Polymorphs of nek 7 inhibitors

Abstract

The present disclosure relates to solid forms of a compound having the following structure (I) or a tautomer thereof. The present disclosure also relates to methods of making and using solid forms of compounds of structure (I). (I).

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Publication Number (43) Publication Date (21) Application Number 202480033899.9 (22) Application Date 2024.05.23 (30) Priority Data 63 / 504,669 2023.05.26 US (85) PCT International Application Entering National Phase Date 2025.11.20 (86) PCT International Application Application Data PCT / US2024 / 030777 2024.05.23 (87) PCT International Application Publication Data WO2024 / 249257 EN 2024.12.05 (71) Applicant: Harya Therapeutics, Inc. Address: Utah, USA (72) Inventors: Alexis Henry Abel Morad, David James Beers, Paul Flynn (74) Patent Agency: Beijing Yingsai Jia Hua Intellectual Property Agency Co., Ltd. 11204 Patent Attorneys: Liu Zhimin, Wang Dazuo (51) Int.Cl. C07D 487 / 04 (2006.01) A61K 31 / 519 (2006.01) A61P 37 / 02 (2006.01) (54) Invention Title: Polymorphs of NEK7 Inhibitors (57) Abstract: This disclosure relates to compounds having the following structure (I) or their tautomers in solid form. This disclosure also relates to methods for preparing and using compounds of structure (I) in solid form. (I). Claims 4 pages, Description 43 pages, Drawings 30 pages, CN 121368594 A 2026.01.20 CN 1 21 36 85 94 A 1. A compound or its tautomer in solid form having the following structure (I): (I) wherein the X-ray powder diffraction pattern of said solid form has peaks at 2θ angles selected from at least two of 7.33±0.2°, 10.51±0.2°, 15.93±0.2°, and 18.92±0.2°. 2. The solid form of claim 1, wherein the X-ray powder diffraction pattern of said solid form has peaks at 2θ angles selected from at least three of 7.33±0.2°, 10.51±0.2°, 15.93±0.2°, and 18.92±0.2°. 3. The solid form of claim 1, wherein the X-ray powder diffraction pattern of the solid form has 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 of claim 1, wherein the X-ray powder diffraction pattern of the solid form has peaks at 2θ angles of at least two selected from 7.33°, 10.51°, 15.93°, and 18.92°.5. The solid form of claim 1, wherein the X-ray powder diffraction pattern of the solid form has peaks at 2θ angles selected from at least three of 7.33°, 10.51°, 15.93°, and 18.92°. 6. The solid form of claim 1, wherein the X-ray powder diffraction pattern of the solid form has peaks at 2θ angles of 7.33°, 10.51°, 15.93°, and 18.92°. 7. The solid form as claimed in claim 1, wherein the X-ray powder diffraction pattern of the solid form has 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 of claim 1, wherein the X-ray powder diffraction pattern of said solid form has 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 of claim 1, wherein said solid form comprises type B solid form. 10. The solid form of claim 1, wherein said solid form is substantially composed of type B solid form. Claims 1 / 4 page 2 CN 121368594 A 11. The solid form of claim 1, wherein said solid form is substantially pure. 12. A solid form of a compound having the following structure (I) or a tautomer thereof: (I) having an X-ray powder diffraction pattern substantially consistent with the X-ray powder diffraction pattern described in FIG. 56. 13. The solid form of any one of claims 1 to 12, characterized by a differential scanning calorimeter including an endothermic peak at 205.7 °C ± 0.5 °C. 14. The solid form of claim 13, wherein the endothermic peak is greater than 100 J / g. 15. The solid form of claim 13, wherein the endothermic peak is greater than 115 J / g. 16. The solid form of any one of claims 1 to 15, characterized by a differential scanning calorimeter substantially consistent with the differential scanning calorimeter described in FIG. 8. 17. A solid form of a compound having the following structure (I) or a tautomer thereof: Claims 2 / 4 Page 3 CN 121368594 A(I) The X-ray powder diffraction pattern of the solid form has peaks at 2θ angles selected from at least two of 4.67 ± 0.2°, 9.35 ± 0.2°, 25.49 ± 0.2°, and 26.93 ± 0.2°. 18. The solid form of claim 17, wherein the X-ray powder diffraction pattern of the solid form has peaks at 2θ angles selected from at least two of 4.67 ± 0.2°, 9.35 ± 0.2°, 25.49 ± 0.2°, and 26.93 ± 0.2°. 19. The solid form of claim 17, wherein the X-ray powder diffraction pattern of the solid form has peaks at 2θ angles selected from at least two of 4.67°, 9.35°, 25.49°, and 26.93°. 20. The solid form of claim 17, wherein the X-ray powder diffraction pattern of the solid form has peaks at 2θ angles of 4.67°, 9.35°, 25.49°, and 26.93°. 21. The solid form of claim 17, wherein the X-ray powder diffraction pattern of the solid form has peaks at 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 of claim 17, wherein the X-ray powder diffraction pattern of said solid form has 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 of claim 17, wherein said solid form comprises a Q-type solid form. 24. The solid form of claim 17, wherein said solid form is substantially composed of a Q-type solid form. 25. The solid form of claim 17, wherein said solid form is substantially pure. 26. A solid form of a compound having the following structure (I) or its tautomer: Claims 3 / 4, page 4, CN 121368594 A (I) having an X-ray powder diffraction pattern substantially consistent with the X-ray powder diffraction pattern described in FIG. 57. 27. The solid form according to any one of claims 17 to 26, characterized in that it includes a differential scanning calorimeter comprising an endothermic peak at 217.0 °C ± 0.5 °C. 28. The solid form according to any one of claims 17 to 27, characterized in that it has a differential scanning calorimeter consistent with the differential scanning calorimeter described in FIG. 47.29. A composition comprising the solid form of any one of claims 1 to 16 and the solid form of any one of claims 17 to 28. 30. A pharmaceutical composition comprising the solid form of any one of claims 1 to 28 and a pharmaceutically acceptable carrier or excipient. 31. The pharmaceutical composition of claim 30, formulated for oral administration. 32. The pharmaceutical composition of claim 30, in the form of a capsule. 33. The pharmaceutical composition of claim 30, in the form of a tablet. 34. A method of treating NLRP3-mediated conditions, comprising administering to an individual in need a therapeutically effective amount of the solid form of any one of claims 1 to 28 or the composition of any one of claims 29 to 33. 35. The method of claim 34, wherein the condition is selected from autoimmune diseases, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial and viral infections, allergic reactions, asthma, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, cancer, transplantation, sperm motility, apoptosis, transplant rejection, lung injury, respiratory diseases, and ischemic conditions. 36. The method of claim 34 or 35, wherein the condition is selected from type II diabetes, atherosclerosis, Alzheimer's disease, aging, fatty liver, metabolic syndrome, asthma, psoriasis, obesity, acute and chronic tissue damage caused by infection, gout, arthritis, macular degeneration, enteritis, hepatitis, peritonitis, silicosis, UV-induced sunburn, contact hypersensitivity, sepsis, cancer, neurodegenerative diseases, multiple sclerosis, Muckle-Wells syndrome, and myelodysplastic syndrome (MDS). Claims 4 / 4 Page 5 CN 121368594 A Polymorphs of NEK7 Inhibitors Technical Field

[0001] Embodiments of this disclosure generally relate to compounds and methods of their preparation and use as therapeutic or preventative agents, for example, for the treatment of inflammation. Background Art

[0002] Inflammasomes are multi-protein complexes whose activation plays an important role in innate immunity and inflammation. To date, four inflammasomes have been described: NLRP1, NLRC4, NLRP3, and AIM2. The NLRP3 inflammasome is composed of NLRP3, ASC, and Caspase-I. Its activation leads to the activation of Caspase-I, which promotes the secretion of IL-1β and IL-18. IL-1β and IL-18 are cytokines that mediate inflammation in animal disease models of several 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. NEK7 acts as an NLRP3-binding protein to regulate NLRP3.Oligomerization and activation. NEK7 is a serine / threonine kinase essential for mitotic entry, cell cycle progression, cell division, and mitotic progression. It is expressed in various tissues such as the brain, heart, lung, liver, and spleen. Overexpression of NEK7 induces the generation of abnormal cells, which is closely associated with tumors such as retinoblastoma, gallbladder cancer, and head and neck cancer.

[0004] Numerous inhibitors have been widely used to interfere with effector signaling pathways involving IL-1β or IL-18 without eliminating the inflammatory response. NLRP3 inflammasome activation inhibitors that block NLRP3-NEK7 interaction have therapeutic or preventative activity in several human diseases such as type 2 diabetes (T2D), atherosclerosis, gout, and neurodegenerative diseases. However, the exact mechanism of NLRP-3-NEK7 is not fully understood.

[0005] Therefore, there is a need to develop inhibitors in solid form that will directly target NEK7 to affect the inflammatory response regulated by the NLRP3 inflammasome in several pathological diseases, such as gout, atherosclerosis, type 2 diabetes, metabolic syndrome, macular degeneration, Alzheimer's disease, multiple sclerosis, and inflammatory bowel disease. Embodiments of this disclosure meet this need and provide further related advantages. Summary of the Invention

[0006] In summary, embodiments of this disclosure provide compounds, including pharmaceutically acceptable salts, solvates, cocrystals, polymorphs, and other solid forms, that can inhibit NEK7 and / or regulate the activity of the NLRP3 inflammasome.

[0007] In one aspect, this disclosure provides a solid form of a compound having the following structure (I) or a tautomer thereof: Specification 1 / 43 page 6 CN 121368594 A

[0008] (I)

[0009] wherein the solid form has an X-ray powder diffraction pattern having peaks at 2θ angles selected from at least two of 7.33±0.2°, 10.51±0.2°, 15.93±0.2° and 18.92±0.2°.

[0010] Another embodiment provides a solid form of a compound having the following structure (I) or a tautomer thereof:

[0011] (I)

[0012] wherein the X-ray powder diffraction pattern of the solid form has peaks at 2θ angles selected from at least two of 4.67±0.2°, 9.35±0.2°, 25.49±0.2° and 26.93±0.2°.

[0013] In another aspect, pharmaceutical compositions comprising the disclosed solid form and methods of using them for treating, for example, inflammation as described on page 2 / 43 of the specification, CN 121368594 A are also provided.

[0014] In the figures, the same reference numerals denote similar elements or actions. The dimensions and relative positions of the elements in the figures are...The elements are not necessarily drawn to scale. For example, the shapes and angles of various elements are not drawn to scale, and some of these elements are enlarged and positioned to improve the readability of the figures. Furthermore, as drawn, the shapes of the elements are not intended to convey any information about the actual shape of the elements, and are chosen only for ease of identification in the figures. The following diagrams are each of the solid forms of the compounds of structure (I), and are their free forms, unless otherwise stated.

[0015] Figure 1 shows a diagram of the solid-state interconversion relationships of the polymorphs of structure (I). The conversions are labeled with numbers corresponding to the following steps: 1. Slurrying in various solvents at room temperature and 50°C; 2. RT slurrying in 1-pentanol or THF / n-heptane, or 50°C slurrying in isoamyl alcohol; 3. 50°C slurrying in IPA; 4. 50°C slurrying in m-xylene; 5. DMSO / ACN at room temperature and 50°C; 6. RT slurrying in 2-BuOH; 7. RT slurrying in acetone / cyclohexane or MEK / cyclohexane; 8. RT slurrying in DCM or ACN; 9. Storage at ~45% RH; 10. Heating to 100°C and cooling to RT under N2 protection; 11. RT slurrying in acetone / H2O (6:4, v:v); 12. Heating to 150°C and cooling to RT under N2 protection; 13. Competitive slurrying in EtOAc / n-heptane at 5°C / RT / 50°C; 14. Heating to 100°C and cooling to RT under N2 protection.

[0016] Figure 2A is an XRPD diffraction pattern in the A-type solid form.

[0017] Figure 2B shows the TGA / DSC curves in the A-type solid form, with the upper trace starting at 13.6° and showing an 8.95% weight decrease at 150.0°C, and the lower trace showing endothermic effects at 87.8°C, 116.6°C, and 128.1°C.

[0018] Figure 3 provides a superposition of XRPD patterns in the A- to F-type solid forms (from top to bottom).

[0019] Figure 4 shows a superposition of XRPD patterns in the G- to L-type solid forms (from top to bottom).

[0020] Figure 5 shows a superposition of XRPD patterns in the M- to Q-type solid forms (from top to bottom).

[0021] Figure 6 provides a superposition of XRPD patterns in the A-type solid form under various conditions, including (from top to bottom) before heating, N2 purging at 30°C for 20 minutes, heating to 100°C, heating to 150°C, cooling to 30°C, and exposure to ambient conditions.

[0022] Figure 7 depicts a superposition of the B-type solid form before (top) and after (bottom) ambient drying.

[0023] Figure 8 is the TGA / DSC curve of the B-type solid form at 205.7°C with endothermic reaction; the upper trace starts at 23.5°C and shows a 2.53% decrease at 150.0°C.

