Solid forms of naphthylamine mitophagy inducers, their preparation methods, pharmaceutical compositions and uses

Abstract

This application discloses solid forms of naphthylamine-based mitophagy inducers, their preparation methods, pharmaceutical compositions, and uses. In this application, various solid forms of the compound of formula (I) have been prepared, including the sodium salt, potassium salt, calcium salt, tromethamine salt, lysine salt, tert-butylamine salt, diisopropylamine salt, ethanolamine salt, and diethanolamine salt of the compound of formula (I).

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims priority to a Chinese patent application filed on March 21, 2023, bearing application number 2023102800439 and entitled "Solid form of naphthylamine mitophagy inducer, preparation method, pharmaceutical composition and use thereof," the entire text of which is incorporated herein by reference.

[0002] This patent application claims priority to a Chinese patent application filed on March 22, 2023, bearing application number 2023103137630 and entitled "Solid form of naphthylamine mitophagy inducer, preparation method, pharmaceutical composition and use thereof," the entire text of which is incorporated herein by reference. [Technical Field]

[0003] The present invention particularly relates to solid forms of naphthylamine mitophagy inducers, their preparation methods, pharmaceutical compositions and uses. [Background technology]

[0004] Mitochondria are important organelles that control various cellular processes and functions. They are not only an intracellular energy source but also regulate cell survival and death. Therefore, quality control of mitochondria themselves is extremely important for cells. Mitochondrial quality control is mainly divided into the removal of damaged mitochondria and the control of newly generated mitochondria, and mitophagy, a selective autophagy process, plays an important role in the removal of damaged mitochondria.

[0005] The primary purpose of mitophagy is to identify and remove dysfunctional mitochondria. Mitochondria play a central role in energy supply through oxidative phosphorylation and perform important functions such as energy metabolism, amino acid production, lipid synthesis, and ion homeostasis. Therefore, they are crucial for maintaining the function of cell types that rely on aerobic metabolism, such as neurons, myocytes, and hepatocytes. Regulation of mitochondrial biogenesis and autophagy homeostasis is a crucial step for maintaining cellular function. Mitophagy dysfunction leads to the accumulation of damaged mitochondria, a decrease in ATP synthesis capacity, and the generation of large amounts of peroxides, which causes changes in cellular intermediate metabolites and leads to a series of pathological consequences. Mitophagy plays a protective role when aging or dysfunctional mitochondria are removed by enhancing mitophagy. Therefore, the development of mitophagy inducers that can effectively induce autophagy in damaged mitochondria, especially those that can selectively induce autophagy in damaged mitochondria, is crucial for preventing or alleviating various acute and chronic diseases caused by mitophagy dysfunction.

[0006] The present applicant previously developed several compounds with naphthylamine structures as mitophagy inducers. Subsequently, the applicant further investigated the effects of these compounds, selected compounds with good efficacy, and prepared solid forms of each compound. This application describes the solid form of the compound most promising for drug discovery and its use. Summary of the Invention

[0007] It is an object of the present invention to provide a solid form of the compound of formula (I).

[0008] Another object of the present invention is to provide a process for preparing the solid form of the compound of formula (I).

[0009] Another object of the present invention is to provide a pharmaceutical composition comprising a solid form of the compound of formula (I).

[0010] Another object of the present invention is to provide the use of a solid form of a compound of formula (I) or a pharmaceutical composition comprising a solid form of a compound of formula (I).

[0011] To solve the above technical problem, a first aspect of the present invention provides a solid form of a pharmaceutically acceptable salt of the compound of formula (I). TIFF2025532455000002.tif46170

[0012] In some preferred embodiments, the solid form of the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a tromethamine salt, a lysine salt, a tert-butylamine salt, a diisopropylamine salt, an ethanolamine salt, or a diethanolamine salt.

[0013] In some preferred embodiments, the solid form is a solid form of the sodium salt of the compound of formula (I) (crystalline form D), and the solid form of the sodium salt of the compound of formula (I) exhibits characteristic peaks (CuKα radiation) at 7.06° (±0.2°) and 20.87° (±0.2°) 2θ in a powder X-ray diffraction pattern.

[0014] In some preferred embodiments, the solid form of the sodium salt of the compound of formula (I) has the structure shown in formula (II): TIFF2025532455000003.tif46170

[0015] Here, x is selected from 0.5 to 2, for example, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2.0.

[0016] In some preferred embodiments, the solid form of the sodium salt of the compound of formula (I) has at least one of the following characteristics: The solid form of the sodium salt of the compound of formula (I) exhibits an endothermic peak at 183.79°C (±3°C) and an exothermic peak at 210.79°C (±3°C) in a differential scanning calorimetric curve; and The solid form of the sodium salt of the compound of formula (I) exhibits a thermogravimetric analysis curve substantially identical to that shown in FIG.

[0017] In some preferred embodiments, the solid form of the sodium salt of the compound of Formula (I) exhibits a characteristic peak in a powder X-ray diffraction pattern at at least one 2θ angle selected from 7.06° (±0.2°), 18.07° (±0.2°), 25.02° (±0.2°), and 20.87° (±0.2°).

[0018] In some preferred embodiments, the solid form of the sodium salt of the compound of Formula (I) exhibits a powder X-ray diffraction pattern that exhibits characteristic peaks at at least one 2θ angle selected from 7.06° (±0.2°), 18.07° (±0.2°), 25.02° (±0.2°), 17.58° (±0.2°), 20.87° (±0.2°), 10.54° (±0.2°), and 23.91° (±0.2°) 2θ.

[0019] In some preferred embodiments, the solid form of the sodium salt of the compound of Formula (I) exhibits a powder X-ray diffraction pattern that exhibits characteristic peaks at at least one 2θ angle selected from 7.06° (±0.2°), 18.07° (±0.2°), 25.02° (±0.2°), 17.58° (±0.2°), 20.87° (±0.2°), 10.54° (±0.2°), 23.91° (±0.2°), 27.65° (±0.2°), 27.05° (±0.2°), 21.68° (±0.2°), and 25.91° (±0.2°).

[0020] In some preferred embodiments, the solid form of the sodium salt of the compound of Formula (I) exhibits a powder X-ray diffraction pattern substantially identical to that shown in FIG.

[0021] In some preferred embodiments, the solid form of the sodium salt of the compound of Formula (I) exhibits a differential scanning calorimetry curve substantially identical to that shown in FIG.

[0022] In some preferred embodiments, the solid form of the sodium salt of the compound of formula (I) (crystalline form A) exhibits characteristic peaks at 6.85° (±0.2°) and 19.43° (±0.2°) 2θ in a powder X-ray diffraction pattern.

[0023] In some preferred embodiments, the solid form of the sodium salt of the compound of formula (I) (crystalline form A) has at least one of the following characteristics: The solid form of the sodium salt of the compound of formula (I) (crystalline form A) shows endothermic peaks at 144.89°C (±3°C) and 150.40°C (±3°C) and an exothermic peak at 214.79°C (±3°C) in a differential scanning calorimetric curve.

[0024] In some preferred embodiments, the solid form of the sodium salt of the compound of formula (I) (crystalline form A) exhibits a powder X-ray diffraction pattern with a characteristic peak at at least one 2θ angle selected from 6.85° (±0.2°), 19.43° (±0.2°), 21.47° (±0.2°), and 4.70° (±0.2°).

[0025] In some preferred embodiments, the solid form of the sodium salt of the compound of Formula (I) exhibits a powder X-ray diffraction pattern substantially identical to that shown in FIG.

[0026] In some preferred embodiments, the solid form of the sodium salt of the compound of Formula (I) exhibits a differential scanning calorimetry curve substantially identical to that shown in FIG.

[0027] In some preferred embodiments, the solid form of the sodium salt of the compound of Formula (I) exhibits a thermogravimetric analysis curve substantially identical to that shown in FIG.

[0028] In some preferred embodiments, the solid form of the sodium salt of the compound of formula (I) (crystalline form B) exhibits characteristic peaks at 7.88° (±0.2°) and 19.29° (±0.2°) 2θ in a powder X-ray diffraction pattern.

[0029] In some preferred embodiments, the solid form of the sodium salt of the compound of formula (I) (crystalline form B) has at least one of the following characteristics: The solid form of the sodium salt of the compound of formula (I) exhibits endothermic peaks at 72.14°C (±3°C) and 145.82°C (±3°C) and an exothermic peak at 184.61°C (±3°C) in a differential scanning calorimetric curve; and The solid form of the sodium salt of the compound of formula (I) exhibits a weight loss peak at 73.50°C (±3°C) in the thermogravimetric analysis curve (preferably, the weight loss amounts to 6.78% (±0.2%) relative to the total weight of the solid form).

[0030] In some preferred embodiments, the solid form of the sodium salt of the compound of Formula (I) exhibits a powder X-ray diffraction pattern with a characteristic peak at at least one 2θ angle selected from 7.88° (±0.2°), 9.64° (±0.2°), 14.42° (±0.2°), 19.29° (±0.2°), and 22.65° (±0.2°).

[0031] In some preferred embodiments, the solid form of the sodium salt of the compound of Formula (I) exhibits a powder X-ray diffraction pattern substantially identical to that shown in FIG.

[0032] In some preferred embodiments, the solid form of the sodium salt of the compound of Formula (I) exhibits a differential scanning calorimetry curve substantially identical to that shown in FIG.

[0033] In some preferred embodiments, the solid form of the sodium salt of the compound of Formula (I) exhibits a thermogravimetric analysis curve substantially identical to that shown in FIG.

[0034] In some preferred embodiments, the solid form of the sodium salt of the compound of formula (I) (crystalline form C) exhibits characteristic peaks at 8.56° (±0.2°) and 19.96° (±0.2°) 2θ in a powder X-ray diffraction pattern.

[0035] In some preferred embodiments, the solid form of the sodium salt of the compound of formula (I) (crystalline form C) has at least one of the following characteristics: The solid form of the sodium salt of the compound of formula (I) exhibits endothermic peaks at 59.75°C (±3°C) and 140.91°C (±3°C) and an exothermic peak at 185.61°C (±3°C) in a differential scanning calorimetric curve; and The solid form of the sodium salt of the compound of formula (I) exhibits a weight loss peak at 70.15°C (±3°C) in the thermogravimetric analysis curve (preferably, the weight loss amounts to 4.96% (±0.2%) relative to the total weight of the solid form).

[0036] In some preferred embodiments, the solid form of the sodium salt of the compound of Formula (I) exhibits a powder X-ray diffraction pattern with a characteristic peak at at least one 2θ angle selected from 8.56° (±0.2°), 13.24° (±0.2°), 14.62° (±0.2°), 19.96° (±0.2°), and 24.542° (±0.2°).

[0037] In some preferred embodiments, the solid form of the sodium salt of the compound of Formula (I) exhibits a powder X-ray diffraction pattern substantially identical to that shown in FIG.

[0038] In some preferred embodiments, the solid form of the sodium salt of the compound of Formula (I) exhibits a differential scanning calorimetry curve substantially identical to that shown in FIG.

[0039] In some preferred embodiments, the solid form of the sodium salt of the compound of Formula (I) exhibits a thermogravimetric analysis curve substantially identical to that shown in FIG.

[0040] In some preferred embodiments, the solid form is a solid form of the potassium salt of the compound of Formula (I), and the solid form of the potassium salt of the compound of Formula (I) exhibits a characteristic peak in a powder X-ray diffraction pattern at at least one 2θ angle selected from 9.67° (±0.2°) and 19.63° (±0.2°).

[0041] In some preferred embodiments, the solid form of the potassium salt of the compound of formula (I) has the structure shown in formula (III) (crystalline form F). TIFF2025532455000004.tif37170

[0042] where x is 0.5-2.0, for example, x is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0.

[0043] In some preferred embodiments, the solid form of the potassium salt of the compound of Formula (I) has at least one of the following characteristics: The solid form of the potassium salt of the compound of formula (I) exhibits, in a differential scanning calorimetry curve, substantially the same as that shown in Figure 17; and The solid form of the potassium salt of the compound of formula (I) exhibits a thermogravimetric analysis curve substantially identical to that shown in FIG.

