processing the granular mixture to obtain a core tablet of a sugar-coated tablet. Suitable excipients include fillers (e.g., sugars such as lactose, sucrose, mannitol, or sorbitol); celluloses (e.g., cereal starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose); or others (e.g., polyvinylpyrrolidone (PVP or povidone) or calcium phosphate). In certain embodiments, disintegrants may be added as appropriate. Disintegrants include, but are not limited to, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof (e.g., sodium alginate).

[0059] In one embodiment, the dosage form (e.g., a core tablet and tablets of a sugar-coated tablet) is provided with one or more suitable coatings. In a particular embodiment, a concentrated sugar solution is used to coat the dosage form. The sugar solution may include, but are not limited to, additional components such as gum arabic, talc, polyvinylpyrrolidone, Carbopol, polyethylene glycol, and / or titanium dioxide, lacquer solution, and suitable organic solvents or solvent mixtures. Dyes and / or pigments may be added to the coating as appropriate for identification. Furthermore, such dyes and / or pigments may be used as appropriate to identify different combinations of active compounds in dosage.

[0060] In one embodiment, a therapeutically effective amount of at least one solid form described herein is formulated into other oral dosage forms. These oral dosage forms include hard capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer (e.g., glycerol or sorbitol). In certain embodiments, the hard capsule contains the active ingredient in a mixture with one or more fillers. The fillers include, but are not limited to, lactose, a binder (e.g., starch), and / or a lubricant (e.g., talc or magnesium stearate), and optionally a stabilizer. In other embodiments, the soft capsule contains one or more active compounds dissolved or suspended in a suitable liquid. Suitable liquids include, but are not limited to, one or more fatty oils, liquid paraffin, or liquid polyethylene glycol. Further stabilizers may be added as needed.

[0061] In further embodiments, the solids described herein are formulated for parenteral administration, including formulations suitable for bolus or continuous infusion. In certain embodiments, injectable formulations exist in single-dose dosage forms (e.g., ampoules) or multi-dose containers. Preservatives may be added to the injectable formulations as appropriate. In further embodiments, the pharmaceutical compositions are formulated in a form suitable for parenteral administration as sterile suspensions, solutions, or emulsions in oily or aqueous vehicles. Parenteral injectable formulations may optionally contain formulation agents such as suspending agents, stabilizers, and / or dispersants. In certain embodiments, the parenteral pharmaceutical formulation includes an aqueous solution of the water-soluble active solid form. In another embodiment, a solid suspension of the compound of structure (I) is prepared as a suitable oily injectable suspension. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, for example, fatty oils (e.g., sesame oil), or synthetic fatty acid esters (e.g., ethyl oleate or triglycerides), or liposomes. In certain embodiments, the aqueous injection suspension contains a substance that increases the viscosity of the suspension (e.g., sodium carboxymethylcellulose, sorbitol, or dextran). The suspension may optionally contain a suitable stabilizer or a substance that increases the solubility of the solid to prepare a high-concentration solution. Alternatively, in other embodiments, the active ingredients are in powder form before use for preparation in a suitable vehicle (e.g., sterile pyrogen-free water).

[0062] A pharmaceutical composition comprises at least one pharmaceutically acceptable carrier, diluent, or excipient, and a solid form of the compound of structure (I) described herein as an active ingredient. The active ingredient exists in the form of a free acid or free base, or a pharmaceutically acceptable salt. Any tautomer of the solids described herein falls within the scope of the solids described herein. Furthermore, the solids described herein include both non-solvated forms and solvated forms with a pharmaceutically acceptable solvent (e.g., water, ethanol, etc.). The solvated forms of the solids described herein are also considered to be disclosed herein. In addition, the pharmaceutical composition may optionally contain other pharmaceutically or pharmaceutical substances, carriers, or adjuvants (e.g., preservatives, stabilizers, wetting agents or emulsifiers, dissolution accelerators, osmotic salts, buffers, and / or other therapeutically effective substances).

[0063] A method for producing a composition containing a solid as described herein is characterized by formulating the solid with one or more inert and pharmaceutically acceptable excipients or carriers to obtain a solid, semi-solid, or liquid form. Examples of solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Examples of liquid compositions include solutions in which the compound is dissolved, emulsions containing the compound, or solutions containing liposomes, micelles, or nanoparticles containing the compound disclosed herein. Examples of semi-solid compositions include, but are not limited to, gels, suspensions, and creams. Examples of pharmaceutical compositions as described herein include solutions or suspensions, solids suitable for use in solutions or suspensions, or emulsions. These compositions may optionally contain small amounts of non-toxic auxiliary substances (e.g., wetting agents or emulsifiers, pH buffers, etc.).

[0064] In some embodiments, a pharmaceutical composition containing a solid compound of structure (I) is, for example, a liquid form in which the drug exists in a solution, a suspension, or both. Generally, when a composition is administered as a suspension, some of the drug exists in a solution state, and the remaining portion exists in the form of particles in the suspension. In some embodiments, the liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous.

[0065] In one embodiment, the aqueous suspension contains one or more polymers as suspending agents. The polymers include water-soluble polymers (e.g., cellulosic polymers such as hydroxypropyl methylcellulose) and water-insoluble polymers (e.g., cross-linked carboxyl-containing polymers). Specific pharmaceutical compositions described herein include mucosal adhesive polymers selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0066] The pharmaceutical composition may optionally contain a solubilizer to promote the dissolution of the solid compound of structure (I). The term "solubilizer" generally includes agents that form a micelle solution or a true solution of the compound. For example, acceptable nonionic surfactants such as polysorbate 80 are useful as solubilizers, and ophthalmologically acceptable glycols, polyglycols (e.g., polyethylene glycol 400), and glycol ethers can also be used as solubilizers.

[0067] Furthermore, the pharmaceutical composition may optionally contain one or more pH adjusters or buffers, including acids (e.g., acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid); bases (e.g., sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and trishydroxymethylaminomethane); and buffers (e.g., citric acid / dextrose, sodium bicarbonate, and ammonium chloride). These acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition within an acceptable range.

[0068] The composition may also optionally contain one or more salts in amounts necessary to adjust the osmotic pressure of the composition to an acceptable range. Such salts may include those having a sodium, potassium, or ammonium cation and an anion of chloride, citric acid, ascorbic acid, boric acid, phosphoric acid, bicarbonate, sulfuric acid, thiosulfate, or bisulfite. Examples of suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0069] Other pharmaceutical compositions may optionally contain one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances (e.g., merfen and thiomersal); stabilized chlorine dioxide; and quaternary ammonium compounds (e.g., benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride).

[0070] The composition may contain one or more surfactants to improve physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils (e.g., polyoxyethylene (60) hydrogenated castor oil), as well as polyoxyethylene alkyl ethers and alkylphenyl ethers (e.g., octoxynol 10, octoxynol 40).

[0071] The composition may contain one or more antioxidants to improve chemical stability as needed. Suitable antioxidants include, for example, ascorbic acid and sodium pyrosulfite.

[0072] In one embodiment, the aqueous suspension composition is packaged in a non-resealable single-dose container. Alternatively, a resealable multi-dose container may be used, in which case the composition typically contains a preservative.

[0073] In another embodiment, other delivery systems are used for hydrophobic pharmaceutical compounds. Liposomes and emulsions are examples of useful delivery vehicles or carriers as described herein. In some embodiments, organic solvents such as N-methylpyrrolidone are also employed. In another embodiment, the solid form described herein is delivered as a sustained-release formulation (e.g., a semipermeable matrix of a hydrophobic solid polymer containing the therapeutic agent). Various sustained-release materials are useful as described herein. In some embodiments, sustained-release capsules release the solid form for a period ranging from several weeks to over 100 days. Depending on the chemical properties and biological stability of the therapeutic agent, other methods are used to stabilize the protein.

[0074] In one embodiment, the formulation described herein includes one or more antioxidants, metal chelating agents, thiol-containing compounds, and / or other common stabilizers. Examples of such stabilizers include, but are not limited to, (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosan polysulfates and other heparin analogs, (m) divalent cations (e.g., magnesium and zinc); or (n) combinations thereof.

