Salt and crystal form of at2r agonist and use thereof in pharmaceutics

Abstract

The present invention relates to a salt and crystal form of an AT2R agonist and use thereof in pharmaceutics, and specifically relates to a salt and crystal form of methyl ((4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate (a compound represented by formula (I)) and use thereof in pharmaceutics.

Description

Salts and crystal forms of AT2R agonists and their pharmaceutical applications

[0001] Priority information

[0002] This application claims priority and benefits to patent applications filed with the China National Intellectual Property Administration on February 21, 2025 and February 5, 2026, with patent application numbers 2025101991550 and 2026101709499, which are incorporated herein by reference in their entirety. Technical Field

[0003] This invention relates to the pharmaceutical field, specifically to a salt and crystal form of an AT2R agonist and its application in pharmaceuticals, and more particularly to a salt and crystal form of methyl carbamate ((4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate (the compound shown in formula (I)) and its application in pharmaceuticals. Background Technology

[0004] AT2R typically refers to angiotensin II receptor type 2 (AngIotensin II Receptor 2), a member of the G protein-coupled receptor (GPCR) family specifically designed to bind angiotensin II (Ang II). Angiotensin II is a peptide hormone that plays a crucial role in the renin-angiotensin system (RAS), regulating blood pressure and fluid homeostasis by binding to specific receptors. Current research suggests that activating AT2R may have potential therapeutic applications for diseases of the gastrointestinal tract, cardiovascular system, respiratory tract, kidneys, eyes, female reproductive system, or central nervous system.

[0005] Different salts and solid forms of a pharmaceutical active ingredient may have different properties. Different salts and solid forms of a pharmaceutical active ingredient can also produce polymorphs or other crystal forms, thus providing more opportunities to evaluate the property variations of a solid active pharmaceutical ingredient. Chinese patent application No. 202411164529.7 describes compound I-9 (the compound represented by formula (I) of this application) having AT2R agonist activity:

[0006] Based on the good biological activity of this compound, it is necessary to develop suitable salt forms and solid forms to obtain improved drug-like properties or other characteristics. Summary of the Invention

[0007] The present invention aims to solve at least one of the technical problems existing in the prior art.

[0008] The inventors of this application have developed a drug with AT2R activating activity ((4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate (the compound shown in formula (I)). To find a solid form with better druggability, the inventors conducted extensive experimental research to obtain the crystal form of the compound shown in formula (I), various salts, and their salt crystal forms, which have advantages such as high purity and good stability. The crystal form, various salts, and their salt crystal forms can serve as AT2R activators.

[0009] Therefore, in a first aspect, the present invention provides a salt of the compound shown in formula (I),

[0010] In some embodiments, the salt described in this invention is an organic alkaline salt or an inorganic alkaline salt.

[0011] In other embodiments, the inorganic alkaline salt of the present invention is at least one of sodium salt, potassium salt, calcium salt and magnesium salt.

[0012] In other embodiments, the organic base salt of the present invention is at least one of tris(hydroxymethyl)aminomethane salt, ethanolamine salt, and imidazole salt.

[0013] According to an embodiment of the present invention, the salt is at least one of a hydrate, a 1,4-dioxane solvate, and a dimethyl sulfoxide solvate.

[0014] According to an embodiment of the present invention, the sodium salt is a sodium salt hydrate, a sodium salt 1,4-dioxane solvate, or a sodium salt dimethyl sulfoxide solvate.

[0015] In some embodiments, the sodium salt hydrate is a sodium salt monohydrate.

[0016] In some embodiments, the potassium salt is a potassium salt hydrate or a potassium salt 1,4-dioxane solvate.

[0017] In some embodiments, the potassium salt hydrate is a potassium salt monohydrate.

[0018] According to embodiments of the present invention, those skilled in the art will understand that when the compound of formula (I) forms a salt with a base, the molar ratio of the compound of formula (I) to the base can be 5:1 to 1:5, for example 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:2.5, or 1:3. The base is an organic or inorganic alkali salt as described above.

[0019] The “2θ or 2θ angle” mentioned in this disclosure refers to the diffraction angle, where θ is the Bragg angle, and the unit is ° or degree; the error range of 2θ for each characteristic peak is ±0.20 (including the case where the number of more than two decimal places is rounded to the nearest even number).

[0020] In some embodiments, the salt of the present invention is the first sodium salt crystal form of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to sodium in the first sodium salt crystal form is 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3; preferably 1:1.

[0021] In some embodiments, the first sodium salt crystal form includes the compound shown in formula (I), sodium ions, and water, wherein the molar ratio of the compound shown in formula (I) to sodium ions and water is (0.5–2):(0.5–2):(0.5–2); preferably, the molar ratio of the compound shown in formula (I) to sodium ions and water is (0.9–1.1):(0.9–1.1):(0.9–1.1); preferably, the molar ratio of the compound shown in formula (I) to sodium ions and water is 1:1:1.

[0022] In some embodiments, the X-ray powder diffraction pattern of the first sodium salt crystal form has diffraction peaks at the following 2θ angles: 6.7±0.2°, 7.2±0.2°, 14.9±0.2°, and 18.1±0.2°.

[0023] Furthermore, the X-ray powder diffraction pattern of the first sodium salt crystal form also has diffraction peaks at one or more of the following 2θ angles: 9.0±0.2°, 16.9±0.2°, 23.8±0.2°, 24.1±0.2°, 26.8±0.2°, 27.4±0.2°.

[0024] In some embodiments, the X-ray powder diffraction pattern of the first sodium salt crystal form has diffraction peaks at the following 2θ angles: 6.7±0.2°, 7.2±0.2°, 9.0±0.2°, 14.2±0.2°, 14.9±0.2°, 18.1±0.2°, 24.1±0.2°, and 27.4±0.2°.

[0025] In some embodiments, the X-ray powder diffraction pattern of the first sodium salt crystal form has diffraction peaks at the following 2θ angles: 6.7±0.2°, 7.2±0.2°, 9.0±0.2°, 14.2±0.2°, 14.9±0.2°, 16.9±0.2°, 18.1±0.2°, 23.8±0.2°, 24.1±0.2°, 26.8±0.2°, and 27.4±0.2°.

[0026] In some embodiments, the positions of the diffraction peaks contained in the X-ray powder of the first sodium salt crystal form are shown in Table 1:

[0027] Table 1

[0028] In some embodiments, the first sodium salt crystal form is sodium salt crystal form A.

[0029] In some embodiments, the first sodium salt crystal form is sodium salt crystal form A, which has an X-ray powder diffraction pattern substantially as shown in FIG9.

[0030] In some embodiments, sodium salt crystal form A has an X-ray powder diffraction pattern substantially as shown in FIG9.

[0031] In some embodiments, the DSC plot of the first sodium salt crystal form includes an endothermic peak at 127.86 °C ± 10 °C.

[0032] In some embodiments, the first sodium salt crystal form is sodium salt crystal form A, which has a DSC diagram substantially as shown in FIG10.

[0033] In some embodiments, the first sodium salt crystal form is sodium salt crystal form A, which has a TGA diagram substantially as shown in FIG11.

[0034] In some embodiments, sodium salt crystal form A has a DSC diagram that is substantially as shown in FIG10.

[0035] In some embodiments, sodium salt crystal form A has a TGA diagram that is substantially as shown in FIG11.

[0036] In some embodiments, the first sodium salt crystal form has a weight loss of 3.4 ± 1% at 139 ± 10 °C.

[0037] In some embodiments, the first sodium salt crystal form is substantially amorphous when heated to 150°C (sodium salt is amorphous).

[0038] In some embodiments, the first sodium salt crystal form is sodium salt crystal form A, which has an X-ray powder diffraction pattern substantially as shown in FIG13 when heated to 150°C.

[0039] In some embodiments, sodium salt crystal form A, when heated to 150°C, has an X-ray powder diffraction pattern substantially as shown in Figure 13.

[0040] In some embodiments, the salt of the present invention is sodium salt crystal form A of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to sodium in sodium salt crystal form A is 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3; preferably 1:1.

[0041] In some embodiments, the sodium salt crystal form A includes the compound shown in formula (I), sodium ions, and water, wherein the molar ratio of the compound shown in formula (I) to sodium ions and water is (0.5–2):(0.5–2):(0.5–2); preferably, the molar ratio of the compound shown in formula (I) to sodium ions and water is (0.9–1.1):(0.9–1.1):(0.9–1.1); preferably, the molar ratio of the compound shown in formula (I) to sodium ions and water is 1:1:1.

[0042] In some embodiments, the X-ray powder diffraction pattern of the sodium salt crystal form A has diffraction peaks at the following 2θ angles: 6.7±0.2°, 7.2±0.2°, 14.9±0.2°, and 18.1±0.2°.

[0043] In some embodiments, the X-ray powder diffraction pattern of the sodium salt crystal form A has diffraction peaks at the following 2θ angles: 6.7±0.2°, 7.2±0.2°, 14.2±0.2°, 14.9±0.2°, and 18.1±0.2°.

[0044] Furthermore, the X-ray powder diffraction pattern of the sodium salt crystal form A also has diffraction peaks at one or more of the following 2θ angles: 9.0±0.2°, 16.9±0.2°, 23.8±0.2°, 24.1±0.2°, 26.8±0.2°, 27.4±0.2°.

[0045] In some embodiments, the X-ray powder diffraction pattern of the sodium salt crystal form A has diffraction peaks at the following 2θ angles: 6.7±0.2°, 7.2±0.2°, 9.0±0.2°, 14.2±0.2°, 14.9±0.2°, 18.1±0.2°, 24.1±0.2°, and 27.4±0.2°.

[0046] In some embodiments, the X-ray powder diffraction pattern of the sodium salt crystal form A has diffraction peaks at the following 2θ angles: 6.7±0.2°, 7.2±0.2°, 9.0±0.2°, 14.2±0.2°, 14.9±0.2°, 16.9±0.2°, 18.1±0.2°, 23.8±0.2°, 24.1±0.2°, 26.8±0.2°, 27.4±0.2°.

[0047] In some embodiments, the positions of the diffraction peaks contained in the X-ray powder of sodium salt crystal form A are shown in Table 1:

[0048] Table 1

[0049] In some embodiments, the sodium salt crystal form A has an X-ray powder diffraction pattern substantially as shown in FIG9.

[0050] In some embodiments, the DSC plot of the sodium salt crystal form A includes an endothermic peak at 127.86 °C ± 10 °C.

[0051] In some embodiments, the sodium salt crystal form A has a DSC diagram substantially as shown in FIG10.

[0052] In some embodiments, the sodium salt crystal form A has a TGA diagram substantially as shown in FIG11.

[0053] In some embodiments, the sodium salt crystal form A has a weight loss of 3.4 ± 1% at 139 ± 10 °C.

[0054] In some embodiments, the sodium salt crystal form A is essentially amorphous when heated to 150°C (sodium salt is amorphous).

[0055] In some embodiments, the sodium salt crystal form A, when heated to 150°C, has an X-ray powder diffraction pattern substantially as shown in FIG13.

[0056] In some embodiments, the salt is an amorphous sodium salt, and the molar ratio of the compound represented by formula (I) to sodium ions is (0.5–2):(0.5–2):(0.5–2); preferably, the molar ratio of the compound represented by formula (I) to sodium ions is (0.9–1.1):(0.9–1.1):(0.9–1.1); preferably, the molar ratio of the compound represented by formula (I) to sodium ions is 1:1.

[0057] In some embodiments, the molar ratio of the compound of formula (I) to sodium in the second sodium salt crystal form is 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3.

[0058] In some embodiments, the molar ratio of the compound of formula (I) in the second sodium salt crystal form to sodium is 1:1.

[0059] In some embodiments, the salt of the present invention is a second sodium salt crystal form of the compound shown in formula (I), the second sodium salt crystal form comprising the compound shown in formula (I), sodium ions, and 1,4-dioxane, wherein the molar ratio of the compound shown in formula (I) to sodium ions and 1,4-dioxane is (0.5–2):(0.5–2):(0.5–2); preferably, the molar ratio of the compound shown in formula (I) to sodium ions and 1,4-dioxane is (0.9–1.1):(0.9–1.1):(0.9–1.1); preferably, the molar ratio of the compound shown in formula (I) to sodium ions and 1,4-dioxane is 1:1:1.

[0060] In some embodiments, the X-ray powder diffraction pattern of the second sodium salt crystal form has diffraction peaks at the following 2θ angles: 6.1±0.2°, 10.6±0.2°, 19.9±0.2°, and 23.2±0.2°. In some embodiments, the X-ray powder diffraction pattern of the second sodium salt crystal form has diffraction peaks at the following 2θ angles: 6.1±0.2°, 7.4±0.2°, 10.6±0.2°, 19.9±0.2°, and 23.2±0.2°.

[0061] Furthermore, the X-ray powder diffraction pattern of the second sodium salt crystal form also has diffraction peaks at one or more of the following 2θ angles: 6.7±0.2°, 8.6±0.2°, 14.5±0.2°, 15.5±0.2°, 17.2±0.2°, 18.1±0.2°, 18.3±0.2°, 25.9±0.2°.

[0062] In some embodiments, the X-ray powder diffraction pattern of the second sodium salt crystal form has diffraction peaks at the following 2θ angles: 6.1±0.2°, 6.7±0.2°, 7.4±0.2°, 8.6±0.2°, 10.6±0.2°, 18.1±0.2°, 19.9±0.2°, and 23.2±0.2°.

[0063] In some embodiments, the X-ray powder diffraction pattern of the second sodium salt crystal form has diffraction peaks at the following 2θ angles: 6.1±0.2°, 6.7±0.2°, 7.4±0.2°, 8.6±0.2°, 10.6±0.2°, 18.1±0.2°, 18.3±0.2°, 19.9±0.2°, and 23.2±0.2°.

[0064] In some embodiments, the X-ray powder diffraction pattern of the second sodium salt crystal form has diffraction peaks at the following 2θ angles: 6.1±0.2°, 6.7±0.2°, 7.4±0.2°, 8.6±0.2°, 10.6±0.2°, 15.5±0.2°, 17.2±0.2°, 18.1±0.2°, 19.9±0.2°, 23.2±0.2°.

[0065] In some embodiments, the X-ray powder diffraction pattern of the second sodium salt crystal form has diffraction peaks at the following 2θ angles: 6.1±0.2°, 6.7±0.2°, 7.4±0.2°, 8.6±0.2°, 10.6±0.2°, 15.5±0.2°, 17.2±0.2°, 18.1±0.2°, 18.3±0.2°, 19.9±0.2°, and 23.2±0.2°.

[0066] In some embodiments, the X-ray powder diffraction pattern of the second sodium salt crystal form has diffraction peaks at the following 2θ angles: 6.1±0.2°, 6.7±0.2°, 7.4±0.2°, 8.6±0.2°, 10.6±0.2°, 14.5±0.2°, 15.5±0.2°, 17.2±0.2°, 18.1±0.2°, 18.3±0.2°, 19.9±0.2°, 23.2±0.2°, and 25.9±0.2°.

[0067] In some embodiments, the X-ray powder diffraction pattern of the second sodium salt crystal form has diffraction peaks at the following 2θ angles: 6.1±0.2°, 6.7±0.2°, 7.4±0.2°, 8.6±0.2°, 10.6±0.2°, 14.5±0.2°, 15.5±0.2°, 17.2±0.2°, 18.1±0.2°, 19.9±0.2°, 23.2±0.2°, and 25.9±0.2°.

[0068] In some embodiments, the X-ray powder diffraction pattern of the second sodium salt crystal form contains the diffraction peak positions shown in Table 2:

[0069] Table 2

[0070] In some embodiments, the second sodium salt crystal form is sodium salt crystal form B.

[0071] In some embodiments, the second sodium salt crystal form is sodium salt crystal form B, which has an X-ray powder diffraction pattern substantially as shown in FIG14.

[0072] In some embodiments, sodium salt crystal form B has an X-ray powder diffraction pattern substantially as shown in FIG14.

[0073] In some embodiments, the DSC diagram of the second sodium salt crystal form includes an endothermic peak at 125.50 °C ± 10 °C.

[0074] In some embodiments, the second sodium salt crystal form is sodium salt crystal form B, which has a DSC diagram substantially as shown in FIG15.

[0075] In some embodiments, the second sodium salt crystal form is sodium salt crystal form B, which has a TGA diagram substantially as shown in FIG16.

[0076] In some embodiments, the sodium salt crystal form B has a DSC diagram substantially as shown in FIG15.

[0077] In some embodiments, the sodium salt crystal form B has a TGA diagram substantially as shown in FIG16.

[0078] In some embodiments, the second sodium salt crystal form has a weight loss of 12.2 ± 1% at 153 ± 10 °C.

[0079] In some embodiments, the salt of the present invention is the third sodium salt crystal form of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to sodium in the third sodium salt crystal form is 3:1, 2:1, 1:0.9, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3.

[0080] In some embodiments, the molar ratio of the compound of formula (I) in the third sodium salt crystal form to sodium is 1:1.

[0081] In some embodiments, the third sodium salt crystal form includes the compound shown in formula (I), sodium ions, and dimethyl sulfoxide, wherein the molar ratio of the compound shown in formula (I) to sodium ions and dimethyl sulfoxide is (0.5–2):(0.5–2):(0.5–2); preferably, the molar ratio of the compound shown in formula (I) to sodium ions and dimethyl sulfoxide is (0.9–1.1):(0.9–1.1):(0.9–1.1); preferably, the molar ratio of the compound shown in formula (I) to sodium ions and dimethyl sulfoxide is 1:1:1.

[0082] In some embodiments, the X-ray powder diffraction pattern of the third sodium salt crystal form has diffraction peaks at the following 2θ angles: 5.9±0.2°, 10.6±0.2°, 18.3±0.2°. In some embodiments, the X-ray powder diffraction pattern of the third sodium salt crystal form has diffraction peaks at the following 2θ angles: 5.9±0.2°, 10.6±0.2°, 18.3±0.2°, 23.4±0.2°.

[0083] Furthermore, the X-ray powder diffraction pattern of the third sodium salt crystal form also has diffraction peaks at one or more of the following 2θ angles: 7.6±0.2°, 14.7±0.2°, 15.6±0.2°, 25.9±0.2°.

[0084] In some embodiments, the X-ray powder diffraction pattern of the third sodium salt crystal form has diffraction peaks at the following 2θ angles: 5.9±0.2°, 7.6±0.2°, 10.6±0.2°, 15.6±0.2°, 18.3±0.2°, and 23.4±0.2°.

[0085] In some embodiments, the X-ray powder diffraction pattern of the third sodium salt crystal form has diffraction peaks at the following 2θ angles: 5.9±0.2°, 7.6±0.2°, 10.6±0.2°, 14.7±0.2°, 15.6±0.2°, 18.3±0.2°, 23.4±0.2°, and 25.9±0.2°.

[0086] In some embodiments, the X-ray powder diffraction pattern of the third sodium salt crystal form contains the diffraction peak positions shown in Table 3:

[0087] Table 3

[0088] In some embodiments, the third sodium salt crystal form is sodium salt crystal form C.