[0044] In some preferred embodiments, the solid form of the potassium salt of the compound of Formula (I) exhibits a powder X-ray diffraction pattern substantially identical to that shown in FIG.

[0045] In some preferred embodiments, the solid form of the potassium salt of the compound of Formula (I) exhibits a characteristic peak in a powder X-ray diffraction pattern at at least one 2θ angle selected from 9.67° (±0.2°), 11.34° (±0.2°), 16.68° (±0.2°), 19.63° (±0.2°), and 22.46° (±0.2°).

[0046] In some preferred embodiments, the solid form is a solid form of the potassium salt of the compound of Formula (I), and the solid form of the potassium salt of the compound of Formula (I) exhibits a characteristic peak at at least one 2θ angle selected from 11.53° (±0.2°) and 21.54° (±0.2°) in a powder X-ray diffraction pattern.

[0047] In some preferred embodiments, the solid form of the calcium salt of the compound of formula (I) has the structure shown in formula (IV) (G crystalline form). TIFF2025532455000005.tif37170

[0048] Here, x is 0.5 to 2.0. For example, x is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0. Preferably, x is 0.8, 0.9, 1, or 1.1. (Crystalline Form G) In some preferred embodiments, the solid form of the calcium salt of the compound of formula (I) has at least one of the following characteristics: The solid form of the calcium salt of the compound of formula (I) exhibits a differential scanning calorimetry curve substantially identical to that shown in Figure 20; and The solid form of the calcium salt of the compound of formula (I) exhibits a thermogravimetric analysis curve substantially identical to that shown in FIG.

[0049] In some preferred embodiments, the solid form of the calcium salt of the compound of Formula (I) exhibits a powder X-ray diffraction pattern substantially identical to that shown in FIG.

[0050] In some preferred embodiments, the solid form of the calcium salt of the compound of Formula (I) exhibits a powder X-ray diffraction pattern with a characteristic peak at at least one 2θ angle selected from 11.53° (±0.2°), 21.54° (±0.2°), 12.46° (±0.2°), 18.56° (±0.2°), 20.92° (±0.2°), 25.20° (±0.2°), and 26.06° (±0.2°).

[0051] In some preferred embodiments, the solid form is a solid form of the tromethamine salt of the compound of Formula (I), and the solid form of the tromethamine salt of the compound of Formula (I) exhibits a characteristic peak at at least one 2θ angle selected from 8.94° (±0.2°) and 14.35° (±0.2°) in a powder X-ray diffraction pattern.

[0052] In some preferred embodiments, the solid form of the tromethamine salt of the compound of formula (I) has the structure shown in formula (V) (crystal form H). TIFF2025532455000006.tif37170

[0053] Here, x is 0.5 to 2.0. For example, x is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0. Preferably, x is 0.8, 0.9, 1, or 1.1.

[0054] In some preferred embodiments, the solid form of the tromethamine salt of the compound of Formula (I) has at least one of the following characteristics: The solid form of the tromethamine salt of the compound of formula (I) exhibits, in a differential scanning calorimetry curve, substantially the same as that shown in Figure 23; and The solid form of the tromethamine salt of the compound of formula (I) exhibits a thermogravimetric analysis curve substantially identical to that shown in FIG.

[0055] In some preferred embodiments, the solid form of the tromethamine salt of the compound of Formula (I) exhibits a powder X-ray diffraction pattern substantially identical to that shown in FIG.

[0056] In some preferred embodiments, the solid form of the tromethamine salt of the compound of Formula (I) exhibits a powder X-ray diffraction pattern with a characteristic peak at at least one 2θ angle selected from 8.94° (±0.2°), 14.35° (±0.2°), 17.09° (±0.2°), 18.69° (±0.2°), 19.76° (±0.2°), 22.19° (±0.2°), 22.59° (±0.2°), 22.99° (±0.2°), 25.40° (±0.2°), and 26.58° (±0.2°).

[0057] In some preferred embodiments, the solid form is a solid form of the lysine salt of the compound of Formula (I), and the solid form of the lysine salt of the compound of Formula (I) exhibits a characteristic peak at at least one 2θ angle selected from 12.31° (±0.2°) and 19.66° (±0.2°) in a powder X-ray diffraction pattern.

[0058] In some preferred embodiments, the solid form of the lysine salt of the compound of formula (I) has the structure shown in formula (VI) (crystal form I). TIFF2025532455000007.tif37170

[0059] Here, x is 0.5 to 2.0. For example, x is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0. Preferably, x is 0.8, 0.9, 1, or 1.1.

[0060] In some preferred embodiments, the solid form of the lysine salt of the compound of formula (I) has at least one of the following characteristics: The solid form of the lysine salt of the compound of formula (I) exhibits a thermogravimetric analysis curve substantially identical to that shown in FIG.

[0061] In some preferred embodiments, the solid form of the lysine salt of the compound of Formula (I) exhibits a powder X-ray diffraction pattern substantially identical to that shown in FIG.

[0062] In some preferred embodiments, the solid form of the lysine salt of the compound of Formula (I) exhibits a characteristic peak in a powder X-ray diffraction pattern at at least one 2θ angle selected from 12.31° (±0.2°), 17.72° (±0.2°), 21.16° (±0.2°), 24.13° (±0.2°), and 19.66° (±0.2°).

[0063] In some preferred embodiments, the solid form is a solid form of the tert-butylamine salt of the compound of Formula (I), and the solid form of the tert-butylamine salt of the compound of Formula (I) exhibits a characteristic peak at at least one 2θ angle selected from 7.15° (±0.2°) and 10.14° (±0.2°) in a powder X-ray diffraction pattern.

[0064] In some preferred embodiments, the solid form of the tert-butylamine salt of the compound of formula (I) has the structure shown in formula (VII) (J crystalline form). TIFF2025532455000008.tif37170

[0065] Here, x is 0.5 to 2.0. For example, x is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0. Preferably, x is 0.8, 0.9, 1, or 1.1.

[0066] In some preferred embodiments, the solid form of the tert-butylamine salt of the compound of Formula (I) has at least one of the following characteristics: The solid form of the tert-butylamine salt of the compound of formula (I) exhibits, in a differential scanning calorimetry curve, substantially the same as that shown in Figure 29; and The solid form of the tert-butylamine salt of the compound of formula (I) exhibits a thermogravimetric analysis curve substantially identical to that shown in FIG.

[0067] In some preferred embodiments, the solid form of the tert-butylamine salt of the compound of Formula (I) exhibits a powder X-ray diffraction pattern substantially identical to that shown in FIG.

[0068] In some preferred embodiments, the solid form of the tert-butylamine salt of the compound of Formula (I) exhibits a powder X-ray diffraction pattern with a characteristic peak at at least one 2θ angle selected from 7.15° (±0.2°), 17.85° (±0.2°), 18.28° (±0.2°), 19.19° (±0.2°), 20.51° (±0.2°), 22.03° (±0.2°), and 10.14° (±0.2°).

[0069] In some preferred embodiments, the solid form is a solid form of the diisopropylamine salt of the compound of Formula (I), and the solid form of the diisopropylamine salt of the compound of Formula (I) exhibits a characteristic peak at at least one 2θ angle selected from 8.87° (±0.2°) and 17.20° (±0.2°) in a powder X-ray diffraction pattern.

[0070] In some preferred embodiments, the solid form of the diisopropylamine salt of the compound of formula (I) has the structure shown in formula (VIII) (crystal form K). TIFF2025532455000009.tif37170

[0071] Here, x is 0.5 to 2.0. For example, x is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0. Preferably, x is 0.8, 0.9, 1, or 1.1.

[0072] In some preferred embodiments, the solid form of the diisopropylamine salt of the compound of Formula (I) has at least one of the following characteristics: The solid form of the diisopropylamine salt of the compound of formula (I) exhibits, in a differential scanning calorimetry curve, substantially the same as that shown in Figure 32; and The solid form of the diisopropylamine salt of the compound of formula (I) exhibits a thermogravimetric analysis curve substantially identical to that shown in FIG.

[0073] In some preferred embodiments, the solid form of the diisopropylamine salt of the compound of Formula (I) exhibits a powder X-ray diffraction pattern substantially identical to that shown in FIG.

[0074] In some preferred embodiments, the solid form of the diisopropylamine salt of the compound of Formula (I) exhibits a powder X-ray diffraction pattern with a characteristic peak at at least one 2θ angle selected from 8.87° (±0.2°), 9.25° (±0.2°), 9.65° (±0.2°), 15.07° (±0.2°), 16.97° (±0.2°), 18.06° (±0.2°), 19.31° (±0.2°), 20.01° (±0.2°), 22.65° (±0.2°), 27.29° (±0.2°), and 17.20° (±0.2°).

[0075] In some preferred embodiments, the solid form is a solid form of an ethanolamine salt of the compound of Formula (I), and the solid form of the ethanolamine salt of the compound of Formula (I) exhibits a characteristic peak at at least one 2θ angle selected from 7.62° (±0.2°) and 19.70° (±0.2°) in a powder X-ray diffraction pattern.

[0076] In some preferred embodiments, the solid form of the ethanolamine salt of the compound of formula (I) has the structure shown in formula (IX) (L crystalline form). TIFF2025532455000010.tif37170

[0077] Here, x is 0.5 to 2.0. For example, x is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0. Preferably, x is 0.8, 0.9, 1, or 1.1.

[0078] In some preferred embodiments, the solid form of the ethanolamine salt of the compound of Formula (I) has at least one of the following characteristics: The solid form of the ethanolamine salt of the compound of formula (I) exhibits, in a differential scanning calorimetry curve, substantially the same as that shown in Figure 35; and The solid form of the ethanolamine salt of the compound of formula (I) exhibits a thermogravimetric analysis curve substantially identical to that shown in FIG.

[0079] In some preferred embodiments, the solid form of the ethanolamine salt of the compound of Formula (I) exhibits a powder X-ray diffraction pattern substantially identical to that shown in FIG.

[0080] In some preferred embodiments, the solid form of the ethanolamine salt of the compound of Formula (I) exhibits a powder X-ray diffraction pattern with a characteristic peak at at least one 2θ angle selected from 7.62° (±0.2°), 9.72° (±0.2°), 14.98° (±0.2°), 19.34° (±0.2°), and 19.70° (±0.2°).

[0081] In some preferred embodiments, the solid form is a solid form of a diethanolamine salt of the compound of Formula (I), and the solid form of the diethanolamine salt of the compound of Formula (I) exhibits a characteristic peak at at least one 2θ angle selected from 6.33° (±0.2°) and 19.87° (±0.2°) in a powder X-ray diffraction pattern.

[0082] In some preferred embodiments, the solid form of the diethanolamine salt of the compound of formula (I) has the structure shown in formula (X) (M crystalline form). TIFF2025532455000011.tif37170

[0083] Here, x is 0.5 to 2.0. For example, x is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0. Preferably, x is 0.8, 0.9, 1, or 1.1.

[0084] In some preferred embodiments, the solid form of the diethanolamine salt of the compound of Formula (I) has at least one of the following characteristics: The solid form of the diethanolamine salt of the compound of formula (I) exhibits, in a differential scanning calorimetry curve, substantially the same as that shown in Figure 38; and The solid form of the diethanolamine salt of the compound of formula (I) exhibits a thermogravimetric analysis curve substantially identical to that shown in FIG.

[0085] In some preferred embodiments, the solid form of the diethanolamine salt of the compound of Formula (I) exhibits a powder X-ray diffraction pattern substantially identical to that shown in FIG.

[0086] In some preferred embodiments, the solid form of the diethanolamine salt of the compound of Formula (I) exhibits a powder X-ray diffraction pattern with a characteristic peak at at least one 2θ angle selected from 6.33° (±0.2°), 7.41° (±0.2°), 12.46° (±0.2°), 22.02° (±0.2°), 28.45° (±0.2°), and 19.87° (±0.2°).