[0075] In some embodiments, the concentrations of the compound of structure (I) in solid form contained in the pharmaceutical composition of the present disclosure are 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, and 15%. 0.50%, 15.25%, 15%, 14.75%, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25%, 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06 %, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or greater than 0.0001% w / w, w / v, or v / v.

[0076] In some embodiments, the concentrations of the compound of structure (I) in solid form contained in the pharmaceutical composition of this disclosure are approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, and approximately 0.07% to approximately 24%. These ranges from approximately 0.08% to 23%, 0.09% to 22%, 0.1% to 21%, 0.2% to 20%, 0.3% to 19%, 0.4% to 18%, 0.5% to 17%, 0.6% to 16%, 0.7% to 15%, 0.8% to 14%, 0.9% to 12%, and 1% to 10%, and are expressed as w / w, w / v, or v / v.

[0077] In some embodiments, the amounts of the compound of structure (I) in solid form contained in the pharmaceutical composition of this disclosure are 10g, 9.5g, 9.0g, 8.5g, 8.0g, 7.5g, 7.0g, 6.5g, 6.0g, 5.5g, 5.0g, 4.5g, 4.0g, 3.5g, 3.0g, 2.5g, 2.0g, 1.5g, 1.0g, 0.95g, 0.9g, 0.85g, 0.8g, 0.75g, 0.7g, 0.65g, 0.6g, 0.55g, 0.5g, 0.45g, 0.4g, 0.35g, 0.3g, 0 The values ​​are 0.25g, 0.2g, 0.15g, 0.1g, 0.09g, 0.08g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g, or 0.0001g or less.

[0078] In some embodiments, the amount of the compound of structure (I) in solid form contained in the pharmaceutical composition of the present disclosure is in the range of 0.0001 to 10 g, 0.0005 to 9 g, 0.001 to 8 g, 0.005 to 7 g, 0.01 to 6 g, 0.05 to 5 g, 0.1 to 4 g, 0.5 to 4 g, or 1 to 3 g.

[0079] Packaging materials used for packaging the pharmaceutical compositions described herein include, for example, those described in U.S. Patents No. 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging materials suitable for the selected formulation and the intended dosage and therapeutic form. For example, these containers may contain one or more solid forms described herein, as a composition or in combination with other agents disclosed herein. Containers may have a sterile access port as necessary (for example, if the container is a bag for intravenous solution or a vial with a stopper that can be punctured with a subcutaneous needle). Such kits may include, as appropriate, markings, labels, or instructions for use in the methods described herein, along with the compound.

[0080] For example, a kit typically includes one or more separate containers, each containing one or more items (e.g., appropriately concentrated reagents and / or devices) that are desirable from a commercial and user perspective for using the compounds described herein. Examples include, but are not limited to, buffers, diluents, filters, needles, syringes, transport articles describing the contents and / or instructions for use, labels for packages, containers, vials and / or tubes, and accompanying documents describing the method of use. Usually, a complete set of instructions is also included. Labels are appropriately affixed to the container or attached to the container. For example, if the letters, numbers, or other symbols constituting the label are affixed, molded, or inscribed on the container itself, the label is on the container; if it is in a container or transport article for maintaining the container, the label is attached to the container (e.g., as accompanying documents). Furthermore, labels are used to indicate that the contents are for use in a particular therapeutic application and to display instructions regarding the use of the contents, such as those described herein. In some embodiments, the pharmaceutical composition is contained in a pack or dispensing device containing one or more unit dosage forms containing the compounds provided herein. The pack may contain, for example, metal or plastic foil, such as in a blister pack. In some embodiments, the pack or dispensing device may be accompanied by instructions for administration. In certain embodiments, the pack or dispensing device may be accompanied by a notice relating to a container of a form prescribed by a government agency that regulates the manufacture, use, or sale of the drug, such notice reflecting that the form as a drug for administration to humans or animals has been approved by the government agency. Such notice may exist, for example, as an approval statement or approval insert by the U.S. Food and Drug Administration for a prescription drug. In some embodiments, compositions of the compounds provided herein are formulated on a suitable pharmaceutical carrier, filled into appropriate containers, and labeled to treat an intended medical condition.

[0081] [method] Embodiments of this disclosure are useful as modulators of the NLRP3 inflammasome by inhibiting NEK7 in the host. Therefore, the solid form of the compound of structure (I) is also useful for treating symptoms mediated by effector signaling molecules such as IL-1β and IL-18.

[0082] The host or patient can be any mammal (e.g., primates (especially humans), rodents such as mice, rats, and hamsters, rabbits, horses, cattle, dogs, cats, etc.). Animal models can serve as therapeutic models for human diseases and are useful in experimental research.

[0083] In one embodiment, the solid form of the disclosure is useful as an inhibitor of the NLRP3 inflammasome activation mechanism. Therefore, the solid form of the compound of structure (I) is useful for treating pathological conditions caused by such activity in the host.

[0084] In another embodiment, the solid form of the compound of structure (I) is useful as an inhibitor of the NLRP3 (protein)-NEK7 (protein) interaction. Therefore, this solid form is also useful for treating pathological conditions caused by NLRP3-NEK7 association in the host.

[0085] In one embodiment, the solid form of the compound of structure (I) is useful in the treatment of human pathological conditions mediated by effectors selected from the group consisting of IL-1β, IL-18, and caspase-1.

[0086] Embodiments of this disclosure relate to the use of the solid and / or physiologically acceptable salts thereof described in Structure (I) for prophylactic or therapeutic treatment and / or monitoring of diseases caused, mediated, and / or regulated by NLRP3 inflammasome activity. Furthermore, embodiments of this disclosure relate to the use of the solid and / or physiologically acceptable salts thereof described in Structure (I) in the manufacture of pharmaceuticals for prophylactic or therapeutic treatment and / or monitoring of diseases caused, mediated, and / or regulated by NLRP3 inflammasome activity. In one embodiment, this disclosure provides the use of the compound described in Structure (I) or a physiologically acceptable salt thereof for the manufacture of pharmaceuticals for the prevention or treatment of NLRP3-mediated diseases.

[0087] In another embodiment, the disclosure relates to a method for treating NLRP3 inflammasome-mediated inflammatory diseases or conditions by administering a therapeutically effective amount of a compound of structure (I) in solid form to a patient in need of treatment.

[0088] In one embodiment, diseases that can be treated with the solid form of the compound of structure (I) include type 2 diabetes, atherosclerosis, Alzheimer's disease, aging, fatty liver, metabolic syndrome, asthma, psoriasis, obesity, acute and chronic tissue injury due to infection, gout, arthritis, enteritis, hepatitis, peritonitis, silicosis, UV-induced sunburn, contact hypersensitivity, sepsis, cancer, neurodegenerative diseases, multiple sclerosis, Muckle-Wells syndrome, and myelodysplastic syndrome (MDS).

[0089] In certain other embodiments, the solid form of the compound of structure (I) is used in methods for treating disorders or diseases selected from autoimmune diseases, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial and viral infections, allergies, asthma, pancreatitis, multiple organ failure, kidney disease, platelet aggregation disorders, transplant-related disorders, sperm motility disorders, anemia, graft rejection, lung disorders, respiratory diseases, ischemic conditions, and cancer. In some more specific embodiments, the solid form of the compound of structure (I) is used in methods for treating myelodysplastic syndrome (MDS).

[0090] In some embodiments, NEK7-related diseases treatable in solid form of the compound of structure (I) are selected from rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyper-IgD syndrome and periodic fever syndromes, cryopyrin-associated periodic fever syndromes, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult Still's disease, gout, pseudogout, SAPHO syndrome, Castleman disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (IL-1 receptor antagonist deficiency), Alzheimer's disease, Parkinson's disease, and cancer.

[0091] This specification also includes therapeutic methods in which the solid form of the compound of structure (I) is administered in combination with an anti-inflammatory or therapeutic agent. Anti-inflammatory agents include, but are not limited to, NSAIDs, nonspecific cyclooxygenase inhibitors and COX-2 selective inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor (TNF) antagonists, immunosuppressants and methotrexate. Examples of NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, nabumetone, sulfasalazine, tolmetin sodium, and hydroxychloroquine.