[0089] In some embodiments, the third sodium salt crystal form is sodium salt crystal form C, which has an X-ray powder diffraction pattern substantially as shown in FIG18.

[0090] In some embodiments, sodium salt crystal form C has an X-ray powder diffraction pattern substantially as shown in FIG18.

[0091] In some embodiments, the DSC diagram of the third sodium salt crystal form includes one or more endothermic peaks among 57.44℃±10℃, 102.84℃±10℃, and 141.86℃±10℃.

[0092] In some embodiments, the third sodium salt crystal form is sodium salt crystal form C, which has a DSC diagram substantially as shown in FIG19.

[0093] In some embodiments, the third sodium salt crystal form is sodium salt crystal form C, which has a TGA diagram substantially as shown in FIG20.

[0094] In some embodiments, sodium salt crystal form C has a DSC diagram that is substantially as shown in FIG19.

[0095] In some embodiments, sodium salt crystal form C has a TGA diagram that is substantially as shown in FIG20.

[0096] In some embodiments, the third sodium salt crystal form exhibits a weight loss of 1 ± 1% at 74 ± 10 °C and a weight loss of 7.7 ± 1% at temperatures ranging from 74 ± 10 °C to 139 ± 10 °C.

[0097] In some embodiments, the salt of the present invention is the fourth sodium salt crystal form of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to sodium in the fourth sodium salt crystal form is 3:1, 2:1, 1:1, 1:1.1, 1:1.5, 1:2, 1:2.5 or 1:3.

[0098] In some embodiments, the molar ratio of the compound of formula (I) in the fourth sodium salt crystal form to sodium is 1:1.

[0099] In some embodiments, the fourth sodium salt crystal form includes the compound shown in formula (I), sodium ions, and water, wherein the molar ratio of the compound shown in formula (I) to sodium ions and water is (0.5–2):(0.5–2):(0.5–2); preferably, the molar ratio of the compound shown in formula (I) to sodium ions and water is (0.9–1.1):(0.9–1.1):(0.9–1.1); preferably, the molar ratio of the compound shown in formula (I) to sodium ions and water is 1:1:1.

[0100] In some embodiments, the X-ray powder diffraction pattern of the fourth sodium salt crystal form has diffraction peaks at the following 2θ angles: 6.8±0.2°, 7.7±0.2°, 17.2±0.2°. In some embodiments, the X-ray powder diffraction pattern of the fourth sodium salt crystal form has diffraction peaks at the following 2θ angles: 6.8±0.2°, 7.7±0.2°, 13.7±0.2°, 15.1±0.2°, 17.2±0.2°.

[0101] Furthermore, the X-ray powder diffraction pattern of the fourth sodium salt crystal form also has diffraction peaks at one or more of the following 2θ angles: 9.9±0.2°, 11.2±0.2°, 14.4±0.2°, 15.6±0.2°, 20.2±0.2°, 20.5±0.2°, 21.3±0.2°, 22.5±0.2°, and 27.9±0.2°.

[0102] In some embodiments, the X-ray powder diffraction pattern of the fourth sodium salt crystal form has diffraction peaks at the following 2θ angles: 6.8±0.2°, 7.7±0.2°, 9.9±0.2°, 11.2±0.2°, 13.7±0.2°, 15.1±0.2°, 15.6±0.2°, 17.2±0.2°, and 20.2±0.2°.

[0103] In some embodiments, the X-ray powder diffraction pattern of the fourth sodium salt crystal form has diffraction peaks at the following 2θ angles: 6.8±0.2°, 7.7±0.2°, 9.9±0.2°, 11.2±0.2°, 13.7±0.2°, 14.4±0.2°, 15.1±0.2°, 15.6±0.2°, 17.2±0.2°, 20.2±0.2°, 20.5±0.2°, 21.3±0.2°, 22.5±0.2°, and 27.9±0.2°.

[0104] In some embodiments, the X-ray powder diffraction pattern of the fourth sodium salt crystal form contains the diffraction peak positions shown in Table 4:

[0105] Table 4

[0106] In some embodiments, the fourth sodium salt crystal form is sodium salt crystal form D.

[0107] In some embodiments, the fourth sodium salt crystal form is sodium salt crystal form D, which has an X-ray powder diffraction pattern substantially as shown in FIG22.

[0108] In some embodiments, the sodium salt crystal form D has an X-ray powder diffraction pattern substantially as shown in FIG22.

[0109] In some embodiments, the DSC plot of the fourth sodium salt crystal form includes an endothermic peak at 129.81 °C ± 10 °C.

[0110] In some embodiments, the fourth sodium salt crystal form is sodium salt crystal form D, which has a DSC diagram substantially as shown in FIG23.

[0111] In some embodiments, the fourth sodium salt crystal form is sodium salt crystal form D, which has a TGA diagram substantially as shown in FIG24.

[0112] In some embodiments, sodium salt crystal form D has a DSC diagram that is substantially as shown in FIG23.

[0113] In some embodiments, sodium salt crystal form D has a TGA diagram that is substantially as shown in FIG24.

[0114] In some embodiments, the fourth sodium salt crystal form has a weight loss of 3.7 ± 1% at 110 ± 10 °C.

[0115] In some embodiments, the sodium salt of the compound of formula (I) of the present invention is a first sodium salt crystal form, a second sodium salt crystal form, a third sodium salt crystal form, or a fourth sodium salt crystal form of the compound of formula (I).

[0116] In some embodiments, the salt of the present invention is a sodium salt crystal form D of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to sodium in sodium salt crystal form D is 3:1, 2:1, 1:1, 1:1.1, 1:1.5, 1:2, 1:2.5 or 1:3.

[0117] In some embodiments, the molar ratio of the compound of formula (I) in sodium salt crystal form D to sodium is 1:1.

[0118] In some embodiments, the sodium salt crystal form D includes the compound shown in formula (I), sodium ions, and water, wherein the molar ratio of the compound shown in formula (I) to sodium ions and water is (0.5–2):(0.5–2):(0.5–2); preferably, the molar ratio of the compound shown in formula (I) to sodium ions and water is (0.9–1.1):(0.9–1.1):(0.9–1.1); preferably, the molar ratio of the compound shown in formula (I) to sodium ions and water is 1:1:1.

[0119] In some embodiments, the X-ray powder diffraction pattern of the sodium salt crystal form D has diffraction peaks at the following 2θ angles: 6.8±0.2°, 7.7±0.2°, 17.2±0.2°.

[0120] In some embodiments, the X-ray powder diffraction pattern of the sodium salt crystal form D has diffraction peaks at the following 2θ angles: 6.8±0.2°, 7.7±0.2°, 13.7±0.2°, 15.1±0.2°, and 17.2±0.2°.

[0121] Furthermore, the X-ray powder diffraction pattern of the sodium salt crystal form D also has diffraction peaks at one or more of the following 2θ angles: 9.9±0.2°, 11.2±0.2°, 14.4±0.2°, 15.6±0.2°, 20.2±0.2°, 20.5±0.2°, 21.3±0.2°, 22.5±0.2°, 27.9±0.2°.

[0122] In some embodiments, the X-ray powder diffraction pattern of the sodium salt crystal form D has diffraction peaks at the following 2θ angles: 6.8±0.2°, 7.7±0.2°, 9.9±0.2°, 11.2±0.2°, 13.7±0.2°, 15.1±0.2°, 15.6±0.2°, 17.2±0.2°, and 20.2±0.2°.

[0123] In some embodiments, the X-ray powder diffraction pattern of the sodium salt crystal form D has diffraction peaks at the following 2θ angles: 6.8±0.2°, 7.7±0.2°, 9.9±0.2°, 11.2±0.2°, 13.7±0.2°, 14.4±0.2°, 15.1±0.2°, 15.6±0.2°, 17.2±0.2°, 20.2±0.2°, 20.5±0.2°, 21.3±0.2°, 22.5±0.2°, and 27.9±0.2°.

[0124] In some embodiments, the X-ray powder diffraction pattern of the sodium salt crystal form D contains the diffraction peak positions shown in Table 4:

[0125] Table 4

[0126] In some embodiments, the sodium salt crystal form D has an X-ray powder diffraction pattern substantially as shown in FIG22.

[0127] In some embodiments, the DSC plot of the sodium salt crystal form D includes an endothermic peak at 129.81 °C ± 10 °C.

[0128] In some embodiments, sodium salt crystal form D has a DSC diagram that is substantially as shown in FIG23.

[0129] In some embodiments, sodium salt crystal form D has a TGA diagram that is substantially as shown in FIG24.

[0130] In some embodiments, the sodium salt crystal form D has a weight loss of 3.7 ± 1% at 110 ± 10 °C.

[0131] In some embodiments, the salt of the present invention is the first potassium salt crystal form of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to potassium in the first potassium salt crystal form is 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3.

[0132] In some embodiments, the molar ratio of the compound of formula (I) in the first potassium salt crystal form to potassium is 1:1.

[0133] In some embodiments, the first potassium salt crystal form includes the compound shown in formula (I), potassium ions, and water, wherein the molar ratio of the compound shown in formula (I) to potassium ions and water is (0.5–2):(0.5–2):(0.5–2); preferably, the molar ratio of the compound shown in formula (I) to potassium ions and water is (0.9–1.1):(0.9–1.1):(0.9–1.1); preferably, the molar ratio of the compound shown in formula (I) to potassium ions and water is 1:1:1.

[0134] In some embodiments, the X-ray powder diffraction pattern of the first potassium salt crystal form has diffraction peaks at the following 2θ angles: 6.8±0.2°, 7.7±0.2°, 10.9±0.2°, and 15.4±0.2°.

[0135] In some embodiments, the X-ray powder diffraction pattern of the first potassium salt crystal form has diffraction peaks at the following 2θ angles: 6.8±0.2°, 7.7±0.2°, 10.9±0.2°, 15.4±0.2°, and 20.2±0.2°.

[0136] Furthermore, the X-ray powder diffraction pattern of the first potassium salt crystal form also has diffraction peaks at one or more of the following 2θ angles: 9.9±0.2°, 13.6±0.2°, 14.2±0.2°, 15.1±0.2°, 17.4±0.2°, 22.9±0.2°, 23.3±0.2°, 24.7±0.2°, 24.9±0.2°.

[0137] In some embodiments, the X-ray powder diffraction pattern of the first potassium salt crystal form has diffraction peaks at the following 2θ angles: 6.8±0.2°, 7.7±0.2°, 10.9±0.2°, 15.4±0.2°, 17.4±0.2°, 20.2±0.2°, and 24.9±0.2°.

[0138] In some embodiments, the X-ray powder diffraction pattern of the first potassium salt crystal form has diffraction peaks at the following 2θ angles: 6.8±0.2°, 7.7±0.2°, 9.9±0.2°, 10.9±0.2°, 14.2±0.2°, 15.1±0.2°, 15.4±0.2°, 17.4±0.2°, 20.2±0.2°, 23.3±0.2°, 24.7±0.2°, and 24.9±0.2°.

[0139] In some embodiments, the X-ray powder diffraction pattern of the first potassium salt crystal form has diffraction peaks at the following 2θ angles: 6.8±0.2°, 7.7±0.2°, 9.9±0.2°, 10.9±0.2°, 13.6±0.2°, 14.2±0.2°, 15.1±0.2°, 15.4±0.2°, 17.4±0.2°, 20.2±0.2°, 22.9±0.2°, 23.3±0.2°, 24.7±0.2°, and 24.9±0.2°.

[0140] In some embodiments, the X-ray powder diffraction pattern of the first potassium salt crystal form contains the diffraction peak positions shown in Table 5:

[0141] Table 5

[0142] In some embodiments, the first potassium salt crystal form is potassium salt crystal form A.

[0143] In some embodiments, the first potassium salt crystal form is potassium salt crystal form A, which has an X-ray powder diffraction pattern substantially as shown in FIG26.

[0144] In some embodiments, potassium salt crystal form A has an X-ray powder diffraction pattern substantially as shown in FIG26.

[0145] In some embodiments, the DSC plot of the first potassium salt crystal form includes one or more endothermic peaks at 127.94℃±10℃ and 137.15℃±10℃.

[0146] In some embodiments, the first potassium salt crystal form is potassium salt crystal form A, which has a DSC diagram substantially as shown in FIG27.

[0147] In some embodiments, the first potassium salt crystal form is potassium salt crystal form A, which has a TGA diagram substantially as shown in FIG28.

[0148] In some embodiments, potassium salt crystal form A has a DSC diagram that is substantially as shown in FIG27.

[0149] In some embodiments, potassium salt crystal form A has a TGA diagram that is substantially as shown in FIG28.

[0150] In some embodiments, the first potassium salt crystal form has a weight loss of 3.2 ± 1% at 120 ± 10 °C.

[0151] In some embodiments, the salt of the present invention is a potassium salt crystal form A of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to potassium in potassium salt crystal form A is 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3.

[0152] In some embodiments, the molar ratio of the compound of formula (I) in potassium salt crystal form A to potassium is 1:1.

[0153] In some embodiments, the potassium salt crystal form A includes the compound shown in formula (I), potassium ions, and water, wherein the molar ratio of the compound shown in formula (I) to potassium ions and water is (0.5–2):(0.5–2):(0.5–2); preferably, the molar ratio of the compound shown in formula (I) to potassium ions and water is (0.9–1.1):(0.9–1.1):(0.9–1.1); preferably, the molar ratio of the compound shown in formula (I) to potassium ions and water is 1:1:1.

[0154] In some embodiments, the X-ray powder diffraction pattern of the potassium salt crystal form A has diffraction peaks at the following 2θ angles: 6.8±0.2°, 7.7±0.2°, 10.9±0.2°, and 15.4±0.2°.

[0155] In some embodiments, the X-ray powder diffraction pattern of the potassium salt crystal form A has diffraction peaks at the following 2θ angles: 6.8±0.2°, 7.7±0.2°, 10.9±0.2°, 15.4±0.2°, and 20.2±0.2°.

[0156] Furthermore, the X-ray powder diffraction pattern of the potassium salt crystal form A also has diffraction peaks at one or more of the following 2θ angles: 9.9±0.2°, 13.6±0.2°, 14.2±0.2°, 15.1±0.2°, 17.4±0.2°, 22.9±0.2°, 23.3±0.2°, 24.7±0.2°, 24.9±0.2°.

[0157] In some embodiments, the X-ray powder diffraction pattern of the potassium salt crystal form A has diffraction peaks at the following 2θ angles: 6.8±0.2°, 7.7±0.2°, 10.9±0.2°, 15.4±0.2°, 17.4±0.2°, 20.2±0.2°, and 24.9±0.2°.

[0158] In some embodiments, the X-ray powder diffraction pattern of the potassium salt crystal form A has diffraction peaks at the following 2θ angles: 6.8±0.2°, 7.7±0.2°, 9.9±0.2°, 10.9±0.2°, 14.2±0.2°, 15.1±0.2°, 15.4±0.2°, 17.4±0.2°, 20.2±0.2°, 23.3±0.2°, 24.7±0.2°, and 24.9±0.2°.

[0159] In some embodiments, the X-ray powder diffraction pattern of the potassium salt crystal form A has diffraction peaks at the following 2θ angles: 6.8±0.2°, 7.7±0.2°, 9.9±0.2°, 10.9±0.2°, 13.6±0.2°, 14.2±0.2°, 15.1±0.2°, 15.4±0.2°, 17.4±0.2°, 20.2±0.2°, 22.9±0.2°, 23.3±0.2°, 24.7±0.2°, 24.9±0.2°.

[0160] In some embodiments, the X-ray powder diffraction pattern of the potassium salt crystal form A contains the diffraction peak positions shown in Table 5:

[0161] Table 5

[0162] In some embodiments, potassium salt crystal form A has an X-ray powder diffraction pattern substantially as shown in FIG26.

[0163] In some embodiments, the DSC plot of the potassium salt crystal form A includes one or more endothermic peaks at 127.94℃±10℃ and 137.15℃±10℃.

[0164] In some embodiments, potassium salt crystal form A has a DSC diagram that is substantially as shown in FIG27.

[0165] In some embodiments, potassium salt crystal form A has a TGA diagram that is substantially as shown in FIG28.

[0166] In some embodiments, the potassium salt crystal form A has a weight loss of 3.2 ± 1% at 120 ± 10 °C.

[0167] In some embodiments, the molar ratio of the compound of formula (I) to potassium in the second potassium salt crystal form is 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3.

[0168] In some embodiments, the molar ratio of the compound of formula (I) in the second potassium salt crystal form to potassium is 1:1.

[0169] In some embodiments, the second potassium salt crystal form comprises the compound shown in formula (I), potassium ions, and 1,4-dioxane, wherein the molar ratio of the compound shown in formula (I) to potassium ions and 1,4-dioxane is (0.5–2):(0.5–2):(0.5–2); preferably, the molar ratio of the compound shown in formula (I) to potassium ions and 1,4-dioxane is (0.9–1.1):(0.9–1.1):(0.9–1.1); preferably, the molar ratio of the compound shown in formula (I) to potassium ions and 1,4-dioxane is 1:1:1.

[0170] In some embodiments, the X-ray powder diffraction pattern of the second potassium salt crystal form has diffraction peaks at the following 2θ angles: 6.4±0.2°, 10.8±0.2°, 21.0±0.2°, 25.7±0.2°.

[0171] In some embodiments, the X-ray powder diffraction pattern of the second potassium salt crystal form has diffraction peaks at the following 2θ angles: 6.4±0.2°, 10.8±0.2°, 18.9±0.2°, 21.0±0.2°, 25.7±0.2°.

[0172] Furthermore, the X-ray powder diffraction pattern of the second potassium salt crystal form also has diffraction peaks at one or more of the following 2θ angles: 7.0±0.2°, 10.5±0.2°, 13.1±0.2°, 16.7±0.2°, 17.7±0.2°, 18.4±0.2°, 19.5±0.2°, 20.7±0.2°, 23.0±0.2°, 32.8±0.2°.

[0173] In some embodiments, the X-ray powder diffraction pattern of the second potassium salt crystal form has diffraction peaks at the following 2θ angles: 6.4±0.2°, 10.5±0.2°, 10.8±0.2°, 18.4±0.2°, 18.9±0.2°, 21.0±0.2°, and 25.7±0.2°.

[0174] In some embodiments, the X-ray powder diffraction pattern of the second potassium salt crystal form has diffraction peaks at the following 2θ angles: 6.4±0.2°, 7.0±0.2°, 10.5±0.2°, 10.8±0.2°, 13.1±0.2°, 16.7±0.2°, 18.4±0.2°, 18.9±0.2°, 19.5±0.2°, 21.0±0.2°, 23.0±0.2°, and 25.7±0.2°.