[0024] Figure 9 shows the XRPD superposition of the type B solid form before heating to 150°C (top) and after heating to 150°C (bottom).

[0025] Figure 10 shows the DVS plot of the type B solid form.

[0026] Figure 11 provides the XRPD superposition of the type B solid form before DVS testing (top) and after DVS testing (bottom).

[0027] Figure 12 depicts the XRPD superposition of the type C solid form before ambient drying (top) and after ambient drying (bottom). Specification 3 / 43 pages 8 CN 121368594 A

[0028] Figure 13 is the TGA / DSC curve of the type C solid form endothermic at 113.8°C, 142.8°C, and 189.6°C; the upper trace starts at 27.8°C and shows a decrease of 4.21% at 115.0°C and a decrease of 5.08% at 150.0°C.

[0029] Figure 14 shows the XRPD stacks of the C-type solid form before heating to 115°C (top) and after heating to 115°C (bottom).

[0030] Figure 15 shows the VT-XRPD stacks of the C-type solid form with the following patterns (from top to bottom): 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.

[0031] Figure 16 provides the XRPD stacks of the D-type solid form before ambient drying (top) and after ambient drying (bottom).

[0032] Figure 17 depicts the TGA / DSC curves of the D-type solid form endothermic at 144.5°C; the upper trace starts at 25.2°C and shows a decrease of 13.73% at 175.0°C.

[0033] Figure 18 is an XRPD superposition of the D-type solid form before heating to 175°C (top) and after heating to 175°C (bottom) (the peak near 17.5° 2θ in the bottom pattern is from the PTFE of the stirrer).

[0034] Figure 19 shows the XRPD superposition of the E-type solid form before ambient drying (top) and after ambient drying (bottom).

[0035] Figure 20 shows the TGA / DSC curves of the E-type solid form at 163.3°C and 165.9°C; the upper trace starts at 27.6°C and shows a 6.53% decrease at 175.0°C.

[0036] Figure 21 provides the XRPD superposition of the E-type solid form before heating to 175°C and cooling to room temperature (top) and after heating to 175°C and cooling to room temperature (bottom) (the peak near 17.5° 2θ in the bottom pattern is from the PTFE of the stirrer).

[0037] Figure 22 depicts the XRPD superposition of the F-type solid form before (top) and after (bottom) environmental drying.

[0038] Figure 23 is the TGA / DSC curve of the F-type solid form at 176.3 °C with heat absorption; the upper trace starts at 22.4 °C and shows a decrease of 10.65% at 175.0 °C.

[0039] Figure 24 shows the XRPD superposition of the F-type solid form before heating (top), after heating to 120°C and cooling to room temperature (middle), and after heating to 160°C and cooling to room temperature (bottom).

[0040] Figure 25 shows the XRPD superposition of the G-type solid form before and after ambient drying (top).

[0041] Figure 26 provides the TGA / DSC curves of the G-type solid form endothermic at 127.4°C and 203.9°C; the upper trace starts at 29.0°C and shows a decrease of 5.31% at 100.0°C and a decrease of 12.96% at 175.0°C.

[0042] Figure 27 depicts the XRPD superposition of the G-type solid form before heating (top) and after heating to 175°C and cooling to room temperature (bottom).

[0043] Figure 28 is the XRPD superposition of the H-type solid form.

[0044] Figure 29 shows the TGA / DSC curve of the H-type solid form endothermic at 130.8°C; the upper trace starts at 20.1°C and shows a 7.57% decrease at 150.0°C.

[0045] Figure 30 shows the XRPD superposition of the H-type solid form before heating (top) and after heating to 150°C and cooling to room temperature (bottom).

[0046] Figure 31 provides the XRPD superposition of the I-type solid form before ambient drying (top) and after ambient drying (bottom).

[0047] Figure 32 depicts the TGA / DSC curve of the I-type solid form endothermic at 161.0°C; the upper trace starts at 30.2°C and shows a 4.31% decrease at 150.0°C.

[0048] Figure 33 is the XRPD superposition of the I-type solid form before heating (top) and after heating to 100°C and cooling to room temperature (bottom).

[0049] Figure 34 shows the XRPD stack of the J-type solid form.

[0050] Figure 35 shows the TGA / DSC curves of the J-type solid form endothermic at 154.6 °C and 160.9 °C; the upper trace starts at 15.3 °C and shows a decrease of 1.24% at 150.0 °C. Specification 4 / 43 pages 9 CN 121368594 A

[0051] Figure 36 provides the XRPD stack of the K-type solid form before (top) and after (bottom) ambient drying.

[0052] Figure 37 depicts the TGA / DSC curve of the K-type solid form endothermic at 104.7 °C; the upper trace starts at 31.1 °C and shows a decrease of 6.47% at 150.0 °C.

[0053] Figure 38 is the XRPD stack of the K-type solid form before heating (top) and after heating to 120 °C and cooling to room temperature (bottom).

[0054] Figure 39 shows the XRPD superposition of the L-type solid form before (top) and after (bottom) environmental drying, and the J-type solid form (middle) as a reference.

[0055] Figure 40 shows the XRPD superposition at 87Figure 41 shows the XRPD superposition of the L-type solid form at 0.6℃ and 157.6℃; the upper trace starts at 29.3℃ and shows a decrease of 8.76% at 175.0℃.

[0056] Figure 42 shows the XRPD superposition of the M-type solid form before heating (top) and after heating to 100℃ and cooling to room temperature (bottom).

[0057] Figure 43 shows the XRPD superposition of the M-type solid form before ambient drying (top) and after ambient drying (bottom).

[0058] Figure 43 shows the TGA / DSC curves of the M-type solid form at 83.2℃, 105.2℃ and 129.3℃; the upper trace starts at 27.6℃ and shows a decrease of 8.28% at 150.0℃.

[0059] Figure 44 shows the XRPD superposition of the N-type solid form.

[0060] Figure 45 shows the XRPD superposition of the O-type solid form.

[0061] Figure 46 provides an XRPD stack of the P-type solid form.

[0062] Figure 47 depicts the XRPD stack of the Q-type solid form before (top) and after (middle) ambient drying, and a pattern of the B-type solid form for reference (bottom).

[0063] Figure 48 is the TGA / DSC curve of the Q-type solid form endothermic at 217.0°C; the upper trace starts at 22.4°C and shows a 4.49% decrease at 150.0°C.

[0064] Figure 49 shows the XRPD stack of the Q-type solid form before heating (top) and after heating to 150°C and cooling to room temperature (bottom).

[0065] Figure 50 shows the DVS plot of the Q-type solid form.

[0066] Figure 51 provides the XRPD stack of the Q-type solid form before (top) and after (bottom) DVS testing.

[0067] Figure 52 depicts the XRPD superposition of the Q-type solid form and the B-type solid form (from top to bottom: EtOAc:n-heptane (1:1 at 5°C), EtOAc:n-heptane (1:1 at room temperature), EtOAc:n-heptane (1:1 at 50°C)), the B-type solid form reference, and the Q-type solid form reference during the following competitive pulping experiments.

[0068] Figure 53 is the XRPD superposition of the Q-type solid form and the B-type solid form (from top to bottom: EtOAc:n-heptane (1:2 at room temperature), EtOAc:n-heptane (2:1 at room temperature)), the B-type solid form reference, and the Q-type solid form reference during the following competitive pulping experiments.

[0069] Figure 54 shows the XRPD superposition pattern of the B-type solid form (top) re-prepared at a scale of 300 mg compared to the reference sample (bottom).

[0070] Figure 55 shows the TGA / DSC curves of the re-prepared type B solid form after endothermic reaction at 209.5 °C; the upper trace starts at 28.8 °C and shows a 3.95% decrease at 150.0 °C.

[0071] Figure 56 shows the XRPD pattern in the B-type solid form; the XRPD diffraction peak data in the pattern is shown in the table below: Specification 5 / 43 page 10 CN 121368594 A

[0072] Figure 57 shows the XRPD pattern in the Q-type solid form; the XRPD diffraction peak data in the pattern is shown in the table below: Specification 6 / 43 page 11 CN 121368594 A

[0073] Unless otherwise stated, all XRPD patterns and overlays are displayed with intensity counts on the y-axis and 2θ values ​​(angles) on the x-axis.

[0074] Unless otherwise stated, each TGA / DSC curve is displayed as % by weight on the left y-axis, heat flux (W / g) on ​​the right y-axis, and temperature on the x-axis. Detailed Description

[0075] The details described herein are by way of example and are for the purpose of discussing embodiments of this disclosure by way of example only. The use of all examples or exemplary language (e.g., “for example” or “such as”) provided herein is intended only to better illustrate this disclosure and does not constitute a limitation on the scope of the claimed disclosure. The language in the specification should not be construed as indicating that any unclaimed element is essential to the practice of this disclosure. Furthermore, all methods described herein may be performed in any suitable order unless otherwise stated herein or clearly contradicted by the context.

[0076] The use of alternatives (e.g., “or”) should be understood to mean one, two, or any combination of alternatives. The various embodiments described above may be combined to provide further embodiments. The grouping of alternative elements or embodiments of this disclosure described herein should not be construed as limiting. Each member of a group may be individually mentioned and claimed, or may be mentioned and claimed in any combination with other members of that group or other elements found herein.

[0077] Each embodiment disclosed herein may include, consist substantially of, or be composed of the specifically stated elements, steps, ingredients, or components. As used herein, the term "comprising / including" means "including / including but not limited to," and allows the inclusion / comprising of unspecified elements, steps, ingredients, or components, even in a substantial amount. As used herein, the phrase "consisting of" excludes any unspecified elements, steps, ingredients, or components. As used herein, the phrase "consisting substantially of" limits the scope of the embodiment to the specified elements, steps, ingredients, or components, and to elements, steps, ingredients, or components that do not substantially affect the basic and novel features of the claimed disclosure.

[0078] The terms “an / a / the / described” and similar articles or terms used in the context of describing this disclosure (particularly in the context of the following claims) shall be construed as covering both singular and plural (i.e., “one or more”) unless otherwise stated herein or clearly contradicted by the context. The ranges of values ​​described herein are intended as a shorthand method for individually referring to each distinct value falling within that range. In this specification, unless otherwise stated, any concentration range, percentage range, ratio range, or integer range shall be understood to include any integer value within the range, and, where appropriate, its fractions (e.g., one-tenth and one-hundredth of an integer). Furthermore, unless otherwise stated, any numerical ranges relating to any physical characteristic, such as size or thickness, described herein shall be understood to include any integer within the range. Unless otherwise stated herein, each individual value is incorporated into the specification as if it were individually referenced herein.

[0079] When used in conjunction with a specified value or range, the term “about” has the meaning reasonably given to it by one of ordinary skill in the art, meaning slightly more or less than the specified value or range, within ±20% of the specified value; ±19% of the specified value; ±18% of the specified value; ±17% of the specified value; ±16% of the specified value; ±15% of the specified value; ±14% of the specified value; ±13% of the specified value; ±12% of the specified value; ±11% of the specified value; ±10% of the specified value; ±9% of the specified value; ±8% of the specified value; ±7% of the specified value; ±6% of the specified value; ±5% of the specified value; ±4% of the specified value; ±3% of the specified value; ±2% of the specified value; or ±1% of the specified value.

[0080] One embodiment provides a solid form of a compound having the following structure (I) or a tautomer thereof:

[0081] (I)

[0082] wherein the X-ray powder diffraction pattern of said solid form has at least two peaks at a 2θ angle selected from 7.33±0.2°, 10.51±0.2°, 15.93±0.2° and 18.92±0.2°.

[0083] One embodiment provides a solid form of a compound having the following structure (I) or a tautomer thereof: Specification 8 / 43 pages 13 CN 121368594 A

[0084] (I)

[0085] wherein the X-ray powder diffraction pattern of said solid form has peaks at a 2θ angle selected from at least two of 7.33±0.2°, 10.51±0.2°, 15.93±0.2° and 18.92±0.2°.

[0086] In some embodiments, the X-ray powder diffraction pattern in solid form has at least three peaks at a 2θ angle selected from 7.33 ± 0.2°, 10.51 ± 0.2°, 15.93 ± 0.2°, and 18.92 ± 0.2°. In some embodiments, the solid form...The X-ray powder diffraction pattern of the solid form has peaks at 2θ angles selected from at least three of 7.33±0.2°, 10.51±0.2°, 15.93±0.2°, and 18.92±0.2°.

[0087] In some embodiments, the X-ray powder diffraction pattern of the solid form has peaks at 2θ angles selected from 7.33±0.2°, 10.51±0.2°, 15.93±0.2°, and 18.92±0.2°.

[0088] In some embodiments, the X-ray powder diffraction pattern of the solid form has at least two peaks at 2θ angles selected from 7.33°, 10.51°, 15.93°, and 18.92°. In some embodiments, the X-ray powder diffraction pattern of the solid form has at least three peaks at 2θ angles selected from 7.33°, 10.51°, 15.93°, and 18.92°.