[0087] A second aspect of the present invention provides a solid form of the free acid of the compound of formula (I) (crystalline form E), which exhibits a characteristic peak at at least one 2θ angle selected from 8.92° (±0.2°) and 23.31° (±0.2°) in a powder X-ray diffraction pattern.

[0088] TIFF2025532455000012.tif46170

[0089] In some preferred embodiments, the solid form of the free acid of the compound of Formula (I) also has at least one of the following characteristics: The solid form of the ethanolamine salt of the compound of formula (I) exhibits, in a differential scanning calorimetry curve, substantially the same as that shown in Figure 14; and The solid form of the ethanolamine salt of the compound of formula (I) exhibits a thermogravimetric analysis curve substantially identical to that shown in FIG.

[0090] In some preferred embodiments, the solid form of the free acid of the compound of Formula (I) exhibits a powder X-ray diffraction pattern that exhibits characteristic peaks at at least one 2θ angle selected from 8.92° (±0.2°), 23.31° (±0.2°), 27.41° (±0.2°), 19.70° (±0.2°), 16.51° (±0.2°), 12.27° (±0.2°), 21.50° (±0.2°), 18.23° (±0.2°), and 18.37° (±0.2°) 2θ.

[0091] A third aspect of the present invention provides a pharmaceutical composition comprising a solid form of a compound of formula (I) according to any one of the first to ninth aspects of the present invention and a pharmaceutically acceptable carrier or excipient.

[0092] A fourth aspect of the present invention provides a method for preparing a solid form of the sodium salt of a compound of formula (I), said method comprising the steps of dissolving a compound of formula (I) in a reaction medium and adding a sodium-containing base to react to obtain a solid form of the sodium salt of a compound of formula (I).

[0093] In some preferred embodiments, the reaction medium is selected from at least one of methanol, ethanol, isopropanol, tert-butanol, acetone, acetonitrile, and ethyl acetate, or a mixture of at least one of methanol, ethanol, isopropanol, tert-butanol, acetone, acetonitrile, and ethyl acetate with water, such as acetone, a mixture of acetone and water, or a mixture of acetonitrile and water.

[0094] In some preferred embodiments, the sodium-containing base is selected from at least one of sodium bicarbonate, sodium carbonate, sodium hydroxide, sodium acetate, sodium formate, sodium methoxide, sodium ethoxide, and sodium tert-butoxide.

[0095] In some preferred embodiments, the molar ratio of the compound of formula (I) to the sodium-containing base in the reaction system is 1:(0.9 to 1.1).

[0096] In some preferred embodiments, the compound of formula (I) is dissolved in acetone at 35 to 55°C (preferably 40 to 50°C), a sodium bicarbonate solution is added, and after a solid precipitates, the mixture is kept warm and allowed to stand for at least 20 minutes (preferably at least 30 minutes), and then cooled to room temperature to obtain a solid form of the sodium salt of the compound of formula (I).

[0097] In some preferred embodiments, the compound of formula (I) is dissolved in acetone at 35 to 55°C, cooled to room temperature, a sodium bicarbonate solution is added and stirred, a solid is precipitated, the solution is kept warm and allowed to stand for at least 20 minutes (preferably at least 30 minutes), and then cooled to room temperature to obtain a solid form of the sodium salt of the compound of formula (I).

[0098] In some preferred embodiments, the compound of formula (I) is dissolved in acetone at 35 to 55°C, a sodium bicarbonate solution is added and stirred, and after a solid precipitates, the mixture is kept warm and stirred for at least 20 minutes (preferably at least 30 minutes), and then cooled to room temperature to obtain a solid form of the sodium salt of the compound of formula (I).

[0099] In some preferred embodiments, the compound of formula (I) is dissolved in acetone at 35 to 55°C, a sodium methoxide methanol solution is added, and the mixture is stirred. After a solid precipitates, the mixture is kept warm and allowed to stand for at least 50 minutes (preferably at least 60 minutes), and then cooled to room temperature and stirred for at least 50 minutes (preferably at least 60 minutes) to obtain a solid form of the sodium salt of the compound of formula (I).

[0100] In some preferred embodiments, the compound of formula (I) is dissolved in acetone at 35 to 55°C, a sodium bicarbonate solution is added, and the mixture is stirred. After a solid precipitates, the mixture is kept warm and allowed to stand for at least 50 minutes (preferably at least 60 minutes). After a solid precipitates, the mixture is kept warm and allowed to stand for at least 50 minutes (preferably at least 60 minutes), to obtain a solid form of the sodium salt of the compound of formula (I).

[0101] A fifth aspect of the present invention provides the use of a solid form according to the first aspect of the invention or the second aspect of the invention, or a pharmaceutical composition according to the third aspect of the invention, for use in: (i) the preparation of a medicament for the prevention and / or treatment of diseases associated with kidney damage; and / or (ii) prevention and / or treatment of diseases associated with kidney damage; and / or (iii) prevention and / or treatment of diseases associated with mitochondrial dysfunction; and / or (iv) Preparation of a medicament for the prevention and / or treatment of a disease associated with mitochondrial dysfunction.

[0102] Compared with the prior art, the present invention has at least the following advantages:

[0103] (1) In the present invention, various solid forms of the compound of formula (I), such as the free acid salt, sodium salt, potassium salt, calcium salt, tromethamine salt, lysine salt, tert-butylamine salt, diisopropylamine salt, ethanolamine salt, and diethanolamine salt of the compound of formula (I), are prepared, and corresponding identification methods are also provided.

[0104] (2) The solid form of the sodium salt of the compound of formula (I) prepared in a preferred embodiment of the present invention has excellent effects in terms of crystal stability, biological activity, safety, bioavailability, etc., and also has low hygroscopicity and low water solubility, making it highly promising for drug discovery.

[0105] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (e.g., in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be described one by one here due to space limitations. [Brief explanation of the drawings]

[0106] One or more embodiments are illustrated by way of example in the figures of the accompanying drawings, and these illustrative illustrations do not constitute limitations on the embodiments. [Figure 1] FIG. 1 is a powder X-ray diffraction pattern of crystalline form A according to an embodiment of the present invention. [Figure 2] FIG. 2 is a differential scanning calorimetry curve of crystalline form A according to an embodiment of the present invention. [Figure 3] FIG. 3 is a thermogravimetric analysis curve of crystalline form A according to an embodiment of the present invention. [Figure 4]FIG. 4 is a powder X-ray diffraction pattern of crystalline form B according to an embodiment of the present invention. [Figure 5] FIG. 5 is a differential scanning calorimetry curve of crystalline form B according to an embodiment of the present invention. [Figure 6] FIG. 6 is a thermogravimetric analysis curve of crystalline form B according to an embodiment of the present invention. [Figure 7] FIG. 7 is a powder X-ray diffraction pattern of crystalline form C according to an embodiment of the present invention. [Figure 8] FIG. 8 is a differential scanning calorimetry curve of crystalline form C according to an embodiment of the present invention. [Figure 9] FIG. 9 is a thermogravimetric analysis curve of crystalline form C according to an embodiment of the present invention. [Figure 10] FIG. 10 is a powder X-ray diffraction pattern of crystalline form D according to an embodiment of the present invention. [Figure 11] FIG. 11 is a differential scanning calorimetry curve of crystalline form D according to an embodiment of the present invention. [Figure 12] FIG. 12 is a thermogravimetric analysis curve of crystalline form D according to an embodiment of the present invention. [Figure 13] FIG. 13 is a powder X-ray diffraction pattern of crystalline form E according to an embodiment of the present invention. [Figure 14] FIG. 14 is a differential scanning calorimetry curve of crystalline form E according to an embodiment of the present invention. [Figure 15] FIG. 15 is a thermogravimetric analysis curve of crystalline form E according to an embodiment of the present invention. [Figure 16] FIG. 16 is a powder X-ray diffraction pattern of crystalline form F according to an embodiment of the present invention. [Figure 17] FIG. 17 is a differential scanning calorimetry curve of crystalline form F according to an embodiment of the present invention. [Figure 18] FIG. 18 is a thermogravimetric analysis curve of the F crystalline form according to an embodiment of the present invention. [Figure 19] FIG. 19 is a powder X-ray diffraction pattern of crystalline form G according to an embodiment of the present invention. [Figure 20] FIG. 20 is a differential scanning calorimetry curve of the G crystalline form according to an embodiment of the present invention. [Figure 21]FIG. 21 is a thermogravimetric analysis curve of the G crystalline form according to an embodiment of the present invention. [Figure 22] FIG. 22 is a powder X-ray diffraction pattern of crystalline form H according to an embodiment of the present invention. [Figure 23] FIG. 23 is a differential scanning calorimetry curve of the H crystalline form according to an embodiment of the present invention. [Figure 24] FIG. 24 is a thermogravimetric analysis curve of the H crystalline form according to an embodiment of the present invention. [Figure 25] FIG. 25 is a powder X-ray diffraction pattern of crystalline form I according to an embodiment of the present invention. [Figure 26] FIG. 26 shows the interconversion relationship between sodium salt polymorphs according to an embodiment of the present invention. [Figure 27] FIG. 27 is a thermogravimetric analysis curve of crystalline form I according to an embodiment of the present invention. [Figure 28] FIG. 28 is a powder X-ray diffraction pattern of crystalline form J according to an embodiment of the present invention. [Figure 29] FIG. 29 is a differential scanning calorimetry curve of crystalline form J according to an embodiment of the present invention. [Figure 30] FIG. 30 is a thermogravimetric analysis curve of crystalline form J according to an embodiment of the present invention. [Figure 31] FIG. 31 is a powder X-ray diffraction pattern of crystalline form K according to an embodiment of the present invention. [Figure 32] FIG. 32 is a differential scanning calorimetry curve of the K crystalline form according to an embodiment of the present invention. [Figure 33] FIG. 33 is a thermogravimetric analysis curve of the K crystalline form according to an embodiment of the present invention. [Figure 34] FIG. 34 is a powder X-ray diffraction pattern of crystalline form L according to an embodiment of the present invention. [Figure 35] FIG. 35 is a differential scanning calorimetry curve diagram of crystalline form L according to an embodiment of the present invention. [Figure 36] FIG. 36 is a thermogravimetric analysis curve of crystalline form L according to an embodiment of the present invention. [Figure 37] FIG. 37 is a powder X-ray diffraction pattern of crystalline form M according to an embodiment of the present invention. [Figure 38]FIG. 38 is a differential scanning calorimetry curve diagram of crystalline form M according to an embodiment of the present invention. [Figure 39] FIG. 39 is a thermogravimetric analysis curve of the M crystalline form according to an embodiment of the present invention. [Figure 40] FIG. 40 is a dvs spectrum of a D crystal form sample according to an embodiment of the present invention. [Figure 41] FIG. 41 is a solubility diagram for crystalline form D in FaSSIF buffer, FeSSIF buffer, water, and SGF, according to an embodiment of the present invention, with the three columns representing 0.5 hours, 2 hours, and 24 hours, from left to right. [Figure 42] FIG. 42 is a heat map of mitophagy levels induced by different concentrations of crystalline form D, according to an embodiment of the present invention. [Figure 43] Figure 43 is a graph showing the changes in blood creatinine before and after administration of crystalline form D in a rat model of renal injury caused by unilateral renal ischemia-reperfusion according to an embodiment of the present invention, and the five columns, from left to right, are the sham-operated group, model control group, TJ0113 3 mg / kg group, TJ0113 10 mg / kg group, and TJ0113 30 mg / kg group. [Figure 44] Figure 44 is a graph showing the change in blood urea nitrogen before and after administration of crystalline form D in a rat model of renal injury caused by unilateral renal ischemia-reperfusion according to an embodiment of the present invention, and the five columns, from left to right, are the sham-operated group, model control group, TJ0113 3 mg / kg group, TJ0113 10 mg / kg group, and TJ0113 30 mg / kg group. [Figure 45] Figure 45 is a graph showing changes in blood creatinine clearance before and after administration of crystalline form D in a rat renal injury model induced by unilateral renal ischemia-reperfusion according to an embodiment of the present invention, and the five columns, from left to right, are the sham-operated group, model control group, TJ0113 3 mg / kg group, TJ0113 10 mg / kg group, and TJ0113 30 mg / kg group. [Figure 46]Figure 46 is a graph showing changes in renal tissue Caspase 9 before and after administration of crystalline form D in a rat model of renal injury caused by unilateral renal ischemia-reperfusion according to an embodiment of the present invention. The five columns, from left to right, are the sham-operated group, model control group, TJ0113 3 mg / kg group, TJ0113 10 mg / kg group, and TJ0113 30 mg / kg group. [Figure 47] Figure 47 is a graph showing changes in renal tissue IL-6 before and after administration of crystalline form D in a rat renal injury model induced by unilateral renal ischemia-reperfusion according to an embodiment of the present invention, and the five columns, from left to right, are the sham-operated group, model control group, TJ0113 3 mg / kg group, TJ0113 10 mg / kg group, and TJ0113 30 mg / kg group. [Figure 48] Figure 48 is a graph showing changes in renal tissue IL-1β before and after administration of crystalline form D in a rat renal injury model induced by unilateral renal ischemia-reperfusion according to an embodiment of the present invention, and the five columns, from left to right, are the sham-operated group, model control group, TJ0113 3 mg / kg group, TJ0113 10 mg / kg group, and TJ0113 30 mg / kg group. [Figure 49] Figure 49 is a graph showing changes in renal tissue TUNEL before and after administration of crystalline form D in a rat model of renal injury caused by unilateral renal ischemia-reperfusion according to an embodiment of the present invention. The five columns, from left to right, are the sham-operated group, model control group, TJ0113 3 mg / kg group, TJ0113 10 mg / kg group, and TJ0113 30 mg / kg group. DETAILED DESCRIPTION OF THE INVENTION