[0092] Examples of NSAIDs also include COX-2 selective inhibitors (e.g., celecoxib, valdecoxib, lumiracoxib, and / or etoricoxib).

[0093] In some embodiments, the anti-inflammatory agent is a salicylate. Salicylates include, but are not limited to, acetylsalicylic acid or aspirin, sodium salicylate, and choline salicylate and magnesium salicylate.

[0094] Furthermore, the anti-inflammatory agent may be a corticosteroid. For example, the corticosteroid may be cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate, or prednisone.

[0095] In another embodiment, the anti-inflammatory agent is a gold compound (e.g., sodium gold thiomalate or auranofin).

[0096] This disclosure also includes embodiments in which the anti-inflammatory agent is a metabolic inhibitor (e.g., a dihydrofolate reductase inhibitor such as methotrexate, or a dihydroorotate dehydrogenase inhibitor such as leflunomide).

[0097] Therapeutic agents may also include drugs for pain and inflammation, such as histamines and antihistamines, bradykinin and bradykinin receptor antagonists, 5-hydroxytryptamine (serotonin), lipid substances produced by the bioconversion of selective hydrolyzed membrane phospholipids, eicosanoids, prostaglandins, thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatory drugs, antipyretic analgesics, agents that inhibit the synthesis of prostaglandins and thromboxanes, selective inhibitors of inducible cyclooxygenase, selective inhibitors of inducible cyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin, cytokines that mediate interactions involved in humoral and cellular immune responses, lipid-derived autacoids, eicosanoids, β-adrenergic receptor agonists, ipratropium, glucocorticoids, methylxanthines, sodium channel blockers, opioid receptor agonists, calcium channel blockers, membrane stabilizers, and leukotriene inhibitors.

[0098] Other embodiments of the present disclosure relate to combinations in which at least one anti-inflammatory compound is an anti-monoclonal antibody (e.g., eculizumab or pexerizumab), a TNF antagonist (e.g., etanercept, or infliximab, which is an anti-TNFα monoclonal antibody).

[0099] Therapeutic agents used in combination with the solid form of the compound of structure (I) may also include small molecule compounds that inhibit the activation of the NLRP3 inflammasome (e.g., MCC950, sulforaphane, isoliquiritigenin, β-hydroxybutyrate, flufenamic acid, mefenamic acid, 3,4-methylenedioxy-β-nitrostyrene (MNS), and parthenolide).

[0100] Further embodiments of the present disclosure relate to combinations in which at least one activator is an immunosuppressive compound selected from, for example, methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, and mycophenolate mofetil.

[0101] The disclosed solid form of the compound of structure (I) may be administered in combination with other known therapeutic agents, including anticancer agents. The term "anticancer agent" as used herein refers to any drug administered to cancer patients for the purpose of treating cancer.

[0102] In some embodiments, the above anticancer drugs are classified into the following categories. Alkylating agents: e.g., altoretamine, bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan tosylate, lomustine, melphalan, mitobronitol, mitractol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan, mechloretamine, carbocon, apadicone, fotemustine, glucosphamide, paliphosphamide, pipobromane, trophosphamide, uramustine, TH-3024, VAL-0834; Platinum compounds: for example, carboplatin, cisplatin, eptaplatin, miriplatin hydrate, oxaliplatin, lovaplatin, nedaplatin, picoplatin, satraplatin, lovaplatin, nedaplatin, picoplatin, satraplatin; DNA modifiers: for example, amrubicin, bisanthren, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine, amsacrin, brostarisin, picantrone, laromustine; Topoisomerase inhibitors: e.g., etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan, amonafide, berotecan, eriptinium acetate, boreroxine; Microtubule modifiers: e.g., cabazitaxel, docetaxel, eribulin, ixabepirone, paclitaxel, vinblastine, vincristine, vinorelbine, vindesine, vinflunin, phosbletabrin, tesetaxel; Antimetabolites: For example, asparaginase-3, azacitidine, levofolinate calcium, capecitabine, cladribine, cytarabine, enocitabine, phloxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur, doxyfluridine, elacitarabine, larcitrexed, sapacitabine, tegafur, trimethrexate; Anticancer antibiotics: for example, bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, rebamisol, miltefosine, mitomycin C, romidepsin, streptozocin, barurubicin, dinostatin, zolubicin, daunorubicin, plicamycin, acralubicin, peplomycin, pirarubicin; Hormones / antagonists: e.g., abarelix, abiraterone, bicalutamide, buserelin, carsterone, chlorotrianicene, degarelix, dexamethasone, estradiol, fluocortone, fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol, mitotane, nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alpha, toremifene, trilostane, triptorelin, diethylstilbestrol, acorbifen, danazol, deslorerin, epithiostanol, orteronel, enzalutamide; Aromatase inhibitors: e.g., aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone, formestane; Small molecule kinase inhibitors: e.g., crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib, afatinib, aricertib, dabrafenib, dacomitinib, dinacyclib, dovicinib B, Enzastaurin, Nintedanib, Lenvatinib, Linifanib, Lincitinib, Masitinib, Midostaurin, Motesanib, Neratinib, Orantinib, Perifosin, Ponatinib, Radotinib, Rigosertib, Tipifalnib, Tivantinib, Tivozanib, Trametinib, Pimasertib, Brivanib Alanine Ester, Sediranib

[0103] In some embodiments, the pharmaceuticals administered in combination with the solid form of the compound of structure (I) described herein include any suitable agents that are efficiently delivered by inhalation. For example, analgesics (e.g., codeine, dihydromorphine, ergotamine, fentanyl, or morphine); antianginal agents (e.g., diltiazem); antiallergic agents (e.g., cromoglycates, ketotifen, or nedocromil); antiinfective agents (e.g., cephalosporins, penicillin antibiotics, streptomycin, sulfonamides, tetracyclines, or pentamidine); antihistamines (e.g., metapyrylene); anti-inflammatory agents (e.g., beclomethasone, flunisolide, budesonide, typredan, triamcinolone acetonide, or fluticasone); antitussives (e.g., noscapine); Bronchodilators (e.g., ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, limiterol, salbutamol, salmeterol, terbutaline, isoethaline, tulobuterol, orciprenaline or (-)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol); diuretics (e.g., amiloride); anticholinergics (e.g., ipratropium, atropine or oxytropium); hormones (e.g., cortisone, hydrocortisone or prednisolone); xanthines (e.g., aminophylline, cholinetheophylline, lysine salt of theophylline or theophylline); and therapeutic proteins and therapeutic peptides (e.g., insulin or glucagon). It will be apparent to those skilled in the art that, if necessary, these pharmaceuticals may be used in the form of salts (e.g., alkali metal or amine salts, or acid addition salts), esters (e.g., lower alkyl esters), or solvates (e.g., hydrates) to optimize their activation and / or stabilization.

[0104] The agents of this disclosure or other suitable agents are administered according to the symptoms being treated. Accordingly, in some embodiments, the compounds of this disclosure are administered simultaneously with the other agents described above. When used in combination therapy, the compounds described herein are administered simultaneously with or separately from the second agent. This combination administration may include administering the two agents simultaneously in the same dosage form, simultaneously in different dosage forms, and separately. That is, the compounds described herein and any of the above agents may be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds of this disclosure and any of the above agents may be administered simultaneously in separate formulations. Alternatively, the compounds of this disclosure may be administered immediately after any of the above agents, or in the reverse order. In some embodiments of the separate administration method, the compounds of this disclosure and any of the above agents are administered at intervals of several minutes, several hours, or several days.

[0105] In some embodiments, the solid form of the compound of structure (I) is administered as monotherapy.

[0106] To identify signaling pathways or mechanisms of action and to detect interactions between various signaling pathways, many researchers have developed appropriate models or model systems (e.g., cell culture models and genetically modified animal models). Interacting compounds can be used to modulate signals in the analysis of specific stages in the signaling cascade. The compounds of this disclosure can also be used as reagents to evaluate NEK7-dependent signaling pathways in animal and / or cell culture models or in the clinical diseases described herein.