[0089] In some embodiments, the solid-state X-ray powder diffraction pattern has peaks at 2θ angles selected from at least two of 7.33°, 10.51°, 15.93°, and 18.92°. In some embodiments, the solid-state X-ray powder diffraction pattern has peaks at 2θ angles selected from at least three of 7.33°, 10.51°, 15.93°, and 18.92°.

[0090] In some embodiments, the solid-state X-ray powder diffraction pattern has peaks at 2θ angles of 7.33°, 10.51°, 15.93°, and 18.92°. In some embodiments, the solid-state X-ray powder diffraction pattern has 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 some embodiments, the X-ray powder diffraction pattern of the solid form has 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°.

[0091] In some embodiments, the solid form comprises type B solid form. In some embodiments, the solid form consists substantially of type B solid form. In some embodiments, the solid form is substantially pure. Specification 9 / 43 pages 14 CN 121368594 A

[0092] Another embodiment provides a solid form of a compound having the following structure (I) or a tautomer thereof:

[0093] (I)

[0094] Having an X-ray powder diffraction pattern substantially consistent with the X-ray powder diffraction pattern described in FIG. 56.

[0095] In some embodiments, the solid form is characterized by a differential scanning calorimeter including an endothermic peak starting at about 202 °C. In some embodiments, the solid form is characterized by a differential scanning calorimeter including an endothermic peak at 205.7 °C ± 0.5 °C. In some embodiments, the endothermic peak is greater than 100 J / g. In some embodiments, the endothermic peak is greater than 115 J / g.

[0096] In some embodiments, the solid form is characterized by a differential scanning calorimeter substantially consistent with the differential scanning calorimeter described in FIG. 8.

[0097] Another embodiment provides a compound having the following structure (I) in a solid form or a tautomer thereof: Specification 10 / 43 pages 15 CN 121368594 A

[0098] (I)

[0099] wherein the X-ray powder diffraction pattern of the solid form has at least two peaks at a 2θ angle selected from 4.67±0.2°, 9.35±0.2°, 25.49±0.2° and 26.93±0.2°.

[0100] Another embodiment provides a compound having the following structure (I) in a solid form or a tautomer thereof:

[0101] (I)

[0102] wherein the X-ray powder diffraction pattern of the solid form has peaks at a 2θ angle selected from at least two of 4.67±0.2°, 9.35±0.2°, 25.49±0.2° and 26.93±0.2°.

[0103] In some embodiments, the X-ray powder diffraction pattern in solid form has peaks at 2θ angles of 4.67±0.2°, 9.35±0.2°, 25.49±0.2°, and 26.93±0.2°. In some embodiments, the X-ray powder diffraction pattern in solid form has at least two peaks at 2θ angles selected from 4.67°, 9.35°, 25.49°, and 26.93°. In some embodiments, the X-ray powder diffraction pattern in solid form has peaks at 2θ angles selected from at least two of 4.67°, 9.35°, 25.49°, and 26.93°.

[0104] In some embodiments, the X-ray powder diffraction pattern in solid form has peaks at 2θ angles of 4.67°, 9.35°, 25.49°, and 26.93°. In some embodiments, the X-ray powder diffraction pattern in solid form has peaks at 4.67° ± 2θ angles of ...Peaks are observed at 2θ angles of 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 X-ray powder diffraction pattern of the solid form has 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°.

[0105] In some embodiments, the solid form comprises a Q-type solid form. In some embodiments, the solid form consists substantially of a Q-type solid form. In some embodiments, the solid form is substantially pure.

[0106] Another embodiment provides a solid form of a compound having the following structure (I) or a tautomer thereof:

[0107] (I)

[0108] Having an X-ray powder diffraction pattern substantially consistent with the X-ray powder diffraction pattern described in FIG. 57.

[0109] In some embodiments, the solid form is characterized by a differential scanning calorimeter including an endothermic peak at 217.0 °C ± 0.5 °C. In some embodiments, the solid form is characterized by a differential scanning calorimeter substantially consistent with the differential scanning calorimeter shown in FIG. 47.

[0110] In some specific embodiments, the solid form comprises a type B solid form. In some embodiments, the solid form consists substantially of type B solid forms. In some embodiments, the solid form is substantially pure (e.g., containing less than 1%, less than 0.5%, or less than 0.1% of any other solid form).

[0111] In some specific embodiments, the solid form comprises a type Q solid form. In some embodiments, the solid form consists substantially of type Q solid forms. In some embodiments, the solid form is substantially pure (e.g., containing less than 1%, less than 0.5%, or less than 0.1% of any other solid form).

[0112] In some embodiments, the solid form comprises a mixture of type B and type Q solid forms. In some embodiments, the solid form consists essentially of a mixture of type B and type Q solid forms. In some embodiments, the solid form is substantially pure (e.g., containing less than 1%, less than 0.5%, or less than 0.1% of any other...).It is in solid form). In some embodiments, the solid form comprises a mixture of type B solid form and type Q solid form, and type B is present at a concentration greater than 99%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, or 55%. In some embodiments, the solid form comprises a mixture of type B solid form and type Q solid form, and type Q is present at a concentration less than 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, or 45%.

[0113] In some embodiments, the solid form comprises type A solid form, is substantially composed of type A solid form, or is composed of type A solid form.

[0114] In some embodiments, the solid form comprises type B solid form, is substantially composed of type B solid form, or is composed of type B solid form.

[0115] In some embodiments, the solid form comprises solid form type C, is substantially composed of solid form type C, or is composed of solid form type C.

[0116] In some embodiments, the solid form comprises a D-type solid form, is substantially composed of a D-type solid form, or is composed of a D-type solid form.

[0117] In some embodiments, the solid form comprises an E-type solid form, is substantially composed of an E-type solid form, or is composed of an E-type solid form.

[0118] In some embodiments, the solid form comprises an F-type solid form, is substantially composed of an F-type solid form, or is composed of an F-type solid form.

[0119] In some embodiments, the solid form comprises a G-type solid form, is substantially composed of a G-type solid form, or is composed of a G-type solid form.

[0120] In some embodiments, the solid form comprises an H-type solid form, is substantially composed of an H-type solid form, or is composed of an H-type solid form.

[0121] In some embodiments, the solid form comprises an I-type solid form, is substantially composed of an I-type solid form, or is composed of an I-type solid form.

[0122] In some embodiments, the solid form comprises a J-type solid form, is substantially composed of a J-type solid form, or is composed of a J-type solid form.

[0123] In some embodiments, the solid form comprises a K-type solid form, is substantially composed of a K-type solid form, or is composed of a K-type solid form.

[0124] In some embodiments, the solid form comprises an L-type solid form, is substantially composed of an L-type solid form, or is composed of an L-type solid form.

[0125] In some embodiments, the solid form comprises an M-type solid form, is substantially composed of an M-type solid form, or is composed of an M-type solid form.

[0126] In some embodiments, the solid form comprises an N-type solid form, is substantially composed of an N-type solid form, or is composed of an N-type solid form.

[0127] In some embodiments, the solid form comprises an O-type solid form, is substantially composed of an O-type solid form, or is composed of an O-type solid form.

[0128] In some embodiments, the solid form comprises a P-type solid form, is substantially composed of a P-type solid form, or is composed of an AP-type solid form (page 13 / 43 of the specification, CN 121368594).

[0129] In some embodiments, the solid form comprises a Q-type solid form, is substantially composed of a Q-type solid form, or is composed of a Q-type solid form.

[0130] Pharmaceutical Composition

[0131] Other embodiments relate to pharmaceutical compositions. The pharmaceutical composition comprises any (or more) of the foregoing solid forms 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 further embodiments, the pharmaceutical composition comprises the compounds disclosed herein and additional therapeutic agents (e.g., anticancer agents). Non-limiting examples of such therapeutic agents are described below.

[0132] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, ocular, nasal, and topical administration. Furthermore, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intracardiac, intraperitoneal, intralymphatic, and intranasal injection.

[0133] In some embodiments, the compounds described herein are administered locally rather than systemically, for example, by direct injection of the compounds into an organ, typically in the form of a reservoir formulation or a sustained-release formulation. In specific embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Furthermore, in other embodiments, the compounds are delivered in a targeted drug delivery system, for example, in liposomes coated with organ-specific antibodies. In such embodiments, the liposomes target the organ and are selectively absorbed by the organ. In other embodiments, the compounds described herein are provided in the form of a rapid-release formulation, a prolonged-release formulation, or an intermediate-release formulation. In other embodiments, the compounds described herein are administered locally.

[0134] In a disclosed treatment method, an effective amount of at least one structure (I) in solid form is administered to an individual who has or has been diagnosed with such a disease, condition, or medical condition. Effective amounts or doses can be determined by methods such as modeling, dose escalation studies, or clinical trials, for example, the pattern or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and progression of the disease, symptom, or condition, the individual's prior or ongoing treatments, the individual's health status and response to the drug, and the judgment of the treating physician.

[0135] The solid form according to this disclosure is effective over a wide dose range. For example, in adult treatment, 10 mg to 5000 mg daily, 100 mg to 5000 mg daily...Doses of 1000 mg to 4000 mg and 1000 mg to 3000 mg daily are examples of dosages used in some embodiments. The exact dosage will depend on the route of administration, the form of the compound being administered, the individual to be treated, the weight of the individual to be treated, and the preferences and experience of the attending physician.

[0136] In some embodiments, the solid form of the present disclosure is administered in a single dose. Typically, such administration will be by injection, such as intravenous injection, to rapidly introduce the agent. However, other routes may be used as appropriate. A single dose of the compound of the present disclosure may also be used to treat acute conditions.

[0137] In some embodiments, the solid form of the present disclosure is administered in multiple doses. In some embodiments, administration is performed about once, twice, three times, four times, five times, six times, or more than six times daily. In other embodiments, administration is performed about once a month, once every two weeks, once a week, or once every other day. In another embodiment, the solid form of the present disclosure is administered together with another agent (e.g., an anticancer agent) about once daily to about six times daily. In another embodiment, the application of the solid form and the pharmaceutical preparation of this disclosure is sustained for less than about 7 days. In another embodiment, the application is sustained for more than about 6 days, 10 days, 14 days, 28 days, 2 months, 6 months, or 1 year. In some cases, continuous administration is achieved and maintained as long as necessary.

[0138] The application of the solid form of this disclosure can be sustained as long as necessary. In some embodiments, the application of the solid form of this disclosure is for more than 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, or 28 days. In some embodiments, the application of the solid form of this disclosure is for less than 28 days, 14 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day. In some embodiments, the solid form disclosed on page 14 / 43 of this specification, 19 CN 121368594 A, is applied on a sustained basis for a long period of time, for example, for the treatment of chronic effects.

[0139] In some embodiments, the solid form of this disclosure is administered in an individualized dosage form. As is known in the art, individualization of dosing regimens is necessary for optimal treatment due to inter-individual variability in the pharmacokinetics of compounds.

[0140] In some embodiments, the solid form described herein is formulated as a pharmaceutical composition. In specific embodiments, the pharmaceutical composition is formulated in a conventional manner using one or more physiologically acceptable carriers, which include excipients and adjuvants that facilitate the processing of the disclosed solid form into a pharmaceutically acceptable formulation. A suitable formulation depends on the chosen route of administration. Any pharmaceutically acceptable technique, carrier, and excipient may be used, provided it is suitable for formulating the pharmaceutical composition 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, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

[0141] This document provides pharmaceutical compositions comprising a compound of structure (I) in solid form and a pharmaceutically acceptable carrier.

[0142] This document provides pharmaceutical compositions comprising a compound of structure (I) in solid form and a pharmaceutically acceptable diluent, excipient, and carrier. In some embodiments, such as in combination therapies, the described solid form is administered as a pharmaceutical composition wherein the solid form of the compound of structure (I) is mixed with other active ingredients. This covers all combinations of active ingredients described herein in the combination therapies section below and throughout this disclosure.

[0143] In one embodiment, the pharmaceutical composition of the solid form of the compound of structure (I) is a modulator of the NLRP3 inflammasome. In a specific embodiment, the pharmaceutical composition of the solid form of the compound of structure (I) inhibits NEK7 when administered to a patient or biological sample.

[0144] As used herein, a pharmaceutical composition refers to a mixture of the solid form of the compound of structure (I) with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. In some embodiments, the pharmaceutical composition facilitates 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 in a pharmaceutical composition to a mammal suffering from a disease, condition, or medical condition to be treated. In a specific embodiment, the mammal is a human. In some implementations, the effective therapeutic dose varies depending on the severity of the disease, the individual's age and relative health, the potency of the compound used, and other factors. The solid form described herein may be used alone or in combination with one or more therapeutic agents as components of a mixture.