[0107] The present invention has prepared various solid forms of compound TJ01-013 (represented by Formula I) and investigated the stability, solubility, safety, bioavailability, etc. of each crystalline form. It has ultimately been found that the D crystalline form of the sodium salt of compound TJ01-013 is the most promising for drug discovery.

[0108] Solid forms of compound TJ01-013 The present invention relates to various solid forms of compound TJ01-013 (represented by Formula I), including the sodium salt of the compound of formula (I), the potassium salt of the compound of formula (I), the calcium salt of the compound of formula (I), the tromethamine salt of the compound of formula (I), the lysine salt of the compound of formula (I), the tert-butylamine salt of the compound of formula (I), the diisopropylamine salt of the compound of formula (I), the ethanolamine salt of the compound of formula (I), and the diethanolamine salt of the compound of formula (I). TIFF2025532455000013.tif46170

[0109] In the present invention, the term "solid form" refers to a type of solid material, including amorphous and crystalline forms. The term "crystalline form" refers to polymorphs, as well as solvates, hydrates, etc. The term "polymorph" refers to a specific crystalline structure with specific physical properties (e.g., X-ray diffraction, melting point, and analogs).

[0110] In the present invention, each of the above solid forms is characterized using conventional methods in the art, such as powder X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis. It should be understood that the positions and relative intensities of peaks in a powder X-ray diffraction pattern may shift slightly due to various factors known to those skilled in the art. For example, shifts in peak positions and relative intensities of peaks in a plot may occur due to the instrument used, the sample preparation method, the preferred packaging and orientation, the radiation source, and the method and length of data collection. However, one skilled in the art would be able to confirm the identity of a solid form by comparing the powder X-ray diffraction patterns shown in the figures herein with those of an unknown solid form. In the present invention, the terms "almost," "substantially," and "essentially" refer to a measurement uncertainty of ±0.3 (expressed in 2θ degrees), preferably ±0.2 (expressed in 2θ degrees), or, when applied to a DSC curve, a measurement uncertainty of ±0.3°C, and, when applied to a TGA thermal analysis graph, a weight loss variation of ±2%.

[0111] (1) Sodium salt of the compound of formula (I) In the present invention, the sodium salt of the compound of formula (I) refers to a salt obtained by contact reaction of the compound of formula (I) with a sodium-containing base (sodium-containing bases include sodium-containing organic bases such as sodium ethoxide; sodium-containing inorganic bases such as sodium hydroxide; and sodium-containing acid salts of strong bases or weak bases such as sodium bicarbonate and sodium dihydrogen carbonate). The sodium salt of the compound of formula (I) preferably has a structure represented by the following formula (II), where x is 0.5 to 2, for example, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0. TIFF2025532455000014.tif46170

[0112] Depending on the preparation method, at least four different crystalline forms (crystalline forms A to D) of the sodium salt of the compound of formula (I) are obtained in the present invention.

[0113] In some embodiments, the solid form of the sodium salt of the compound of Formula (I) is prepared by a method comprising the steps of dissolving the compound of Formula (I) in acetone at 40-50°C and adding a sodium-containing base to the resulting solution.

[0114] In some examples, the compound of formula (I) is dissolved in acetone at 40-50°C, sodium bicarbonate solution is added, and after a solid precipitates, the mixture is kept warm and allowed to stand for at least 30 minutes, then cooled to room temperature, and filtered by suction to obtain a solid form of the sodium salt of the compound of formula (I) (crystalline form A).

[0115] In some examples, the compound of formula (I) is dissolved in acetone at 40-50°C, cooled to room temperature, and sodium bicarbonate solution is added and stirred. After a solid precipitates, the solution is kept warm and allowed to stand for at least 30 minutes to obtain a solid form of the sodium salt of the compound of formula (I) (crystalline form B).

[0116] In some examples, the compound of formula (I) is dissolved in acetone at 40-50°C, and sodium bicarbonate solution is added and stirred. After a solid precipitates, the mixture is kept warm and stirred for at least 30 minutes, then cooled to room temperature, and filtered by suction to obtain a solid form of the sodium salt of the compound of formula (I) (crystalline form C).

[0117] In some preferred embodiments, the compound of formula (I) is dissolved in acetone at 40-50°C, and a solution of sodium methoxide in methanol is added and stirred. After a solid precipitates, the solution is kept warm and allowed to stand for at least 60 minutes, then cooled to room temperature, stirred for at least 60 minutes, and filtered by suction to obtain a solid form of the sodium salt of the compound of formula (I) (Crystal Form D).

[0118] In some preferred embodiments, the compound of formula (I) is dissolved in acetone at 40-50°C, and sodium bicarbonate solution is added thereto and stirred. After a solid precipitates, the solution is kept warm for at least 60 minutes, allowed to stand, and then filtered by suction to obtain a solid form of the sodium salt of the compound of formula (I) (Crystal Form D).

[0119] As a solid form of the sodium salt of the compound of formula (I) (crystalline form D), its powder X-ray diffraction pattern has at least the following characteristics: it exhibits characteristic peaks at 7.06° (±0.2°) and 20.87° (±0.2°) 2θ in the powder X-ray diffraction pattern; more preferably, it exhibits characteristic peaks at 7.06° (±0.2°) and 20.87° (±0.2°) 2θ in the powder X-ray diffraction pattern, and 1 and more preferably, the powder X-ray diffraction pattern exhibits characteristic peaks at 2θ of 7.06° (±0.2°) and 20.87° (±0.2°), as well as characteristic peaks at 2θ of 18.07° (±0.2°), 17.58° (±0.2°), 10.54° (±0.2°), 23.91° (±0.2°), and 25. and more preferably, in a powder X-ray diffraction pattern, the powder X-ray diffraction pattern exhibits characteristic peaks at 2θ of 7.06° (±0.2°) and 20.87° (±0.2°), as well as characteristic peaks at 2θ of 18.07° (±0.2°), 17.58° (±0.2°), 10.54° (±0.2°), 23.91° (±0.2°), 27.65° (±0.2°), 27.05° (±0.2°). and more preferably, the solid form of the sodium salt of the compound of formula (I) exhibits in its powder X-ray diffraction pattern the characteristic peaks at 2θ shown in Table 1-1 below; and the solid form of the sodium salt of the compound of formula (I) exhibits substantially the same powder X-ray diffraction pattern as shown in Figure 10.

[0120] [Table 1-1]

[0121] As a solid form of the sodium salt of the compound of formula (I) (crystalline form D), its differential scanning calorimetry curve has an endothermic peak at 183.79°C (±3°C), a thermal enthalpy value of 3.9256 J / g, an onset temperature of 175.04°C, and an exothermic peak at 210.79°C (±3°C); more preferably, the solid form of the sodium salt of the compound of formula (I) exhibits a differential scanning calorimetry curve substantially identical to that shown in Figure 11.

[0122] For the solid form of the sodium salt of the compound of formula (I) (crystalline form D), the thermogravimetric analysis curve shows that the sample has no weight loss before decomposition; more preferably, the solid form of the sodium salt of the compound of formula (I) exhibits a thermogravimetric analysis curve substantially identical to that shown in Figure 12.

[0123] (2) Potassium salt of the compound of formula (I) In the present invention, the solid form of the sodium salt of the compound of formula (I) refers to a salt obtained by contacting the compound of formula (I) with a potassium-containing base. Preferably, it has a structure represented by formula (III), where x is selected from 0.5 to 2, for example, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0. TIFF2025532455000016.tif37170

[0124] As a solid form of the potassium salt of the compound of formula (I), the powder X-ray diffraction pattern exhibits characteristic peaks at 9.67° (±0.2°) and 19.63° (±0.2°) 2θ; more preferably, the powder X-ray diffraction pattern exhibits characteristic peaks at 9.67° (±0.2°) and 19.63° (±0.2°) 2θ, and at least one characteristic peak at 2θ selected from 11.34° (±0.2°), 16.68° (±0.2°), and 22.46° (±0.2°); more preferably, the solid form of the potassium salt of the compound of formula (I) exhibits a powder X-ray diffraction pattern substantially identical to that shown in FIG. 16.

[0125] As a solid form of the potassium salt of the compound of formula (I), its differential scanning calorimetry curve exhibits a differential scanning calorimetry curve substantially identical to that shown in FIG.

[0126] As a solid form of the potassium salt of the compound of formula (I), its thermogravimetric analysis curve exhibits substantially the same thermogravimetric analysis curve as that shown in FIG.

[0127] (3) Calcium salt of the compound of formula (I) In the present invention, the solid form of the calcium salt of the compound of formula (I) refers to a salt obtained by contacting the compound of formula (I) with a calcium-containing base. Preferably, it has a structure represented by formula (IV), where x is selected from 0.5 to 2, for example, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0. TIFF2025532455000017.tif37170

[0128] As a solid form of the calcium salt of the compound of Formula (I), the powder X-ray diffraction pattern exhibits characteristic peaks at 11.53° (±0.2°) and 21.54° (±0.2°) 2θ; more preferably, the powder X-ray diffraction pattern exhibits characteristic peaks at 11.53° (±0.2°) and 21.54° (±0.2°) 2θ, and at least one characteristic peak at 2θ selected from 12.46° (±0.2°), 18.56° (±0.2°), 20.92° (±0.2°), 25.20° (±0.2°), and 26.06° (±0.2°); more preferably, the solid form of the calcium salt of the compound of Formula (I) exhibits a powder X-ray diffraction pattern substantially identical to that shown in Figure 19.

[0129] As a solid form of the calcium salt of the compound of formula (I), its differential scanning calorimetry curve exhibits a differential scanning calorimetry curve substantially identical to that shown in FIG.

[0130] As a solid form of the calcium salt of the compound of formula (I), its thermogravimetric analysis curve exhibits substantially the same thermogravimetric analysis curve as that shown in FIG.