[0107] The method described herein can be performed either in vitro or in vivo. The sensitivity of specific cells to treatment with the solid form of the compound of structure (I) can be specifically determined by in vitro testing, either at the research or clinical stage. Generally, cultured cells are treated with various concentrations of the compound for a time sufficient for the active ingredient to inhibit NEK7 activity (usually about 1 hour to about 1 week). In vitro treatment can be performed using cultured cells or cell lines derived from biopsy samples.

[0108] Furthermore, this disclosure provides a method for preparing a solid form of a compound of structure (I). In some embodiments, a solid form of type A is dissolved and a poor solvent is added to form solid forms of type B and / or Q. In certain embodiments, the method further comprises a step of drying the solid forms of type B and / or Q (e.g., evaporation of the solvent at ambient temperature). In some embodiments, the solid form of type A is dissolved in ethyl acetate. In some embodiments, the solid form of type A is dissolved in ethanol, isopropyl alcohol, acetone, methyl isobutyl ketone, isopropyl acetate, ethyl formate, anisole, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, or CHCl3.

[0109] In some embodiments, the poor solvent is n-heptane. In some embodiments, the poor solvent is dichloromethane. In some embodiments, the above method is carried out while heating or cooling the composition / mixture to a temperature of 0-5°C, 20-30°C (e.g., room temperature), or 45-55°C.

[0110] In some embodiments, the method is characterized by dissolving a type A solid in a solvent and then evaporating the solvent from the resulting mixture to form type B and / or type Q solids. In some embodiments, the solvent is acetone, ethyl acetate, isopropyl acetate, or tert-butyl methyl ether.

[0111] [Examples] Abbreviation / Acronym [Table 3] 13 ¹¹¹ NMR = Carbon Nuclear Magnetic Resonance; 1 ¹H NMR = Proton Nuclear Magnetic Resonance; 1-PrOH = 1-propanol; 2D = Two-dimensional; 2-Me-1-PrOH = 2-methyl-1-propanol; ADD = Additional Peak; API = Active Pharmaceutical Ingredient; AS = Poor Solvent; ASR = Analysis Report; ca. = Approximate; D-PAS = Immersion Probe Absorption Spectroscopy; DSC = Differential Scanning Calorimetry; DVS = Dynamic Vapor Solvation; Eq / Eq. / Equiv. = Equivalent; FaSSGF = Simulated Gastric Juice under Fasting; FaSSIF = Simulated Intestinal Juice under Fasting; FeSSIF = Simulated Intestinal Juice under Feeding; GVS = Vapor Adsorption Measurement by Gravimetric Method; H₂O = Water; HBr = Hydrobromic Acid; HCl = Hydrochloric Acid; HPLC = High-Performance Liquid Chromatography; Hr or hr = Time; HSM = Heat Stage Microscopy; IC = Ion Chromatography; ID = Identification; IPA = 2-propanol; IR = Infrared Spectroscopy; ISA = Ionic Strength Adjustment; KF = Karl Fischer method; MALe = maleate; MALi = L-malate; MDSC = temperature-modulated differential scanning calorimetry; MEK = methyl ethyl ketone; Min or min = minute; mol = Mohler; MS = mass spectrometry; N / A = not applicable; NMR = nuclear magnetic resonance; No. = number; P = pattern; PE = polyethylene; PLM = polarized light microscopy; PTFE = polytetrafluoroethylene; RH = relative humidity; RRT = relative retention time; RT = room temperature; SCXRD = single-crystal X-ray diffraction; SGF = simulated gastric juice; SIF = simulated intestinal juice; SUC = succinate; TAR = L-tartaric acid (or its salt); Temp = temperature; TFA = trifluoroacetic acid; Tg = glass transition temperature; TGA = thermogravimetric analysis; TRIS = trishydroxymethylaminomethane; USP = United States Pharmacopeia; UV = ultraviolet light; v / v = volume ratio; vac = vacuum; Vol = volume; w / w = weight ratio; wt=mass; wt%=weight%; XRPD=powder X-ray diffraction

[0112] [Powder X-ray Diffraction (XRPD)] XRPD analysis was performed using an X-ray powder diffractometer manufactured by PANalytical. The parameters used are shown in the table below. [Table 4]

[0113] [TGA and DSC] TGA measurements were performed using TA Q5000 and Discovery 5500 TGA from TA Instruments, and DSC measurements were performed using TA Q2000 and Discovery 2500 DSC from TA Instruments. Details of the parameters used are shown in the table below. [Table 5]

[0114] [DVS] DVS measurements were performed using a DVS Intrinsic from SMS (Surface Measurement Systems). Relative humidity at 25°C was calibrated using the deliquescence points of LiCl, Mg(NO3)2, and KCl as references. The parameters used in the DVS trial are shown in the table below. [Table 6]

[0115] [ 1 [H NMR] solution 1 ¹H NMR was performed using a Bruker 400M NMR Spectrometer with DMSO-d6 or MeOH-d4 as the solvent.

[0116] [HPLC] Measurements were performed using an Agilent 1260 with a DAD detector. Detailed chromatography conditions for purity and solubility measurements are shown in the table below. [Table 7]

[0117] Example 1: Summary of the study on solid form Structure (I) is currently under development, and no polymorphic studies have been conducted to date. The main objective of this project is to conduct polymorphic screening of the compound in order to identify crystalline forms with good crystallinity and excellent solid-state properties that are suitable for further development.

[0118] Structure (I), when synthesized according to Synthesis Example 1, exists as a type A solid form. The type A solid form was used as the starting material for 75 designed polymorph screening experiments. Based on the results of X-ray powder diffraction (XRPD) in the polymorph screening and subsequent experiments, a total of 17 crystalline forms of structure (I) have been identified to date. These include the type B / J / O / Q solid forms as anhydrous, the type A / H / K / L solid forms as hydrate solids, the type C / D / E / F / G / I solid forms as solvates, the type P solid form as anhydrous or hydrate, and the unidentified type M / N solid form. Figure 1 shows the interconversion relationships in the solid state for the polymorphs of structure (I). A summary of the properties of each obtained form is shown in the table below.

[0119] For the solid forms of types B and Q, slurry competition experiments were conducted in ethyl acetate / n-heptane solvents at 5°C, room temperature, and 50°C to further investigate the thermodynamic relationship between these two anhydrides. As a result, only type B was obtained under all conditions, indicating that type B is thermodynamically more stable than type Q under the conditions investigated.

[0120] Polymorphic screening experiments and subsequent processing of structure (I) revealed a total of 17 crystalline forms. Based on the results of polymorphic screening and slurry competition experiments, the solid form of type B showed unexpectedly good properties and was shown to be a useful candidate for further development. On the other hand, since the solid form of type Q can be generated in the current manufacturing process (addition of a poor solvent in an ethyl acetate / n-heptane system), special attention should be paid to polymorphic control in process development. Furthermore, physicochemical stability evaluation is strongly recommended for type B.