[0175] In some embodiments, the X-ray powder diffraction pattern of the second potassium salt crystal form has diffraction peaks at the following 2θ angles: 6.4±0.2°, 7.0±0.2°, 10.5±0.2°, 10.8±0.2°, 13.1±0.2°, 16.7±0.2°, 17.7±0.2°, 18.4±0.2°, 18.9±0.2°, 19.5±0.2°, 20.7±0.2°, 21.0±0.2°, 23.0±0.2°, 25.7±0.2°, and 32.8±0.2°.

[0176] In some embodiments, the positions of the diffraction peaks contained in the second potassium salt crystal form are shown in Table 6:

[0177] Table 6

[0178] In some embodiments, the second potassium salt crystal form is potassium salt crystal form B.

[0179] In some embodiments, the second potassium salt crystal form is potassium salt crystal form B, which has an X-ray powder diffraction pattern substantially as shown in FIG30.

[0180] In some embodiments, potassium salt crystal form B has an X-ray powder diffraction pattern substantially as shown in FIG30.

[0181] In some embodiments, the DSC plot of the second potassium salt crystal form includes one or more endothermic peaks at 120.94℃±10℃ and 136.50℃±10℃.

[0182] In some embodiments, the second potassium salt crystal form is potassium salt crystal form B, which has a DSC diagram substantially as shown in FIG31.

[0183] In some embodiments, the second potassium salt crystal form is potassium salt crystal form B, which has a TGA diagram substantially as shown in FIG32.

[0184] In some embodiments, the potassium salt crystal form B has a DSC diagram substantially as shown in FIG31.

[0185] In some embodiments, the potassium salt crystal form B has a TGA diagram substantially as shown in FIG32.

[0186] In some embodiments, the second potassium salt crystal form has a weight loss of 8.2 ± 1% at 130 ± 10 °C.

[0187] In some embodiments, the potassium salt of the compound of formula (I) of the present invention is a first potassium salt crystal form or a second potassium salt crystal form of the compound of formula (I).

[0188] In some embodiments, the salt of the present invention is the first trihydroxymethylaminomethane salt crystal form of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to trihydroxymethylaminomethane in the first trihydroxymethylaminomethane salt crystal form is 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3.

[0189] In some embodiments, the molar ratio of the compound of formula (I) in the first trihydroxymethylaminomethane salt crystal form to trihydroxymethylaminomethane is 1:1.

[0190] In some embodiments, the salt of the present invention is the first trihydroxymethylaminomethane salt crystal form of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to trihydroxymethylaminomethane is (0.5-2):(0.5-2); preferably, the molar ratio of the compound shown in formula (I) to trihydroxymethylaminomethane is (0.9-1.1):(0.9-1.1); preferably, the molar ratio of the compound shown in formula (I) to the trihydroxymethylaminomethane is 1:1.

[0191] In some embodiments, the X-ray powder diffraction pattern of the first trihydroxymethylaminomethane salt crystal form has diffraction peaks at the following 2θ angles: 6.5±0.2°, 9.5±0.2°, 14.3±0.2°, and 17.7±0.2°.

[0192] In some embodiments, the X-ray powder diffraction pattern of the first trihydroxymethylaminomethane salt crystal form has diffraction peaks at the following 2θ angles: 6.5±0.2°, 9.5±0.2°, 14.3±0.2°, 17.7±0.2°, and 30.0±0.2°.

[0193] Furthermore, the X-ray powder diffraction pattern of the first tris(hydroxymethyl)aminomethane salt crystal form also has diffraction peaks at one or more of the following 2θ angles: 14.9±0.2°, 17.0±0.2°, 17.4±0.2°, 18.2±0.2°, 20.0±0.2°, 20.7±0.2°, 21.1±0.2°, 21.6±0.2°, 22.5±0.2°, 23.1±0.2°, 23.5±0.2°, 24.2±0.2°, 26.2±0.2°, 28.7±0.2°, 31.8±0.2°.

[0194] In some embodiments, the X-ray powder diffraction pattern of the first tris(hydroxymethyl)aminomethane salt crystal form has diffraction peaks at the following 2θ angles: 6.5±0.2°, 9.5±0.2°, 14.3±0.2°, 17.0±0.2°, 17.7±0.2°, 18.2±0.2°, 21.6±0.2°, 22.5±0.2°, and 30.0±0.2°.

[0195] In some embodiments, the X-ray powder diffraction pattern of the first tris(hydroxymethyl)aminomethane salt crystal form has diffraction peaks at the following 2θ angles: 6.5±0.2°, 9.5±0.2°, 14.3±0.2°, 17.0±0.2°, 17.4±0.2°, 17.7±0.2°, 18.2±0.2°, 20.7±0.2°, 21.6±0.2°, 22.5±0.2°, 23.1±0.2°, 24.2±0.2°, 26.2±0.2°, 28.7±0.2°, and 30.0±0.2°.

[0196] In some embodiments, the X-ray powder diffraction pattern of the first tris(hydroxymethyl)aminomethane salt crystal form has diffraction peaks at the following 2θ angles: 6.5±0.2°, 9.5±0.2°, 14.3±0.2°, 14.9±0.2°, 17.0±0.2°, 17.4±0.2°, 17.7±0.2°, 18.2±0.2°, 20.0±0.2°, 20.7±0.2°, 21.1±0.2°, 21.6±0.2°, 22.5±0.2°, 23.1±0.2°, 23.5±0.2°, 24.2±0.2°, 26.2±0.2°, 28.7±0.2°, 30.0±0.2°, and 31.8±0.2°.

[0197] In some embodiments, the X-ray powder diffraction pattern of the first tris(hydroxymethyl)aminomethane salt crystal form contains the diffraction peak positions shown in Table 7:

[0198] Table 7

[0199] In some embodiments, the first trihydroxymethylaminomethane salt crystal form is trihydroxymethylaminomethane salt crystal form A.

[0200] In some embodiments, the first trihydroxymethylaminomethane salt crystal form is trihydroxymethylaminomethane salt crystal form A, which has an X-ray powder diffraction pattern substantially as shown in FIG34.

[0201] In some embodiments, the tris(hydroxymethyl)aminomethane salt crystal form A has an X-ray powder diffraction pattern substantially as shown in FIG34.

[0202] In some embodiments, the DSC plot of the first trihydroxymethylaminomethane salt crystal form includes one or more endothermic peaks at 135.07℃±10℃ and 203.43℃±10℃.

[0203] In some embodiments, the first trihydroxymethylaminomethane salt crystal form is trihydroxymethylaminomethane salt crystal form A, which has a DSC diagram substantially as shown in FIG35.

[0204] In some embodiments, the first trihydroxymethylaminomethane salt crystal form is trihydroxymethylaminomethane salt crystal form A, which has a TGA diagram substantially as shown in FIG36.

[0205] In some embodiments, the tris(hydroxymethyl)aminomethane salt crystal form A has a DSC diagram substantially as shown in FIG35.

[0206] In some embodiments, the tris(hydroxymethyl)aminomethane salt crystal form A has a TGA diagram substantially as shown in FIG36.

[0207] In some embodiments, the first trihydroxymethylaminomethane salt crystal form has a weight loss of 6.9±1% at 175±10°C.

[0208] In some embodiments, the molar ratio of the compound represented by formula (I) in the second trihydroxymethylaminomethane salt crystal form to trihydroxymethylaminomethane is 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3.

[0209] In some embodiments, the salt of the present invention is the second tris(hydroxymethyl)aminomethane salt crystal form of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to tris(hydroxymethyl)aminomethane is (0.5-2):(0.5-2); preferably, the molar ratio of the compound shown in formula (I) to tris(hydroxymethyl)aminomethane is (0.9-1.1):(0.9-1.1); preferably, the molar ratio of the compound shown in formula (I) to tris(hydroxymethyl)aminomethane is 1:1.

[0210] In some embodiments, the X-ray powder diffraction pattern of the second tris(hydroxymethyl)aminomethane salt crystal form has diffraction peaks at the following 2θ angles: 6.5±0.2°, 7.3±0.2°, 9.9±0.2°. In some embodiments, the X-ray powder diffraction pattern of the second tris(hydroxymethyl)aminomethane salt crystal form has diffraction peaks at the following 2θ angles: 6.5±0.2°, 7.3±0.2°, 9.9±0.2°, 17.6±0.2°, 20.3±0.2°.

[0211] Furthermore, the X-ray powder diffraction pattern of the second trihydroxymethylaminomethane salt crystal form also has diffraction peaks at one or more of the following 2θ angles: 6.9±0.2°, 10.2±0.2°, 14.7±0.2°, 14.9±0.2°, 15.0±0.2°, 15.5±0.2°, 16.0±0.2°, 17.9±0.2°, 19.5±0.2°, 26.0±0.2°.

[0212] In some embodiments, the X-ray powder diffraction pattern of the second trihydroxymethylaminomethane salt crystal form has diffraction peaks at the following 2θ angles: 6.5±0.2°, 6.9±0.2°, 7.3±0.2°, 9.9±0.2°, 10.2±0.2°, 14.9±0.2°, 16.0±0.2°, 17.6±0.2°, 19.5±0.2°, and 20.3±0.2°.

[0213] In some embodiments, the X-ray powder diffraction pattern of the second trihydroxymethylaminomethane salt crystal form has diffraction peaks at the following 2θ angles: 6.5±0.2°, 6.9±0.2°, 7.3±0.2°, 9.9±0.2°, 14.9±0.2°, 16.0±0.2°, 17.6±0.2°, 19.5±0.2°, and 20.3±0.2°.

[0214] In some embodiments, the X-ray powder diffraction pattern of the second trihydroxymethylaminomethane salt crystal form has diffraction peaks at the following 2θ angles: 6.5±0.2°, 6.9±0.2°, 7.3±0.2°, 9.9±0.2°, 10.2±0.2°, 14.7±0.2°, 14.9±0.2°, 15.0±0.2°, 15.5±0.2°, 16.0±0.2°, 17.6±0.2°, 17.9±0.2°, 19.5±0.2°, 20.3±0.2°, and 26.0±0.2°.

[0215] In some embodiments, the X-ray powder diffraction pattern of the second trihydroxymethylaminomethane salt crystal form has diffraction peaks at the following 2θ angles: 6.5±0.2°, 6.9±0.2°, 7.3±0.2°, 9.9±0.2°, 14.7±0.2°, 14.9±0.2°, 15.0±0.2°, 15.5±0.2°, 16.0±0.2°, 17.6±0.2°, 17.9±0.2°, 19.5±0.2°, 20.3±0.2°, and 26.0±0.2°.

[0216] In some embodiments, the X-ray powder diffraction pattern of the second tris(hydroxymethyl)aminomethane salt crystal form contains the diffraction peak positions shown in Table 8:

[0217] Table 8

[0218] In some embodiments, the second trihydroxymethylaminomethane salt crystal form is trihydroxymethylaminomethane salt crystal form B.

[0219] In some embodiments, the second trihydroxymethylaminomethane salt crystal form is trihydroxymethylaminomethane salt crystal form B, which has an X-ray powder diffraction pattern substantially as shown in FIG38.

[0220] In some embodiments, the tris(hydroxymethyl)aminomethane salt crystal form B has an X-ray powder diffraction pattern substantially as shown in FIG38.

[0221] In some embodiments, the DSC plot of the second trihydroxymethylaminomethane salt crystal form includes one or more endothermic peaks at 143.28℃±10℃ and 203.19℃±10℃.

[0222] In some embodiments, the second trihydroxymethylaminomethane salt crystal form is trihydroxymethylaminomethane salt crystal form B, which has a DSC diagram substantially as shown in FIG39.

[0223] In some embodiments, the second trihydroxymethylaminomethane salt crystal form is trihydroxymethylaminomethane salt crystal form B, which has a TGA diagram substantially as shown in FIG40.

[0224] In some embodiments, the tris(hydroxymethyl)aminomethane salt crystal form B has a DSC diagram substantially as shown in FIG39.

[0225] In some embodiments, the tris(hydroxymethyl)aminomethane salt crystal form B has a TGA diagram substantially as shown in FIG40.

[0226] In some embodiments, the second trihydroxymethylaminomethane salt crystal form has a weight loss of 0.4±1% at 105±10°C, or the second trihydroxymethylaminomethane salt crystal form has a weight loss of 8.0±1% at temperatures ranging from 105±10°C to 175±10°C.

[0227] In some embodiments, the trihydroxymethylaminomethane salt of the compound of formula (I) of the present invention is either the first or second trihydroxymethylaminomethane salt crystal form of the compound of formula (I).

[0228] In some embodiments, the salt of the present invention is the ethanolamine salt crystal form of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to ethanolamine in the ethanolamine salt crystal form is 3:1, 2:1, 1:0.7, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3.

[0229] In some embodiments, the salt of the present invention is the ethanolamine salt crystal form of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to ethanolamine is (0.5-2):(0.5-2); preferably, the molar ratio of the compound shown in formula (I) to ethanolamine is (0.9-1.1):(0.9-1.1); preferably, the molar ratio of the compound shown in formula (I) to ethanolamine is 1:1.

[0230] In some embodiments, the X-ray powder diffraction pattern of the ethanolamine salt crystal form has diffraction peaks at the following 2θ angles: 9.4±0.2°, 19.5±0.2°, 20.2±0.2°, and 22.9±0.2°.

[0231] In some embodiments, the X-ray powder diffraction pattern of the ethanolamine salt crystal form has diffraction peaks at the following 2θ angles: 9.4±0.2°, 17.9±0.2°, 19.5±0.2°, 20.2±0.2°, and 22.9±0.2°.

[0232] Furthermore, the X-ray powder diffraction pattern of the ethanolamine salt crystal form also has diffraction peaks at one or more of the following 2θ angles: 10.1±0.2°, 11.9±0.2°, 12.3±0.2°, 14.2±0.2°, 14.5±0.2°, 16.7±0.2°, 17.6±0.2°, 20.5±0.2°, 27.4±0.2°, 28.0±0.2°, 28.4±0.2°.

[0233] In some embodiments, the X-ray powder diffraction pattern of the ethanolamine salt crystal form has diffraction peaks at the following 2θ angles: 9.4±0.2°, 10.1±0.2°, 11.9±0.2°, 14.5±0.2°, 17.6±0.2°, 17.9±0.2°, 19.5±0.2°, 20.2±0.2°, and 22.9±0.2°.

[0234] In some embodiments, the X-ray powder diffraction pattern of the ethanolamine salt crystal form has diffraction peaks at the following 2θ angles: 9.4±0.2°, 10.1±0.2°, 11.9±0.2°, 12.3±0.2°, 14.2±0.2°, 14.5±0.2°, 16.7±0.2°, 17.6±0.2°, 17.9±0.2°, 19.5±0.2°, 20.2±0.2°, 20.5±0.2°, 22.9±0.2°, 27.4±0.2°, 28.0±0.2°, 28.4±0.2°.

[0235] In some embodiments, the X-ray powder diffraction pattern of the ethanolamine salt crystal form contains the diffraction peak positions shown in Table 9:

[0236] Table 9

[0237] In some embodiments, the ethanolamine salt crystal form is ethanolamine salt crystal form A.

[0238] In some embodiments, the ethanolamine salt crystal form is ethanolamine salt crystal form A, which has an X-ray powder diffraction pattern substantially as shown in FIG42.

[0239] In some embodiments, ethanolamine salt crystal form A has an X-ray powder diffraction pattern substantially as shown in FIG42.

[0240] In some embodiments, the DSC plot of the ethanolamine salt crystal form includes an endothermic peak at 134.61 °C ± 10 °C.

[0241] In some embodiments, the ethanolamine salt crystal form is ethanolamine salt crystal form A, which has a DSC diagram substantially as shown in FIG43.

[0242] In some embodiments, the ethanolamine salt crystal form is ethanolamine salt crystal form A, which has a TGA diagram substantially as shown in FIG44.

[0243] In some embodiments, ethanolamine salt crystal form A has a DSC diagram that is substantially as shown in FIG43.

[0244] In some embodiments, ethanolamine salt crystal form A has a TGA diagram that is substantially as shown in FIG44.

[0245] In some embodiments, the ethanolamine salt crystal form exhibits a weight loss of 7.6 ± 1% at 175 ± 10 °C.

[0246] In some embodiments, the salt of the present invention is the first imidazole salt crystal form of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to imidazole in the first imidazole salt crystal form is 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3.

[0247] In some embodiments, the salt of the present invention is the first imidazole salt crystal form of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to imidazole is (0.5-2):(0.5-2); preferably, the molar ratio of the compound shown in formula (I) to imidazole is (0.9-1.1):(0.9-1.1); preferably, the molar ratio of the compound shown in formula (I) to imidazole is 1:1.

[0248] In some embodiments, the X-ray powder diffraction pattern of the first imidazole salt crystal form has diffraction peaks at the following 2θ angles: 7.4±0.2°, 14.7±0.2°, 18.7±0.2°, 19.9±0.2°.

[0249] In some embodiments, the X-ray powder diffraction pattern of the first imidazole salt crystal form has diffraction peaks at the following 2θ angles: 6.2±0.2°, 6.9±0.2°, 7.4±0.2°, 14.7±0.2°, 18.7±0.2°, and 19.9±0.2°.

[0250] Furthermore, the X-ray powder diffraction pattern of the first imidazole salt crystal form also has diffraction peaks at one or more of the following 2θ angles: 10.8±0.2°, 12.4±0.2°, 12.9±0.2°, 16.3±0.3°, 19.3±0.2°, 22.1±0.2°, 23.3±0.2°, 27.1±0.2°.

[0251] In some embodiments, the X-ray powder diffraction pattern of the first imidazole salt crystal form has diffraction peaks at the following 2θ angles: 6.2±0.2°, 6.9±0.2°, 7.4±0.2°, 12.9±0.2°, 14.7±0.2°, 16.3±0.2°, 18.7±0.2°, 19.3±0.2°, and 19.9±0.2°.

[0252] In some embodiments, the X-ray powder diffraction pattern of the first imidazole salt crystal form has diffraction peaks at the following 2θ angles: 6.2±0.2°, 6.9±0.2°, 7.4±0.2°, 10.8±0.2°, 12.4±0.2°, 12.9±0.2°, 14.7±0.2°, 16.3±0.2°, 18.7±0.2°, 19.3±0.2°, 19.9±0.2°, 22.1±0.2°, 23.3±0.2°, and 27.1±0.2°.

[0253] In some embodiments, the X-ray powder diffraction pattern of the first imidazole salt crystal form contains the diffraction peak positions shown in Table 10:

[0254] Table 10

[0255] In some embodiments, the first imidazole salt crystal form is imidazole salt crystal form A.

[0256] In some embodiments, the first imidazole salt crystal form is imidazole salt crystal form A, which has an X-ray powder diffraction pattern substantially as shown in FIG46.

[0257] In some embodiments, imidazole salt crystal form A has an X-ray powder diffraction pattern substantially as shown in FIG46.

[0258] In some embodiments, the DSC plot of the first imidazole salt crystal form includes one or more endothermic peaks at 154.65℃±10℃, 162.92℃±10℃, 177.76℃±10℃, and 200.00℃±10℃.

[0259] In some embodiments, the first imidazole salt crystal form is imidazole salt crystal form A, which has a DSC diagram substantially as shown in FIG47.