[0131] (4) Tromethamine salt of the compound of formula (I) In the present invention, the solid tromethamine salt of the compound of formula (I) refers to a salt obtained by contacting the compound of formula (I) with a tromethamine-containing base. Preferably, it has a structure represented by formula (V), where x is selected from 0.5 to 2, for example, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0. TIFF2025532455000018.tif37170

[0132] As a solid form of the tromethamine salt of the compound of formula (I), its powder X-ray diffraction pattern exhibits characteristic peaks at 2θ of 8.94° (±0.2°) and 14.35° (±0.2°); more preferably, in its powder X-ray diffraction pattern, and a characteristic peak at 2θ of 0.35° (±0.2°), and at least one characteristic peak at 2θ selected from 17.09° (±0.2°), 18.69° (±0.2°), 19.76° (±0.2°), 22.19° (±0.2°), 22.59° (±0.2°), 22.99° (±0.2°), 25.40° (±0.2°), and 26.58° (±0.2°); more preferably, the solid form of the tromethamine salt of compound of formula (I) exhibits a powder X-ray diffraction pattern substantially identical to that shown in Figure 22.

[0133] As a solid form, the tromethamine salt of the compound of formula (I) exhibits a differential scanning calorimetry curve substantially identical to that shown in FIG.

[0134] As a solid form, the tromethamine salt of the compound of formula (I) exhibits a thermogravimetric analysis curve substantially identical to that shown in FIG.

[0135] (5) Lysine salt of the compound of formula (I) In the present invention, the solid form of the lysine salt of the compound of formula (I) refers to a salt obtained by contact reaction of the compound of formula (I) with a lysine-containing base. Preferably, it has a structure represented by formula (VI), where x is 0.5 to 2.0. For example, x is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0. Preferably, x is 0.8, 0.9, 1, or 1.1. TIFF2025532455000019.tif37170

[0136] As a solid form of the lysine salt of the compound of Formula (I), the powder X-ray diffraction pattern exhibits characteristic peaks at 12.31° (±0.2°) and 19.66° (±0.2°) 2θ; more preferably, the powder X-ray diffraction pattern exhibits characteristic peaks at 12.31° (±0.2°) and 19.66° (±0.2°) 2θ, and at least one characteristic peak at 2θ selected from 17.72° (±0.2°), 21.16° (±0.2°), and 24.13° (±0.2°); more preferably, the solid form of the lysine salt of the compound of Formula (I) exhibits a powder X-ray diffraction pattern substantially identical to that shown in FIG. 25.

[0137] As a solid form of the lysine salt of the compound of formula (I), its thermogravimetric analysis curve exhibits substantially the same thermogravimetric analysis curve as that shown in FIG.

[0138] (6) tert-butylamine salt of the compound of formula (I) In the present invention, the solid form of the tert-butylamine salt of the compound of formula (I) refers to a salt obtained by contacting the compound of formula (I) with a base containing tert-butylamine. Preferably, it has a structure represented by formula (VII), where x is 0.5 to 2.0. For example, x is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0. Preferably, x is 0.8, 0.9, 1, or 1.1. TIFF2025532455000020.tif37170

[0139] The solid form of the tert-butylamine salt of the compound of Formula (I) exhibits an X-ray powder diffraction pattern that exhibits characteristic peaks at 7.15° (±0.2°) and 10.14° (±0.2°) 2θ; more preferably, the X-ray powder diffraction pattern exhibits characteristic peaks at 7.15° (±0.2°) and 10.14° (±0.2°) 2θ, and at least one characteristic peak at 17.85° (±0.2°), 18.28° (±0.2°), 19.19° (±0.2°), 20.51° (±0.2°), and 22.03° (±0.2°) 2θ; more preferably, the solid form of the tert-butylamine salt of the compound of Formula (I) exhibits an X-ray powder diffraction pattern substantially identical to that shown in FIG. 28.

[0140] As a solid form of the tert-butylamine salt of the compound of formula (I), its differential scanning calorimetry curve exhibits a differential scanning calorimetry curve substantially identical to that shown in FIG.

[0141] As a solid form of the tert-butylamine salt of the compound of formula (I), its thermogravimetric analysis curve exhibits substantially the same thermogravimetric analysis curve as that shown in FIG.

[0142] (7) Diisopropylamine salt of the compound of formula (I) In the present invention, the solid form of the diisopropylamine salt of the compound of formula (I) refers to a salt obtained by contact reaction of the compound of formula (I) with a diisopropylamine-containing base. Preferably, it has a structure represented by formula (VIII), where x is 0.5 to 2.0. For example, x is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0. Preferably, x is 0.8, 0.9, 1, or 1.1. TIFF2025532455000021.tif37170

[0143] As a solid form of the diisopropylamine salt of the compound of formula (I), its powder X-ray diffraction pattern exhibits characteristic peaks at 2θ of 8.87° (±0.2°) and 17.20° (±0.2°); more preferably, in its powder X-ray diffraction pattern, characteristic peaks at 2θ of 8.87° (±0.2°) and 17.20° (±0.2°), as well as characteristic peaks at 2θ of 9.25° (±0.2°), 9.65° (±0.2°), 15.07° (±0.2°), 16.07° (±0.2°), 17.20° (±0.2°), 18.07° (±0.2°), 19.07° (±0.2°), 20.07° (±0.2°), 21.07° (±0.2°), 22.07° (±0.2°), 23.07° (±0.2°), 24.07° (±0.2°), 25.07° (±0.2°), 26.07° (±0.2°), 27.07° (±0.2°), 28.07° (±0.2°), 29.07° (±0.2°), 30.07° (±0.2°), 31.07° (±0.2°), 32.07° (±0.2°), 33.07° (±0.2°), 34.07° (±0.2°), 35.07° (±0.2°), 36.07° (±0.2°), 37.07° (±0.2°), 38.07° (±0.2°), 39.07° (±0.2°), 40.07° (±0.2 more preferably, the solid form of the diisopropylamine salt of the compound of Formula (I) exhibits a powder X-ray diffraction pattern substantially identical to that shown in Figure 31.

[0144] As a solid form of the diisopropylamine salt of the compound of formula (I), its differential scanning calorimetry curve exhibits a differential scanning calorimetry curve substantially identical to that shown in FIG.

[0145] As a solid form of the diisopropylamine salt of the compound of formula (I), its thermogravimetric analysis curve exhibits substantially the same thermogravimetric analysis curve as that shown in FIG.

[0146] (8) Ethanolamine salt of the compound of formula (I) In the present invention, the solid form of the ethanolamine salt of the compound of formula (I) refers to a salt obtained by contact reaction of the compound of formula (I) with an ethanolamine-containing base. Preferably, it has a structure represented by formula (IX), where x is 0.5 to 2.0. For example, x is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0. Preferably, x is 0.8, 0.9, 1, or 1.1. TIFF2025532455000022.tif37170

[0147] The solid form of the ethanolamine salt of the compound of Formula (I) exhibits an X-ray powder diffraction pattern that exhibits characteristic peaks at 7.62° (±0.2°) and 19.70° (±0.2°) 2θ; more preferably, the X-ray powder diffraction pattern exhibits characteristic peaks at 7.62° (±0.2°) and 19.70° (±0.2°) 2θ, and at least one characteristic peak at 2θ selected from 9.72° (±0.2°), 14.98° (±0.2°), and 19.34° (±0.2°); more preferably, the solid form of the ethanolamine salt of the compound of Formula (I) exhibits an X-ray powder diffraction pattern substantially identical to that shown in Figure 34.

[0148] As a solid form of the ethanolamine salt of the compound of formula (I), its differential scanning calorimetry curve exhibits a differential scanning calorimetry curve substantially identical to that shown in FIG.

[0149] As a solid form of the ethanolamine salt of the compound of formula (I), its thermogravimetric analysis curve exhibits substantially the same thermogravimetric analysis curve as that shown in FIG.

[0150] (9) Diethanolamine salt of the compound of formula (I) In the present invention, the solid form of the diethanolamine salt of the compound of formula (I) refers to a salt obtained by contact reaction of the compound of formula (I) with a diethanolamine-containing base. Preferably, it has a structure represented by formula (X), where x is 0.5 to 2.0. For example, x is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0. Preferably, x is 0.8, 0.9, 1, or 1.1. TIFF2025532455000023.tif37170

[0151] As a solid form of the diethanolamine salt of the compound of Formula (I), the powder X-ray diffraction pattern exhibits characteristic peaks at 6.33° (±0.2°) and 19.87° (±0.2°) 2θ; more preferably, the powder X-ray diffraction pattern exhibits characteristic peaks at 6.33° (±0.2°) and 19.87° (±0.2°) 2θ, and at least one characteristic peak at 2θ selected from 7.41° (±0.2°), 12.46° (±0.2°), 22.02° (±0.2°), and 28.45° (±0.2°); more preferably, the solid form of the diethanolamine salt of the compound of Formula (I) exhibits substantially the same powder X-ray diffraction pattern as shown in Figure 37.

[0152] As a solid form of the diethanolamine salt of the compound of formula (I), its differential scanning calorimetry curve exhibits a differential scanning calorimetry curve substantially identical to that shown in FIG.

[0153] As a solid form of the diethanolamine salt of the compound of formula (I), its thermogravimetric analysis curve exhibits substantially the same thermogravimetric analysis curve as that shown in FIG.

[0154] (10) Solid form of the free acid of the compound of formula (I) In the present invention, the solid form of the free acid of the compound of formula (I) refers to a solid of the compound of formula (I). The solid form of the free acid of the compound of formula (I) has a powder X-ray diffraction pattern that exhibits at least one characteristic peak at 2θ selected from 8.92° (±0.2°) and 23.31° (±0.2°); more preferably, the solid form of the free acid of the compound of formula (I) has a powder X-ray diffraction pattern that exhibits at least one characteristic peak at 2θ selected from 8.92° (±0.2°), 23.31° (±0.2°), 27.41° (±0.2°). , 19.70° (±0.2°), 16.51° (±0.2°), 12.27° (±0.2°), 21.50° (±0.2°), 18.23° (±0.2°) and 18.37° (±0.2°); more preferably, the solid form of the free acid of the compound of Formula (I) exhibits a powder X-ray diffraction pattern substantially identical to that shown in Figure 13.

[0155] As a solid form of the free acid of the compound of formula (I), its differential scanning calorimetry curve exhibits a differential scanning calorimetry curve substantially identical to that shown in FIG.

[0156] As a solid form of the free acid of the compound of formula (I), its thermogravimetric analysis curve exhibits a thermogravimetric analysis curve substantially identical to that shown in FIG.

[0157] Pharmaceutical Composition The present invention also relates to pharmaceutical compositions comprising a solid form of a compound of formula (I), comprising a solid form of a compound of formula (I) and a pharmaceutically acceptable carrier or excipient.

[0158] The term "composition" as used herein refers to a pharmaceutical preparation containing at least one pharmaceutically active compound, including solid or amorphous forms, suitable for administration to a given individual for therapeutic purposes. The composition may also contain at least one pharmaceutically acceptable component of a suitable carrier or excipient to provide an improved formulation of the compound.

[0159] The term "pharmaceutically acceptable" indicates that the indicated material does not possess properties that would prevent a reasonably prudent physician from administering said material to a patient, taking into account the disease or condition to be treated and the respective route of administration. For example, such materials are often required to be substantially sterile, such as in the case of injectable solutions.

[0160] use The present invention also relates to the use of solid forms or pharmaceutical compositions of compounds of formula (I) for: (i) the preparation of a medicament for the prevention and / or treatment of diseases associated with kidney damage; and / or (ii) prevention and / or treatment of diseases associated with kidney damage; and / or (iii) prevention and / or treatment of diseases associated with mitochondrial dysfunction; and / or (iv) Preparation of a medicament for the prevention and / or treatment of a disease associated with mitochondrial dysfunction.

[0161] In some preferred embodiments, the disease associated with kidney damage includes acute kidney injury and chronic kidney injury, preferably chronic kidney injury.

[0162] In some preferred embodiments, the disease associated with renal damage is selected from the group consisting of acute renal ischemia-reperfusion injury, septic nephropathy, nephrotoxic injury, primary glomerulonephritis, hypertensive renal arteriosclerosis, diabetic nephropathy, secondary glomerulonephritis, tubulointerstitial lesions, ischemic nephropathy, and hereditary nephropathy.