[0145] In one embodiment, the solid form of the compound of structure (I) is formulated into an aqueous solution. In a specific embodiment, by way of example only, the aqueous solution is selected from physiologically compatible buffers, such as Hank's solution, Ringer's solution, or physiological saline buffer. In other embodiments, the solid form of the compound of structure (I) is formulated for transmucosal administration. In a specific embodiment, the transmucosal formulation includes a permeabilizing agent suitable for the barrier to be penetrated. In other embodiments where the solid form described herein is formulated for other parenteral injections, suitable formulations include aqueous or non-aqueous solutions. In a specific embodiment, such solutions include physiologically compatible buffers and / or excipients.

[0146] In another embodiment, the solid form described herein is formulated for oral administration. The solid form described herein is formulated by combining the active solid form with, for example, a pharmaceutically acceptable carrier or excipient. In various embodiments, on pages 15 / 43 of document 20 CN 121368594 A, the solid forms described herein are formulated as oral dosage forms, which include (by way of example only) tablets, powders, pills, sugar-coated pills, capsules, liquids, gels, syrups, elixirs, pastes, suspensions, etc.

[0147] 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.

[0148] In some embodiments, the pharmaceutical formulation for oral use is obtained by mixing one or more solid excipients with one or more solid forms described herein, optionally grinding the resulting mixture, and processing the granular mixture after adding suitable adjuvants (if desired) to obtain tablets or sugar-coated pill cores. Suitable excipients are fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose formulations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, astragalus gum, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or others, such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, a disintegrant is optionally added. By way of example only, disintegrants include cross-linked croscarmellose sodium carboxymethylcellulose, polyvinylpyrrolidone, agar, or alginate or its salts such as sodium alginate.

[0149] In one embodiment, the dosage form (e.g., sugar-coated cores and tablets) has one or more suitable coatings. In specific embodiments, a concentrated sugar solution is used to coat the dosage form. By way of example only, sugar solutions (optionally containing additional components) may include, for example, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. For identification purposes, dyes...Materials and / or pigments are also optionally added to the coating. Additionally, dyes and / or pigments are optionally used to characterize different combinations of active compound dosages.

[0150] In some embodiments, a therapeutically effective amount of at least one of the solid forms described herein is formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin, and soft-sealable capsules made of gelatin and plasticizers (e.g., glycerin or sorbitol). In specific embodiments, push-fit capsules contain an active ingredient mixed with one or more fillers. Fillers include (by way of example only) lactose, binders (e.g., starch) and / or lubricants (e.g., talc or magnesium stearate), and optionally, stabilizers. In other embodiments, soft capsules contain one or more active compounds dissolved or suspended in a suitable liquid. Suitable liquids include (by way of example only) one or more fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers are optionally added.

[0151] In other embodiments, the solid forms described herein are formulated for parenteral injection, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, the formulation for injection is provided in unit dosage form (e.g., in an ampoule) or in a multi-dose container. Optionally, a preservative is added to the injectable formulation. In other embodiments, the pharmaceutical composition is formulated as a form suitable for parenteral injection, such as a sterile suspension, solution, or emulsion in an oily or aqueous medium. The parenteral injection formulation optionally contains a formulation, such as a suspending agent, stabilizer, and / or dispersant. In specific embodiments, the pharmaceutical formulation for parenteral administration comprises an aqueous solution in an active solid form that is water-soluble. In further embodiments, where appropriate, a suspension of the compound of structure (I) in solid form is prepared as an oily injectable suspension. Suitable lipophilic solvents or mediators for the pharmaceutical compositions described herein include (by way of example only) fatty oils (e.g., sesame oil) or synthetic fatty acid esters (e.g., ethyl oleate or triglycerides) or liposomes. In some specific embodiments, the aqueous injectable suspension contains a substance that increases the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension contains a suitable stabilizer or a reagent that increases the solubility in the solid form to allow for the preparation of a highly concentrated solution. Alternatively, in other embodiments, the active ingredient is in powder form to be combined with a suitable medium (e.g., sterile, pyrogen-free water) prior to use.

[0152] The pharmaceutical composition comprises at least one pharmaceutically acceptable carrier, diluent, or excipient, and a compound of structure (I) of the active ingredient described herein (page 16 / 43, CN 121368594 A). The active ingredient is in the form of a free acid or free base or a pharmaceutically acceptable salt. All tautomers of the solid forms described herein are included in the solid forms provided herein.Within the scope of. Furthermore, the solid forms described herein encompass both non-solventized forms and solvated forms with pharmaceutically acceptable solvents (e.g., water, ethanol, etc.). Solvated forms of the solid forms provided herein are also considered to be disclosed herein. Additionally, pharmaceutical compositions optionally contain other drugs or pharmaceutical agents, carriers, excipients (e.g., preservatives, stabilizers, wetting agents, or emulsifiers), solubilizers, salts for adjusting osmotic pressure, buffers, and / or other substances of therapeutic value.

[0153] Methods for preparing compositions comprising the solid forms described herein include formulating the solid form with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid, or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, pouches, and suppositories. Liquid compositions include solutions in which compounds are dissolved, emulsions containing compounds, or solutions containing liposomes, micelles, or nanoparticles comprising compounds disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The pharmaceutical compositions described herein may be in the form of liquid solutions or suspensions, solid forms suitable for dissolving or suspending in a liquid prior to use, or as emulsions. These compositions may also optionally contain small amounts of non-toxic excipients, such as wetting agents or emulsifiers, pH buffers, etc.

[0154] In some embodiments, pharmaceutical compositions comprising the solid form of the compound of structure (I) are exemplary in liquid form, wherein the pharmaceutical agent is present in a solution, suspension, or both. Typically, when the composition is administered as a suspension, a first portion of the pharmaceutical agent is present in a solution, and a second portion of the pharmaceutical agent is present in particulate form in a suspension within a liquid matrix. In some embodiments, the liquid composition comprises a gel formulation. In other embodiments, the liquid composition is aqueous.

[0155] In some embodiments, the aqueous suspension contains one or more polymers as suspending agents. Polymers include water-soluble polymers (e.g., cellulose polymers, such as hydroxypropyl methylcellulose) and water-insoluble polymers (e.g., cross-linked carboxyl-containing polymers). Some of the pharmaceutical compositions described herein contain a mucosal adhesion polymer selected, for example, from carboxymethyl cellulose, carbomer (acrylic polymer), poly(methyl methacrylate), polyacrylamide, polycarbofil, acrylate / butyl acrylate copolymer, sodium alginate, and dextran.

[0156] The pharmaceutical composition also optionally contains a solubilizer to promote the solubility of the compound of structure (I) in solid form. The term "sorcerer" generally includes an agent that results in the formation of a micelle solution or true solution of the pharmaceutical agent. Certain acceptable nonionic surfactants, such as polysorbate 80, are useful as solubilizers, and ophthalmologically acceptable glycols, polyethylene glycols (e.g., polyethylene glycol 400), and glycol ethers may also be used.

[0157] In addition, the pharmaceutical composition optionally includes one or more pH adjusters or buffers, including acids, such as acetic acid,Boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; bases, such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris(hydroxymethyl)aminomethane; and buffers, such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are contained in amounts necessary to maintain the pH of the composition within an acceptable range.

[0158] Optionally, the composition also contains one or more salts in an amount necessary to achieve an acceptable osmotic molar concentration. Such salts include salts having sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0159] Other pharmaceutical compositions optionally contain one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances, such as Merfen and thimerosal; stabilized chlorine dioxide; and quaternary ammonium compounds, such as benzalkonium chloride, hexadecyltrimethylammonium bromide, and hexadecylpyridine chloride.

[0160] The composition may contain one or more surfactants to enhance physical stability or for other purposes. Nonionic surfactants of suitable specification 17 / 43 pages 22 CN 121368594 A include polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers, such as octylphenol polyether 10 and octylphenol polyether 40.

[0161] The composition may contain one or more antioxidants to enhance chemical stability when needed. By way of example only, suitable antioxidants include ascorbic acid and sodium metabisulfite.

[0162] In some embodiments, the aqueous suspension composition is packaged in a single-dose non-resealable container. Alternatively, multi-dose resealable containers are used, in which case the composition typically contains a preservative.

[0163] In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are used. Liposomes and emulsions are examples of delivery media or carriers useful herein. In some embodiments, organic solvents, such as N-methylpyrrolidone, are also used. In other embodiments, sustained-release systems (e.g., a semi-permeable matrix containing a solid hydrophobic polymer of a therapeutic agent) are used to deliver the solid form described herein. Various sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the solid form for several weeks to more than 100 days. Additional protein stabilization strategies are employed depending on the chemical properties and biological stability of the therapeutic agent.

[0164] In some embodiments, the formulations described herein comprise one or more antioxidants, metal chelators, thiol-containing compounds, and / or other general stabilizers. Examples of such stabilizers include, but are not limited to: (a) about 0.5% to about 2%.(a) glycerol w / v, (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) about 0.003% to about 0.02% w / v polysorbate 80, (g) about 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, (l) pentosan polysulfate and other heparin-like substances, (m) divalent cations, such as magnesium and zinc; or (n) combinations thereof.

[0165] In some embodiments, the concentration of the compound of structure (I) provided in the pharmaceutical compositions of this disclosure in solid form is greater than 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%, 15.50%, 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%, 125%, 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 0.0001% w / w, w / v or v / v.

[0166] In some embodiments, the concentration of the compound of structure (I) provided in the pharmaceutical composition of this disclosure in solid form is about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, about 1% to about 10% w / w, w / v, or v / v.

[0167] In some embodiments, the amount of the compound of structure (I) provided in the pharmaceutical composition of this disclosure in solid form is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g. g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g or 0.0001 g.

[0168] In some embodiments, the amount of the compound of structure (I) provided in the pharmaceutical composition of this disclosure in solid form is 0.0001 g to 10 g, 0.0005 g to 9 g, 0.001 g to 8 g, 0.005 g to 7 g, 0.01 g to 6 g, 0.05 g to 5 g, 0.1 g to 4 g, 0.5 g to 4 g, or 1 g to 3 g.

[0169] Packaging materials used in packaging the pharmaceutical compositions described herein include, for example, those found in U.S. Patents 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 material suitable for the selected formulation and the intended mode of administration and treatment. For example, a container may contain one or more solid forms described herein, optionally in the composition or in combination with another pharmaceutical agent disclosed herein. The container may optionally have a sterile inlet (e.g., the container is an intravenous solution bag, or a vial with a stopper that can be punctured by a hypodermic needle). Optionally, such a kit product contains the compound along with an identifiable description or label or instructions relating to its use in the methods described herein.

[0170] For example, a kit product typically contains one or more additional containers, each having one or more of the various materials (e.g., reagents (optionally in concentrated form) and / or devices) desired from a commercial and user perspective for the use of the compounds described herein. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; labels listing the contents and / or instructions for use, packages, containers, vials, and / or tubes; and package inserts with instructions for use. A set of instructions will also typically be included. The label may optionally be located on or associated with the container. For example, when the letters, numbers, or other characters forming the label are attached, molded, or etched to the container itself, the label is located on the container; when the label is present within a reservoir or carrier (which also contains the container), the label is associated with the container, for example, as a package insert. Furthermore, the label is used to indicate that the contents will be used for a specific therapeutic application. Additionally, the label indicates instructions for use of the contents, such as those described herein. In some embodiments, the pharmaceutical composition is provided in a packaging or dispenser device containing one or more unit dosage forms containing the compounds provided herein. The packaging may contain, for example, metal or plastic foil, such as blister packs. In some embodiments, the packaging or dispenser device is accompanied by instructions for use. In some embodiments, the packaging or dispenser is accompanied by a notification associated with the container in the form prescribed by the government agency that administers, uses, or markets the drug, reflecting that agency's approval of that form of the drug for human or veterinary use. Such notification is, for example, a label for a prescription drug approved by the U.S. Food and Drug Administration, or an approved product insert. In some embodiments, a composition containing the compounds provided herein formulated in a compatible drug carrier is prepared, placed in a suitable container, and labeled for the treatment of a specified condition.

[0171] Methods

[0172] The embodiments of this disclosure act as modulators of the NLRP3 inflammasome by inhibiting NEK7 in the host species.Therefore, the solid form of the compound of structure (I) is also useful in treating conditions mediated by effector signaling molecules such as IL-β and IL-18.

[0173] The host or patient can belong to any mammalian species, such as primates, especially humans; rodents, including mice, rats and hamsters; rabbits; horses, cattle, dogs, cats, etc. Animal models are of interest for experimental studies and provide models for treating human diseases.

[0174] In one embodiment, the solid form of the present disclosure is useful as an inhibitor of the NLRP3 inflammasome activation mechanism, as described on page 19 / 43 of the specification, CN 121368594 A. Therefore, the solid form of the compound of structure (I) is useful in treating conditions in host species caused by NLRP3 inflammasome activation.

[0175] 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, the solid form is useful in treating conditions in the host species caused by association with NLRP3-NEK7.

[0176] In some embodiments, the solid form of the compound of structure (I) is useful in treating human conditions mediated by effectors selected from IL-β, IL-18, and caspase-1.