[0260] In some embodiments, the first imidazole salt crystal form is imidazole salt crystal form A, which has a TGA diagram substantially as shown in FIG48.

[0261] In some embodiments, imidazole salt crystal form A has a DSC diagram that is substantially as shown in FIG47.

[0262] In some embodiments, imidazole salt crystal form A has a TGA diagram that is substantially as shown in FIG48.

[0263] In some embodiments, the first imidazole salt crystal form has a weight loss of 4.3±1% at 150±10°C and a weight loss of 16.4±1% at temperatures ranging from 150±10°C to 220±10°C.

[0264] In some embodiments, the molar ratio of the compound of formula (I) to imidazole in the second imidazole salt crystal form is 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3.

[0265] In some embodiments, the salt of the present invention is the second imidazole salt crystal form of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to imidazole is (0.5-2):(0.5-2); preferably, the molar ratio of the compound shown in formula (I) to imidazole is (0.9-1.1):(0.9-1.1); preferably, the molar ratio of the compound shown in formula (I) to imidazole is 1:1.

[0266] In some embodiments, the X-ray powder diffraction pattern of the second imidazole salt crystal form has diffraction peaks at the following 2θ angles: 4.6±0.2°, 9.3±0.2°, 13.0±0.2°, and 28.0±0.2°.

[0267] Furthermore, the X-ray powder diffraction pattern of the second imidazole salt crystal form also has diffraction peaks at one or more of the following 2θ angles: 11.1±0.2°, 12.2±0.2°, 14.0±0.2°, 15.8±0.2°, 17.8±0.2°, 23.3±0.2°.

[0268] In some embodiments, the X-ray powder diffraction pattern of the second imidazole salt crystal form has diffraction peaks at the following 2θ angles: 4.6±0.2°, 9.3±0.2°, 13.0±0.2°, 23.3±0.2°, and 28.0±0.2°.

[0269] In some embodiments, the X-ray powder diffraction pattern of the second imidazole salt crystal form has diffraction peaks at the following 2θ angles: 4.6±0.2°, 9.3±0.2°, 12.2±0.2°, 13.0±0.2°, 23.3±0.2°, and 28.0±0.2°.

[0270] In some embodiments, the X-ray powder diffraction pattern of the second imidazole salt crystal form has diffraction peaks at the following 2θ angles: 4.6±0.2°, 9.3±0.2°, 11.1±0.2°, 13.0±0.2°, 23.3±0.2°, and 28.0±0.2°.

[0271] In some embodiments, the X-ray powder diffraction pattern of the second imidazole salt crystal form has diffraction peaks at the following 2θ angles: 4.6±0.2°, 9.3±0.2°, 11.1±0.2°, 12.2±0.2°, 13.0±0.2°, 23.3±0.2°, and 28.0±0.2°.

[0272] In some embodiments, the X-ray powder diffraction pattern of the second imidazole salt crystal form has diffraction peaks at the following 2θ angles: 4.6±0.2°, 9.3±0.2°, 11.1±0.2°, 12.2±0.2°, 13.0±0.2°, 14.0±0.2°, 15.8±0.2°, 23.3±0.2°, and 28.0±0.2°.

[0273] In some embodiments, the X-ray powder diffraction pattern of the second imidazole salt crystal form has diffraction peaks at the following 2θ angles: 4.6±0.2°, 9.3±0.2°, 11.1±0.2°, 13.0±0.2°, 17.8±0.2°, 23.3±0.2°, and 28.0±0.2°.

[0274] In some embodiments, the X-ray powder diffraction pattern of the second imidazole salt crystal form has diffraction peaks at the following 2θ angles: 4.6±0.2°, 9.3±0.2°, 11.1±0.2°, 12.2±0.2°, 13.0±0.2°, 14.0±0.2°, 17.8±0.2°, 23.3±0.2°, and 28.0±0.2°.

[0275] In some embodiments, the X-ray powder diffraction pattern of the second imidazole salt crystal form has diffraction peaks at the following 2θ angles: 4.6±0.2°, 9.3±0.2°, 11.1±0.2°, 12.2±0.2°, 13.0±0.2°, 14.0±0.2°, 15.8±0.2°, 17.8±0.2°, 23.3±0.2°, and 28.0±0.2°.

[0276] In some embodiments, the X-ray powder diffraction pattern of the second imidazole salt crystal form contains the diffraction peak positions shown in Table 11:

[0277] Table 11

[0278] In some embodiments, the second imidazole salt crystal form is imidazole salt crystal form B.

[0279] In some embodiments, the second imidazole salt crystal form is imidazole salt crystal form B, which has an X-ray powder diffraction pattern substantially as shown in FIG50.

[0280] In some embodiments, imidazole salt crystal form B has an X-ray powder diffraction pattern substantially as shown in FIG50.

[0281] In some embodiments, the DSC plot of the second imidazole salt crystal form includes one or more endothermic peaks at 85.33℃±10℃, 143.11℃±10℃, and 162.71℃±10℃, and an exothermic peak at 147.45℃±10℃.

[0282] In some embodiments, the second imidazole salt crystal form is imidazole salt crystal form B, which has a DSC diagram substantially as shown in FIG51.

[0283] In some embodiments, the second imidazole salt crystal form is imidazole salt crystal form B, which has a TGA diagram substantially as shown in FIG52.

[0284] In some embodiments, imidazole salt crystal form B has a DSC diagram that is substantially as shown in FIG51.

[0285] In some embodiments, imidazole salt crystal form B has a TGA diagram that is substantially as shown in FIG52.

[0286] In some embodiments, the second imidazole salt crystal form exhibits a weight loss of 1.2±1% at 80±10°C, a weight loss of 3.3±1% at 80±10°C to 140±10°C, and a weight loss of 17.2±1% at 140±10°C to 210±10°C.

[0287] In some embodiments, the imidazole salt of the compound of formula (I) of the present invention is either the first imidazole salt crystal form or the second imidazole salt crystal form of the compound of formula (I).

[0288] In some embodiments, the calcium salt of the compound of formula (I) described in this invention is an amorphous calcium salt of the compound of formula (I).

[0289] In some embodiments, the salt of the present invention is an amorphous calcium salt of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to calcium in the amorphous calcium salt is 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3.

[0290] In some embodiments, the molar ratio of the compound represented by formula (I) to calcium ions in the amorphous calcium salt is (0.5-2):(0.5-2); preferably, the molar ratio of the compound represented by formula (I) to calcium ions is (0.9-2):(0.9-1.1); preferably, the molar ratio of the compound represented by formula (I) to calcium ions is 2:1.

[0291] In some embodiments, the X-ray powder diffraction pattern of the amorphous calcium salt exhibits diffuse diffraction peaks in the 2θ angle range of 10±0.2° to 35±0.2°.

[0292] In some embodiments, the calcium salt amorphous has an X-ray powder diffraction pattern substantially as shown in FIG54.

[0293] In some embodiments, the sodium salt of the compound of formula (I) described in this invention is an amorphous sodium salt of the compound of formula (I).

[0294] In some embodiments, the salt of the present invention is an amorphous sodium salt of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to sodium in the amorphous sodium salt is 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3.

[0295] In some embodiments, the molar ratio of the compound represented by formula (I) to sodium ions in the amorphous sodium salt is (0.5–2):(0.5–2); preferably, the molar ratio of the compound represented by formula (I) to sodium ions is (0.9–1.1):(0.9–1.1); preferably, the molar ratio of the compound represented by formula (I) to sodium ions is 1:1.

[0296] In some embodiments, the X-ray powder diffraction pattern of the sodium salt amorphous exhibits diffuse diffraction peaks in the 2θ angle range of 10±0.2° to 35±0.2°.

[0297] In some embodiments, the sodium salt amorphous form has an X-ray powder diffraction pattern substantially as shown in Figure 13.

[0298] In some embodiments, the magnesium salt of the compound of formula (I) described in this invention is the magnesium salt crystal form of the compound of formula (I).

[0299] In some embodiments, the salt of the present invention is a magnesium salt crystal form of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to magnesium in the magnesium salt crystal form is 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3.

[0300] In some embodiments, the molar ratio of the compound represented by formula (I) to magnesium ions in the magnesium salt crystal form is (0.5-2):(0.5-2); preferably, the molar ratio of the compound represented by formula (I) to magnesium ions is (0.9-2):(0.9-1.1); preferably, the molar ratio of the compound represented by formula (I) to magnesium ions is 2:1.

[0301] In some embodiments, the X-ray powder diffraction pattern of the magnesium salt crystal form has diffraction peaks at the following 2θ angles: 5.6±0.2°, 11.2±0.2°, and 16.8±0.2°. In some embodiments, the X-ray powder diffraction pattern of the magnesium salt crystal form A has diffraction peaks at the following 2θ angles: 5.6±0.2°, 11.2±0.2°, 16.8±0.2°, and 22.4±0.2°.

[0302] Furthermore, the X-ray powder diffraction pattern of the magnesium salt crystal form also has diffraction peaks at one or more of the following 2θ angles: 12.3±0.2°, 17.1±0.2°, 17.5±0.2°, 27.6±0.2°, 28.1±0.2°, 28.6±0.2°.

[0303] In some embodiments, the X-ray powder diffraction pattern of the magnesium salt crystal form has diffraction peaks at the following 2θ angles: 5.6±0.2°, 11.2±0.2°, 16.8±0.2°, 17.5±0.2°, 22.4±0.2°, 27.6±0.2°.

[0304] In some embodiments, the X-ray powder diffraction pattern of the magnesium salt crystal form has diffraction peaks at the following 2θ angles: 5.6±0.2°, 11.2±0.2°, 12.3±0.2°, 16.8±0.2°, 17.1±0.2°, 17.5±0.2°, 22.4±0.2°, 27.6±0.2°, 28.1±0.2°, 28.6±0.2°.

[0305] In some embodiments, the X-ray powder diffraction patterns of the magnesium salt crystal form contain the diffraction peak positions shown in Table 12:

[0306] Table 12

[0307] In some embodiments, the magnesium salt crystal form is magnesium salt crystal form A.

[0308] In some embodiments, the magnesium salt crystal form is magnesium salt crystal form A, which has an X-ray powder diffraction pattern substantially as shown in FIG56.

[0309] In some embodiments, magnesium salt crystal form A has an X-ray powder diffraction pattern substantially as shown in FIG56.

[0310] In some embodiments, the DSC plot of the magnesium salt crystal form includes one or more endothermic peaks at 65.43℃±10℃ and 115.89℃±10℃.

[0311] In some embodiments, the magnesium salt crystal form is magnesium salt crystal form A, which has a DSC diagram substantially as shown in FIG57.

[0312] In some embodiments, the magnesium salt crystal form is magnesium salt crystal form A, which has a TGA diagram substantially as shown in FIG58.

[0313] In some embodiments, magnesium salt crystal form A has a DSC diagram that is substantially as shown in FIG57.

[0314] In some embodiments, magnesium salt crystal form A has a TGA diagram that is substantially as shown in FIG58.

[0315] In some embodiments, the magnesium salt crystal form exhibits a weight loss of 1.9±1% at 75±10°C, a weight loss of 7.8±1% between 75±10°C and 150±10°C, and a weight loss of 11.7±1% between 150±10°C and 250±10°C.

[0316] In a second aspect, the present invention provides a crystal form of the compound represented by formula (I).

[0317] In some embodiments, the crystal form of the present invention is the free state crystal form of the compound shown in formula (I), and the X-ray powder diffraction pattern of the free state crystal form has diffraction peaks at the following 2θ angles: 4.9±0.2°, 9.7±0.2°, 18.7±0.2°, 19.4±0.2°.

[0318] In some embodiments, the X-ray powder diffraction pattern of the free crystal form has diffraction peaks at the following 2θ angles: 4.9±0.2°, 9.7±0.2°, 16.9±0.2°, 18.7±0.2°, 19.4±0.2°, and 24.2±0.2°.

[0319] Furthermore, the X-ray powder diffraction pattern of the free-state crystal form also has diffraction peaks at one or more of the following 2θ angles: 12.0±0.2°, 14.5±0.2°, 18.4±0.2°, 18.0±0.2°, 27.7±0.2°.

[0320] In some embodiments, the X-ray powder diffraction pattern of the free crystal form has diffraction peaks at the following 2θ angles: 4.9±0.2°, 9.7±0.2°, 16.9±0.2°, 18.0±0.2°, 18.4±0.2°, 18.7±0.2°, 19.4±0.2°, and 24.2±0.2°.

[0321] In some embodiments, the X-ray powder diffraction pattern of the free crystal form has diffraction peaks at the following 2θ angles: 4.9±0.2°, 9.7±0.2°, 12.0±0.2°, 14.5±0.2°, 16.9±0.2°, 18.0±0.2°, 18.4±0.2°, 18.7±0.2°, 19.4±0.2°, 24.2±0.2°, 27.7±0.2°.

[0322] In some embodiments, the positions of the diffraction peaks contained in the free-state crystal form are shown in Table 13 below:

[0323] Table 13

[0324] In some embodiments, the free state crystal form is free state crystal form A.

[0325] In some embodiments, the free state crystal form is free state crystal form A, which has an X-ray powder diffraction pattern substantially as shown in FIG2.

[0326] In some embodiments, the free crystal form A has an X-ray powder diffraction pattern substantially as shown in FIG2.

[0327] In some embodiments, the DSC diagram of the free-state crystal includes an endothermic peak at 157.48℃±10℃.

[0328] In some embodiments, the free crystal form has a weight loss of 0.02±1% at 113±10°C.

[0329] In some embodiments, the free state crystal form is free state crystal form A, which has a DSC diagram substantially as shown in FIG3.

[0330] In some embodiments, the free state crystal form is free state crystal form A, which has a TGA diagram substantially as shown in FIG4.

[0331] In some embodiments, the free crystal form A has a DSC diagram that is substantially as shown in FIG3.

[0332] In some embodiments, the free crystal form A has a TGA diagram that is substantially as shown in FIG4.

[0333] In some embodiments, the crystal form of the present invention is the free crystal form A of the compound shown in formula (I), and the X-ray powder diffraction pattern of the free crystal form A has diffraction peaks at the following 2θ angles: 4.9±0.2°, 9.7±0.2°, 18.7±0.2°, 19.4±0.2°.

[0334] In some embodiments, the X-ray powder diffraction pattern of the free crystal form A has diffraction peaks at the following 2θ angles: 4.9±0.2°, 9.7±0.2°, 16.9±0.2°, 18.7±0.2°, 19.4±0.2°, and 24.2±0.2°.

[0335] Furthermore, the X-ray powder diffraction pattern of the free crystal form A also has diffraction peaks at one or more of the following 2θ angles: 12.0±0.2°, 14.5±0.2°, 18.4±0.2°, 18.0±0.2°, 27.7±0.2°.

[0336] In some embodiments, the X-ray powder diffraction pattern of the free crystal form A has diffraction peaks at the following 2θ angles: 4.9±0.2°, 9.7±0.2°, 16.9±0.2°, 18.0±0.2°, 18.4±0.2°, 18.7±0.2°, 19.4±0.2°, and 24.2±0.2°.

[0337] In some embodiments, the X-ray powder diffraction pattern of the free crystal form A has diffraction peaks at the following 2θ angles: 4.9±0.2°, 9.7±0.2°, 12.0±0.2°, 14.5±0.2°, 16.9±0.2°, 18.0±0.2°, 18.4±0.2°, 18.7±0.2°, 19.4±0.2°, 24.2±0.2°, and 27.7±0.2°.

[0338] In some embodiments, the positions of the diffraction peaks contained in the free-state crystal form A are shown in Table 13 below:

[0339] Table 13

[0340] In some embodiments, the DSC diagram of the free crystal A includes an endothermic peak at 157.48℃ ± 10℃.

[0341] In some embodiments, the free crystal form A has a weight loss of 0.02±1% at 113±10℃.

[0342] In a third aspect of the invention, a method for preparing the crystalline form of the compound of formula (I) described in the first aspect or its salt is provided. According to an embodiment of the invention, the method comprises the following steps: stirring the compound of formula (I) or the free crystalline form of the compound of formula (I) with a salt-forming reagent (e.g., an organic or inorganic base) in a first solvent at 50°C for 1-4 hours, for example, 1, 2, 3, or 4 hours; then cooling to room temperature for a first pulping to obtain a solid; separating the solid and performing a first drying; wherein the first solvent is selected from one or a mixture of several of alcohols, MEK, acetonitrile, IPAc, EA, Acetone, 1,4-dioxane, THF, DMSO, DMF, heptane, MTBE, NMP, Toluene, and water; wherein the alcohol is selected from methanol or ethanol; the first drying is selected from vacuum drying, and the first drying temperature is 20-50°C, preferably 30°C; the first pulping time is 1-3 days, for example, 1, 2, or 3 days;

[0343] According to an embodiment of the present invention, the second method includes the following steps: stirring the compound shown in formula (I) or the free crystal form of the compound shown in formula (I) with a salt-forming reagent (e.g., an organic base or an inorganic base) in a second solvent at 50°C for 1-4 hours, for example, 1, 2, 3, 4 hours, then cooling to room temperature and stirring for 1-3 days, for example, 1, 2, 3 days; placing it in an ice bath to precipitate a solid; if no solid precipitates, placing the clear solution at room temperature to slowly evaporate to obtain a solid, separating the solid and performing a second drying; the second solvent is selected from one or a mixture of several of alcohols, MEK, acetonitrile, IPAc, EA, Acetone, 1,4-dioxane, THF, DMSO, DMF, heptane, MTBE, NMP, Toluene and water; the alcohol is selected from methanol and ethanol; the second drying is selected from vacuum drying, and the second drying temperature is 20-50°C, preferably 30°C or 50°C;

[0344] According to an embodiment of the present invention, method three includes the following steps: stirring the compound shown in formula (I) or the free crystal form of the compound shown in formula (I) with a salt-forming reagent (e.g., an organic base or an inorganic base) in a third solvent at 50°C for 1-4 hours, for example, 1, 2, 3, 4 hours, then cooling to room temperature and stirring for 1-3 days, for example, 1, 2, 3 days; adding an antisolvent to obtain a solid, separating the solid and performing a third drying; the third solvent is selected from one or a mixture of several of alcohols, MEK, acetonitrile, IPAc, EA, Acetone, 1,4-dioxane, THF, DMSO, DMF, heptane, MTBE, NMP, Toluene, and water; the alcohol is selected from methanol and ethanol; the third drying is selected from vacuum drying, and the third drying temperature is 20-50°C, preferably 30°C or 50°C; the antisolvent is selected from heptane, MTBE, and toluene;

[0345] According to an embodiment of the present invention, method four includes the following steps: stirring the compound shown in formula (I) or the free crystal form of the compound shown in formula (I) in a fourth solvent for about 10-30 min to obtain a suspension; adding a salt-forming reagent (e.g., an organic base or an inorganic base) to the above suspension; adding seed crystals; stirring for 10-30 min until clear; stirring at 50°C for 1-4 h, for example, 1, 2, 3, 4 h; then cooling to room temperature for a second pulping to obtain a solid; separating the solid and performing a fourth drying; the fourth solvent is selected from one or a mixture of alcohols, acetonitrile, and acetone; the alcohol is selected from methanol and ethanol; the fourth drying is selected from vacuum drying, and the drying temperature is 20-50°C, preferably 50°C; the second pulping time is 1-3 days, for example, 1, 2, 3 days.