[0121] The properties of each solid in structure (I) are shown in the table below. [Table 8]

[0122] Example 2: Identification of Starting Materials Starting material of structure (I) is obtained, and XRPD, TGA, DSC and 1 Characterization was performed by 1H NMR. As shown in Figure 2A, the starting material was crystalline and was named Type A. From the TGA / DSC results (Figure 2B), a 9.0% mass loss was observed up to 150°C, and three endothermic peaks were observed at 87.8°C, 116.6°C, and 128.1°C. 1 ¹H NMR measurements were performed using DMSO-d6, and no obvious organic solvent residue was detected. The approximate solubility of the starting materials was evaluated at room temperature using 20 different solvents. In each test, approximately 2 mg of the solid was weighed into a 3 mL glass vial, and the corresponding solvent was added in stages in the order of 50 / 50 / 100 / 200 / 600 / 1000 μL, observing whether the solid completely dissolved. Solvent addition was stopped when the solid dissolved or when the total volume reached 2.0 mL. The approximate solubility was calculated based on the mass of the solid and the volume of the solvent. The solubility results are summarized in the table below. These results were used as a guideline for solvent selection in polymorphic screening design. [Table 9]

[0123] Example 3: Polymorphic screening and characterization Using type A solid form as the starting material, 75 polymorph screening experiments were conducted. Based on characterization data from XRPD and TGA / DSC, and the resulting experimental results, 17 crystalline forms of structure (I) were obtained, including anhydrous type B / J / O / Q solid forms, hydrated type A / H / K / L solid forms, solvated type C / D / E / F / G / I solid forms, anhydrous or hydrated type P solid form, and unidentified type M / N solid forms. The superposition of XRPD diffraction patterns is shown in Figures 3, 4, and 5. Five types of polymorph screening experiments were performed. Based on characterization data from XRPD and TGA / DSC, and the resulting experimental results, 17 types of crystals of structure (I) were obtained, including the anhydrous solid forms of types B / J / O / Q, the hydrated solid forms of types A / H / K / L, the solvated solid forms of types C / D / E / F / G / I, the anhydrous or hydrated solid form of type P, and the solid forms of type M / N. The superposition of XRPD diffraction patterns is shown in Figures 3, 4, and 5.

[0124] Example 4: Solid form of Type A For the solid form of type A, VT-XRPD was performed for morphological identification. According to the VT-XRPD results in Figure 6, the morphological change from the solid form of type A to another solid form newly named type O was first observed during N2 substitution and completed by heating to 100°C. 1 Based on the 1H NMR spectrum and VT-XRPD results, the solid form of type A was identified as a hydrate.

[0125] Example 5: Solid form of Type B The solid form of type B was obtained by adding 2.0 mL of n - heptane as a poor solvent to 0.5 mL of an EtOAc solution. As shown in Figure 7, no morphological changes were observed before and after drying overnight under ambient conditions. From the TGA / DSC curves (Figure 8), a 2.5% mass loss was observed up to 150 °C, and one endothermic peak was observed at 205.7 °C. 1 1H NMR measurements were performed using DMSO - d6 as the solvent, and it was shown that the molar ratios of residual EtOAc and residual n - heptane to the API were 0.04 (0.7 wt%) and 0.05 (1.0 wt%), respectively. For the solid form of type B, a heating experiment was conducted for morphological identification. According to the XRPD results in Figure 9, no morphological changes were observed before and after heating the solid form of type B up to 150 °C and cooling to room temperature. Based on the limited mass loss in TGA, distinct DSC curves, 1 slight solvent residues in 1H NMR, and the results of the heating experiment, the solid form of type B was identified as an anhydrate. DVS was performed on a sample of the solid form of type B. The results of sample preparation and characterization are described herein. As shown in Figure 10, the water uptake at 25 °C / 80% RH was less than 0.2 wt%, indicating that the solid form of type B has little hygroscopicity. Based on the XRPD overlay shown in Figure 11, no morphological changes were observed before and after the DVS measurement.

[0126] Example 6: Solid Form of Type C The solid form of type C was obtained by adding 2.0 mL of n - heptane as a poor solvent to 0.5 mL of a THF solution. As shown in Figure 12, no morphological changes were observed before and after drying overnight under ambient conditions. From the TGA / DSC curves (Figure 13), a 4.2% mass loss was observed up to 115 °C, and a further 5.1% mass loss was observed from 115 °C to 150 °C. Three endothermic peaks were observed at 113.8 °C, 142.8 °C, and 189.6 °C. 11H NMR measurements were performed using DMSO-d6 as the solvent, and it was shown that the molar ratio of residual THF to API was approximately 0.36 (4.9 wt%). For the solid form of type C, heating experiments were performed to identify its morphology. Figure 14 and 1 According to the 1H NMR results, no morphological change was observed in the type C solid form before and after heating to 115°C and cooling to room temperature, and the molar ratio of residual THF to API was 0.24 (3.3 wt%). According to the VT-XRPD results in Figure 15, a decrease in crystallinity was observed when heated to 120°C, and amorphous state was observed when heated to 175°C. Based on the results of the above experiments, the type C solid form was identified as a (THF) solvate. The same XRPD pattern was observed in other solvents (e.g., isoamyl alcohol, 1-pentanol, and 2-MeTHF), suggesting the possibility of isomorphisms in this form.

[0127] Example 7: Solid form of Type D The solid form of type D was obtained by slurrying the starting material in IPA at 50°C for approximately 5 days. As shown in Figure 16, no morphological changes were observed before and after overnight drying under ambient conditions. From the TGA / DSC curve (Figure 17), a mass loss of 13.7% was observed up to 175°C, and a single endothermic peak was observed at 144.5°C. 1 1H NMR measurements were performed using DMSO-d6 as the solvent, and it was shown that the molar ratio of residual IPA to API was approximately 0.93 (10.0 wt%). For the solid form of type D, heating experiments were conducted to identify its morphology. According to the results of the heating experiment shown in Figure 18, when the solid form of type D was heated to 175°C and then cooled to room temperature, amorphization was observed. 1 Based on the results of 1H NMR, mass loss in TGA, and residual solvent determined by heating experiments, the solid form of type D was identified as the solvate of IPA.

[0128] Example 8: Solid form of Type E The solid form of type E was obtained by slurrying the starting material in m-xylene at 50°C for approximately 5 days. As shown in Figure 19, no morphological changes were observed before and after overnight drying under ambient conditions. From the TGA / DSC curve (Figure 20), a mass loss of 6.5% was observed up to 175°C, and two endothermic peaks were observed at 163.3°C and 165.9°C. 1 ¹H NMR measurements were performed using DMSO-d6 as the solvent, and it was shown that the molar ratio of residual m-xylene to API was approximately 0.31 (6.2 wt%). For the solid form of type E, heating experiments were conducted to identify its morphology. According to the results of the heating experiment shown in Figure 21, the type E solid changes to an amorphous state when heated to 165°C and then cooled to room temperature. 1 Based on 1H NMR, mass loss in TGA, and residual solvent determined from heating experiments, the solid form of type E was identified as a solvate of m-xylene.

[0129] Example 9: Solid form of Type F The solid form of type F was obtained by slurrying the starting material in DMSO / ACN (1:19, v:v) at 50°C for approximately 5 days. As shown in Figure 22, no morphological changes were observed before and after overnight drying under ambient conditions. From the TGA / DSC curve (Figure 23), a mass loss of 10.7% was observed up to 175°C, and three endothermic peaks were observed at 81.0°C, 142.1°C, and 176.3°C. 1 ¹H NMR measurements were performed using MeOH-d4 as the solvent, and it was shown that the molar ratio of residual DMSO to API was approximately 1.2 (15.8 wt%). For the solid form of type F, heating experiments were conducted to identify its morphology. According to the results of the heating experiments shown in Figure 24, when the solid form of type F was heated to 120°C and then cooled to room temperature, no morphological change was observed. However, when heated to 160°C and then cooled to room temperature, the solid form of type F changed to an amorphous state. 1 The 1H NMR spectrum showed that the molar ratio of residual DMSO to API after heating to 120°C was approximately 0.8 (11.1 wt%). 1Based on 1H NMR, mass loss in TGA, and residual solvent determined from heating experiments, the solid form of type F was identified as a solvate of DMSO.

[0130] Example 9: Solid form of Type G The solid form of type G was obtained by slurrying the starting material in 2-BuOH at room temperature for approximately 6 days. As shown in Figure 25, no morphological changes were observed before and after overnight drying under ambient conditions. From the TGA / DSC curve (Figure 26), a mass loss of 5.3% was observed up to 100°C, and a further mass loss of 13.0% was observed between 100°C and 175°C. In the DSC curve, two endothermic peaks were observed at 127.4°C and 203.9°C, and one exothermic peak was observed at 129.3°C. 1 1H NMR measurements were performed using DMSO-d6 as the solvent, and it was shown that the molar ratio of residual 2-BuOH to API was approximately 1.10 (13.9 wt%). For the solid form of type G, heating experiments were conducted to identify its morphology. According to the results of the heating experiment shown in Figure 27, the solid form of type G changes to an amorphous state when heated to 175°C and then cooled to room temperature. 1 Based on 1H NMR, mass loss in TGA, and residual solvent determined by heating experiments, the solid form of type G was identified as the solvate of 2-BuOH.