[0177] Embodiments of this disclosure also relate to the use of the solid form of structure (I) and / or its physiologically acceptable salts for the preventive 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 compound of structure (I) and / or its physiologically acceptable salts in the preparation of medicaments for the preventive or therapeutic treatment and / or monitoring of diseases caused, mediated, and / or regulated by NLRP3 inflammasome activity. In some embodiments, this disclosure provides the use of the compound of structure (I) or its physiologically acceptable salts in the preparation of medicaments for the preventive or therapeutic treatment of NLRP3-mediated conditions.

[0178] In another embodiment, this disclosure relates to a method of treating inflammatory diseases or conditions mediated by the NLRP3 inflammasome by administering a therapeutically effective amount of the compound of structure (I) in solid form to a patient in need.

[0179] In some embodiments, diseases that can be treated with the compound of structure (I) in solid form include type II diabetes, atherosclerosis, Alzheimer's disease, aging, fatty liver, metabolic syndrome, asthma, psoriasis, obesity, acute and chronic tissue damage caused by infection, gout, arthritis, enteritis, hepatitis, peritonitis, silicosis, UV-induced sunburn, contact hypersensitivity, sepsis, cancer, neurodegenerative diseases, multiple sclerosis, Muckle-Wells syndrome, and bone marrow disorders.Myelodysplastic syndrome (MDS).

[0180] In some other embodiments, the solid form of the compound of structure (I) is used in methods of treating conditions or diseases selected from: autoimmune diseases, inflammatory conditions, cardiovascular diseases, neurodegenerative diseases, bacterial and viral infections, allergic reactions, asthma, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, transplantation, sperm motility, apoptosis, transplant rejection, lung injury, respiratory diseases, ischemic conditions, and cancer. In some more specific embodiments, the solid form of the compound of structure (I) is used in methods of treating myelodysplastic syndrome (MDS).

[0181] In some embodiments, NEK7-related conditions that can be treated with the 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 I diabetes, type II diabetes, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyperimmunoglobulinemia D and periodic fever syndrome, Cryopyrin-associated periodic syndrome, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, pseudogout, SAPHO syndrome, Castleman's disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (IL-1 receptor antagonist deficiency), Alzheimer's disease, Parkinson's disease, and cancer.

[0182] This document also includes treatment methods in which the solid form of the compound of structure (I) is administered in combination with an anti-inflammatory agent or therapeutic agent. Anti-inflammatory agents include, but are not limited to, NSAIDs, non-specific and COX-2 specific cyclooxygenase 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, a combination of diclofenac sodium and misoprostol, sulindac, oxaprazine, diflunisal, piroxicam, indomethacin, etodoxacin, fenoprofen calcium, ketoprofen, nabumetone sodium, sulfasalazine, tometetin sodium, and hydroxychloroquine.

[0183] Examples of NSAIDs also include COX-2 specific inhibitors, such as celecoxib, vardicoxib, romecoxib, and / or etodoxacin.

[0184] In some embodiments, the anti-inflammatory agent is a salicylate. Salicylates include, but are not limited to, acetylsalicylic acid or aspirin, sodium salicylate, choline, and magnesium salicylate.

[0185] Anti-inflammatory agents may also be corticosteroids. For example, corticosteroids may be cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone phosphate, or prednisone.

[0186] In another embodiment, the anti-inflammatory agent is a gold compound, such as sodium auronide thiomalate or auronophen.

[0187] This disclosure also includes embodiments in which the anti-inflammatory agent is a metabolic inhibitor, such as a dihydrofolate reductase inhibitor (e.g., methotrexate) or a dihydroorotate dehydrogenase inhibitor (e.g., leflunomide).

[0188] Therapeutic agents may also include agents targeting pain and inflammation, such as histamine and histamine antagonists, bradykinin and bradykinin antagonists, serotonin (5-hydroxytryptamine), lipid substances produced by biotransformation of selective hydrolysis products of membrane phospholipids, arachidic acid, prostaglandins, thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatory agents, analgesics and antipyretics, agents that inhibit the synthesis of prostaglandins and thromboxanes, selective inhibitors of inducible cyclooxygenase, selective inhibitors of inducible cyclooxygenase-2, endocrine hormones, paracrine hormones, somatostatin, gastrin, cytokines that mediate interactions involved in humoral and cellular immune responses, lipid-derived endocrine hormones, arachidic acid, β-adrenergic agonists, ipratropium bromide, glucocorticoids, methylxanthine, sodium channel blockers, opioid receptor agonists, calcium channel blockers, membrane stabilizers, and leukotriene inhibitors.

[0189] Other embodiments of this disclosure involve combinations in which at least one anti-inflammatory compound is an anti-monoclonal antibody (e.g., eculizumab or pecrolimus), a TNF antagonist (e.g., etanercept), or infliximab (which is an anti-TNFα monoclonal antibody).

[0190] Therapeutic agents used in combination with the solid form of the compound of structure (I) may also include small molecule compounds that inhibit NLRP3 inflammasome activation, such as MCC950, sulforaphane, isoliquiritigenin, β-hydroxybutyrate, flufenamic acid, mefenamic acid, 3,4-methylenedioxy-β-nitrostyrene (MNS), and parthenolide.

[0191] Further embodiments of this disclosure involve combinations in which at least one active agent is an immunosuppressive compound, such as an immunosuppressive compound selected from methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, and mycophenolate mofetil.

[0192] The solid form of the compound of structure (I) disclosed may be administered in combination with other known therapeutic agents, including anticancer agents. As used herein, the term "anticancer agent" refers to any agent administered to a patient with cancer for the purpose of treating cancer.

[0193] In some embodiments, the anticancer agent belongs to the following category: Alkylating agents: such as hexamethylmelamine, bendamustine, busulfan, carmustine, chlorambucil, nitrogen mustard, cyclophosphamide, dacarbazine, ifosfamide, inprofen, tocilizumab, lomustine, melphalan, dibromomannitol, dibromoeusine, nimustine, ramustine, temozolomide, thiotepa, tresorvastatin, mechloretamine, carboquinone;Apaziquone, formustin, glucosamine, palivami, Pipobroman, trafosamide, uramustine, TH-3024, VAL-0834; Platinum compounds: e.g., carboplatin, cisplatin, etaplatin, miplatin hydrate, oxaliplatin, lobaplatin, nedaplatin, pyrplatin, sapaplatin; lobaplatin, nedaplatin, pyrplatin, sapaplatin; DNA altering agents: e.g., amrubicin, bifenthrin, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine; acridine, brostallicin, pifenoxanone, laromustine 1,3; Topoisomerase inhibitors: e.g., etoposide, irinotecan, razorizine, sobuzosen, teniposide, topaz; 21 / 43 pages 26 CN 121368594 A tecon; aminonaphthylfentanyl, belotecone, eletidine, voreloxin; Microtubule modulators: such as cabazitaxel, docetaxel, elebulin, ixaprilone, paclitaxel, vincristine, vinorelbine, vindesine, vinflunine; fosbretabulin, testataxel; Antimetabolites: such as asparaginase 3, azacitidine, leucovorin calcium, capecitabine, cladribine, cytarabine, enoxabin, fluorouridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmoflu; deoxyfluorouridine, esilaribine, raltitrexed, sapattabine, tegafur 2,3, trimethoprim; Anticancer antibiotics: such as bleomycin, actinomycin D, doxorubicin, epirubicin, idarubicin, levamisole, mitifenza, mitomycin C, romidesin, streptozotocin, pentorubicin, fentoxin, zolpidem, daunorubicin, procainox; arubicin, pyraclostrobin, pirarubicin; Hormones / antagonists: such as abaricicliz, abiraterone, bicalutamide, busherin, calotestosterone, chlorestradiol, degarelix, dexamethasone, estradiol, fluclofenac, flutamide, fulvestrant, goserelin, histaminerelin. Leuprorelin, medroxyprogesterone acetate, mitotane, nafarelin, nandrolone, nilumethicone, octreotide, prednisolone, raloxifene, tamoxifen, thyroid-stimulating hormone alpha, toremifene, triplosterlin, triptorelin, diethylstilbestrol; acobifen, danazol, diloxacin, epitiostanol, orteronel, enzalutamide 1,3; aromatase inhibitors: such as amylase, anastrozole, exemestane, fazodazole, letrozole, testosterone; formestan; small molecule kinase inhibitors: such as crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxotinib, sorafenib, sunitinib, vandetanib, vemurafenib, buspironeNifetinib, Gefitinib, Axitinib; Afatinib, Alisetinib, Dabrafenib, Dacotinib, Dinacilib, Dovitinib, Enzartolin, Nintedanib, Lenvatinib, Linivanib, Lincitinib, Masatitinib, Midotaurin, Motisanib, Lenatinib, Orantinib, Perifoxine, Penatinib, Radotinib, Rigosertib, Tipyranib, Tivatinib, Trametinib, Pimasertib, Alanine Brinib, Sildinib.

[0194] In some embodiments, the medicaments administered in combination with the solid form of the compound of structure (I) described herein include any suitable medicaments that are effectively delivered by inhalation, such as analgesics, such as codeine, dihydromorphine, ergotamine, fentanyl, or morphine; angina preparations, such as diltiazem; antihistamines, such as cromoglycine, ketotifen, or nedolome; anti-infectives, such as cephalosporins, penicillin, streptomycin, sulfonamides, tetracycline, or pentamiprid; antihistamines, such as dexaspirin; anti-inflammatory drugs, such as beclomethasone, flunisolone, budesonide, teprednisolone, triamcinolone, or fluticasone; antitussives, such as noscarpine; bronchodilators, such as ephedrine, adrenaline, fenoterol, formoterol, isoproterenol, etc. Metaproterenol, phenylephrine, phenylpropanolamine, pibuterol, reproterol, limterol, salbutamol, salmeterol, terbutaline, isotharine, tobuterol, orsinarine or (-)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridyl)ethoxy]hexyl]-amino]methyl]benzyl alcohol; diuretics, such as amiloride; anticholinergics, such as ipratropium bromide, atropine, or oxytropium bromide; hormones, such as cortisone, hydrocortisone, or prednisolone; xanthines, such as aminophylline, choline theophylline, lysine theophylline, or theophylline; and therapeutic proteins and peptides, such as insulin or glucagon. Those skilled in the art will recognize that, where appropriate, drugs are used in the form of salts (e.g., as alkali metal or amine salts or as acid addition salts) or as esters (e.g., lower alkyl esters) or as solvates (e.g., hydrates) to optimize drug activity and / or stability.

[0195] The pharmaceutical agents disclosed herein or other suitable pharmaceutical agents are administered according to the condition being treated. Thus, in some embodiments, the compounds of this disclosure will be administered co-administered with other pharmaceutical agents as described above. When used in combination therapy, the compounds described herein (pages 22 / 43, 27 CN 121368594 A) are administered simultaneously or separately with a second pharmaceutical agent. Such combination administration may include simultaneous administration of both pharmaceutical agents in the same dosage form, simultaneous administration in different dosage forms, and separate administration. That is, the compounds described herein and any of the pharmaceutical agents described above may be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds of this disclosure and any of the pharmaceutical agents described above may be administered simultaneously.The two agents are administered in different formulations. In another alternative, the compound of this disclosure may be administered immediately after any of the above-described agents, or vice versa. In some embodiments of the separate administration regimen, the compound of this disclosure is administered minutes, hours, or days apart from any of the above-described agents.

[0196] In some embodiments, the solid form of the compound of structure (I) is administered as a single therapy.

[0197] To identify signal transduction or mechanistic pathways and to detect interactions between various signal transduction pathways, many scientists have developed suitable models or model systems, such as cell culture models and transgenic animal models. To determine certain stages in a signal transduction cascade, interacting compounds can be used to modulate signals. The compounds of this disclosure can also be used as reagents for testing NEK7-dependent signal transduction pathways in animal and / or cell culture models or in the clinical diseases mentioned in this application.

[0198] The methods of this disclosure can be performed 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 assays, whether during research or clinical application. Typically, cell cultures are combined with compounds of various concentrations for a period of time sufficient for the activator to inhibit NEK7 activity, typically from about 1 hour to 1 week. In vitro treatment can be performed using cultured cells from biopsy samples or cell lines.

[0199] This document also provides methods for preparing the compound of structure (I) in solid form. In some embodiments, the type A solid form is dissolved in a solution and an antisolvent is added to form a type B solid form and / or a type Q solid form. In some embodiments, the method further includes drying (e.g., solvent evaporation at ambient temperature) the type B solid form and / or the type Q solid form. In some embodiments, the type A solid form is dissolved in ethyl acetate. In some embodiments, the type A solid form is dissolved in ethanol, isopropanol, acetone, methyl isobutyl ketone, isopropyl acetate, ethyl formate, anisole, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, or CHCl3.

[0200] In some embodiments, the antisolvent is n-heptane. In some embodiments, the antisolvent is dichloromethane. In some embodiments, the method is performed while heating or cooling the composition / mixture at temperatures of 0°C to 5°C, 20°C to 30°C (e.g., room temperature), or 45°C to 55°C.