[0346] In a fourth aspect, the present invention provides a method for preparing the free crystalline form of the compound shown in formula (I). According to embodiments of the present invention, the method comprises at least one of the following methods:

[0347] Method 1: Dissolve the compound shown in formula (I) in a fifth solvent at room temperature, add a sixth solvent dropwise until a solid precipitates, continue stirring for about 2 hours, filter, and dry the filter cake under vacuum at 30°C to obtain a solid. Optionally, the fifth solvent includes at least one of methanol and ethyl acetate, and optionally, the sixth solvent includes at least one of purified water and n-heptane.

[0348] Method 2: Dissolve the compound shown in formula (I) at room temperature in a seventh solvent under ultrasonic conditions, and allow it to stand at room temperature to evaporate to obtain a solid. Optionally, the seventh solvent includes methanol.

[0349] Method 3: The compound shown in formula (I) is dissolved at room temperature in an eighth solvent under ultrasonic conditions. The dissolved product is placed in a sample bottle containing purified water, the sample bottle is sealed and allowed to stand at room temperature to crystallize. The solid is filtered and the filter cake is vacuum dried at 30°C to obtain a solid. Optionally, the eighth solvent includes DMSO.

[0350] In a fifth aspect, the present invention provides a pharmaceutical composition comprising any salt of a compound of formula (I) or a free crystalline form of a compound of formula (I), or a combination thereof. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or a combination thereof. In some embodiments, the salt in the pharmaceutical composition of the present invention may be any crystalline form of the salt, specifically any crystalline form, amorphous form, or any combination thereof. In some embodiments, the pharmaceutical composition of the present invention comprises any salt of a compound of formula (I), or any crystalline form or amorphous form of the compound of the present invention, or any combination of the salt, crystalline form, and amorphous form.

[0351] In a sixth aspect, the present invention provides for the use of a salt of the compound represented by formula (I) or a free crystalline form of the compound represented by formula (I), or a combination thereof, or the pharmaceutical composition thereof, in the preparation of a medicament for the prevention and / or treatment of diseases with insufficient endogenous production of Ang II; and / or, the medicament for the prevention and / or treatment of diseases for which increased Ang II activity is desired or required; and / or, the medicament for the prevention and / or treatment of diseases in which AT2R is expressed and for which stimulation is desired or necessary. Further, the use comprises administering an effective therapeutic dose of the salt or the pharmaceutical composition of the present invention to a human or animal. Wherein, the salt of the compound represented by formula (I) is any one or more of the above-described salts and crystalline forms of the salts thereof.

[0352] In a seventh aspect of the invention, the invention provides for the use of a salt of the compound represented by formula (I) or a free crystal form of the compound represented by formula (I) or a combination thereof or the pharmaceutical composition thereof in the preparation of an AT2R agonist.

[0353] In an eighth aspect, the present invention provides a method for preventing and / or treating diseases of insufficient endogenous production of Ang II. According to embodiments of the invention, the method comprises administering to a patient a pharmaceutically acceptable dose of a crystalline form of the aforementioned compound or a salt thereof, or a pharmaceutical composition described above.

[0354] In a ninth aspect of the invention, a method for preventing and / or treating diseases for which an increased effect of Ang II is desired or required is provided. According to embodiments of the invention, the method comprises administering to a patient a pharmaceutically acceptable dose of a crystalline form of the aforementioned compound or a salt thereof, or a pharmaceutical composition described above.

[0355] In a tenth aspect of the invention, a method for preventing and / or treating diseases in which AT2R is expressed and which are desired or necessary to be stimulated is provided. According to an embodiment of the invention, the method comprises administering to a patient a pharmaceutically acceptable dose of a crystalline form of the aforementioned compound or a salt thereof, or a pharmaceutical composition described above.

[0356] In some embodiments, the diseases of insufficient endogenous production of Ang II described in this invention are diseases of the gastrointestinal tract, cardiovascular system, respiratory tract, kidney, eye, female reproductive system, or central nervous system.

[0357] In some embodiments, the disease is asthma, obstructive pulmonary disease, pneumonia, pulmonary hypertension, adult respiratory distress syndrome, or idiopathic pulmonary fibrosis.

[0358] In the eleventh aspect of the invention, the invention provides crystal forms of the compounds described above or salts thereof or pharmaceutical compositions described above for the prevention and / or treatment of diseases with insufficient endogenous production of Ang II; or for the prevention and / or treatment of diseases for which increased Ang II action is desired or required; or for the prevention and / or treatment of diseases in which AT2R is expressed and for which stimulation is desired or required; or for the preparation of AT2R agonists.

[0359] Definitions and general terms

[0360] Unless otherwise stated, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents and publications related to this invention are incorporated herein by reference in their entirety. Although any methods and substances similar to or identical to those described herein may be used in the practice or testing of this invention, preferred methods, apparatus, and substances are described herein.

[0361] In this article, the ordinal numbers such as "first," "second," and "third" used before crystal forms are only used to distinguish different crystal forms and do not have any substantial meaning of sequence or order. For example, "first sodium salt crystal form" and "second sodium salt crystal form" indicate two different sodium salt crystal forms.

[0362] "Crystal form" or "crystalline form" refers to a solid with a highly regular chemical structure, including, but not limited to, single-component or multi-component crystals, and / or polymorphs of compounds, solvates, hydrates, inclusion compounds, eutectics, solvates of salts, and hydrates of salts.

[0363] "Inorganic base salt" refers to a salt formed by the reaction of the compound shown in formula (I) (in its free state) with various suitable inorganic bases, including but not limited to the sodium salt, potassium salt, calcium salt, magnesium salt, etc., described in this invention. The term "inorganic base salt of the compound shown in formula (I)" includes the amorphous or crystalline form of the salt, its solvate form (e.g., hydrate form), and its polymorphic form. For example, the sodium salt of the compound shown in formula (I) includes the amorphous form, various crystalline forms, various solvates, various hydrates, and also the polymorphic form of this type of salt.

[0364] "Organic base salt" refers to a salt formed by the reaction of the compound shown in formula (I) (in its free state) with various suitable organic bases, including but not limited to the tris(hydroxymethyl)aminomethane salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, meglumine salt, imidazole salt, etc., described in this invention. The term "organic base salt of the compound shown in formula (I)" includes the amorphous or crystalline form of the salt, its solvated form (e.g., hydrated form), and its polymorphic form. For example, the tris(hydroxymethyl)aminomethane salt of the compound shown in formula (I) includes the amorphous form, various crystalline forms, various solvates, various hydrates, and also the polymorphic form of this type of salt.

[0365] "Salt of the compound shown in formula (I)" refers to the salt formed by the reaction of the compound shown in (I) (in the free state) with various suitable bases, including "inorganic base salts" and "organic base salts", wherein the "inorganic base salts" and "organic base salts" have the above-mentioned definitions of "inorganic base salts" and "organic base salts".

[0366] "Amorphous" or "amorphous" refers to matter formed when the particles (molecules, atoms, ions) of a substance are arranged in a non-periodic manner in three-dimensional space.

[0367] "Solvates" or "solvent compounds" refer to complexes or eutectics formed by one or more solvent molecules being embedded in a molecular lattice in a certain stoichiometric or non-stoichiometric ratio.

[0368] "Hydrate" refers to a solid state in which molecules and water of crystallization form a eutectic. It is a special type of solvate, where the solvent molecule is water.

[0369] Karl Fischer titration is a method for directly determining the absolute water content (free and bound water) in a sample, expressed as a percentage (%w / w) or ppm. It is commonly used as a standard method for water determination in pharmacopoeias (e.g., USP). <921> (EP 2.5.12). It has high sensitivity for detecting trace moisture (down to ppm level) but cannot distinguish the hygroscopic behavior of the sample (such as the moisture adsorption capacity under different humidity levels). All hydrates in this application were titrated using Karl Fischer titration.

[0370] In this application, RH refers to relative humidity. It is defined as the ratio of the actual water vapor content (absolute humidity) in the air at a specific temperature to the saturated water vapor content at the same temperature, usually expressed as a percentage (%).

[0371] X-ray powder diffraction (XRPD) can detect changes in crystal form, crystallinity, and crystal structure, and is a commonly used method for identifying crystal forms. The peak positions in XRPD spectra depend primarily on the crystal structure and are relatively insensitive to experimental details, while their relative peak heights depend on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystal form of the present invention is characterized by an XRPD spectrum with certain peak positions, which is essentially as shown in the XRPD spectrum provided in the accompanying drawings. Furthermore, the measurement of 2θ in XRPD spectra can be subject to experimental error; the measurement of 2θ in XRPD spectra may vary slightly between different instruments and different samples, therefore the value of 2θ should not be considered absolute. In the context of this invention, 2θ values ​​in X-ray powder diffraction patterns are expressed in degrees (°). In some embodiments, a tolerance of ±0.2° is provided for the diffraction peaks.

[0372] Differential scanning calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference (commonly α-Al₂O₃) as a function of temperature by continuously heating or cooling under programmed control. Therefore, in some embodiments, the crystal form described in this invention is substantially as shown in the DSC diagram provided in the accompanying drawings. However, DSC spectra may be subject to experimental error; the peak positions and peak values ​​may vary slightly between different instruments and different samples. Therefore, the peak positions or peak values ​​of the DSC endothermic peaks cannot be considered absolute.

[0373] Thermogravimetric analysis (TGA) is a technique used under programmed control to determine the change in mass of a substance with temperature. It is suitable for examining the loss of solvent in crystals or the sublimation and decomposition of samples, and can infer the presence of water of crystallization or crystallization solvent in the crystal. The mass change shown by the TGA curve depends on many factors, such as sample preparation and instrumentation; the mass change detected by TGA varies slightly between different instruments and different samples.

[0374] The term “basically as shown” means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks are shown in an X-ray powder diffraction pattern, DSC pattern, Raman spectrum, or infrared spectrum.

[0375] In the context of this invention, when using, or regardless of whether, terms such as “about” or “approximately” are used (e.g., temperature or temperature range), it means within 10% of a given value or range, appropriately within 5%, and particularly within 1%. Alternatively, for those skilled in the art, the term “about” or “approximately” means within an acceptable standard error range of the average value. Whenever a number with a value of N is disclosed, any number having a value within N+ / –1%, N+ / –2%, N+ / –3%, N+ / –5%, N+ / –7%, N+ / –8%, or N+ / –10% is within an acceptable range, where “+ / –” means addition or subtraction.

[0376] Unless otherwise indicated, the structural formulas described in this invention include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compounds of this invention, or its enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers), is within the scope of this invention.

[0377] Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. Attached Figure Description

[0378] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which:

[0379] Figure 1 is an XRPD spectrum of an amorphous sample of compound I obtained according to Example 1 of the present invention.

[0380] Figure 2 is the XRPD spectrum of free crystal form A of compound I obtained according to Example 2 of the present invention.

[0381] Figure 3 is the DSC spectrum of free crystal form A of compound I obtained according to Example 2 of the present invention.

[0382] Figure 4 is the TGA spectrum of the free crystal form A of compound I obtained according to Example 2 of the present invention.

[0383] Figure 5 shows the free crystal form A of compound I obtained according to Example 2 of the present invention.1 H NMR spectrum.

[0384] Figure 6 is the XRPD spectrum of the mixed crystal of free crystal form A and free crystal form B obtained according to Example 3 of the present invention.

[0385] Figure 7 is an XRPD overlay image of the sample heated to 90°C according to Example 3 of the present invention.

[0386] Figure 8 is an XRPD overlay image of the sample obtained in Example 3 of the present invention after heating to 110°C.

[0387] Figure 9 is the XRPD spectrum of sodium salt crystal form A obtained according to Example 4 of the present invention.

[0388] Figure 10 is the DSC spectrum of sodium salt crystal form A obtained according to Example 4 of the present invention.

[0389] Figure 11 is the TGA spectrum of sodium salt crystal form A obtained according to Example 4 of the present invention.

[0390] Figure 12 shows the sodium salt crystal form A obtained according to Example 4 of the present invention. 1 H-NMR spectrum.

[0391] Figure 13 is the XRPD spectrum of sodium salt crystal form A obtained according to Example 4 of the present invention after heating to 150°C.

[0392] Figure 14 is the XRPD spectrum of sodium salt crystal form B obtained according to Example 4 of the present invention.

[0393] Figure 15 is the DSC spectrum of sodium salt crystal form B obtained according to Example 4 of the present invention.

[0394] Figure 16 is the TGA spectrum of sodium salt crystal form B obtained according to Example 4 of the present invention.

[0395] Figure 17 shows the sodium salt crystal form B obtained according to Example 4 of the present invention. 1 H-NMR spectrum.

[0396] Figure 18 is the XRPD spectrum of sodium salt crystal form C obtained according to Example 4 of the present invention.

[0397] Figure 19 is the DSC spectrum of sodium salt crystal form C obtained according to Example 4 of the present invention.

[0398] Figure 20 is the TGA spectrum of sodium salt crystal form C obtained according to Example 4 of the present invention.

[0399] Figure 21 shows the sodium salt crystal form C obtained according to Example 4 of the present invention. 1 H-NMR spectrum.

[0400] Figure 22 is the XRPD spectrum of sodium salt crystal form D obtained according to Example 4 of the present invention.

[0401] Figure 23 is the DSC spectrum of sodium salt crystal form D obtained according to Example 4 of the present invention.

[0402] Figure 24 is the TGA spectrum of sodium salt crystal form D obtained according to Example 4 of the present invention.

[0403] Figure 25 shows the sodium salt crystal form D obtained according to Example 4 of the present invention. 1 H-NMR spectrum.

[0404] Figure 26 is the XRPD spectrum of potassium salt crystal form A obtained according to Example 5 of the present invention.

[0405] Figure 27 is the DSC spectrum of potassium salt crystal form A obtained according to Example 5 of the present invention.

[0406] Figure 28 is the TGA spectrum of potassium salt crystal form A obtained according to Example 5 of the present invention.

[0407] Figure 29 shows the potassium salt crystal form A obtained according to Example 5 of the present invention. 1 H-NMR spectrum.

[0408] Figure 30 is the XRPD spectrum of potassium salt crystal form B obtained according to Example 5 of the present invention.

[0409] Figure 31 is a DSC spectrum of potassium salt crystal form B obtained according to Example 5 of the present invention.

[0410] Figure 32 is a TGA spectrum of potassium salt crystal form B obtained according to Example 5 of the present invention.

[0411] Figure 33 shows the potassium salt crystal form B obtained according to Example 5 of the present invention. 1 H-NMR spectrum.

[0412] Figure 34 is the XRPD spectrum of the trihydroxymethylaminomethane salt crystal form A obtained according to Example 6 of the present invention.

[0413] Figure 35 is the DSC spectrum of trihydroxymethylaminomethane salt crystal form A obtained according to Example 6 of the present invention.

[0414] Figure 36 is a TGA spectrum of the trihydroxymethylaminomethane salt crystal form A obtained according to Example 6 of the present invention.

[0415] Figure 37 shows the crystal form A of tris(hydroxymethyl)aminomethane salt obtained according to Example 6 of the present invention. 1 H-NMR spectrum.

[0416] Figure 38 is the XRPD spectrum of trihydroxymethylaminomethane salt crystal form B obtained according to Example 6 of the present invention.

[0417] Figure 39 is the DSC spectrum of trihydroxymethylaminomethane salt crystal form B obtained according to Example 6 of the present invention.

[0418] Figure 40 is a TGA spectrum of tris(hydroxymethyl)aminomethane salt crystal form B obtained according to Example 6 of the present invention.

[0419] Figure 41 shows the crystal form B of tris(hydroxymethyl)aminomethane salt obtained according to Example 6 of the present invention. 1 H-NMR spectrum.

[0420] Figure 42 is the XRPD spectrum of ethanolamine salt crystal form A obtained according to Example 6 of the present invention.

[0421] Figure 43 is the DSC spectrum of ethanolamine salt crystal form A obtained according to Example 6 of the present invention.

[0422] Figure 44 is the TGA spectrum of ethanolamine salt crystal form A obtained according to Example 6 of the present invention.

[0423] Figure 45 shows the ethanolamine salt crystal form A obtained according to Example 6 of the present invention. 1 H-NMR spectrum.

[0424] Figure 46 is the XRPD spectrum of imidazole salt crystal form A obtained according to Example 6 of the present invention.

[0425] Figure 47 is the DSC spectrum of imidazole salt crystal form A obtained according to Example 6 of the present invention.

[0426] Figure 48 is the TGA spectrum of imidazole salt crystal form A obtained according to Example 6 of the present invention.

[0427] Figure 49 shows the imidazole salt crystal form A obtained according to Example 6 of the present invention. 1 H-NMR spectrum.

[0428] Figure 50 is the XRPD spectrum of imidazole salt crystal form B obtained according to Example 6 of the present invention.

[0429] Figure 51 is a DSC spectrum of imidazole salt crystal form B obtained according to Example 6 of the present invention.

[0430] Figure 52 is a TGA spectrum of imidazole salt crystal form B obtained according to Example 6 of the present invention.

[0431] Figure 53 shows the imidazole salt crystal form B obtained according to Example 6 of the present invention. 1 H-NMR spectrum.

[0432] Figure 54 is an XRPD spectrum of the amorphous calcium salt obtained according to Example 6 of the present invention.

[0433] Figure 55 shows the amorphous calcium salt obtained according to Example 6 of the present invention. 1 H-NMR spectrum.

[0434] Figure 56 is the XRPD spectrum of magnesium salt crystal form A obtained according to Example 6 of the present invention.

[0435] Figure 57 is the DSC spectrum of magnesium salt crystal form A obtained according to Example 6 of the present invention.

[0436] Figure 58 is the TGA spectrum of magnesium salt crystal form A obtained according to Example 6 of the present invention.

[0437] Figure 59 shows magnesium salt crystal form A obtained according to Example 6 of the present invention. 1 H-NMR spectrum.

[0438] Figure 60 is the XRPD spectrum of sodium salt crystal form A obtained according to Example 7 of the present invention.

[0439] Figure 61 is the DSC spectrum of sodium salt crystal form A obtained according to Example 7 of the present invention.

[0440] Figure 62 is the TGA spectrum of sodium salt crystal form A obtained according to Example 7 of the present invention.

[0441] Figure 63 shows sodium salt crystal form A obtained according to Example 7 of the present invention. 1 H-NMR spectrum.

[0442] Figure 64 is the XRPD spectrum of potassium salt crystal form A obtained according to Example 8 of the present invention.