[0163] In some preferred embodiments, the tubulointerstitial lesion is selected from the group consisting of chronic pyelonephritis, chronic uric acid nephropathy, obstructive nephropathy, and drug-induced nephropathy.

[0164] In some preferred embodiments, the hereditary nephropathy is selected from the group consisting of polycystic kidney disease and hereditary nephritis.

[0165] In some preferred embodiments, the disease associated with mitochondrial dysfunction is selected from at least one of inflammatory bowel disease; lung injury; fibrotic disease; sepsis; prostate disease; cardiovascular disease; neurological disease; and aging-related disease.

[0166] In some preferred embodiments, the inflammatory bowel disease is selected from at least one of ulcerative colitis and Crohn's disease.

[0167] In some preferred embodiments, the fibrotic disease is selected from at least one of tubulointerstitial fibrosis, interstitial lung disease (ILD), idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease fibrosis, tissue fibrosis, arthrofibrosis, liver fibrosis, skin fibrosis, fibromatosis, myelofibrosis, cardiac fibrosis, and cystic fibrosis.

[0168] In some preferred embodiments, the cardiovascular disease is selected from at least one of atherosclerosis, heart failure, myocardial ischemia / reperfusion injury and hypertension, cardiomyopathy, and cardiovascular complications of diabetes.

[0169] In some preferred embodiments, the neurological disorder is selected from at least one of sensorineural hearing loss, abnormalities of brain development, congenital hydrocephalus, congenital cranial nerve diseases, congenital perforating vein malformations, metabolic dysfunction, congenital auditory aphasia, congenital visual aphasia, cerebral palsy, depression, schizophrenia, bipolar disorder, delusional disorder, mania, obsessive-compulsive disorder, psychiatric disorders such as autism, Parkinson's disease, Alzheimer's disease, brain injury, amyotrophic lateral sclerosis, epilepsy, Huntington's disease, spinocerebellar ataxia, and cerebral ischemia.

[0170] In some preferred embodiments, the aging-related disease is progeria.

[0171] In some preferred embodiments, the aging-related disease is skin aging, and more preferably, the aging-related disease is radiation-induced skin aging or damage.

[0172] In order to clarify the purpose, technical solutions, and advantages of the embodiments of the present invention, the present invention will be further described below in connection with specific examples. It should be understood that these examples are used only to illustrate the present invention and do not limit the scope of the present invention. In the following examples, experimental methods without specific conditions are usually carried out according to conventional conditions or conditions recommended by manufacturers. Unless otherwise specified, percentages and parts are by weight. Experimental materials and reagents used in the following examples can be obtained from commercial sources unless otherwise specified.

[0173] Unless otherwise specified, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. It should be noted that the terms used herein are intended to describe particular embodiments only and are not intended to limit the exemplary embodiments of the present application.

[0174] Example 1 In this example, crystalline form A of compound TJ01-013 (sodium salt of compound TJ) was prepared. The specific procedure is as follows:

[0175] 0.300 g of the compound of formula (I) was weighed into a 20 mL vial, and 12 mL of acetone was added. The sample dissolved and became transparent. 0.520 g of a 10% aqueous solution of sodium bicarbonate was added dropwise without stirring. A solid precipitated and sank to the bottom. The mixture was kept warm for 30 minutes, slowly cooled to room temperature (about 20°C), suction filtered, washed with a small amount of acetone, and vacuum dried at room temperature to obtain a sample of crystalline form A.

[0176] Example 2 In this example, the crystalline form B of compound TJ01-013 was prepared. The specific procedure is as follows:

[0177] 0.300 g of the compound of formula (I) was weighed into a 20 mL vial, 12 mL of acetone was added, and the mixture was heated to about 45°C until the sample dissolved and became transparent. After cooling to room temperature (about 20°C), 0.520 g of a 10% aqueous sodium bicarbonate solution was added, followed by magnetic stirring (rotation speed: 1000 rpm). After a solid precipitated, the mixture was kept warm for 30 minutes, suction filtered, and washed with a small amount of acetone to obtain a sample of crystalline form B.

[0178] Example 3 In this example, the crystalline form C of compound TJ01-013 was prepared. The specific procedure is as follows:

[0179] 0.100 g of the compound of formula (I) was weighed into a 20 mL vial, 4 mL of acetone was added, and the temperature was raised to about 45°C. When the sample dissolved and became transparent, 0.173 g of a 10% aqueous solution of sodium bicarbonate was added dropwise, and the mixture was stirred magnetically. After a solid precipitated, the stirring was accelerated and the mixture was kept warm for 30 minutes. The mixture was then cooled to room temperature (about 20°C), suction filtered, washed with a small amount of acetone, and vacuum dried at room temperature to obtain a sample of crystalline form C.

[0180] Example 4 In this example, crystalline form D of compound TJ01-013 was prepared by the following two methods.

[0181] (1) Method 1 0.100 g of the compound of formula (I) was weighed, 4 mL of acetone was added, and the mixture was heated to approximately 45°C and stirred until the mixture became clear. 0.223 g of a methanol solution of sodium methoxide was added dropwise at approximately 45°C. A small amount of solid was observed during the addition, but the solid dissolved and became clear upon stirring. After stirring, a solid slowly precipitated, and the mixture was kept at approximately 45°C for 1 hour. After keeping the mixture warm, the mixture was cooled to approximately 20°C and stirred for 1 hour. The mixture was suction filtered and washed with a small amount of acetone. The mixture was dried in vacuo at room temperature (without heating) for approximately 20 hours. The product was detected as crystalline form D.

[0182] [Table 2-1]

[0183] (2) Method 2 3.00 g of the compound of formula (I) was weighed out and 120 ml of acetone was added. The mixture was heated to approximately 45°C and stirred until the solution became clear. 5.20 g of a 10% aqueous solution of sodium bicarbonate was added dropwise at approximately 45°C. A small amount of solid was present during the addition, but the solid dissolved with stirring. After stirring, a solid slowly precipitated, and the mixture was kept at approximately 45°C for 1 hour. After keeping the mixture warm, the mixture was cooled to approximately 20°C and stirred for 1 hour. The mixture was filtered by suction and washed with a small amount of acetone. The mixture was dried in vacuo at room temperature (without heating) for approximately 20 hours. The product was detected as crystalline form D.

[0184] [Table 2-2]

[0185] Example 5 In this example, the potassium salt of compound TJ01-013, crystalline form F, was prepared by the following procedure:

[0186] 0.3 g of the compound of formula (I) was weighed, 12 mL of acetone was added, and the mixture was heated to about 45°C to dissolve transparently. 0.62 g of 10% potassium bicarbonate was added, and the mixture was dissolved transparently. After that, a solid precipitated (a small amount of seed crystals may be added), and the mixture was cooled to about 20°C and filtered by suction.

[0187] Example 6 In this example, the calcium salt of compound TJ01-013, crystalline form G, was prepared by the following procedure:

[0188] 0.3 g of the compound of formula (I) was weighed, 12 mL of acetone was added, and the mixture was heated to about 45°C to give a clear solution. 0.98 g of 10% calcium acetate was added, and the mixture was clear and dissolved. However, no crystals were precipitated. The solvent was blown dry with nitrogen, and 12 mL of isopropanol was added to precipitate a solid. The mixture was cooled to about 20°C and filtered by suction.

[0189] Example 7 In this example, the crystalline form H of the tromethamine salt of compound TJ01-013 was prepared. The specific procedure is as follows:

[0190] 0.3 g of the compound of formula (I) was weighed, 10 mL of methanol was added, and the mixture was heated to approximately 45°C to dissolve it transparently. 1.5 g of a 5% aqueous solution of tromethamine was added, and the mixture was kept at the same temperature for 0.5 to 1 hour. The solvent was blown dry with nitrogen, and 10 mL of ethyl acetate was added to precipitate a solid. The mixture was cooled to approximately 20°C and filtered by suction.

[0191] Example 8 In this example, the lysine salt of compound TJ01-013 was prepared in crystalline form I. The specific procedure is as follows:

[0192] 0.05 g of the compound of formula (I) was weighed, 3 mL of acetone was added, and the mixture was heated to about 45°C to dissolve transparently. 0.30 g of a 5% aqueous lysine solution was added to dissolve transparently, and the mixture was cooled to precipitate a solid. The solid was then cooled to about 20°C and filtered by suction.

[0193] Example 9 In this example, the crystalline form J of the tert-butylamine salt of compound TJ01-013 was prepared by the following procedure:

[0194] 0.3 g of the compound of formula (I) was weighed, 12 mL of acetone was added, and the mixture was heated to about 45°C to dissolve transparently. 0.906 g of a 5% acetone solution of tert-butylamine was added to dissolve transparently, and then a solid was precipitated. The mixture was cooled to about 20°C and filtered by suction.

[0195] Example 10 In this example, the crystalline form K of the diisopropylamine salt of compound TJ01-013 was prepared by the following procedure:

[0196] 0.3 g of the compound of formula (I) was weighed, 12 mL of acetone was added, and the mixture was heated to about 45°C to dissolve transparently. 1.253 g of a 5% acetone solution of diisopropylamine was added to dissolve transparently, and then a solid was precipitated. The mixture was cooled to about 20°C and filtered by suction.

[0197] Example 11 In this example, the crystalline form L of the ethanolamine salt of compound TJ01-013 was prepared by the following procedure:

[0198] 0.3 g of the compound of formula (I) was weighed, 12 mL of acetone was added, and the mixture was heated to about 45°C to dissolve transparently. 0.756 g of a 5% acetone solution of ethanolamine was added to dissolve transparently, and then a solid was precipitated. The mixture was cooled to about 20°C and filtered by suction.

[0199] Example 12 In this example, the crystalline form M of the diethanolamine salt of compound TJ01-013 was prepared by the following procedure:

[0200] 0.3 g of the compound of formula (I) was weighed, 12 mL of acetone was added, and the mixture was heated to about 45°C to dissolve transparently. 1.302 g of a 5% acetone solution of diethanolamine was added to dissolve transparently, and then a solid was precipitated. The mixture was cooled to about 20°C and filtered by suction.

[0201] Example 13 In this example, the crystalline form E of the free acid of compound TJ01-013 was prepared. The specific procedure is as follows: TIFF2025532455000026.tif39170

[0202] UMI-77 (15 mg, 0.032 mmol) was suspended in DCM (0.5 mL) and stirred in an ice-water bath. 85% mCPBA (6.5 mg, 0.032 mmol) was added, and the mixture was then slowly cooled to room temperature. The mixture was filtered under suction, and the filter cake was washed with DCM and dried to obtain the product TJ01-013 (crystalline form E, 6 mg).

[0203] In the present invention, X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis were used to characterize samples of each crystalline form prepared in the above examples.

[0204] [X-ray diffraction method] Each of the crystalline forms of the products prepared above was analyzed using a PANalytacal Empyrean powder X-ray diffraction analyzer, with the scanning parameters shown in Table 3 below.

[0205] [Table 3]

[0206] The peak positions and intensities of characteristic peaks in the powder X-ray diffraction pattern of crystalline form A are shown in Table 4-1 below, and the XRPD pattern is shown in FIG.

[0207] [Table 4-1]

[0208] The peak positions and intensities of characteristic peaks in the powder X-ray diffraction pattern of crystalline form B are shown in Table 4-2 below, and the XRPD pattern is shown in FIG.

[0209] [Table 4-2]

[0210] The peak positions and intensities of characteristic peaks in the powder X-ray diffraction pattern of crystalline form C are shown in Table 4-3 below, and the XRPD pattern is shown in FIG.

[0211] [Table 4-3]

[0212] The peak positions and intensities of characteristic peaks in the powder X-ray diffraction pattern of crystalline form D are shown in Table 4-4 below, and the XRPD pattern is shown in FIG.

[0213] [Table 4-4]

[0214] The peak positions and intensities of characteristic peaks in the powder X-ray diffraction pattern of crystalline form E are shown in Tables 4-5 below, and the XRPD pattern is shown in FIG.