[0201] In some embodiments, the method includes dissolving the type A solid form in a solvent and then evaporating the solvent from the resulting mixture to produce a type B solid form and / or a type Q solid form. In some embodiments, the solvent is acetone, ethyl acetate, isopropyl acetate, or methyl tert-butyl ether.

[0202] Examples

[0203] Abbreviations / Acronyms / Abbreviations Specification 23 / 43 Pages 28CN 121368594 A

[0204] 13C NMR = carbon nuclear magnetic resonance; 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 = antisolvent; ASR = analytical service report; ca. =Approx.; D-PAS = Immersion probe absorption spectroscopy; DSC = Differential scanning calorimetry; DVS = Dynamic vapor adsorption; Eq / Eq. / Equiv. = Equivalent; FaSSGF = Fasting state simulated gastric fluid; FaSSIF = Fasting state simulated intestinal fluid; FeSSIF = Feeding state simulated intestinal fluid; GVS = Gravimetric vapor adsorption; H2O = Water; HBr = Hydrobromic acid; HCl = Hydrochloric acid; HPLC = High performance liquid chromatography; Hr or hr = Hour; HSM = Hot stage microscopy; IC = Ion chromatography; ID = Identity; IPA = 2-propanol; IR = Infrared spectroscopy; ISA = Ion intensity modulation; KF = Karl Fischer; MALe = Maleate / ester; MALi = L-malate / ester; MDSC = Modulated differential scanning calorimetry; MEK = Methyl ethyl ketone; Min or min = Minute; mol = Mole; MS = Mass spectrometry; N / A = Not applicable; NMR = Nuclear magnetic resonance; No.= Number; P = Pattern; PE = Polyethylene; PLM = Polarizing Microscopy; PTFE = Polytetrafluoroethylene; RH = Relative Humidity; RRT = Relative Retention Time; RT = Room Temperature; SCXRD = Single Crystal X-ray Diffraction; SGF = Simulated Gastric Fluid; SIF = Simulated Intestinal Fluid; SUC = Succinate / Ester; TAR = L-Tartaric Acid (or its salt); Temp = Temperature; TFA = Trifluoroacetic Acid; Tg = Glass Transition Temperature; TGA = Thermogravimetric Analysis; TRIS = Tris(hydroxymethyl)aminomethane; USP = United States Pharmacopeia; UV = Ultraviolet; v / v = Volume Ratio; vac = Vacuum; Vol = Volume; w / w = Weight Ratio; wt = Weight; wt% = Weight%; XRPD = X-ray Powder Diffraction

[0205] X-ray Powder Diffraction (XRPD)

[0206] For XRPD analysis, a PANalytical X-ray Powder Diffractometer was used. The parameters used are listed in the table below. Instruction manual, 24 / 43 pages, 29 CN 121368594 A

[0207]

[0208] TGA and DSC

[0209] TGA data was collected using TA Instruments' TA Q5000 and Discovery 5500 TGA, and DSC was performed using TA Instruments' TA Q2000 and Discovery 2500 DSC. Detailed parameters used are listed in the table below.

[0210]

[0211] DVS

[0212] Via SMS(Surface Measurement System) DVS Intrinsic measures DVS. Relative humidity at 25°C is calibrated relative to the deliquescence points of LiCl, Mg(NO3)2, and KCl. The parameters for DVS testing are listed in the table below. Instruction manual 25 / 43 pages 30 CN 121368594 A

[0213]

[0214] 1H NMR

[0215] 1H solution NMR was collected on a Bruker 400M NMR spectrometer using DMSO-d6 or MeOH-d4 as solvents.

[0216] HPLC

[0217] An Agilent 1260 with a DAD detector was used, and detailed chromatographic conditions for purity and solubility measurements are listed in the table below. Specification 26 / 43 pages 31 CN 121368594 A

[0218]

[0219] Example 1

[0220] Overview of Solid Form Study Specification 27 / 43 pages 32 CN 121368594 A

[0221] Structure (I) is currently in the development stage and no polymorph studies have been conducted previously. The main objective of this project is to conduct polymorph screening of this compound to identify any crystalline form with good crystallinity and good solid-state properties for further development.

[0222] When synthesized according to Synthesis Example 1, structure (I) exists in type A solid form. Type A solid form was used as the starting material for 75 designed polymorph screening experiments. Based on the XRPD results of polymorph screening and subsequent experiments, a total of 17 polymorphs of structure (I) have been discovered to date, including the B / J / O / Q type solid forms as anhydrous, the A / H / K / L type solid forms as hydrates, the C / D / E / F / G / I type solid forms as solvates, the P type solid forms as anhydrous or hydrates, and the unidentified M / N type solid forms. The solid-state interconversion relationships of the polymorphs of structure (I) are illustrated in Figure 1. The characterization of the obtained forms is summarized in the table below.

[0223] Slurry competition experiments were conducted on the B type solid form and the Q type solid form in ethyl acetate / n-heptane at 5 °C / RT / 50 °C to further investigate the thermodynamic relationship between the two anhydrous forms. As the results show, only the B type was obtained, indicating that the B type is thermodynamically more stable than the Q type under the studied conditions.

[0224] In summary, 17 polymorphs of structure (I) were discovered in the polymorph screening experiments and subsequent treatments. Based on polymorph screening and competitive slurry experiments, the B-type solid form unexpectedly exhibited promising properties for use as a candidate in further development. Since the Q-type solid form may occur in the current processing method (addition of an antisolvent in ethyl acetate / n-heptane), special attention should be paid to polymorph control in processing development, and the B-type form is highly recommended.The physicochemical stability was evaluated.

[0225] The characterization of structure (I) in solid form is shown in the table below. Specification 28 / 43 pages 33 CN 121368594 A

[0226]

[0227] --: No data collected

[0228] #: Potential isomorphism

[0229] Example 2

[0230] Characterization of starting material

[0231] The starting material of structure (I) was received and characterized by XRPD, TGA, DSC and 1H NMR. As shown in Figure 2A, the starting material was crystalline and named as type A solid form. The TGA / DSC results (Figure 2B) show a 9.0% weight loss up to 150°C, and three endothermic peaks at 87.8°C, 116.6°C and 128.1°C. 1H NMR was performed using DMSO-d6, and no obvious residual organic solvent was observed.

[0232] The approximate solubility of the starting material was tested in 20 solvents at room temperature. In the experiment, ~2 mg of solid was weighed into each 3 mL glass vial, and then the corresponding solvent was added stepwise (50 μL / 50 μL / 100 μL / 200 μL / 600 μL / 1000 μL), and the solid was observed to dissolve completely. When the solid dissolved or the total volume reached 2.0 mL, the addition of solvent was stopped. 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, which is used to guide the selection of solvents in the polymorph screening design.

[0233]

[0234] Example 3

[0235] Polymorph Screening and Characterization

[0236] 75 polymorph screening experiments were conducted using type A solid form as the starting material. Based on XRPD, TGA / DSC characterization data and subsequent experimental results, 17 crystal forms of structure (I) were obtained, including the B / J / O / Q type solid form as an anhydrous substance, the A / H / K / L type solid form as a hydrate, the C / D / E / F / G / I type solid form as a solvate, the P type solid form as an anhydrous substance or a hydrate, and the unidentified M / N type solid form. XRPD superimposed images are shown in Figures 3, 4, and 5.

[0237] Five polymorph screening experiments were conducted. Based on XRPD, TGA / DSC characterization data and subsequent experimental results, 17 crystal forms of structure (I) were obtained, including the B / J / O / Q type solid form as an anhydrous substance, the A / H / K / L type solid form as a hydrate, the C / D / E / F / G / I type solid form as a solvate, the P type solid form as an anhydrous substance or a hydrate, and the M / N type solid form. XRPD overlays are shown in Figures 3, 4, and 5.

[0238] Example 4

[0239] Description of Type A solid formPage 30 / 43 35 CN 121368594 A

[0240] VT-XRPD was performed on the type A solid form for form identification. According to the VT-XRPD results in Figure 6, the form change from the type A solid form to another new form (referred to as the type O solid form) was initially observed during N2 purging and ended when heated to 100 °C. Based on the 1H NMR spectrum and the VT-XRPD results, the type A solid form was classified as a hydrate.

[0241] Example 5

[0242] Type B solid form

[0243] The type B solid form was obtained by adding 2.0 mL of n-heptane as an antisolvent to 0.5 mL of EtOAc solution of the starting material. As shown in Figure 7, no form change was observed before and after overnight ambient drying. The TGA / DSC curve (Figure 8) shows a 2.5% weight loss up to 150 °C and a single endothermic peak at 205.7 °C. 1H NMR analysis was performed using DMSO-d6 as the solvent, showing residual EtOAc and n-heptane to API molar ratios of 0.04 (0.7 wt%) and 0.05 (1.0 wt%), respectively.

[0244] Heating experiments were conducted on the B-type solid form for form identification. Based on the XRPD results in Figure 9, no form change was observed before and after heating the B-type solid form to 150 °C and then cooling it to RT. Based on the limited TGA weight loss, net DSC curve, small amount of solvent residue in 1H NMR, and heating experiment results, the B-type solid form was classified as anhydrous.

[0245] DVS was performed on the B-type solid form sample (the preparation and characterization results of which are described herein). As shown in Figure 10, water absorption at 25 °C / 80% RH was less than 0.2 wt%, indicating that the B-type solid form is almost non-hygroscopic. Based on the XRPD stack shown in Figure 11, no form change was observed before and after the DVS test.

[0246] Example 6

[0247] C-type solid form

[0248] The C-type solid form was obtained by adding 2.0 mL of n-heptane as an antisolvent to 0.5 mL of the starting material in a THF solution. As shown in Figure 12, no form change was observed before and after overnight ambient drying. The TGA / DSC curves (Figure 13) show a 4.2% weight loss up to 115 °C and a 5.1% weight loss from 115 °C to 150 °C, as well as three endothermic peaks at 113.8 °C, 142.8 °C, and 189.6 °C. 1H NMR analysis using DMSO-d6 as a solvent showed a residual THF to API molar ratio of approximately 0.36 (4.9 wt%).

[0249] Heating experiments were performed on the C-type solid form for form identification. Based on the results shown in Figure 14 and the 1H NMR, inNo change in form was observed after heating the C-type solid form to 115°C and then cooling it to RT, 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 heating to 120°C, and amorphization was observed when heating to 175°C. Based on the above experimental results, the C-type solid form is classified as a (THF) solvate. Since this XRPD pattern has also been observed in other solvents (e.g., isoamyl alcohol, 1-pentanol, and 2-MeTHF), this form may be isomorphic.

[0250] Example 7

[0251] D-type solid form

[0252] The D-type solid form was obtained by slurrying the starting material in IPA at 50°C for about 5 days. As shown in Figure 16, no change in form was observed before and after overnight ambient drying. The TGA / DSC curve (Figure 17) shows a 13.7% weight loss up to 175°C and a single endothermic peak at 144.5°C. 1H NMR analysis using DMSO-d6 as solvent showed a residual IPA to API molar ratio of approximately 0.93 (10.0 wt%).

[0253] Heating experiments were performed on the D-type solid form for form identification. According to the heating experiment results in Figure 18, amorphization was observed after heating the D-type solid form to 175°C and then cooling it to RT. Based on the solvent residue, TGA weight loss, and heating experiment results determined by 1H NMR, the D-type solid form was classified as an IPA solvate.

[0254] Example 8 Specification 31 / 43 pages 36 CN 121368594 A

[0255] E-type solid form

[0256] The E-type solid form was obtained by slurrying the starting material in m-xylene at 50°C for approximately 5 days. As shown in Figure 19, no form change was observed before and after overnight drying in the environment. The TGA / DSC curve (Figure 20) shows a 6.5% weight loss up to 175°C, and two endothermic peaks at 163.3°C and 165.9°C. 1H NMR analysis using DMSO-d6 as the solvent showed a residual m-xylene to API molar ratio of approximately 0.31 (6.2 wt%).

[0257] Heating experiments were performed on the E-type solid form for form identification. According to the heating experiment results in Figure 21, the E-type solid form became amorphous when heated to 165°C and cooled to RT. Based on the solvent residue, TGA weight loss, and heating experiment results determined by 1H NMR, the E-type solid form was classified as a m-xylene solvate.

[0258] Example 9

[0259] F-type solid form

[0260] The F-type solid form was obtained by pulping the starting material in DMSO / ACN (1:19, v:v) at 50°C for about 5 days.As shown in Figure 22, no form change was observed before and after overnight drying in the environment. The TGA / DSC curve (Figure 23) shows a 10.7% weight loss up to 175°C, and three endothermic peaks at 81.0°C, 142.1°C, and 176.3°C. 1H NMR analysis using MeOH-d4 as the solvent showed a residual DMSO to API molar ratio of approximately 1.2 (15.8 wt%).