[0131] Example 10: Solid form of Type H The solid form of type H was obtained by slowly evaporating THF from a THF solution of the starting material. The XRPD diffraction pattern of the solid form of type H is shown in Figure 28. From the TGA / DSC curve (Figure 29), a mass loss of 7.6% was observed up to 150°C, and a single endothermic peak was observed at 130.8°C. 1 ¹H NMR measurements were performed using DMSO-d6 as the solvent, and it was shown that the molar ratio of residual THF to API was approximately 0.18 (2.5 wt%). For the solid form of type H, heating experiments were performed to identify its morphology. According to the results of the heating experiments shown in Figure 30, the solid form of type H changes to an amorphous state when heated to 150°C and then cooled to room temperature. Based on the mass loss in TGA, the residual solvent in NMR, and the results of the heating experiments, the solid form of type H was identified as a hydrate.

[0132] Example 11: Solid form of Type I The Type I solid form was obtained by slurrying the starting material in DCM at room temperature for approximately 6 days. As shown in Figure 31, no morphological changes were observed before and after overnight drying under ambient conditions. From the TGA / DSC curve (Figure 32), a mass loss of 4.3% was observed up to 150°C, and two endothermic peaks were observed at 66.3°C and 161.0°C. 1 1H NMR measurements were performed using DMSO-d6 as the solvent, and it was shown that the molar ratio of residual DCM to API was approximately 0.18 (3.7 wt%). For the solid form of Type I, heating experiments were conducted to identify its morphology. According to the results of the heating experiment shown in Figure 33, the solid form of Type I underwent a morphological change after being heated to 100°C and then cooled to room temperature, and no DCM remained in the heated sample. The obtained solid form was named Type P. 1 Based on the 1H NMR spectrum and heating experiment results, the type I solid form was identified as the solvate of DCM. Considering that the type I solid form was also obtained by slurry treatment with ACN, it is suggested that isomorphs may exist in this form.

[0133] Example 12: Solid form of Type J The solid form of type J was obtained by slowly evaporating CHCl3 from a CHCl3 solution of the starting material. The XRPD diffraction pattern of the solid form of type J is shown in Figure 34. From the TGA / DSC curve (Figure 35), a mass loss of 1.2% was observed up to 150°C, and two endothermic peaks were observed at 154.6°C and 160.9°C. 1¹H NMR measurements were performed using DMSO-d6 as the solvent, and the molar ratio of residual CHCl3 to API was shown to be approximately 0.03 (0.7 wt%). Limited mass loss in TGA, clear DSC curve, and 1 Based on slight solvent residue in the 1H NMR spectrum, the solid form of type J was identified as an anhydrous. Furthermore, the solid form of type J can transform into the solid form of type L when stored overnight under ambient conditions of approximately 45% RH.

[0134] Example 13: Solid form of Type K The solid form of type K was obtained by slurrying the starting material in acetone / H2O (v:v=6:4) at room temperature for approximately 6 days. As shown in Figure 36, no morphological changes were observed before and after overnight drying under ambient conditions. From the TGA / DSC curve (Figure 37), a mass loss of 6.5% was observed up to 150°C. In the DSC curve, two endothermic peaks were observed at 104.7°C and 142.8°C. 1 1H NMR measurements were performed using DMSO-d6 as the solvent, and no acetone residue was observed. For the solid form of type K, heating experiments were conducted to identify its morphology. As shown in Figure 38, when the solid form of type K was heated to 120°C and cooled to room temperature, its crystallinity decreased significantly, thus identifying the solid form of type K as a hydrate.

[0135] Example 14: Solid form of Type L The solid form of type L was obtained by storing the starting material overnight under ambient conditions of approximately 45% RH. This starting material is presumed to be a mixture of solid forms J and L, and was obtained by slurry treatment of the starting material in acetone / H2O (v:v=986:14) at room temperature for approximately 6 days. The morphological changes are shown in Figure 39. From the TGA / DSC curve (Figure 40), a mass loss of 8.8% is observed up to 175°C. In the DSC curve, two endothermic peaks were observed at 87.6°C and 157.6°C. 1¹H NMR measurements were performed using DMSO-d6 as the solvent, and it was shown that the molar ratio of residual acetone to API was approximately 0.50 (5.5 wt%). For the solid form of type L, a heating experiment was conducted to identify its morphology. As shown in Figure 41, the morphological change to type J was observed by heating the solid form of type L to 100°C and then cooling it to room temperature. Based on the fact that the solid form of type J, which is anhydrous, changed to the solid form of type L, and based on the results of the heating experiment, the solid form of type L was identified as a hydrate.

[0136] Example 15: Solid form of Type M The solid form of type M was obtained by slowly cooling an EtOH solution of the starting material. As shown in Figure 42, no morphological changes were observed before and after overnight drying under ambient conditions. From the TGA / DSC curve (Figure 43), a mass loss of 8.3% was observed up to 150°C. In the DSC curve, three endothermic peaks were observed at 83.2°C, 105.2°C, and 129.3°C. 1 1H NMR measurements were performed using DMSO-d6 as the solvent, and it was shown that the molar ratio of residual EtOH to API was approximately 0.21 (1.9 wt%).

[0137] Example 16: Solid form of Type N The solid form of type N was obtained as follows: A clear solution was obtained by slowly cooling the starting material IPAc / cyclohexane (v:v=1:1) solution, and then the solution was evaporated at room temperature to obtain the solid. The XRPD diffraction pattern is shown in Figure 44. Due to insufficient sample quantity, further characterization was not performed.

[0138] Example 17: Solid form of Type O The solid form of type O was obtained by heating the starting material to 150°C, then cooling it to room temperature and leaving it for 30 minutes under ambient conditions. The XRPD diffraction pattern is shown in Figure 45. Further characterization has not been performed. Since this form was generated under high-temperature conditions, the solid form of type O was identified as an anhydrous form.

[0139] Example 18: Solid form of Type P The solid form of type P was obtained by heating the solid form of type I to 100°C and then cooling it to room temperature. The XRPD diffraction pattern is shown in Figure 46. Further characterization has not been performed. Based on the experimental conditions, the solid form of type P was identified as either an anhydrous or hydrated form.

[0140] Example 19: Solid form of Type Q The solid form of type Q was obtained as follows. 601.9 mg of the solid form of type A was dissolved in ¼ mL of toluene while sonicating. This solution was filtered through a 0.45 μm PTFE membrane, and 3 mL of the solution was taken and a poor solvent was added. n-heptane was added dropwise to the solution while stirring, and when 2 mL of n-heptane had been added, a small amount of the solid form of type B was added as a seed crystal. A total of 8 mL of n-heptane was added. After slurry treatment overnight at room temperature, the solid was recovered by vacuum filtration and measured by XRPD. The superposition of XRPD diffraction patterns is shown in Figure 47. No morphological changes were observed when the obtained solid was dried overnight under ambient conditions. From the TGA / DSC curve (Figure 48), a 4.5% mass loss was observed up to 150 °C, and a single endothermic peak was observed at 217.0 °C. 1 ¹H NMR measurements were performed using DMSO-d6 as the solvent, and the molar ratios of residual siRNA and residual n-heptane relative to API were 0.05 (0.9 wt%) and 0.02 (0.4 wt%), respectively. The HPLC purity of the solid form of type Q was 98.6% by area percentage. For the solid form of type Q, heating experiments were performed to identify its morphology. According to the XRPD results in Figure 49, no morphological changes were observed before and after heating the solid form of type Q to 150°C and cooling to room temperature, and no residual solvent was detected in the heated sample. Limited mass loss in TGA, clear DSC curve, 1 Based on the presence of a small amount of residual solvent in 1H NMR and the results of heating experiments, the solid form of type Q was identified as anhydrous. DVS was performed on the solid form of type Q. As shown in Figure 50, the water absorption at 25°C / 80%RH was greater than 0.2 wt% but less than 2 wt%, indicating that the solid form of type Q is slightly hygroscopic. As shown in Figure 51, the superposition of XRPD diffraction patterns showed no morphological changes before and after the DVS measurement.