[0215] [Table 4-5]

[0216] The peak positions and intensities of characteristic peaks in the powder X-ray diffraction pattern of crystalline form F are shown in Tables 4-6 below, and the XRPD pattern is shown in FIG.

[0217] [Table 4-6]

[0218] The peak positions and intensities of characteristic peaks in the powder X-ray diffraction pattern of crystalline form G are shown in Table 4-7 below, and the XRPD pattern is shown in FIG.

[0219] [Table 4-7]

[0220] The peak positions and intensities of characteristic peaks in the powder X-ray diffraction pattern of crystalline form H are shown in Table 4-8 below, and the XRPD pattern is shown in FIG.

[0221] [Table 4-8]

[0222] The peak positions and intensities of characteristic peaks in the powder X-ray diffraction pattern of crystalline form I are shown in Tables 4-9 below, and the XRPD pattern is shown in FIG.

[0223] [Table 4-9]

[0224] The peak positions and intensities of characteristic peaks in the powder X-ray diffraction pattern of crystalline form I are shown in Table 4-10 below, and the XRPD pattern is shown in FIG.

[0225] [Table 4-10]

[0226] The peak positions and intensities of characteristic peaks in the powder X-ray diffraction pattern of crystalline form K are shown in Table 4-11 below, and the XRPD pattern is shown in FIG.

[0227] [Table 4-11]

[0228] The peak positions and intensities of characteristic peaks in the powder X-ray diffraction pattern of crystalline form L are shown in Table 4-12 below, and the XRPD pattern is shown in FIG.

[0229] [Table 4-12]

[0230] The peak positions and intensities of characteristic peaks in the powder X-ray diffraction pattern of crystalline form M are shown in Table 4-13 below, and the XRPD pattern is shown in FIG.

[0231] [Table 4-13]

[0232] [Differential scanning calorimetry] The crystals prepared in each of the above examples were tested using a TA Q200 / 2000 differential scanning calorimeter, with the test parameters shown in Table 5 below. TIFF2025532455000041.tif53170

[0233] The DSC spectrum of Crystalline Form A is shown in Figure 2, and the differential scanning calorimetric curve of Crystalline Form A has endothermic peaks at 144.89°C ± 3°C and 150.40°C ± 3°C, and an exothermic peak at 214.79°C ± 3°C.

[0234] The DSC spectrum of crystalline form B is shown in Figure 5, and the differential scanning calorimetry curve of crystalline form B has endothermic peaks at 72.14°C ± 3°C and 145.82°C ± 3°C, and an exothermic peak at 184.61°C ± 3°C.

[0235] The DSC spectrum of crystalline form C is shown in Figure 8, and the differential scanning calorimetry curve of crystalline form C has endothermic peaks at 59.75°C ± 3°C and 140.91°C ± 3°C, and an exothermic peak at 185.61°C ± 3°C.

[0236] The DSC spectrum of crystalline form D is shown in FIG. 11, and the differential scanning calorimetric curve of crystalline form D has an endothermic peak at 183.79°C (±3°C) and an exothermic peak at 210.79°C ±3°C.

[0237] The DSC spectrum of crystalline form E is shown in Figure 14, and the differential scanning calorimetric curve of crystalline form E has an endothermic peak at 184.18±3°C and an exothermic peak at 198.31±3°C.

[0238] The DSC spectrum of crystalline form F is shown in FIG.

[0239] The DSC spectrum of crystalline form G is shown in FIG.

[0240] The DSC spectrum of the H crystalline form is shown in FIG.

[0241] The DSC spectrum of the J crystal form is shown in FIG.

[0242] The DSC spectrum of the K crystal form is shown in FIG.

[0243] The DSC spectrum of the L crystal form is shown in FIG.

[0244] The DSC spectrum of the M crystalline form is shown in FIG.

[0245] [Thermogravimetric analysis method] The crystals prepared in each of the above examples were tested using a TA Q500 / 5000 thermogravimetric analyzer, with the test parameters shown in Table 6 below.

[0246] [Table 6]

[0247] The TGA spectrum of crystalline form B is shown in Figure 6, and the thermogravimetric analysis curve of crystalline form B shows a weight loss of 6.78±0.2% at 73.50±3°C.

[0248] The TGA spectrum of crystalline form C is shown in Figure 9, and the thermogravimetric analysis curve of crystalline form C shows a weight loss of 4.96±0.2% at 70.15±3°C.

[0249] The TGA spectrum of crystalline form D is shown in Figure 12, and the thermogravimetric analysis curve of crystalline form D shows that there is no weight loss before the sample decomposes.

[0250] The TGA spectrum of crystalline form E is shown in FIG.

[0251] The TGA spectrum of crystalline form F is shown in FIG.

[0252] The TGA spectrum of crystalline form G is shown in FIG.

[0253] The TGA spectrum of the H crystal form is shown in FIG.

[0254] The TGA spectrum of crystalline form I is shown in FIG.

[0255] The TGA spectrum of crystalline form J is shown in FIG.

[0256] The TGA spectrum of the K crystal form is shown in FIG.

[0257] The TGA spectrum of crystalline form L is shown in FIG.

[0258] The TGA spectrum of the M crystalline form is shown in FIG.

[0259] Furthermore, the present inventors also investigated the properties of each crystalline form sample prepared in each of the above examples.

[0260] [Hygroscopicity] Single crystal samples of compound TJ01-013 were tested using a Waters moisture sorption apparatus. A dry weighing disc was taken, and the single crystal sample was placed flat on the disc, approximately 1 / 3 to 2 / 3 of the disc's volume. The instrument parameters were set as follows: temperature: 25°C; balance: dm / dt = 0.01% / min (minimum: 10 min, maximum: 180 min); drying: 120 min at 0% RH; RH (%) test step: 10%; RH (%) test step range: 0%-90%-0%. The hygroscopicity of each crystal sample was tested at 90% relative humidity, and the results are shown in Table 7 below. TIFF2025532455000043.tif116170

[0261] From Table 7, it can be seen that the D crystalline form of the sodium salt of compound TJ01-013, the F crystalline form of the potassium salt of compound TJ01-013, the J crystalline form of the tert-butylamine salt of compound TJ01-013, the K crystalline form of the diisopropylamine salt of compound TJ01-013, the L crystalline form of the ethanolamine salt of compound TJ01-013, the H crystalline form of the tromethamine salt of compound TJ01-013, and the E crystalline form of compound of formula (I) are slightly hygroscopic, while the other crystalline forms are strongly hygroscopic.

[0262] FIG. 40 exemplarily shows the dvs spectrum of a sample of crystalline form D of the sodium salt of compound TJ01-013.

[0263] [Solubility] Equal amounts of the samples were placed in FaSSIF buffer, FeSSIF buffer, water, and SGF, and their solubilities were tested at 0.5 hours, 2 hours, and 24 hours, respectively. The results for the D crystalline form samples of compound TJ01-013 are shown in Table 8.

[0264] [Table 8]

[0265] According to FIG. 41, the D crystalline form of compound TJ01-013 has high solubility in water, FaSSIF, and FeSSIF, but low solubility in SGF.

[0266] [Crystal morphology change] In this example, the intertransformation relationship between the various crystalline forms of sodium salt ABCD was further investigated through heat treatment under nitrogen protection and suspension competition tests. The experimental results showed that crystalline form B could be converted to crystalline form C by heating to 106°C and then cooling to room temperature. A stirring competition test after physically mixing equal amounts of four crystalline form samples at different temperatures (RT / 50) showed that after approximately 20 hours of magnetic stirring (approximately 1000 rpm), crystalline forms A and B could be converted to crystalline form A by mixing and pulsating, crystalline forms A and C could be converted to crystalline form A by mixing and pulsating, crystalline forms B and D could be converted to crystalline form D by mixing and pulsating, and crystalline forms C and D could be converted to crystalline form D by mixing. In other words, crystalline forms B and C can be converted to crystalline forms A and D, respectively, which means that crystalline forms A and D are more stable than crystalline forms B and C. The conversion relationship between each crystalline form is shown in Figure 26.

[0267] However, the thermodynamic transformation relationship between Form A and Form D cannot be studied using the heating, suspension pulping, and grinding methods. To further investigate the thermodynamic transformation relationship between Form A and Form D, the DSC spectrum of Form A was measured. From the DSC spectrum analysis, the DSC of Form A is shown in Figure 2, and the DSC of Form D is shown in Figure 11. The melting point of Form A is higher than that of Form D, and the melting enthalpy of Form A is much lower than that of Form D. From the thermodynamic stability relationship table, if TA > TD and ΔHf,A > ΔHf,D, Form A and Form D have a univariate relationship, and Form A is stable. If TA > TD and ΔHf,A < ΔHf,D, Form A and Form D have an tautomeric relationship, and Form A is stable above the crystal transition temperature, and Form D is stable below the crystal transition temperature. From the DSC data of crystalline forms A and D in Tables 9 and 10 below, it can be seen that TA>TD and ΔHf,A<ΔHf,D, i.e., at low temperatures, crystalline form D is more stable.

[0268] [Table 9]

[0269] [Table 10]

[0270] [Affinity test of recombinant Mcl-1 protein] In vitro surface plasmon resonance (SPR) experiments were performed using a Biacore analyzer to measure the binding affinity of the sodium salt of TJ 01-013 to Mcl-1 protein in the D crystal form, using a CM5 chip coupled to the protein. The experimental results are shown in Table 11 below.

[0271] [Table 11]

[0272] Experimental conclusion: In SPR test, the D crystal form of sodium salt of TJ 01-013 can specifically bind to Mcl-1 protein.

[0273] [Selective induction of injury mitophagy in Keima HEK293 cell model] In vitro, the coral-derived Keima fluorescent protein was fused to the mitochondrial localization sequence of cytochrome C oxidase subunit IV to form mtKeima protein in HEK293T cells. Hoechst 33342 nuclear dye was used for nuclear staining, and the fluorescent protein was analyzed using Thermo CellInsight TMThe CX7 LZR high-content screening (HCS) platform was used to assess mitophagy levels at an EX / EM wavelength of 594 nm and 620 nm. 3 μM of carbonyl cyanide 3-chlorophenylhydrazone (CCCP) was used to disrupt mitochondrial membrane potential, causing mitochondrial damage, and then autophagy levels in damaged mitochondria were examined. As shown in Figure 42, the D crystal form of the sodium salt of TJ01-013 selectively induced autophagy in damaged mitochondria at different concentrations (0 μM, 2.5 μM, 5 μM, and 10 μM) (T test, two-tailed test, P=0.0425), demonstrating good dose-dependence and selectivity.

[0274] [Pharmacokinetic study in rats] Pharmacokinetic study of the D crystal form of the sodium salt of compound TJ01-013 in rats Healthy SD rats were administered three doses of the D-crystalline form of the sodium salt of TJ01-013 by single oral gavage, multiple single doses of the D-crystalline form, and a single intravenous injection. The plasma kinetics of the prototype drug in rats were analyzed. This included the absorption rate and exposure of the D-crystalline form of TJ01-013, individual variability, dose-response relationship, excretion rate, steady-state status, and accumulation potential. SD rats were administered a single oral gavage dose of 10, 30, or 90 mg / kg of the D-crystalline form of TJ01-013, 30 mg / kg of the D-crystalline form once daily for 7 consecutive days by oral gavage, and a single intravenous injection of 10 mg / kg. Data on the plasma concentrations of the prototype drug in each animal at each time point were calculated by fitting using WinNonlin software. The mean pharmacokinetic parameters for each group of six rats (half male and half female) are summarized in Table 12 below.

[0275] [Table 12] Note:*:T max Statistics are median (min, max).

[0276] As shown in Table 12 above, after a single oral gavage and intravenous administration of TJ01-013 D crystalline form to SD rats, the pharmacokinetic properties showed rapid absorption, a small apparent distribution volume, and a moderate excretion rate.