[0261] Heating experiments were performed on the F-type solid form for form identification. According to the heating experiment results in Figure 24, no form change was observed when the F-type solid form was heated to 120°C and cooled to RT, and when heated to 160°C and cooled to RT, the F-type solid form became amorphous. 1H NMR spectra showed that after heating to 120°C, the residual DMSO to API molar ratio was approximately 0.8 (11.1 wt%). Based on the solvent residue, TGA weight loss, and heating experiment results determined by 1H NMR, the F-type solid form was classified as a DMSO solvate.

[0262] Example 9

[0263] G-type solid form

[0264] The G-type solid form was obtained by RT slurrying the starting material in 2-BuOH for approximately 6 days. As shown in Figure 25, no form change was observed before and after overnight ambient drying. The TGA / DSC curve (Figure 26) shows a 5.3% weight loss up to 100°C and a 13.0% weight loss from 100°C to 175°C. Two endothermic signals (peaks) at 127.4°C and 203.9°C and one exothermic signal (peak) at 129.3°C were observed in the DSC curve. 1H NMR testing using DMSO-d6 as the solvent showed that the molar ratio of residual 2-BuOH to API was approximately 1.10 (13.9 wt%).

[0265] Heating experiments were performed on the G-type solid form for form identification. According to the heating experiment results in Figure 27, when heated to 175°C and cooled to RT, the G-type solid form became amorphous. Based on the solvent residue, TGA weight loss, and heating experiment results determined by 1H NMR, the G-type solid form was classified as a 2-BuOH solvate.

[0266] Example 10

[0267] H-type solid form

[0268] The H-type solid form was obtained by slow evaporation of the THF solution of the starting material. The XRPD pattern of the H-type solid form is shown in Figure 28. The TGA / DSC curve (Figure 29) shows a 7.6% weight loss up to 150°C and a single endothermic peak at 130.8°C. 1H NMR testing using DMSO-d6 as the solvent showed that the molar ratio of residual THF to API was approximately 0.18 (2.5 wt%).

[0269] Heating experiments were conducted on the H-type solid form for form identification. According to the heating experiment results in Figure 30, the H-type solid form became amorphous when heated to 150°C and cooled to RT. Based on the TGA weight loss, solvent residue in NMR, and heating experiment results, the H-type solid form was classified as a hydrate. Specification 32 / 43 pages 37 CN 121368594 A

[0270] Example 11

[0271] Type I solid form

[0272] The Type I solid form was obtained by RT slurrying the starting material in DCM for about 6 days. As shown in Figure 31, no form change was observed before and after overnight ambient drying. The TGA / DSC curve (Figure 32) shows a 4.3% weight loss up to 150°C, and two endothermic peaks at 66.3°C and 161.0°C. 1H NMR tests were performed using DMSO-d6 as the solvent, and the molar ratio of residual DCM to API was about 0.18 (3.7 wt%).

[0273] Heating experiments were conducted on the type I solid form for form identification. According to the heating experiment results in Figure 33, a form change was observed when the type I solid form was heated to 100°C and cooled to RT, and DCM was not present in the heated sample. The obtained sample was named the type P solid form. Based on the 1H NMR spectrum and heating experiment results, the type I solid form was classified as a DCM solvate. Considering that the type I solid form was also obtained in the ACN slurry system, isomorphism may exist.

[0274] Example 12

[0275] Type J solid form

[0276] The type J solid form was obtained by slowly evaporating the starting material CHCl3 solution. Figure 34 shows the XRPD pattern of the type J solid form. The TGA / DSC curve (Figure 35) shows a 1.2% weight loss up to 150°C, and two endothermic peaks at 154.6°C and 160.9°C. 1H NMR analysis was performed using DMSO-d6 as the solvent, and the molar ratio of residual CHCl3 to API was approximately 0.03 (0.7 wt%). Based on the limited TGA weight loss, net DSC signal, and small amount of solvent residue in the 1H NMR spectrum, the J-type solid form was classified as anhydrous. Furthermore, the J-type solid form may convert to the L-type solid form when stored overnight at approximately ~45% RH under ambient conditions.

[0277] Example 13

[0278] K-type solid form

[0279] The K-type solid form was obtained by RT slurrying the starting material in acetone / H2O (6:4, v:v) for approximately 6 days. As shown in Figure 36, no change in form was observed before and after overnight ambient drying. The TGA / DSC curve (Figure 37) shows a 6.5% weight loss up to 150°C. Two endothermic events were observed in the DSC curve at 104.7°C and 142.8°C. DMSO-d6 was used as the solvent for…1H NMR testing showed no residual acetone.

[0280] Heating experiments were performed on the K-type solid form for form identification. According to the heating experiment results in Figure 38, a significant decrease in crystallinity was observed when the K-type solid form was heated to 120°C and cooled to RT, and therefore the K-type solid form was classified as a hydrate.

[0281] Example 14

[0282] L-type solid form

[0283] An L-type solid form was obtained by environmental storage of the starting material overnight (~45% RH), which was presumed to be a J+L-type solid form, and it was prepared by slurrying the starting material in acetone / H2O (986:14, v:v) for about 6 days. The form transformation is shown in Figure 39. The TGA / DSC curve (Figure 40) shows an 8.8% weight loss up to 175°C. Two endothermic events were observed in the DSC curve at 87.6°C and 157.6°C. 1H NMR analysis using DMSO-d6 as solvent showed a residual acetone to API molar ratio of approximately 0.50 (5.5 wt%).

[0284] Heating experiments were performed on the L-type solid form for form identification. According to the heating experiment results in Figure 41, when the L-type solid form was heated to 100°C and cooled to RT, a form change to the J-type solid form was observed. Based on the fact that the L-type solid form was converted from the anhydrous J-type solid form and the heating experiment results, the L-type solid form was classified as a hydrate.

[0285] Example 15

[0286] Specification for M-type solid form 33 / 43 pages 38 CN 121368594 A

[0287] The M-type solid form was obtained by slow cooling of the EtOH solution of the starting material. As shown in Figure 42, no form change was observed before and after overnight ambient drying. The TGA / DSC curve (Figure 43) shows an 8.3% weight loss up to 150°C. Three endothermic peaks were observed at 83.2 °C, 105.2 °C, and 129.3 °C in the DSC curve. 1H NMR analysis using DMSO-d6 as solvent showed a residual EtOH to API molar ratio of approximately 0.21 (1.9 wt%).

[0288] Example 16

[0289] N-type solid form

[0290] The N-type solid form was obtained as follows: a clear solution was obtained by slowly cooling the starting material IPAc / cyclohexane (1:1, v:v) solution, and then the solution was transferred for RT evaporation to obtain a solid. The XRPD pattern is shown in Figure 44, and no further characterization was performed due to insufficient quantity.

[0291] Example 17

[0292] O-type solid form

[0293] An O-type solid was obtained by heating the starting material to 150 °C, cooling to RT, and exposing it to ambient conditions for 30 minutes.Solid form. The XRPD pattern is shown in Figure 45 and no further characterization was performed. Due to its formation at elevated temperatures, the O-type solid form is classified as anhydrous.

[0294] Example 18

[0295] P-type solid form

[0296] The P-type solid form was obtained by heating the I-type solid form to 100°C and cooling it to RT. The XRPD pattern is shown in Figure 46 and no further characterization was performed. Based on the experimental conditions, the P-type solid form is classified as anhydrous or hydrated.

[0297] Example 19

[0298] Q-type solid form

[0299] The Q-type solid form was prepared as follows: 601.9 mg of the A-type solid form was dissolved in 10 mL of EtOAc under ultrasonic assistance. The solution was filtered through a 0.45 μm PTFE membrane and 3 mL of the solution was used for antisolvent addition. Heptane was added dropwise to the solution with stirring. After adding 2 mL of heptane (and a total of 8 mL of heptane in the experiment), a small amount of the B-type solid form was added as a seed crystal. After overnight RT slurrying, the solid was collected by vacuum filtration and tested by XRPD. The XRPD stack is shown in Figure 47, and no form change was observed after the solid was air-dried overnight. The TGA / DSC curve (Figure 48) shows a 4.5% weight loss up to 150 °C and a single endothermic peak at 217.0 °C. 1H NMR was performed using DMSO-d6 as a solvent, which showed that the residual EtOAc and the molar ratio of heptane to API were 0.05 (0.9 wt%) and 0.02 (0.4 wt%), respectively. The HPLC purity of the Q-type solid form was 98.6 area%.

[0300] Heating experiments were performed on the Q-type solid form for form identification. According to the XRPD results in Figure 49, no form change was observed before and after heating the Q-type solid form to 150°C and cooling it to RT. No solvent residue was detected for the heated sample. Based on the limited TGA weight loss, net DSC curve, small amount of solvent residue in 1H NMR and heating experiment results, the Q-type solid form was classified as anhydrous.

[0301] DVS was performed on the Q-type solid form. As shown in Figure 50, the water absorption at 25°C / 80% RH was greater than 0.2 wt% and less than 2 wt%, indicating that the Q-type solid form is slightly hygroscopic. Based on the XRPD stack shown in Figure 51, no form change was observed before and after the DVS test.

[0302] Example 20

[0303] Thermodynamic relationship between B and Q solid forms

[0304] In order to further study the thermodynamic relationship between the two anhydrous B-type solid forms and Q-type solid forms, a slurry competition experiment was conducted in EtOAc / n-heptane at 5°C / RT / 50°C. The results are summarized in the table below. As shown in Figures 52 and 53, see page 34 / 43 of the instruction manual, page 39.CN 121368594 A shows (for better comparison, XRPD is shown from 3° to 20° (2θ)), only type B was obtained, indicating that type B is the thermodynamically preferred form under the conditions studied.

[0305]

[0306] Procedure: The corresponding solvent was pre-saturated with the Q-type solid form and filtered to obtain a weighed sample containing both the B-type and Q-type solid forms. After slurrying at the corresponding temperature for 2 to 4 days, the wet sample was tested by XRPD.

[0307] Example 21

[0308] Experimental Summary

[0309] In summary, 17 crystal forms of structure (I) were found in the polymorph screening experiment and subsequent treatment. As the anhydrous B-type solid form showed unexpectedly good solid-state properties. The Q-type solid form may appear in the current treatment method used to obtain the B-type solid form.

[0310] Example 22

[0311] Polymorph Screening Results

[0312] The results of polymorph screening are summarized in the table below, and the detailed experimental procedures and solvents used are listed here.

[0313]

[0314] Example 23

[0315] Addition of Antisolvent

[0316] Approximately 20 mg of the starting material was added to a 20 mL glass vial and dissolved in 0.3 mL to 3.0 mL of the corresponding solvent listed in the table below to obtain a clear solution (the suspension was filtered through a 0.45 μm PTFE membrane). The solution was magnetically stirred while adding the antisolvent until precipitation occurred or the total volume of the antisolvent reached 5.0 mL. The resulting precipitate was separated and used for XRPD analysis. The results in the table below show that A / B / C / A+C type solid / weakly crystalline / amorphous samples and clear solutions were produced.

[0317]

[0318] NA: Amount insufficient to characterize.

[0319] Example 24

[0320] Slow Evaporation Experiment

[0321] Approximately 20 mg of the starting material was added to a 3 mL vial, dissolved in the corresponding solvent in the table below, and filtered through a 0.45 μm PTFE membrane into another 4 mL Shell vial. The clear solution was allowed to evaporate at room temperature in a vial sealed with a PE cap (stamped with 5 or 10 small holes). The results summarized in the table below indicate that additional peaks of A / B / D / H / J / A+ were produced in the form of a solid sample. Specification 36 / 43 pages 41 CN 121368594 A

[0322]

[0323] Example 25

[0324] Slow Cooling Experiment

[0325] Approximately 20 mg of the starting material was added to a 3 mL vial, suspended in the corresponding solvent in the table below, equilibrated at 50°C for 2 hours, and then filtered through a 0.45 μm PTFE membrane into another vial. Seal the clear solution with a cap and spray at 0.1℃ / min.Cooling rate was from 50°C to 5°C. The results summarized in the table below indicate that additional peak-shaped solid forms (B / H / M / N / A+) and weakly crystalline samples were produced. Specification 37 / 43 pages 42 CN 121368594 A

[0326] Slow cooling produced a clear solution, and the solid was eventually obtained by RT evaporation.