[0443] Figure 65 is a DSC spectrum of potassium salt crystal form A obtained according to Example 8 of the present invention.

[0444] Figure 66 is the TGA spectrum of potassium salt crystal form A obtained according to Example 8 of the present invention.

[0445] Figure 67 shows the potassium salt crystal form A obtained according to Example 8 of the present invention. 1 H-NMR spectrum.

[0446] Figure 68 is a dynamic solubility curve of compound I in FaSSIF at 37°C for free crystal form A, sodium salt crystal form A and potassium salt crystal form A of the present invention, according to Example 9 of the present invention.

[0447] Figure 69 is a dynamic solubility curve of compound I in FeSSIF at 37°C for free crystal form A, sodium salt crystal form A and potassium salt crystal form A of the present invention, according to Example 9 of the present invention.

[0448] Figure 70 is a dynamic solubility curve of compound I in PBS at 37°C for free crystal form A, sodium salt crystal form A and potassium salt crystal form A according to Example 9 of the present invention.

[0449] Figure 71 is an XRPD overlay of the sample obtained from the solid stability evaluation of the free crystal form A of compound I according to Example 10 of the present invention after 31 days under different influencing factors.

[0450] Figure 72 is an XRPD overlay of the sample obtained from the solid stability evaluation of sodium salt crystal form A of compound I according to Example 10 of the present invention under different influencing factors for 31 days.

[0451] Figure 73 is an XRPD overlay of the potassium salt crystal form A of Compound I according to Example 10 of the present invention, obtained from the solid stability evaluation of the sample under different influencing factors for 31 days.

[0452] Figure 74 is a DVS diagram of the free crystal form A according to Example 11 of the present invention.

[0453] Figure 75 is an XRPD overlay image of free crystal form A before and after testing according to Example 11 of the present invention.

[0454] Figure 76 is a DVS diagram of sodium salt crystal form A according to Example 11 of the present invention.

[0455] Figure 77 is an XRPD overlay image before and after DVS test of sodium salt crystal form A according to Example 11 of the present invention.

[0456] Figure 78 is a DVS diagram of potassium salt crystal form A according to Example 11 of the present invention.

[0457] Figure 79 is an XRPD overlay diagram of potassium salt crystal form A according to Example 11 of the present invention. Detailed Implementation

[0458] The embodiments of the present invention are described in detail below. These embodiments are exemplary and are only used to explain the present invention, and should not be construed as limiting the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the art or according to the product instructions. Reagents or instruments used, unless otherwise specified, are all commercially available conventional products.

[0459] Symbols or units:

[0460] IC 50 The half-maximum inhibitory concentration (MCC) is the concentration at which half of the maximum inhibitory effect is achieved.

[0461] M: mol / L, for example, n-butyllithium (14.56 mL, 29.1 mmol, 2.5 M n-hexane solution) means a n-butyllithium n-hexane solution with a molar concentration of 2.5 mol / L;

[0462] N: Equivalent concentration, for example, 2N hydrochloric acid means a 2 mol / L hydrochloric acid solution.

[0463] General Experiment

[0464] 1. Instrument Information and Methods

[0465] X-ray powder diffraction (XRPD)

[0466] The XRPD images were acquired using an X-ray powder diffractometer, and the scanning parameters are shown in Table 14.

[0467] Table 14: XRPD Test Parameters

[0468] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)

[0469] The TGA and DSC plots were acquired on a TAQ500 thermogravimetric analyzer and a TAQ2000 differential scanning calorimeter, respectively. Table 15 lists the test parameters.

[0470] Table 15: TGA and DSC Test Parameters

[0471] Liquid NMR ( 1 H NMR)

[0472] Liquid NMR spectra were acquired on a Bruker 400M NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d6) as the solvent.

[0473] Liquid chromatography and ion chromatography (HPLC / IC)

[0474] The results of purity, dynamic solubility and stability tests in the experiment were collected by high performance liquid chromatography, and the results of ion salt formation molar ratio were collected by ion chromatography. The analytical conditions are shown in Tables 16 and 17.

[0475] Table 16: Liquid Chromatography Test Conditions

[0476] Table 17: Ion Chromatography Test Conditions

[0477] Dynamic moisture adsorption (DVS)

[0478] Dynamic moisture adsorption (DVS) curves were acquired using the DVS Intrinsic on the SMS (Surface Measurement Systems) device. The DVS test parameters are shown in Table 18.

[0479] Table 18: Dynamic Moisture Adsorption Test Conditions

[0480] Solvent English-Chinese Glossary

[0481] Table 19 shows the abbreviations of solvents and their corresponding Chinese names.

[0482] Table 19: Chinese-English Bilingual Table

[0483] Example 1: Preparation method of compound I

[0484] In the embodiments of the present invention, the preparation method of compound I ((4-fluoro-5-isobutyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonyl)carbamate and (2-(N-(tert-butyl)aminosulfonyl)-5-isobutyl-4-methylthiophen-3-yl)boronic acid) is described in reference to patent CN202411164529.7. The structure of compound I is shown below.

[0485] The synthesis route is shown below:

[0486] Step 1: Synthesis of 1-(4-bromophenylmethyl)-2-(trifluoromethyl)-1H-imidazolium

[0487] 1-Bromo-4-(bromomethyl)benzene (1.00 g, 4.00 mmol) and 2-(trifluoromethyl)-1H-imidazole (544 mg, 4.00 mmol) were dissolved in N,N-dimethylformamide (10 mL), and then potassium carbonate (1.66 mg, 12.0 mmol) was added. The mixture was reacted at 50 °C for 2 hours. The reaction solution was poured into water (100 mL), extracted three times with ethyl acetate (80 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 1-(4-bromophenylmethyl)-2-(trifluoromethyl)-1H-imidazole.

[0488] LC-MS, M / Z (ESI): 304.9 [M+H] +

[0489] Step 2: Synthesis of N-(tert-butyl)-5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide

[0490] (2-(N-(tert-butyl)aminosulfonyl)-5-isobutyl-4-methylthiophene-3-yl)boronic acid (400 mg, 1.20 mmol) was dissolved in tetrahydrofuran (10 mL) and water (3 mL), 1-(4-bromophenylmethyl)-2-(trifluoromethyl)-1H-imidazolium (330 mg, 1.08 mmol) was added, followed by potassium phosphate (1.27 g, 6.00 mmol) and XPos Pd G4 (103 mg, 120 μmol / L ol), and the mixture was stirred at 60 °C for 2 hours under nitrogen protection. The reaction solution was concentrated to obtain a crude product, which was then purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 5:1-0:1) to obtain the compound N-(tert-butyl)-5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide.

[0491] LC-MS, M / Z (ESI): 514.0 [M+H] +

[0492] Step 3: Synthesis of 5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide

[0493] N-(tert-butyl)-5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (550 mg, 1.07 mmol) was dissolved in trifluoroacetic acid (8 mL) and dichloromethane (4 mL) and reacted at 40 °C for 2 hours. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1-1:1) to give compound 5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide.

[0494] LC-MS, M / Z (ESI): 458.1 [M+H] +

[0495] Step 4: Synthesis of methyl (5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophen-2-yl)sulfonylcarbamate

[0496] 5-Isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-sulfonamide (470 mg, 1.03 mmol) and methyl chloroformate (194 mg, 2.05 mmol) were dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (398 mg, 3.08 mmol) was added. The mixture was stirred at 0 °C for 0.5 hours. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution (20 mL), extracted three times with dichloromethane (20 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated and purified by high performance liquid chromatography (column: Welch Xtimate 150*25mm*5 μmol / L; solvent: A = water + 0.05 v / v formic acid (30%), B = acetonitrile; gradient: 58%-78%, 10 min) to obtain the product (methyl 5-isobutyl-4-methyl-3-(4-((2-(trifluoromethyl)-1H-imidazol-1-yl)methyl)phenyl)thiophene-2-yl)sulfonylcarbamate).

[0497] As shown in Figure 1, the XRPD results indicate that the obtained compound sample of Formula I is basically in an amorphous state.

[0498] LC-MS, M / Z (ESI): 516.1 [M+H] +

[0499] 1 HNMR(400MHz,DMSO-d6)δ:11.83(s,1H),7.60(d,1H),7.17-7.23(m,4H),7.15(d,1H) ,5.42(s,2H),3.53(s,3H),2.67(d,2H),1.81-1.91(m,1H),1.75(s,3H),0.93(d,6H).

[0500] Example 2: Preparation of the free crystal form of compound I

[0501] Method 1: Weigh 40 mg of compound I prepared in Example 1 into an 8 mL sample vial, add 1.5 mL of methanol, stir at room temperature until the sample dissolves, add 3 mL of purified water, and a solid precipitates. Continue stirring for about 2 hours, filter, and dry the filter cake under vacuum at 30 °C to obtain a solid. Perform X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC) tests, naming it free crystalline form A. The XRPD results are shown in Figure 2, and the XRPD diffraction peak data of free crystalline form A are shown in Table 20. The DSC results show that the sample has one endothermic peak at 157.48 °C (peak temperature). 1¹H NMR results showed no solvent residue in the sample. The free crystalline form A exhibited a weight loss of 0.02% upon heating to 113℃, which is low, indicating that free crystalline form A is amorphous. Thermogravimetric analysis results are shown in Figure 4, and differential scanning calorimetry results are shown in Figure 3. 1 The HNMR results are shown in Figure 5.

[0502] Table 20: XRPD diffraction peak data of free crystal form A

[0503] Method 2: Weigh out about 40 mg of compound I prepared in Example 1 and add it to an 8 mL sample bottle. Add 1 mL of ethyl acetate and stir at room temperature until the sample dissolves. Add 4 mL of n-heptane and a solid precipitates. Continue stirring for about 2 hours. Filter the sample and dry the filter cake under vacuum at 30 °C to obtain a solid. Perform XPRD testing to show that it is free crystal form A.

[0504] Method 3: Weigh out about 30 mg of compound I prepared in Example 1 and add it to a 2 mL sample bottle. Add methanol (1.5 mL) and sonicate until the sample dissolves. Seal the bottle with a sealing film, make several small holes, and let it stand at room temperature to evaporate to obtain a solid. Perform an XPRD test to show that it is free crystal form A.

[0505] Method 4: Weigh approximately 40 mg of compound I prepared in Example 1 into a 2 mL sample vial, add 0.1 mL of DMSO, and sonicate until the sample dissolves. Place the 2 mL sample vial open into a 20 mL sample vial containing 3 mL of purified water. Seal the 20 mL sample vial and allow it to stand at room temperature to crystallize. Filter the solid, and vacuum dry the filter cake at 30°C to obtain a solid. Perform XPRD testing, which shows that it is a free crystalline form A.

[0506] Example 3: Screening of free crystal forms of compound I

[0507] (1) 25℃ suspension method

[0508] Approximately 60 mg of compound I (free crystal form A prepared in Example 2) was weighed into 2 mL transparent sample vials. 0.1–0.5 mL of solvent was added to each vial, and the mixture was magnetically stirred at 25 °C for approximately two weeks. The solids obtained in the sample vials were dried under vacuum at 30 °C and then subjected to XRPD testing. The results are shown in Table 21.

[0509] Table 21: 25℃ Suspension Method

[0510] (2) 50℃ suspension method

[0511] Approximately 60 mg of compound I (free crystal form A prepared in Example 2) was weighed into 2 mL transparent sample vials. 0.1–0.5 mL of solvent was added to each vial, and the mixture was magnetically stirred at 50 °C for approximately one week. The solids obtained in the sample vials were dried under vacuum at 30 °C and then subjected to XRPD testing. The results are shown in Table 22.

[0512] Table 22: Crystallization of suspension at 50℃

[0513] (3) Slow evaporation method

[0514] Approximately 40 mg of compound I (free crystalline form A prepared in Example 2) was weighed into 10 mL transparent sample vials. The sample was dissolved in 2–7 mL of solvent, and the resulting solution was filtered through a 0.22 μmol / L filter membrane. The clarified solution was then allowed to evaporate slowly at room temperature. The solid obtained in the sample vials was subjected to XRPD testing, and the results are shown in Table 23.

[0515] Table 23: Slow Evaporation Method

[0516] Figure 6 shows the XRPD spectra of the mixed crystals of free crystal form A and free crystal form B obtained when the solvent is DCM.

[0517] The XRPD overlay image of the sample after heating to 90℃ was obtained in DCM by the slow volatilization method, as shown in Figure 7. After heating to 90℃, the mixed crystals of free crystal form A and free crystal form B were transformed into free crystal form A.

[0518] (4) Antisolvent method

[0519] Approximately 40 mg of compound I (free crystalline form A prepared in Example 2) was weighed into 2 mL transparent sample vials. The sample was dissolved in a small amount of good solvent at room temperature, and the resulting solution was filtered through a 0.22 μmol / L filter membrane. Then, 2-4 times the volume of poor solvent was slowly added to the filtered clear solution until a solid precipitated. The solid obtained in the sample vials was dried under vacuum at 30 °C and subjected to XRPD testing. The results are shown in Table 24.

[0520] Table 24: Antisolvent Method

[0521] (5) Gas-solid diffusion method

[0522] Approximately 30 mg of compound I (free crystalline form A prepared in Example 2) was weighed into a 2 mL transparent sample vial. 3 mL of solvent was added to a 20 mL sample vial. The 2 mL transparent sample vial was placed open inside the 20 mL sample vial, and the 20 mL sample vial was sealed and allowed to stand at room temperature for a period of time. The solid obtained in the sample vial was subjected to XRPD testing, and the results are shown in Table 25.

[0523] Table 25: Gas-Solid Diffusion Method

[0524] (6) Gas-liquid diffusion method

[0525] Approximately 40 mg of compound I (free crystalline form A prepared in Example 2) was weighed into two 2 mL transparent sample vials. A small amount of solvent was added to each vial at room temperature, and the samples were shaken to dissolve completely. The resulting solution was filtered through a 0.22 μmol / L filter membrane into another 2 mL transparent sample vial. 3 mL of antisolvent was added to a separate 20 mL sample vial. The 2 mL transparent sample vial containing the filtered clear solution was placed open inside the 20 mL sample vial. The 20 mL sample vial was then sealed and allowed to stand at room temperature to precipitate a solid. The solid obtained in the sample vial was dried under vacuum at 30 °C and then subjected to XRPD testing. The results are shown in Table 26.

[0526] Table 26: Gas-Liquid Diffusion Method

[0527] (7) Cooling method

[0528] Approximately 40 mg of compound I (free crystalline form A obtained in Example 2) was weighed into 2 mL transparent sample vials. The sample was dissolved in a small amount of solvent at 50 °C, and the resulting solution was filtered through a 0.22 μmol / L filter membrane. The clarified solution after filtration was allowed to cool slowly at room temperature with magnetic stirring. The solid obtained in the sample vials was dried under vacuum at 30 °C and then subjected to XRPD testing. The results are shown in Table 27.

[0529] Table 27: Rapid Cooling Method

[0530] (8) Gas-solid diffusion method

[0531] Approximately 40 mg of compound I (the amorphous compound prepared in Example 1) was weighed into a 2 mL transparent sample vial. 3 mL of solvent was added to a 20 mL sample vial. The 2 mL transparent sample vial was placed open inside the 20 mL sample vial, which was then sealed and allowed to stand at room temperature. The solid obtained in the sample vial was subjected to XRPD testing, and the results are shown in Table 28.

[0532] Table 28: Gas-Solid Diffusion Method

[0533] The XRPD overlay of the sample after heating to 110℃ was obtained in Toluene by amorphous gas-solid diffusion method, as shown in Figure 8. The mixed crystal of free crystal form A and free crystal form B is transformed into free crystal form A after heating to 110℃.

[0534] Free crystalline form A can be obtained from most solvent systems via suspension, evaporation, antisolvent methods, gas-solid diffusion, gas-liquid diffusion, and cooling methods. XRPD shows that free crystalline form A has high crystallinity, DSC results indicate that its endothermic peak temperature is 157.48℃, and TGA results show that the sample loses approximately 0.02% weight when heated to 113℃. There is no significant weight loss before the sample decomposes, indicating that free crystalline form A is anhydrous.

[0535] Free crystal form B is a metastable crystal form and cannot be obtained alone. Starting with free crystal form A, a mixed crystal of free crystal form A and free crystal form B can be obtained in DCM by slow volatilization, or starting with amorphous crystals in Toluene by gas-solid diffusion. After heating and drying, the mixed crystals are completely converted into free crystal form A.

[0536] Example 4: Preparation of the sodium salt of compound I

[0537] Using the free crystal form A of compound I prepared in Example 2 as the starting material, the suspension method, cooling method, antisolvent method and volatilization method were used for screening. The screening results are listed in Table 30.

[0538] Approximately 50 mg of compound I (free crystal form A) and 1 equivalent of NaOH were weighed into separate 2 mL transparent sample vials. 0.1–0.5 mL of solvent was added to each vial at room temperature. The resulting solutions were magnetically stirred at 50 °C for 2 h, then cooled to 25 °C and stirred for 1 day. The solids obtained in the sample vials were vacuum dried at 30 °C for 2 h before XRPD analysis.

[0539] The clear solution from which no solids precipitated during the suspension method was placed in an ice bath to precipitate solids. The solids obtained in the sample vial were dried under vacuum at 30°C for 2 hours before XRPD testing.

[0540] The clear solution from which no solids precipitated during the cooling method was precipitated using the antisolvent method and the evaporation method. The solids obtained in the sample vial were dried under vacuum at 30°C for 2 hours before XRPD testing.

[0541] Table 30: Sodium Salt Screening Experiment

[0542] 1: In solvent systems of MeOH, EtOH, IPAc, MEK, Acetone, THF, 1,4-dioxane / H2O, Acetone / heptane, and THF / heptane, heptane is used as an antisolvent to precipitate solids. If no solids precipitate, the evaporation method is used for crystallization.

[0543] 2: In solvent systems of ACN, MeOH / H2O, ACN / H2O and NMP / MTBE, MTBE is used as an antisolvent to precipitate solids. If no solids precipitate, the volatilization method is used for crystallization.

[0544] 3: In solvent systems of DMSO, DMF, and DMSO / toluene, toluene is used as an antisolvent to precipitate solids. If no solids precipitate, the evaporation method is used for crystallization.

[0545] Through screening of sodium salts, four sodium salt crystal forms were obtained: sodium salt crystal form A (monohydrate), sodium salt crystal form B (1,4-dioxane compound), sodium salt crystal form C (DMSO compound), and sodium salt crystal form D (monohydrate).

[0546] The XRPD pattern of sodium salt crystal form A is shown in Figure 9, and the XRPD data are shown in Table 31 below. The DSC / TGA results are shown in Figures 10 and 11. The TGA results show that the sample loses 3.4% of its weight when heated to 139℃; the DSC results show that the sample has an endothermic peak at 127.86℃ (peak temperature). 1 The 1H NMR results are shown in Figure 12. The XRPD pattern of sodium salt crystal form A heated to 150℃ is shown in Figure 13, exhibiting an amorphous shape.