[0141] Example 20: Investigation of thermodynamic relationships in solid forms of Type B and Type Q To further investigate the thermodynamic relationship between the anhydrous solid forms of type B and type Q, slurry competition experiments were conducted in an toluene / n-heptane solvent at 5°C, room temperature, and 50°C, and the results are summarized in the table below. As shown in Figures 52 and 53 (for ease of comparison, XRPD is shown in the range of 2θ = 3° to 20°), only type B was obtained, indicating that type B is the thermodynamically preferred form under the conditions investigated. [Table 10] Procedure: The corresponding solvent was pre-saturated with the solid form of type Q, filtered, and then combined with a weighed sample containing the solid forms of type B and type Q. After slurry treatment at the corresponding temperature for 2-4 days, the wet sample was measured by XRPD.

[0142] Example 21: Experiment Overview In summary, 17 different crystalline structures (I) were detected through polymorphic screening experiments and subsequent treatments. The anhydrous type B solid form exhibited unexpectedly good solid-state properties. On the other hand, the current manufacturing process used to obtain the type B solid form may also generate the type Q solid form.

[0143] Example 22: Results of polymorphic screening The results of the polymorphic screening are summarized in the table below. Detailed experimental procedures and the solvents used are listed herein. [Table 11]

[0144] Example 23: Poor solvent addition Approximately 20 mg of the starting material was placed in a glass vial (20 mL) and dissolved in the corresponding solvent (0.3-3.0 mL) as shown in the table below. (The suspension was filtered through a 0.45 μm PTFE membrane to obtain a clear solution.) The resulting solution was magnetically stirred while adding the poor solvent until a precipitate formed or the total volume of the poor solvent reached 5.0 mL. The resulting precipitate was isolated for XRPD analysis. The results in the table below show that samples in solid form / low-crystalline solid / amorphous solid and clear solutions of types A, B, C, A+C were obtained. [Table 12]

[0145] Example 24: Slow evaporation Approximately 20 mg of the starting material was placed in a vial (3 mL), dissolved in the corresponding solvent shown in the table below, and filtered into another shell vial (4 mL) using a 0.45 μm PTFE membrane. The clear solution was evaporated at room temperature in a vial sealed with a PE cap perforated with 5 or 10 small holes. The results summarized in the table below show that a type A solid-state sample was obtained, with type A, B, D, H, and J solid-state / unidentified peaks. [Table 13]

[0146] Example 25: Slow cooling Approximately 20 mg of the starting material was placed in a vial (3 mL), suspended in the corresponding solvent shown in the table below, and equilibrated at 50°C for 2 hours. The mixture was then filtered into another vial using a 0.45 μm PTFE membrane. The clear solution was capped and sealed, and cooled from 50°C to 5°C at a cooling rate of 0.1°C / min. The results summarized in the table below show that solid-state samples of type B, H, M, and N, as well as type A solid-state samples and low-crystallinity solids with unidentified peaks, were obtained. [Table 14]

[0147] Example 26: Slurry treatment at room temperature Approximately 20 mg of type A solid was suspended in an HPLC vial in the corresponding solvent (0.5 mL) shown in the table below. After slurry processing with magnetic stirring (~750 rpm) at room temperature for 9 days, the remaining solid was isolated by centrifugation for XRPD analysis. The results summarized in the table below show that solid forms of types B, C, D, F, G, H, I, K, J+L, solid form of type A with unidentified peaks, and low-crystallinity solid samples were obtained. [Table 15]

[0148] Example 27: Slurry treatment at 50°C Approximately 20 mg of the starting material was suspended in an HPLC vial in the corresponding solvent (0.5 mL) shown in the table below. After slurry processing with magnetic stirring (~750 rpm) at 50°C for 3 days, the remaining solid was isolated by centrifugation for XRPD analysis. The results summarized in the table below show that samples were obtained in the form of solids of types B, C, D, E, and F / solids of type B with unidentified peaks / solids of type C with unidentified peaks. [Table 16]

[0149] Example 28: Method for scaling up the preparation of a solid form of type B For DVS measurement and investigation of thermodynamic relationships, a 300 mg solid form of type B was prepared. The solid form of type B was obtained as follows: The starting material (301.2 mg) was dissolved in ¼ mL of ¼ under sonication. This solution was filtered into another vial using a 0.45 μm PTFE membrane. When n-heptane was added dropwise to this solution with stirring, a precipitate formed after 5 mL of n-heptane was added. A total of 10 mL of n-heptane was added. After slurry treatment overnight at room temperature, the solid was recovered by suction filtration and dried under reduced pressure at 50 °C for 3.5 hours to obtain 239.4 mg of solid (yield: 87.3%). The XRPD diffraction pattern of the re-prepared type B solid form is shown in Figure 54. From the TGA / DSC curve in Figure 55, a 4.0% mass loss was observed up to 150°C, and two endothermic peaks were observed at 209.5°C and 211.9°C. 1 ¹H NMR measurements were performed using DMSO-d6 as the solvent, and the molar ratios of residual SiO and residual n-heptane relative to the API were 0.09 (1.6 wt%) and 0.03 (0.6 wt%), respectively. The HPLC purity of the re-prepared type B solid form was 98.7% by area percentage.

[0150] Synthesis Example 1 Structure (I) · Type A synthesis Step 1: Synthesis of 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-D]pyrimidine-4-amine [ka] A mixture of 7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine-4-amine (0.160 g, 0.533 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.190 g, 0.800 mmol), and K2CO3 (0.221 g, 1.599 mmol) / 1,4-dioxane (1 mL) and water (0.3 mL) was purged with N2 for 10 minutes, then Pd(PPh3)4 (0.062 g, 0.053 mmol) was added, and the reaction mixture was stirred at 100°C for 12 hours. After the reaction was complete (confirmed by TLC), the resulting mixture was filtered through diatomaceous earth (e.g., Celite®) and then rinsed with ethyl acetate (2 × 10 mL). The filtrates were combined and concentrated under reduced pressure to obtain a crude product, which was purified by flash chromatography (silica gel: 230-400 mesh, elution solvent: 3% methanol / dichloromethane) to obtain the title compound as a yellow solid (0.110 g, 73% yield). 1 H NMR (400MHz, DMSO-d6)δ=8.14(s, 1H), 7.13(s, 1H), 7.05-7.09(m, 1H), 6.95-6.98(m, 1H), 6.82-6.86(m, 1H), 6.10(bs, 2H), 5.22(bs, 2H), 3.52-3.58(m, 1H), 1.00-1.04(m, 4H); LCMS: 284.1 [M+H]

[0151] Step 2: Synthesis of phenyl(5-(1-(trifluoromethyl)cyclopropyl)isoxazole-3-yl)carbamate [ka] To a solution of 5-(1-(trifluoromethyl)cyclopropyl)isoxazole-3-amine (1.0 equivalent) / THF (10 vol), pyridine (1.2 equivalents) and phenyl chloroformate (1.5 equivalents) were added at 0°C. The reaction mixture was heated to 25°C and stirred for 12 hours. After the reaction was complete (confirmed by TLC), the resulting mixture was diluted with ethyl acetate (10 mL) and washed with saline solution (5 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. This was purified by flash chromatography (silica gel: 230-400 mesh, elution solvent: 10-20% ethyl acetate / petroleum) to obtain the target carbamate. LC / MS 312.9 [M+H]

[0152] Step 3: Synthesis of 1-(4-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazole-3-yl)urea (structure (I)) [ka] Triethylamine (2.0 equivalents) was added to a mixture of 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-D]pyrimidine-4-amine (1.0 equivalent) and phenyl(5-(1-(trifluoromethyl)cyclopropyl)isoxazole-3-yl)carbamate (1.0 equivalent) / THF (10 vol), and the mixture was stirred in a sealed tube at 60°C for 12 hours. After completion of the reaction (confirmed by LC-MS), the reaction mixture was concentrated under reduced pressure to obtain the crude product. This was purified by reverse-phase preparative HPLC to obtain the desired product as a grayish-white solid (0.010 g, 6% yield). 1H NMR (400MHz, DMSO-d6)δ=9.99(bs, 1H), 8.86(bs, 1H), 8.14-8.18(m, 2H), 7.24-7.36(m, 3H), 6.90(s, 1H), 6.15(bs, 2H), 3.56-3.61(m, 1H), 1.48-1.57(m, 4H), 1.02-1.07(m, 4H); LCMS: 502.2 [M+H]

[0153] Further embodiments may be provided by combining the various embodiments described above. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent literature referenced herein and / or listed in the application data sheet, including U.S. Provisional Application No. 63 / 504,669 filed May 26, 2023, are incorporated herein by reference in their entirety unless otherwise noted. Each element of an embodiment can be modified as necessary to incorporate concepts described in various patents, patent applications, and publications, thereby providing yet another embodiment.