[0327] Example 26

[0328] Pulping test at room temperature

[0329] Approximately 20 mg of the A-type solid form was suspended in 0.5 mL of the corresponding solvent in the table below in an HPLC vial. After 9 days of magnetic pulping at RT (~750 rpm), the remaining solid was separated by centrifugation for XRPD analysis. The results summarized in the table below indicate that additional peak-shaped solid forms (B / C / D / F / G / H / I / K / J+L / A+) / weakly crystalline samples were produced. Instruction manual 38 / 43 pages 43 CN 121368594 A

[0330]

[0331] Example 27

[0332] Slurrying experiment at 50°C

[0333] Approximately 20 mg of the starting material was suspended in 0.5 mL of the corresponding solvent in the table below in an HPLC vial. After magnetic slurrying at 50°C for 3 days (~750 rpm), the remaining solids were separated by centrifugation for XRPD analysis. The results summarized in the table below show that samples of type B / C / D / E / F / B solid form + additional peak / type C solid form + additional peak were obtained. Instruction manual 39 / 43 pages 44 CN 121368594 A

[0334]

[0335] Example 28

[0336] Scale-up preparation of type B solid form

[0337] Type B solid form was prepared at a scale of 300 mg for DVS testing and thermodynamic relationship studies. The B-type solid form was prepared as follows: 301.2 mg of starting material was dissolved in 5.5 mL of EtOAc under ultrasonic assistance. The solution was filtered through a 0.45 μm PTFE membrane into another vial. Heptane was added dropwise to the solution with stirring, and a precipitate was formed with the addition of 5 mL of heptane, and a total of 10 mL of heptane was added in the experiment. After overnight RT slurrying, the solid was collected by vacuum filtration and vacuum dried at 50 °C for 3.5 h. 239.4 mg of solid was collected (yield: 87.3%).

[0338] The XRPD pattern of the re-prepared B-type solid form is shown in Figure 54. The TGA / DSC curve in Figure 55 shows a 4.0% weight loss up to 150 °C, and two endothermic signals (peaks) at 209.5 °C and 211.9 °C. Using DMSO-d6 as the solvent, 1H NMR analysis showed that the molar ratios of residual EtOAc and n-heptane to API were 0.09 (1.6).0.03 (0.6 wt%) and 0.03 (0.6 wt%). The HPLC purity of the reconstituted B-type solid form was 98.7% (area).

[0339] Synthesis Example 1

[0340] Synthesis of Structure (I)-A

[0341] Step 1: Synthesis of 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-D]pyrimidine-4-amine

[0342] 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-dioxaborhexacyclopentan-2-yl)aniline (0.190 g, 0.800 mmol) and K2CO3 (0.221 g, 1.599 mmol) in 1,4-dioxane (1 mL) and water (0.3 mL) was purged with N2 for 10 minutes. min. Then Pd(PPh3)4 (0.062 g, 0.053 mmol) was added, and the reaction mixture was stirred at 100 °C for 12 h. After the reaction was complete (as shown by TLC), the mixture was filtered through a diatomaceous earth pad (e.g., Celite®), and the pad was washed with ethyl acetate (2 × 10 mL). The combined filtrates were concentrated under reduced pressure to give a crude material, which was purified by rapid chromatography (silica gel 230-400 mesh, eluted with 3% methanol in dichloromethane) to give the title compound (0.110 g, 73% yield) as a yellow solid. 1H NMR (400 MHz, 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].

[0344] Step 2: Synthesis of (5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)carbamate

[0345] Pyridine (1.2 equivalents) and phenyl chloroformate (1.5 equivalents) were added at 0°C to a solution of 5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-amine (1.0 equivalent) in THF (10 vol). The reaction mixture was warmed to 25°C and stirred for 12 h. After the reaction was complete (as shown by TLC), the mixture was diluted with ethyl acetate (10 mL) and washed with brine (5 mL).The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude material. The crude material was purified by rapid chromatography (silica gel 230-400 mesh, eluted with 10%-20% ethyl acetate from petroleum) to obtain the desired carbamate. LC / MS 312.9 [M+H]. Instructions for Use, Pages 41 / 43, 46, CN 121368594 A

[0346] Step 3: Synthesis of 1-(4-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-3-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)urea (structure (I))

[0347] Triethylamine (2.0 eq.) was added to a mixture of 5-(4-amino-3-fluorophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-D]pyrimidin-4-amine (1.0 equivalent) and (5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)carbamate (1.0 equivalent) in THF (10 vol.), and the resulting mixture was stirred in a sealed tube at 60°C for 12 h. After the reaction was complete (as shown in LCMS), the reaction mixture was concentrated under reduced pressure to obtain a crude material, which was then purified by reversed-phase preparative HPLC to obtain the desired product (0.010 g, 6% yield) in the form of a grayish-white solid. Specification page 42 / 43 47 CN 121368594 A

[0348] 1H NMR (400 MHz, DMSO-d 6) 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].

[0349] The various embodiments described above can be combined to provide further embodiments. Unless otherwise stated, all U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications mentioned in this specification and / or listed in the application data sheets are incorporated herein by reference, including by reference U.S. Provisional Patent Application No. 63 / 504,669, filed May 26, 2023, which is incorporated herein in its entirety. If necessary, aspects of the embodiments may be modified to incorporate the concepts of various patents, applications and publications to provide further embodiments.

[0350] In view of the above detailed description, these and other changes may be made to the embodiments. Generally, in the subsequent claims...The terminology used herein should not be construed as limiting the claims to the specific embodiments disclosed in the specification and claims, but should be interpreted to include all possible embodiments and the full scope of equivalents covered by these claims. Therefore, the claims are not limited by this disclosure. Instruction manual page 43 / 43 48 CN 121368594 A Figure 1 Instruction manual drawing page 1 / 30 49 CN 121368594 A Figure 2A Figure 2B Instruction manual drawing page 2 / 30 50 CN 121368594 A Figure 3 Figure 4 Instruction manual drawing page 3 / 30 51 CN 121368594 A Figure 5 Figure 6 Instruction manual drawing page 4 / 30 52 CN 121368594 A Figure 7 Figure 8 Instruction manual drawing page 5 / 30 53 CN 121368594 A Figure 9 Figure 10 Instruction manual drawing page 6 / 30 54 CN 121368594 A Figure 11 Figure 12 Instruction manual drawing page 7 / 30 55 CN 121368594 A Figure 13 Figure 14 Instruction manual drawing page 8 / 30 56 CN 121368594 A Figure 15 Figure 16 Instruction manual illustrations, pages 9 / 30, 57 CN 121368594 A, Figure 17, Figure 18; Instruction manual illustrations, pages 10 / 30, 58 CN 121368594 A, Figure 19, Figure 20; Instruction manual illustrations, pages 11 / 30, 59 CN 121368594 A, Figure 21, Figure 22; Instruction manual illustrations, pages 12 / 30, 60 CN 121368594 A, Figure 23, Figure 24; Instruction manual illustrations, pages 13 / 30, 61 CN 121368594 A, Figure 25, Figure 26; Instruction manual illustrations, pages 14 / 30, 62 CN 121368594 A, Figure 27, Figure 28; Instruction manual illustrations, pages 15 / 30, 63 CN 121368594 A, Figure 29, Figure 30; Instruction manual illustrations, pages 16 / 30, 64 CN 121368594 A, Figure 31, Figure 32; Instruction manual illustrations, pages 17 / 30, 65 CN 121368594 A Figure 33 Figure 34 Instruction Manual Drawings 18 / 30 Page 66 CN 121368594 A Figure 35 Figure 36 Instruction Manual Drawings 19 / 30 Page 67 CN 121368594 A Figure 37 Figure 38 Instruction ManualFigure 20 / 30, page 68, CN 121368594 A, Figure 39, Figure 40; Figure 21 / 30, page 69, CN 121368594 A, Figure 41, Figure 42; Figure 22 / 30, page 70, CN 121368594 A, Figure 43, Figure 44; Figure 23 / 30, page 71, CN 121368594 A, Figure 45, Figure 46; Figure 24 / 30, page 72, CN 121368594 A, Figure 47, Figure 48; Figure 25 / 30, page 73, CN 121368594 A, Figure 49; Figure 26 / 30, page 74, CN 121368594 A, Figure 50, Figure 51; Figure 27 / 30, page 75, CN 121368594 A, Figure 52, Figure 53; Figure 28 / 30, page 76, CN 121368594 A Figure 54 Figure 55 Instruction Manual Drawings Page 29 / 30 77 CN 121368594 A Figure 56 Figure 57 Instruction Manual Drawings Page 30 / 30 78 CN 121368594 A

Claims

1. A solid form of a compound having the following structure (I): or a tautomer thereof: (I) wherein the X-ray powder diffraction pattern of the solid form has peaks at at least two of the 2 theta angles chosen from 7.33 ± 0.2°, 10.51 ± 0.2°, 15.93 ± 0.2°, and 18.92 ± 0.2°.

2. The solid form of claim 1, wherein the X-ray powder diffraction pattern of the solid form has peaks at at least three of the 2 theta angles chosen from 7.33 ± 0.2°, 10.51 ± 0.2°, 15.93 ± 0.2°, and 18.92 ± 0.2°.

3. The solid form of claim 1, wherein the X-ray powder diffraction pattern of the solid form has peaks at the 2 theta angles of 7.33 ± 0.2°, 10.51 ± 0.2°, 15.93 ± 0.2°, and 18.92 ± 0.2°.

4. The solid form of claim 1, wherein the X-ray powder diffraction pattern of the solid form has peaks at at least two of the 2 theta angles chosen from 7.33°, 10.51°, 15.93°, and 18.92°.

5. The solid form of claim 1, wherein the X-ray powder diffraction pattern of the solid form has peaks at at least three of the 2 theta angles chosen from 7.33°, 10.51°, 15.93°, and 18.92°.

6. The solid form of claim 1, wherein the X-ray powder diffraction pattern of the solid form has peaks at the 2 theta angles of 7.33°, 10.51°, 15.93°, and 18.92°.

7. The solid form of claim 1, wherein the X-ray powder diffraction pattern of the solid form has peaks at the 2 theta 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 of claim 1, wherein the X-ray powder diffraction pattern of the solid form has peaks at the 2 theta 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 of claim 1, wherein the solid form comprises a Form B solid form.

10. The solid form of claim 1, wherein the solid form consists essentially of a Form B solid form.

11. The solid form of claim 1, wherein the solid form is substantially pure.

12. A solid form of a compound having the following structure (I): or a tautomer thereof: (I) having an X-ray powder diffraction pattern substantially in accordance with that depicted in FIG.

56.

13. The solid form of any one of claims 1 to 12, wherein a differential scanning calorimetry profile comprising an endothermic peak at 205.7 °C ± 0.5 °C.

14. The solid form of claim 13, wherein the endothermic peak is greater than 100 J / g.

15. The solid form of claim 13, wherein the endothermic peak is greater than 115 J / g.

16. The solid form of any one of claims 1 to 15, wherein a differential scanning calorimetry profile substantially in accordance with that depicted in FIG.

8.

17. A solid form of a compound having the following structure (I): or a tautomer thereof: (I) wherein the X-ray powder diffraction pattern of the solid form has peaks at at least two of the 2 theta angles chosen from 4.67 ± 0.2°, 9.35 ± 0.2°, 25.49 ± 0.2°, and 26.93 ± 0.2°.

18. The solid form of claim 17, wherein the X-ray powder diffraction pattern of the solid form has peaks at the 2 theta angles of 4.67 ± 0.2°, 9.35 ± 0.2°, 25.49 ± 0.2°, and 26.93 ± 0.2°.

19. The solid form of claim 17, wherein the X-ray powder diffraction pattern of the solid form has peaks at at least two of the 2 theta angles chosen from 4.67°, 9.35°, 25.49°, and 26.93°.

20. The solid form of claim 17, wherein the X-ray powder diffraction pattern of the solid form has peaks at the 2 theta angles of 4.67°, 9.35°, 25.49°, and 26.93°.

21. The solid form of claim 17, wherein the X-ray powder diffraction pattern of the solid form has peaks at 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 of claim 17, wherein the X-ray powder diffraction pattern of the solid form has peaks at the 2 theta 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 of claim 17, wherein the solid form comprises a Q-type solid form.

24. The solid form of claim 17, wherein the solid form consists essentially of a Q-type solid form.

25. The solid form of claim 17, wherein the solid form is substantially pure.

26. A compound having the structure (I) or a solid form of a tautomer thereof: (I) having an X-ray powder diffraction pattern substantially in accordance with that depicted in FIG.

57.

27. The solid form of any one of claims 17-26, wherein a differential scanning calorimetry profile comprising an endothermic peak at 217.0 °C ± 0.5 °C.

28. The solid form of any one of claims 17-27, wherein a differential scanning calorimetry profile substantially in accordance with that depicted in FIG.

47.

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

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

31. The pharmaceutical composition of claim 30, formulated for oral administration.

32. The pharmaceutical composition of claim 30, in the form of a capsule.

33. The pharmaceutical composition of claim 30, in the form of a tablet.

34. A method of treating a NLRP3-mediated disorder comprising administering to an individual in need thereof a therapeutically effective amount of the solid form of any one of claims 1 to 28 or the composition of any one of claims 29 to 33.

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

36. The method of claim 34 or 35, wherein the disorder is selected from the group consisting of type II diabetes, atherosclerosis, Alzheimer’s disease, aging, fatty liver, metabolic syndrome, asthma, psoriasis, obesity, acute and chronic tissue damage caused by infection, gout, arthritis, macular degeneration, enteritis, hepatitis, peritonitis, silicosis, UV-induced skin sunburn, contact hypersensitivity, sepsis, cancer, neurodegenerative disease, multiple sclerosis, Muckle-Wells syndrome, and myelodysplastic syndrome (MDS).

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