[0547] Table 31: XRPD diffraction peak data of sodium salt crystal form A

[0548] The XRPD pattern of sodium salt crystal form B is shown in Figure 14, and the XRPD data are shown in Table 32 below. The DSC / TGA results are shown in Figures 15 and 16. The TGA results show that the sample loses 12.2% of its weight when heated to 153℃; the DSC results show that the sample has an endothermic peak at 125.50℃ (peak temperature). 1 The H NMR results are shown in Figure 17.

[0549] Table 32: XRPD diffraction peak data of sodium salt crystal form B

[0550] The XRPD pattern of the sodium salt crystal form C sample is shown in Figure 18, and the XRPD data are shown in Table 33 below. The DSC / TGA results are shown in Figures 19 and 20. The TGA results show that the sample loses 1.0% weight when heated to 74℃ and 7.7% weight when heated from 74℃ to 139℃; the DSC results show that the sample has three endothermic peaks at 57.44℃, 102.84℃, and 141.86℃ (peak temperature). 1 The HNMR results are shown in Figure 21.

[0551] Table 33: XRPD diffraction peak data of sodium salt crystal form C

[0552] The XRPD pattern of the sodium salt crystal form D sample is shown in Figure 22, and the XRPD data are shown in Table 34 below. The DSC / TGA results are shown in Figures 23 and 24. The TGA results show that the sample loses 3.7% of its weight when heated to 110℃; the DSC results show that the sample has an endothermic peak at 129.81℃ (peak temperature). 1 The H NMR results are shown in Figure 25.

[0553] Table 34: XRPD diffraction peak data of sodium salt crystal form D

[0554] Sodium salt crystal form A exhibits favorable physicochemical properties, including high crystallinity, suitable endothermic peak temperature, and good pharmaceutical safety.

[0555] Example 5: Preparation of potassium salt of compound I

[0556] Using the free crystal form A of compound I prepared in Example 2 as the starting material, the suspension method, cooling method, antisolvent method and volatilization method were used for screening. The screening results are listed in Table 35.

[0557] Approximately 50 mg of compound I (free crystal form A) and 1 equivalent of KOH were weighed into separate 2 mL transparent sample vials. 0.1–0.5 mL of solvent was added to each vial at room temperature. The resulting solutions were magnetically stirred at 50 °C for 2 h, then cooled to 25 °C and stirred for 1 day. The solids obtained in the sample vials were vacuum dried at 30 °C for 2 h before XRPD analysis.

[0558] The clear solution from which no solids precipitated during the suspension method was placed in an ice bath to precipitate solids. The solids obtained in the sample vial were dried under vacuum at 30°C for 2 hours before XRPD testing.

[0559] The clear solution from which no solids precipitated during the cooling method was used to precipitate solids using the antisolvent method and the evaporation method. The solids obtained in the sample vial were dried under vacuum at 30°C for 2 hours before XRPD testing.

[0560] Table 35: Potassium Salt Screening Experiment

[0561] 1: In the solvent system of MeOH and DMF, MTBE is used as the antisolvent to precipitate solids. If no solids precipitate, the evaporation method is used for crystallization.

[0562] 2: In DMSO and DMSO / toluene solvent systems, toluene is used as an antisolvent to precipitate solids. If no solids precipitate, the evaporation method is used for crystallization.

[0563] Two potassium salt crystal forms were obtained through potassium salt screening experiments: potassium salt crystal form A (monohydrate) and potassium salt crystal form B (1,4-dioxane solvate).

[0564] The XRPD pattern of potassium salt crystal form A is shown in Figure 26, and the XRPD data are shown in Table 36 below. The DSC / TGA results are shown in Figures 27 and 28. The TGA results show that the sample loses 3.2% of its weight when heated to 120℃; the DSC results show that the sample has two endothermic peaks at 127.94℃ and 137.15℃ (peak temperature). 1 The H NMR results are shown in Figure 29.

[0565] Table 36: XRPD diffraction peak data of potassium salt crystal form A

[0566] The XRPD pattern of the potassium salt crystal form B sample is shown in Figure 30, and the XRPD data are shown in Table 37 below. The DSC / TGA results are shown in Figures 31 and 32. The TGA results show that the sample loses 8.2% of its weight when heated to 130℃; the DSC results show that the sample has two endothermic peaks at 120.94℃ and 136.50℃ (peak temperature). 1 The H NMR results are shown in Figure 33.

[0567] Table 37: XRPD diffraction peak data of potassium salt crystal form B

[0568] Potassium salt crystal forms A and B exhibit favorable physicochemical properties, including high crystallinity, suitable endothermic peak temperature, and good pharmaceutical safety.

[0569] Example 6: Preparation of other salt forms of compound I

[0570] Using the free crystal form A of compound I prepared in Example 2 as the starting material, the suspension method, cooling method and antisolvent method were used for screening. The screening results are listed in Table 38.

[0571] Approximately 50 mg of compound I (free crystal form A) and 0.5 or 1 equivalent of the ligand were weighed into separate 2 mL transparent sample vials. 0.1–0.5 mL of solvent was added to each vial at room temperature. The resulting solutions were magnetically stirred at 50 °C for 2 h, then cooled to 25 °C and stirred for 1 day. The solids obtained in the sample vials were vacuum dried at 50 °C for 2 h before XRPD analysis.

[0572] The clear solution from which no solids precipitate during the suspension method was placed in an ice bath to precipitate solids. The solids obtained in the sample vial were dried under vacuum at 50°C for 2 hours before XRPD testing.

[0573] The clear solution from which no solids precipitated during the cooling method was precipitated using an anti-solvent method or a evaporation method. The solids obtained in the sample vial were dried under vacuum at 50°C for 2 hours before XRPD testing.

[0574] Table 38: Other Salt Type Screening Experiments

[0575] 1: MTBE is used as an antisolvent in the MeOH and ACN / H2O solvent system to precipitate solids. If no solids precipitate, the volatilization method is used for crystallization.

[0576] 2: In the MEK and EtOH solvent system, heptane is used as the antisolvent to precipitate the solid. If no solid precipitates, the volatilization method is used for crystallization.

[0577] 3: Use 0.5 equivalents of calcium chloride and magnesium chloride to react with sodium salt to form salt.

[0578] The XRPD pattern of the tris(hydroxymethyl)aminomethane salt crystal form A sample is shown in Figure 34, and the XRPD data are shown in Table 39 below. The DSC / TGA results are shown in Figures 35 and 36. The TGA results show that the sample loses 6.9% of its weight when heated to 175℃; the DSC results show that the sample has two endothermic peaks at 135.07℃ and 203.43℃ (peak temperature). 1 The 1H NMR results are shown in Figure 37.

[0579] Table 39: XRPD diffraction peak data of Tris(hydroxymethyl)aminomethane salt crystal form A

[0580] The XRPD pattern of the tris(hydroxymethyl)aminomethane salt crystal form B sample is shown in Figure 38, and the XRPD data are shown in Table 40. The DSC / TGA results are shown in Figures 39 and 40. The TGA results show that the sample loses 0.4% weight when heated to 105℃ and 8.0% weight when heated from 105℃ to 175℃; the DSC results show that the sample has two endothermic peaks at 143.28℃ and 203.19℃ (peak temperature). 1 The HNMR results are shown in Figure 41.

[0581] Table 40: XRPD diffraction peak data of Tris(hydroxymethyl)aminomethane salt crystal form B

[0582] The XRPD pattern of the ethanolamine salt crystal form A sample is shown in Figure 42, and the XRPD data are shown in Table 41 below. The DSC / TGA results are shown in Figures 43 and 44. The TGA results show that the sample loses 7.6% of its weight when heated to 175℃; the DSC results show that the sample has an endothermic peak at 134.61℃ (peak temperature). 1 The H NMR results are shown in Figure 45.

[0583] Table 41: XRPD diffraction peak data of ethanolamine salt crystal form A

[0584] The XRPD pattern of the imidazole salt crystal form A sample is shown in Figure 46, and the XRPD data are shown in Table 42 below. The DSC / TGA results are shown in Figures 47 and 48. The TGA results show that the sample loses 4.3% of its weight when heated to 150℃ and 16.4% of its weight when heated from 150℃ to 220℃; the DSC results show that the sample has four endothermic peaks at 154.65℃, 162.92℃, 177.76℃, and 200.00℃ (peak temperature). 1 The HNMR results are shown in Figure 49.

[0585] Table 42: XRPD diffraction peak data of imidazole salt crystal form A

[0586] The XRPD pattern of the imidazole salt crystal form B sample is shown in Figure 50, and the XRPD data are shown in Table 43 below. The DSC / TGA results are shown in Figures 51 and 52. The TGA results show that the sample loses 1.2% weight when heated to 80℃, 3.3% weight when heated from 80℃ to 140℃, and 17.2% weight when heated from 140℃ to 210℃. The DSC results show that the sample has three endothermic peaks at 85.33℃, 143.11℃, and 162.71℃ (peak temperature), and one exothermic peak at 147.45℃ (peak temperature). 1 The HNMR results are shown in Figure 53.

[0587] Table 43: XRPD diffraction peak data of imidazole salt crystal form B

[0588] The XRPD pattern of the amorphous calcium salt sample is shown in Figure 54. 1 The H NMR results are shown in Figure 55.

[0589] The XRPD pattern of magnesium salt crystal form A is shown in Figure 56, and the XRPD data are shown in Table 44 below. The DSC / TGA results are shown in Figures 57 and 58. The TGA results show that the sample loses 1.9% weight when heated to 75℃, 7.8% weight when heated from 75℃ to 150℃, and 11.7% weight when heated from 150℃ to 250℃; the DSC results show that the sample has two endothermic peaks at 65.43℃ and 115.89℃ (peak temperature). 1 The H NMR results are shown in Figure 59.

[0590] Table 44: XRPD diffraction peak data of magnesium salt crystal form A

[0591] Example 7: Preparation of sodium salt crystal form A

[0592] Weigh 800 mg of the free crystalline form A of compound I prepared in Example 2 into a 20 mL transparent sample bottle. Add 3.7 mL of acetone to the sample bottle at room temperature and stir magnetically for about 10 min until a white suspension forms. Add 66 mg of NaOH (approximately 1 equivalent) to the suspension, then add approximately 5 mg of sodium salt crystalline form A seed crystals. Continue stirring for about 10 min until the solution becomes clear. After stirring at 50 °C for about 1 h, allow to cool naturally to 25 °C; a large amount of solid precipitates out. Continue stirring at 25 °C for 1 day, then collect the solid by filtration. Dry the solid under vacuum at 50 °C for about 2 h, yielding 719 mg of white solid. The XRPD spectrum of sodium salt crystalline form A is shown in Figure 60, and the XRPD data are shown in Table 45. The DSC spectrum of sodium salt crystalline form A is shown in Figure 61. The TGA spectrum of sodium salt crystalline form A is shown in Figure 62. 1 The H-NMR spectrum is shown in Figure 63.

[0593] Sodium salt crystal form A is a monohydrate with high crystallinity. DSC results show that its endothermic peak temperature is 134.81℃, and TGA results show that the sample loses approximately 3.0% weight when heated to 150℃. 1 H-NMR results showed no solvent residue in the sample, and the ion content results showed that the molar ratio of sodium ions to free ions was approximately 0.93. The moisture test results by Karl Fischer titration showed that the sample contained 3.517% (1.09 equivalents) of water.

[0594] Table 45: XRPD diffraction peak data of sodium salt crystal form A

[0595] Example 8: Preparation of potassium salt crystal form A

[0596] Weigh 800 mg of the free crystal form A of compound I prepared in Example 2 into a 20 mL transparent sample vial. Add 6.4 mL of EA to the vial at room temperature and stir magnetically for about 10 min until a white suspension forms. Add 103 mg of KOH (approximately 1 equivalent) to the suspension, followed by about 5 mg of potassium salt crystal form A seed crystals. Stir at 50 °C for about 1 h, then allow to cool naturally to 25 °C. Continue stirring at 25 °C for 1 day, then filter to collect the solid. Dry the solid under vacuum at 50 °C for about 2 h, yielding 724 mg of a white solid.

[0597] The XRPD spectrum of potassium salt crystal form A is shown in Figure 64, and the XRPD data are shown in Table 46 below.

[0598] The DSC spectrum of potassium salt crystal form A is shown in Figure 65. The TGA spectrum of potassium salt crystal form A is shown in Figure 66.

[0599] Potassium salt crystal form A is a monohydrate with high crystallinity. DSC results show that its endothermic peak temperature is 129.27℃, and TGA results show that the sample loses approximately 3.1% of its weight when heated to 120℃. 1 The H-NMR results, shown in Figure 67, indicate that no solvent residue was found in the sample. Ion content results showed a potassium ion to free molar ratio of approximately 0.89, and moisture content analysis by Karl Fischer titration indicated that the sample contained 3.804% (1.22 equivalents) of water.

[0600] Table 46: XRPD diffraction peak data of potassium salt crystal form A

[0601] Example 9: Dynamic solubility

[0602] The dynamic solubility of free crystalline form A, sodium salt crystalline form A, and potassium salt crystalline form A samples in FaSSGF (pH 1.6), FaSSIF (pH 6.5), FeSSIF (pH 5.0), and PBS (pH 7.4) was tested at 37℃. Samples were mixed at concentrations of 3-5 mg / mL in a shaker at 37℃, and the solubility of each sample was measured at different time points (0, 1, 2, 4, and 24 h). Samples were filtered after each time point, and the HPLC concentration of the filtrate was determined. The results of the dynamic solubility test are summarized in Table 47.

[0603] Table 47: Dynamic Solubility

[0604] 1. ND indicates that the concentration is below the detection limit of 5 μg / mL and was not detected.

[0605] Figure 68 shows the dynamic solubility curves of free crystal form A, sodium salt crystal form A, and potassium salt crystal form A in FaSSIF at 37℃.

[0606] Figure 69 shows the dynamic solubility curves of free crystal form A, sodium salt crystal form A, and potassium salt crystal form A in FeSSIF at 37℃.

[0607] Figure 70 shows the dynamic solubility curves of free crystal form A, sodium salt crystal form A, and potassium salt crystal form A in PBS at 37°C.

[0608] Dynamic solubility results showed that the solubility of free crystalline form A, sodium salt crystalline form A, and potassium salt crystalline form A increased with increasing solution pH. Furthermore, in FaSSIF, FeSSIF, and PBS, the solubility of sodium salt crystalline form A and potassium salt crystalline form A was higher than that of free crystalline form A. Sodium and potassium salts dissociate into their free states under low pH conditions; therefore, in FaSSGF, the solubility of free crystalline form A, as well as sodium salt and potassium salt crystalline forms A, was below the detection limit of 5 μg / mL.

[0609] Example 10: Solid stability

[0610] Free crystalline form A, sodium salt crystalline form A, and potassium salt crystalline form A were left exposed to air for 11 days and 31 days under conditions of high temperature (60°C), high humidity (92.5% RH), and light irradiation (5000 lx), respectively. The physical and chemical stability of the samples was determined by XRPD and HPLC. The results of the solid stability test are summarized in Table 48.

[0611] Table 48: Solid Stability

[0612] Figure 71 shows the XRPD overlay of the sample obtained from the 31-day solid stability assessment of free crystal form A under different influencing factors.

[0613] Figure 72 shows the XRPD overlay of the sodium salt crystal form A sample obtained from the 31-day solid stability assessment under different influencing factors.

[0614] Figure 73 shows the XRPD overlay of the potassium salt crystal form A sample obtained from the 31-day solid stability assessment under different influencing factors.

[0615] Stability results showed that after 31 days of storage, the crystal form and crystallinity of free crystal form A, sodium salt crystal form A, and potassium salt crystal form A did not change significantly under different conditions. Potassium salt crystal form A was relatively stable under high humidity and light conditions, with no significant change in purity, although the total impurities increased slightly over time under high temperature conditions. Sodium salt crystal form A remained stable under all conditions, with no significant changes in purity or crystal form after the 31-day solid-state stability test.

[0616] Example 11: Hygroscopicity

[0617] The hygroscopicity of free crystal form A, sodium salt crystal form A, and potassium salt crystal form A was evaluated using a dynamic water vapor adsorption (DVS) instrument. The percentage change in sample mass with varying humidity under a constant temperature of 25°C was collected. The DVS test results are summarized in Table 49.

[0618] Table 49: Hygroscopicity

[0619] The DVS diagram of free crystal form A is shown in Figure 74.

[0620] Figure 75 shows the XRPD overlay images of free crystal form A before and after DVS testing.

[0621] The DVS diagram of sodium salt crystal form A is shown in Figure 76.

[0622] Figure 77 shows the XRPD overlay images of sodium salt crystal form A before and after DVS testing.

[0623] The DVS diagram of potassium salt crystal form A is shown in Figure 78.

[0624] Figure 79 shows the XRPD overlay images of potassium salt crystal form A before and after DVS testing.

[0625] The results showed that the water adsorption rates of free crystal form A, sodium salt crystal form A, and potassium salt crystal form A at 25℃ / 80%RH were 0.21%, 0.48%, and 2.25%, respectively, indicating that free crystal form A and sodium salt crystal form A are slightly hygroscopic. XRD results showed that the crystal forms of all samples remained unchanged after DVS testing.

[0626] Test case

[0627] In the test examples of this invention, the preparation method of the control compound is based on patent WO2021229244A1, and its structure is shown below.

[0628] Biological testing

[0629] The following testing methods can be used.

[0630] Test Example 1: Compound Binding Test with AT2R

[0631] The experimental procedure was performed according to the instructions of the Angiotensin AT2 Receptor Ligand Binding Assay kit (#C1TT1AT2, Cisbio). First, the 10 mM stock solution was serially diluted 5× times (containing 10 concentrations, each diluted twice), and 160 nL of each concentration of the test compound was added to a 384-well plate. 40 μL of 1×TLB (TLB: Tag-lite buffer) was added to each well, and the plate was vortexed at room temperature for 15 minutes. A 15 mL centrifuge tube containing 5 mL of 1×TLB was prepared beforehand. The frozen labeled cells were thawed in a 37°C water bath (1-2 minutes), and the thawed cells were quickly transferred to the aforementioned 15 mL centrifuge tube. After mixing, the cells were centrifuged at 1000g for 5 minutes at room temperature. The supernatant was discarded, and 2.7 mL of 1×TLB was added to resuspend the cells. A new 384-well plate was prepared, and 10 μL of the mixed cells were added to the corresponding wells according to the experimental design. Add 5 μL of 4× Compound I solution and 5 μL of 4× Tag-lite red fluorescently labeled ligand to each well. After incubation at room temperature for 1 hour, data were read using EnVision's HTRF mode. The excitation light intensities at 665 nM and 615 nM in each well were read, and the ratio (Ratio = A665 nM / B615 nM) was calculated. The IC50 was then calculated using GraphPad Prism8 software. 50 Numerical values, X: the logarithm of the concentration of the compound to be tested; Y: the ratio of A665nM to B615nM.