[0154] In consideration of the aforementioned "modes for carrying out the invention," the embodiments may be modified in the manner described above and in other ways. In general, the terms used in the following claims should not be interpreted to limit the claims to any specific embodiment disclosed in the specification and claims, but rather to encompass all embodiments that may fall within the scope of the rights of such claims and their equivalents. Accordingly, the claims of this application are not limited by this disclosure.

Claims

1. The following structure (I): 【Chemistry 1】 A solid form of a compound having or a tautomer thereof, which exhibits a powder X-ray diffraction pattern having peaks at 2θ angles selected from at least two of the following: 7.33±0.2°, 10.51±0.2°, 15.93±0.2°, and 18.92±0.2°.

2. The solid form according to claim 1, exhibiting a powder X-ray diffraction pattern having peaks at 2θ angles selected from at least three of the following: 7.33±0.2°, 10.51±0.2°, 15.93±0.2°, and 18.92±0.2°.

3. The solid form according to claim 1, exhibiting a powder X-ray diffraction pattern having peaks at 2θ angles of 7.33±0.2°, 10.51±0.2°, 15.93±0.2°, and 18.92±0.2°.

4. The solid form according to claim 1, exhibiting a powder X-ray diffraction pattern having peaks at 2θ angles selected from at least two of 7.33°, 10.51°, 15.93°, and 18.92°.

5. The solid form according to claim 1, exhibiting a powder X-ray diffraction pattern having peaks at 2θ angles selected from at least three of the following: 7.33°, 10.51°, 15.93°, and 18.92°.

6. The solid form according to claim 1, exhibiting a powder X-ray diffraction pattern having peaks at 2θ angles of 7.33°, 10.51°, 15.93°, and 18.92°.

7. The solid form according to claim 1, exhibiting a powder X-ray diffraction pattern having peaks at 2θ angles of 3.87±0.2°, 7.73±0.2°, 10.51±0.2°, 12.71±0.2°, 13.53±0.2°, 13.99±0.2°, 15.93±0.2°, 18.92±0.2°, 21.56±0.2°, 22.74±0.2°, 23.19±0.2°, 24.53±0.2°, 25.63±0.2°, 27.73±0.2°, 31.17±0.2°, and 36.49±0.2°.

8. The solid form according to claim 1, exhibiting a powder X-ray diffraction pattern having peaks at 2θ angles of 3.87°, 7.73°, 10.51°, 12.71°, 13.53°, 13.99°, 15.93°, 18.92°, 21.56°, 22.74°, 23.19°, 24.53°, 25.63°, 27.73°, 31.17°, and 36.49°.

9. The solid form according to claim 1, including a solid form of type B.

10. The solid form according to claim 1, which essentially includes a solid form of type B.

11. The solid form according to claim 1, which is substantially pure.

12. The following structure (I) shows a powder X-ray diffraction pattern that is substantially consistent with that shown in Figure 56: 【Chemistry 2】 A compound having the same properties or a solid form of its tautomer.

13. The solid form according to any one of claims 1 to 12, characterized by a differential scanning calorimetry (DSC) thermogram having an endothermic peak at 205.7℃ ± 0.5℃.

14. The solid form according to claim 13, wherein the endothermic peak exceeds 100 J / g.

15. The solid form according to claim 13, wherein the endothermic peak exceeds 115 J / g.

16. The solid form according to any one of claims 1 to 15, characterized by a DSC thermogram substantially consistent with that shown in Figure 8.

17. The following structure (I): 【Transformation 3】 A solid form of a compound having the same or a tautomer thereof, exhibiting a powder X-ray diffraction pattern with peaks at 2θ angles selected from at least two of the following: 4.67±0.2°, 9.35±0.2°, 25.49±0.2°, and 26.93±0.2°.

18. The solid form according to claim 17, exhibiting a powder X-ray diffraction pattern having peaks at 2θ angles of 4.67±0.2°, 9.35±0.2°, 25.49±0.2°, and 26.93±0.2°.

19. The solid form according to claim 17, exhibiting a powder X-ray diffraction pattern having peaks at 2θ angles selected from at least two of 4.67°, 9.35°, 25.49°, and 26.93°.

20. The solid form according to claim 17, exhibiting a powder X-ray diffraction pattern having peaks at 2θ angles of 4.67°, 9.35°, 25.49°, and 26.93°.

21. The solid form according to claim 17, exhibiting a powder X-ray diffraction pattern having peaks at 2θ angles of 4.67±0.2°, 5.41±0.2°, 9.35±0.2°, 11.32±0.2°, 13.49±0.2°, 15.35±0.2°, 17.15±0.2°, 18.73±0.2°, 20.57±0.2°, 22.87±0.2°, 24.27±0.2°, 25.49±0.2°, 26.93±0.2°, and 29.97±0.2°.

22. The solid form according to claim 17, exhibiting a powder X-ray diffraction pattern having peaks at 2θ angles of 4.67°, 5.41°, 9.35°, 11.32°, 13.49°, 15.35°, 17.15°, 18.73°, 20.57°, 22.87°, 24.27°, 25.49°, 26.93°, and 29.97°.

23. The solid form according to claim 17, including a solid form of type Q.

24. The solid form according to claim 17, which essentially includes a solid form of type Q.

25. The solid form according to claim 17, which is substantially pure.

26. The following structure (I) shows a powder X-ray diffraction pattern that is substantially consistent with that shown in Figure 57: 【Chemistry 4】 A compound having the same properties or a solid form of its tautomer.

27. The solid form according to any one of claims 17 to 26, characterized by a DSC thermogram having an endothermic peak at 217.0℃ ± 0.5℃.

28. The solid form according to any one of claims 17 to 27, characterized by a DSC thermogram substantially consistent with that shown in Figure 47.

29. A composition comprising a solid form according to any one of claims 1 to 16 and a solid form according to any one of claims 17 to 28.

30. A pharmaceutical composition comprising a solid form according to any one of claims 1 to 28, and a pharmaceutically acceptable carrier or excipient.

31. A pharmaceutical composition according to claim 30, formulated for oral administration.

32. The pharmaceutical composition according to claim 30, which is a capsule.

33. The pharmaceutical composition according to claim 30, which is in the form of a tablet.

34. A method for treating NLRP3-mediated disease, characterized by administering a therapeutically effective amount of the solid form described in any one of claims 1 to 28, or the composition described in any one of claims 29 to 33, to a patient in need of treatment.

35. The method according to claim 34, wherein the disease is selected from autoimmune diseases, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial and viral infections, allergies, asthma, pancreatitis, multiple organ failure, kidney disease, platelet aggregation disorders, cancer, transplantation, sperm motility disorders, anemia, graft rejection, lung injury, respiratory diseases, and ischemic conditions.

36. The method according to claim 34 or 35, wherein the disease is selected from type 2 diabetes, atherosclerosis, Alzheimer's disease, aging, fatty liver, metabolic syndrome, asthma, psoriasis, obesity, acute and chronic tissue injury due to infection, gout, arthritis, macular degeneration, enteritis, hepatitis, peritonitis, silicosis, UV-induced sunburn, contact hypersensitivity, sepsis, cancer, neurodegenerative disease, multiple sclerosis, Mackle-Wells syndrome, and myelodysplastic syndrome (MDS).

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