[0277] Plasma exposure of the D crystalline form of prototype TJ01-013 after single oral gavage administration of three doses of 10, 30, and 90 mg / kg to SD rats. max were 3.13±1.66, 4.73±1.20, and 9.98±1.85 μg / mL, respectively, and AUC 0-24h were 10.7±4.44, 22.1±6.66, and 49.9±12.2 μg / mL, respectively, and increased with increasing dose, although the rate of increase was smaller than that of the dose.

[0278] When 30 mg / kg was administered orally for 7 consecutive days by gavage, a steady state was reached on the 4th day, and C on the 7th day was significantly higher than that on the first day of administration. max , AUC 0-24h and T max is basically unchanged, and t 1 / 2 showed a tendency to decrease, suggesting that there was no clear accumulation even when 30 mg / kg was administered by oral gavage once a day for 7 consecutive days, but that excretion tended to be rapid.

[0279] After a single intravenous administration to SD rats, V ss The absolute bioavailability of the prototype TJ01-013 D-crystalline form was 9.55% when administered by oral gavage at a single dose of 10 mg / kg to SD rats compared to the same dose of TJ01-013 D-crystalline form administered intravenously.

[0280] After a single intravenous injection, a single oral gavage, and multiple oral gavage administrations to SD rats, the plasma pharmacokinetic parameters of the D crystalline form of the prototype TJ01-013 were similar between male and female animals, with no obvious differences between males and females.

[0281] [In vivo efficacy study: acute kidney injury model induced by unilateral renal ischemia-reperfusion in rats] The pharmacodynamic effects of the D crystalline form of TJ01-013 were investigated in a renal ischemia-reperfusion (I / R) model in SD rats. Twelve male rats (280-300 g each) were administered the compound by oral gavage once daily for three consecutive days. Three groups were divided into three dose groups: 3 mg / kg, 10 mg / kg, and 30 mg / kg. The sham-operated and model control groups received an equal dose of the vehicle, 0.5% CMC-Na. On the fourth day, the left renal artery was ligated 1 hour after administration. After 45 minutes of ischemia, blood flow was restored, and a right nephrectomy was performed before reperfusion. The compound was then administered daily for three days after administration. The experimental endpoint was three days after administration. The results are shown in Figures 43-49.

[0282] Compared with the model control group, the 3, 10, and 30 mg / kg groups had no significant effect on body weight at 72 hours after reperfusion. Compared with the model control group, the 10 mg / kg group showed a significant decrease in creatinine levels at 24, 48, and 72 hours after ischemia-reperfusion, with the difference being statistically significant (P<0.05-0.01). The 30 mg / kg group also showed a significant decrease in creatinine levels at 24 and 72 hours after reperfusion (P<0.05). The 10 mg / kg and 30 mg / kg groups showed a trend toward a significant decrease in urea nitrogen levels at 72 hours after ischemia-reperfusion. Creatinine clearance improved to different degrees in the 3 mg / kg, 10 mg / kg, and 30 mg / kg groups, with the creatinine clearance in the 10 mg / kg group being statistically significant compared with the model control group (P<0.05). Compared with the model control group, the 10 mg / kg and 30 mg / kg groups showed significantly reduced expression of the apoptotic factor caspase 9 in renal tissue (P<0.001). The 3 mg / kg, 10 mg / kg, and 30 mg / kg groups also showed significantly reduced expression of the inflammatory factors IL-6 and IL-1β in renal tissue (P<0.05-0.001). Compared with the model control group, the 10 mg / kg and 30 mg / kg groups showed significantly reduced apoptotic cell rates in renal tissue (P<0.001). Compared with the model control group, the 10 mg / kg group significantly reduced the severity of lesions such as tubular dilatation, necrosis, glomerular atrophy, interstitial inflammatory cell infiltration, edema, fibrous tissue hyperplasia, glomerular capillary dilatation, Bowman's capsule dilatation, and tubular mineralization, and the 30 mg / kg group tended to reduce these lesions.

[0283] [In vivo efficacy test: PAN-induced renal damage model in rats] The effect of the D-crystalline form of TJ01-013 on renal function was investigated using an aminonucleoside-puromycin (PAN) model in SD rats. Twelve male rats weighing 160-180 g were administered a single intraperitoneal injection of 100 mg / kg of PAN (aminonucleoside-puromycin) to each group on day 1 of the experiment, except for the normal control group, to induce proteinuria. After modeling, the rats were randomly divided into a model control group, three dose groups of the D-crystalline form of TJ01-013 (3 mg / kg, 10 mg / kg, and 30 mg / kg), and a normal control group. Simultaneously with the modeling by intraperitoneal injection of PAN, oral gavage was initiated at a volume of 10 mL / kg once daily for four consecutive weeks.

[0284] Compared with the model control group, the 3, 10, and 30 mg / kg groups showed varying degrees of decrease in urinary protein concentration after 7 and 12 days of administration, a decrease in 24-hour urinary protein after 7 days of administration, and a consistent trend of decrease in 24-hour urinary protein after 12 days of administration. Compared with the model control group, the 3, 10, and 30 mg / kg groups showed varying degrees of increase in blood albumin after 7 and 12 days of administration, with the 3 mg / kg group showing statistically significant differences (P<0.05). The 3, 10, and 30 mg / kg groups showed varying degrees of decrease in urinary protein concentration after 7 and 12 days of administration, a decrease in 24-hour urinary protein after 7 days of administration, and a consistent trend of decrease in 24-hour urinary protein after 12 days of administration. At the same time, blood albumin increased to varying degrees after 7 and 12 days of administration.

[0285] As a result, oral gavage of 3mg / kg, 10mg / kg, and 30mg / kg of the D crystalline form of TJ01-013 demonstrated significant therapeutic effects on PAN-induced renal injury. Pathological microscopic observations showed that the low-, medium-, and high-dose groups were able to reduce the severity of lesions such as tubular dilatation, basophilic changes, hyaline casts, glomerular atrophy, Bowman's capsule dilatation, cyst wall thickening, and interstitial inflammatory cell infiltration.

[0286] It will be understood by those skilled in the art that the above-described embodiments are specific examples for implementing the present invention, and that in actual applications, various changes in form and details may be made without departing from the spirit and scope of the present invention.

Claims

1. A solid form of a pharmaceutically acceptable salt of a compound of formula (I).

2. 2. The solid form of claim 1, wherein the pharmaceutically acceptable salt solid form is a sodium salt, a potassium salt, a calcium salt, a tromethamine salt, a lysine salt, a tert-butylamine salt, a diisopropylamine salt, an ethanolamine salt, or a diethanolamine salt.

3. 2. The solid form of claim 1, wherein the solid form is a sodium salt of the compound of formula (I), and the solid form of the sodium salt of the compound of formula (I) exhibits characteristic peaks (Cu Kα radiation) at 2θ of 7.06° (±0.2°) and 20.87° (±0.2°) in a powder X-ray diffraction pattern.

4. 4. The solid form of the sodium salt of the compound of formula (I) according to claim 3, wherein the solid form exhibits a characteristic peak in a powder X-ray diffraction pattern at at least one 2θ angle selected from 7.06° (±0.2°), 18.07° (±0.2°), 25.02° (±0.2°), and 20.87° (±0.2°).

5. 4. The solid form of claim 3, wherein the solid form of the sodium salt of the compound of formula (I) exhibits a characteristic peak in a powder X-ray diffraction pattern at at least one 2θ angle selected from 7.06° (±0.2°), 18.07° (±0.2°), 25.02° (±0.2°), 17.58° (±0.2°), 20.87° (±0.2°), 10.54° (±0.2°), and 23.91° (±0.2°).

6. 4. The solid form of claim 3, wherein the solid form of the sodium salt of the compound of formula (I) exhibits a characteristic peak in a powder X-ray diffraction pattern at least one 2θ angle selected from 7.06° (±0.2°), 18.07° (±0.2°), 25.02° (±0.2°), 17.58° (±0.2°), 20.87° (±0.2°), 10.54° (±0.2°), 23.91° (±0.2°), 27.65° (±0.2°), 27.05° (±0.2°), 21.68° (±0.2°), and 25.91° (±0.2°).

7. 4. The solid form of claim 3, wherein the solid form of the sodium salt of the compound of formula (I) exhibits a powder X-ray diffraction pattern substantially identical to that shown in Figure 10.

8. The solid form of the sodium salt of the compound of formula (I) may further comprise The solid form of the sodium salt of the compound of formula (I) exhibits one endothermic peak at 183.79°C (±3°C) and one exothermic peak at 210.79°C (±3°C) in a differential scanning calorimetric curve; and The solid form of the sodium salt of the compound of formula (I) exhibits a thermogravimetric analysis curve substantially identical to that shown in Figure 12.

4. The solid form of claim 3, having at least one of the following characteristics:

9. The solid form is a solid form of the potassium salt of the compound of formula (I), and the solid form of the potassium salt of the compound of formula (I) exhibits a characteristic peak at at least one 2θ angle selected from 9.67° (±0.2°) and 19.63° (±0.2°) in a powder X-ray diffraction pattern; and / or said solid form is a solid form of the calcium salt of the compound of formula (I), wherein said solid form of the calcium salt of the compound of formula (I) exhibits, in a powder X-ray diffraction pattern, a characteristic peak at at least one 2θ angle selected from 11.53° (±0.2°) and 21.54° (±0.2°); and / or the solid form is a solid form of a tromethamine salt of the compound of formula (I), wherein the solid form of the tromethamine salt of the compound of formula (I) exhibits a characteristic peak at at least one 2θ angle selected from 8.94° (±0.2°) and 14.35° (±0.2°) in a powder X-ray diffraction pattern; and / or the solid form is a solid form of a lysine salt of the compound of formula (I), wherein the solid form of the lysine salt of the compound of formula (I) exhibits a characteristic peak at at least one 2θ angle selected from 12.31° (±0.2°) and 19.66° (±0.2°) 2θ in a powder X-ray diffraction pattern; and / or the solid form is a solid form of tert-butylamine salt of the compound of formula (I), and the solid form of tert-butylamine salt of the compound of formula (I) exhibits a characteristic peak at at least one 2θ selected from 7.15° (±0.2°) and 10.14° (±0.2°) 2θ in a powder X-ray diffraction pattern; and / or the solid form is a solid form of a diisopropylamine salt of the compound of formula (I), wherein the solid form of the diisopropylamine salt of the compound of formula (I) exhibits a characteristic peak at at least one 2θ angle selected from 8.87° (±0.2°) and 17.20° (±0.2°) in a powder X-ray diffraction pattern; and / or the solid form is a solid form of an ethanolamine salt of the compound of formula (I), wherein the solid form of the ethanolamine salt of the compound of formula (I) exhibits a characteristic peak at at least one 2θ angle selected from 7.62° (±0.2°) and 19.70° (±0.2°) in a powder X-ray diffraction pattern; and / or the solid form is a solid form of a diethanolamine salt of the compound of formula (I), and the solid form of the diethanolamine salt of the compound of formula (I) exhibits a characteristic peak at at least one 2θ angle selected from 6.33° (±0.2°) and 19.87° (±0.2°) in a powder X-ray diffraction pattern.

2. The solid form of claim 1.

10. A solid form of the free acid of the compound of formula (I) characterized in that it exhibits a characteristic peak at at least one 2θ angle selected from 8.92° (±0.2°) and 23.31° (±0.2°) in a powder X-ray diffraction pattern.

11. A method for preparing a solid form of the sodium salt of the compound of formula (I), comprising the steps of dissolving the compound of formula (I) in a reaction medium and adding a sodium-containing base to the compound to obtain a solid form of the sodium salt of the compound of formula (I).

12. A pharmaceutical composition comprising a solid form of a compound of formula (I) according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier or excipient.

13. (i) the preparation of a medicament for the prevention and / or treatment of diseases associated with renal impairment; and / or (ii) prevention and / or treatment of diseases associated with kidney damage; and / or (iii) prevention and / or treatment of diseases associated with mitochondrial dysfunction; and / or (iv) Preparation of a medicament for the prevention and / or treatment of diseases associated with mitochondrial dysfunction; 13. Use of the solid form according to any one of claims 1 to 10 or the pharmaceutical composition according to claim 12 for the treatment of

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