[0632] Table 50: Binding activity of compounds with AT2R

[0633] Experimental results show that compound I of the present invention has a stronger binding ability to AT2R than the control compound.

[0634] Test Example 2: CYP Inhibition Experiment of Compounds

[0635] The inhibitory effects of the test compounds on six enzymes—CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 (midazolam), and CYP2B6—were evaluated at 10 μM. Human liver microsomes were stored at -80°C before use, thawed in a 37°C water bath, and operated on ice. 100 μL of the microsome working solution was taken, and 2 μL of the test compound or positive inhibitor working solution was added to each. 2 μL of solvent was added to the solvent control, and the mixture was pre-incubated in a 37°C water bath for 10 minutes. After pre-incubation, 98 μL of NADPH regeneration solution was added to all samples to initiate the reaction. The mixture was then returned to the water bath for incubation for a period of time. The reaction was quenched with 200 μL of stop solution. The mixture was centrifuged at 3220 g for 10 minutes, and 100 μL of the supernatant was transferred, mixed thoroughly with 100 μL of water, and analyzed by LC / MS / MS.

[0636] Table 51: CYP450 inhibition results of the compounds

[0637] Experimental results show that compound I in this invention has a weaker inhibitory effect on CYP enzymes compared with the control compound, and does not affect the body's normal metabolism, indicating a lower possibility of drug-drug interactions in the human body and higher safety. Test Example 3: Free Plasma Protein Binding (PPB) Experiment of the Compound

[0638] After soaking the dried dialysis membrane in ultrapure water for 1 hour, it was then soaked in 20% ethanol for 20 minutes, followed by rinsing with ultrapure water 2-3 times. Finally, it was soaked in ultrapure water for 20 minutes before use. Frozen plasma was thawed in a 37°C water bath for approximately 20 minutes. After complete thawing, the plasma pH was measured and adjusted to 7.4 using 1% phosphoric acid solution or 0.1M sodium hydroxide solution. The compound was diluted in preheated 37°C plasma to a final concentration of 1 μmol / L, and the internal control warfarin concentration in plasma was 2 μmol / L. The pretreated dialysis membrane was assembled into a dialysis plate according to the product instructions, and 100 μL of receiving buffer (100 mM phosphate buffer with 0.002% Tween 80) was added to one side of each well. 20 μL of the final solutions of the test compound and the control compound were respectively added to a 96-well sample plate for analysis, resulting in two duplicate samples (T0 sample), which were stored at -20°C. Take another 100 μL of the final solution and add it to the other side of the membrane in the dialysis apparatus, making two duplicate samples. Incubate at 37°C with shaking for 6 hours. After 6 hours of incubation, take 20 μL each of the dialysis receiving fluid and the administered plasma, making two duplicate samples, to obtain samples B and A. Add the corresponding volume of blank plasma or receiving fluid to samples B and A, respectively, so that the plasma to buffer volume ratio in each sample well is 1:1. Add 300 μL of sample containing internal standard acetonitrile solution to all sample wells, mix well, and centrifuge at 5500×g for 10 minutes. Add 150 μL of the corresponding ultrapure water to the corresponding sample well in the 96-well sample plate, take 150 μL of the supernatant, transfer it to the sample well, mix well, and perform LC / MS / MS analysis. fu calculation formula:

[0639] CR: Peak area ratio measured by the receiving chamber aperture;

[0640] CD: Peak area ratio measured at the supply chamber orifice.

[0641] The degree of freeness of a compound in plasma is related to its efficacy in the body. Experimental results show that compound I in this invention has a higher degree of freeness compared with the control compound, which is beneficial for the compound and its crystal form to reach the target organ.

[0642] Test Example 4: Liver Microsomal Stability Experiment of Compounds

[0643] The stability assay for human liver microsomes was performed by co-incubating the compound with human liver microsomes in vitro. First, the test compound was prepared as a 10 mM stock solution in DMSO, and then diluted to 0.5 mM with acetonitrile. Human liver microsomes (Corning) were diluted with PBS to prepare a microsome / buffer solution, and this solution was used to dilute 0.5 mM of the test compound to prepare the working solution. The concentration of the test compound in the working solution was 1.5 μmol / L, and the concentration of human liver microsomes was 0.75 mg / mL. 30 μL of the working solution was added to each well of a deep-well plate, followed by 15 μL of preheated 6 mM NADPH solution to initiate the reaction, which was incubated at 37°C. At 0, 5, 15, 30, and 45 minutes of incubation, 135 μL of acetonitrile was added to the corresponding well to terminate the reaction. After terminating the reaction with acetonitrile at the last 45 minutes, the deep-well plate was vortexed for 10 minutes (600 rpm / min) and then centrifuged for 15 minutes. After centrifugation, the supernatant was collected and purified water was added at a 1:1 ratio. LC-MS / MS analysis was performed to obtain the ratio of the compound peak area to the internal standard peak area at each time point. The peak area ratios at 5, 15, 30, and 45 minutes were compared with the ratio at 0 minutes to calculate the remaining percentage of the compound at each time point. The Tt value was calculated using Graphpad 8 software. 1 / 2 .

[0644] Table 52: Liver microsomal stability of the compounds

[0645] The stability of a compound in liver microsomes reflects its risk of being metabolized and cleared in vivo. Experimental results showed that test compound I exhibited good stability in humans compared to the control compound.

[0646] Test Example 5: Study on the bidirectional permeability of compounds in CACO-2 cells

[0647] Caco-2 cells were fed at a rate of 1×10 5 cells / cm 2The cells were seeded onto polyethylene (PET) membranes in 96-well insert plates at a controlled rate, with the culture medium changed every 4–5 days until days 21–28 to form a confluent cell monolayer. The transport buffer used in the experiment was HBSS and 10.0 mM HEPES, pH 7.40 ± 0.05. Bidirectional testing of the test compounds was performed at 2.00 μmol / L in both the presence and absence of 10.0 μmol / L GF120918. Digoxin was tested bidirectionally at 10.0 μmol / L in both the presence and absence of 10.0 μmol / L GF120918, while nadolol and metoprolol were tested in the absence of 10.0 μmol / L GF120918 at 2.00 μmol / L in both directions (A to B). All tests were performed in duplicate. The final DMSO concentration was adjusted to less than 1%. The plates were incubated in a CO2 incubator at 37 ± 1 °C for 2 hours with 5% CO2 added under saturated humidity, without shaking. All samples were mixed with acetonitrile containing the internal standard and centrifuged at 3200 g for 10 min. For nadolol and metoprolol, 200 μL of the supernatant was diluted with 600 μL of distilled water and analyzed by LC-MS / MS. For digoxin and the test compound, 200 μL of the supernatant was diluted with 200 μL of distilled water and analyzed by LC-MS / MS. The concentrations of the test and control compounds in the starting, donor, and acceptor solutions were quantified by LC-MS / MS using the analyte / internal standard peak area ratio.

[0648] Table 53: Bidirectional permeability of compounds in Caco-2 cells

[0649] The stability of a compound in liver microsomes reflects its risk of being metabolized and cleared in vivo. Experimental results showed that test compound I exhibited good stability in humans compared to the control compound.

[0650] Test Example 6: Induction of CYP3A4 enzyme by the compound

[0651] Cell viability was assessed in revived hepatocytes, and the hepatocytes were diluted to 0.7 × 10⁻⁶ in the inoculation culture medium. 6Cells / µL. 100µL of pre-warmed inoculation medium was added to each well of a 48-well collagen-coated plate to pre-wet the plate, then the medium was discarded. 200µL of cells were added to each well of the pre-coated collagen-coated 48-well plate, and the plates were incubated at 37°C in a 95% humidity, 5% CO2 incubator. Four hours after cell attachment, the inoculation medium was aspirated, and 200µL of incubation medium containing 2% matrix protease was added to each well. The next day, the cell culture plates were removed, the supernatant was aspirated, and 200µL of the test compound solution was added to each well sequentially. The plates were then incubated again. After 24 hours and 48 hours, the 48-well plates were removed from the incubator, and 100µL of medium from each well was transferred to a clean 96-well cell culture plate for LDH cell viability assay.

[0652] Enzyme activity assay:

[0653] At 48 h, the supernatant was aspirated and washed twice with 400 μL / well preheated HBSS solution. After HBSS aspiration, 100 μL of enzyme-labeled substrate working solution was added to each well. The cell plate was then incubated for 30 min in an incubator, and the reaction was stopped by transferring the supernatant to a 96-well plate containing stop solution. The plate was sealed, shaken, and centrifuged to collect the supernatant. The supernatant was then diluted in 0.1% FA water at a ratio of 1:4. All samples were mixed and analyzed by liquid chromatography / mass spectrometry (LC / MS / MS). Calibration was performed using the peak area ratio of metabolites to internal standards (IS). CYP enzyme activity was calculated using a standard curve consisting of 7 standard concentrations, and the fold change relative to the carrier control (0.1% dimethyl sulfoxide) was calculated. The fold change was calculated as: enzyme activity of the compound-treated sample / enzyme activity of the carrier control.

[0654] Enzyme gene induction assay:

[0655] 1. Total RNA extraction from cells

[0656] After 48 hours, aspirate the supernatant and wash once with 400 μL / well HBSS. Add RLT buffer (QIAGEN, cat: 1015762) to the plate and proceed according to the QIAGEN RNA extraction kit instructions.

[0657] 2. cDNA synthesis

[0658] cDNA was synthesized using ABI's High-Efficiency cDNA Reverse Transcription Kit (CAT: 4368813).

[0659] 3. Real-time quantitative PCR reaction

[0660] Add nuclease-free water to a fresh plate, add the cDNA sample, and gently mix to dilute. Prepare reaction mixtures for 18S rRNA and CYP3A4 separately, with 18S rRNA used as an internal standard. Seal the real-time quantitative PCR plate and centrifuge briefly to remove air bubbles and allow liquid to settle at the bottom of the tube. Transfer the plate to a real-time quantitative PCR instrument and analyze according to the supplier's protocol. PCR conditions: 50°C for 2 minutes, 95°C for 10 minutes, 40 cycles followed by the following two steps: 95°C for 15 seconds, 60°C for 1 minute.

[0661] 4. Real-time quantitative PCR data analysis

[0662] The fold change in relative expression = 2 - ΔCt, where ΔCt = Ct (target gene) - Ct (18S rRNA), and ΔCt = ΔCt (treated sample) - ΔCt (untreated control).

[0663] Experimental results showed that the tested compound had no toxic effect on hepatocytes, had a weak induction of CYP3A4 enzyme activity, and a relatively weak positive internal control for CYP3A4 enzyme gene induction.

[0664] Test Example 7: Pharmacokinetic Study of Compound Administered Orally by Gavage to Cynomolgus Monkeys

[0665] The compound was dissolved in a solvent of 5% DMSO + 10% Solutol + 85% Saline to prepare a concentration of 1 mg / mL, with a dosage of 5 mpk. Before administration, the patient was weighed, and the dosage was calculated based on body weight. The medication was administered orally via gavage. Blood was collected via the femoral vein or other suitable method at time points of 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. Approximately 1 mL of each sample was collected per time point. Heparin sodium was used for anticoagulation, and the samples were placed on ice after collection. Blood samples were placed on ice after collection and centrifuged within 1 hour to separate plasma (centrifugation conditions: 2200g, 10 minutes, 2-8℃). Plasma samples were stored at -80℃ before analysis.

[0666] The biological sample analysis methods and the analysis of all samples were completed by the analytical laboratory of Medicilon Medical Technology (Shanghai) Co., Ltd. At the same time as the sample analysis, the intraday accuracy of the quality control samples was evaluated, and it was required that the accuracy of more than 66.7% of the quality control samples be between 80-120%.

[0667] Table 54: Pharmacokinetics of the compounds in monkeys

[0668] Experimental results showed that the test compound I had higher Cmax and exposure levels than the control compound, indicating that it could have a better stimulating effect.

[0669] Test Example 8: IPF Efficacy Experiment of Compound in Mice

[0670] This experiment requires a specific mouse IPF model, which was established and the efficacy experiments of the compound were conducted by Shanghai Pengli Company. All animal experimental procedures were approved by Pengli IACUC (Laboratory Animal Management and Use Committee).

[0671] The experimental steps include:

[0672] 1. Compound preparation: Weigh an appropriate amount of compound powder, prepare a DMSO stock solution, and dispense it into the actual daily dosage required. Prepare the solution fresh each day. Add the required amount of 10% solubilol according to the dilution ratio, vortex to dissolve and mix well, and finally add the required amount of 85% saline according to the dilution ratio. The final DMSO content is 5%, and a clear solution of 0.03 mg / mL is prepared.

[0673] 2. Animal grouping: On the day of modeling, 10 animals were randomly selected and directly included in the G1 blank group. All other animals received intratracheal injection of bleomycin for model construction. After bleomycin injection, based on changes in animal weight, body weight, and animal condition, animals were randomly assigned to groups using BioBook before the first administration to achieve approximately equal weight in each group and reduce inter-group bias.

[0674] 3. Model Establishment: An appropriate amount of bleomycin was dissolved in commercially available physiological saline. Animals in the model group were anesthetized by inhalation of 1-4% isoflurane and administered 2 U / kg of bleomycin via trachea; the specific dosage was calculated based on the animal's body weight. Mice in the G1 group were anesthetized with 1-4% isoflurane and injected intratracheally with an equal volume of physiological saline.

[0675] 4. Administration: The day of bleomycin injection is considered day 0 of the trial. The administration regimen is shown in Table 55:

[0676] Table 55: Grouping and Dosing Regimens a: The solvent is 5% DMSO + 10% solubilol + 85% saline; b: bid, once in the morning and once in the afternoon, with an interval of about 6 hours; no medication is given on the morning of day 22.

[0677] 5. Lung function test: On day 22, all experimental animals were anesthetized with salbutamol (25-50 mg / kg) and toluidine (5-10 mg / kg). Lung function was tested using a pulmonary function test (PFT), including PV curve, FVC, IC, VC, Cdyn, and Cchord (quasi-static lung compliance) indicators.

[0678] 6. Lung tissue pathological examination: Lung tissue was collected, rinsed twice, dried with filter paper, and weighed. After weighing, the left lung was perfused and fixed with 10% neutral formaldehyde solution, and then immersed in 10% neutral formaldehyde solution for preservation and histopathological scoring. The formaldehyde-fixed left lung was transversely divided into three segments (upper, middle, and lower), embedded in the same paraffin block, sectioned, stained with Masson's stain, and then evaluated histopathologically by a pathologist. The scoring criteria are shown in Table 56.

[0679] Table 56: Fibrosis Scoring Criteria

[0680] 7. Animal euthanasia: All laboratory animals will be euthanized using CO2 and cervical dislocation methods after the in vivo experiments are completed.

[0681] Statistical analysis: Experimental data are expressed as mean ± standard error (mean ± SEM). SPSS or Graphpad Prism were used to analyze the data. P < 0.05 was considered statistically significant.

[0682] Experimental results show that, compared with the control compound, the compound of the present invention can significantly improve FVC, IC, and VC lung function indicators, and can significantly improve pulmonary fibrosis scores.

[0683] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0684] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A crystalline form of a compound of Formula (I) or a salt thereof, wherein The crystal form of the compound represented by formula (I) is a free form, The X-ray powder diffraction pattern of the free form has diffraction peaks at the following 2θ angles: 4.9±0.2°, 9.7±0.2°, 18.7±0.2°, 19.4±0.2°. The salt is an organic base salt or an inorganic base salt.

2. The crystalline form of the compound as shown in formula (I) or a salt thereof according to claim 1, characterized in that, The inorganic base salt is at least one of a sodium salt, a potassium salt, a calcium salt and a magnesium salt. The organic base salt is at least one of a tris-hydroxymethyl aminomethane salt, an ethanolamine salt and an imidazole salt.

3. The crystalline form of the compound as shown in formula (I) or a salt thereof according to claim 1, characterized in that, The salt of the compound represented by formula (I) is at least one of a sodium salt hydrate, a sodium salt 1,4-dioxane solvate, a sodium salt dimethyl sulfoxide solvate, a potassium salt hydrate, a potassium salt 1,4-dioxane solvate, a calcium salt, a magnesium salt, a tris-hydroxymethyl aminomethane salt, an ethanolamine salt and an imidazole salt. Preferably, the sodium salt hydrate is a sodium salt monohydrate. Preferably, the potassium salt hydrate is a potassium salt monohydrate.

4. The crystalline form of the compound as represented by formula (I) or a salt thereof according to claim 1, wherein, The salt is a first sodium salt crystal form, the first sodium salt crystal form comprising the compound represented by formula (I), sodium ions and water, the molar ratio of the compound represented by formula (I) to the sodium ions, water being (0.5-2):(0.5-2):(0.5-2); preferably, the molar ratio of the compound represented by formula (I) to the sodium ions, water being (0.9-1.1):(0.9-1.1):(0.9-1.1); preferably, the molar ratio of the compound represented by formula (I) to the sodium ion, water being 1:1:1; or The salt is a second sodium salt crystal form, the second sodium salt crystal form comprising the compound represented by formula (I), sodium ions and 1,4-dioxane, the molar ratio of the compound represented by formula (I) to the sodium ions, 1,4-dioxane being (0.5-2):(0.5-2):(0.5-2), preferably, the molar ratio of the compound represented by formula (I) to the sodium ions and 1,4-dioxane being (0.9-1.1):(0.9-1.1):(0,9-1.1); preferably, the molar ratio of the compound represented by formula (1) to the sodium ion and 1,4-dioxane being 1:1:1; or The salt is a third sodium salt crystal form, the third sodium salt crystal form comprising the compound represented by formula (I), sodium ions and dimethyl sulfoxide, the molar ratio of the compound represented by formula (I) to the sodium ions, the dimethyl sulfoxide being (0.5-2):(0.5-2):(0.5-2). Preferably, the molar ratio of the compound represented by formula (I) to the sodium ions and dimethyl sulfoxide being (0.9-1.1):(0.9-1.1):(0-9-1.1); preferably, the molar ratio of the compound represented by formula (l) to the sodium ion and dimethyl sulfoxide being 1:1:1; or The salt is a fourth sodium salt crystal form, the fourth sodium salt crystal form comprising a compound represented by Formula (I), sodium ions, and water, the molar ratio of the compound represented by Formula (I) to the sodium ions, water being (0.5-2):(0.5-2):(0.5-2); preferably, the molar ratio of the compound represented by Formula (I) to the sodium ions, water being (0.9-1.1):(0.9-1.1):(0.9-1.1); preferably, the molar ratio of the compound represented by Formula (I) to the sodium ions, water being 1:1:1; or The salt is a first potassium salt crystal form, the first potassium salt crystal form comprising a compound represented by Formula (I), potassium ions, and water, the molar ratio of the compound represented by Formula (I) to the potassium ions, water being (0.5-2):(0.5-2):(0.5-2); preferably, the molar ratio of the compound represented by Formula (I) to the potassium ions, water being (0.9-1.1):(0.9-1.1):(0.9-1.1); preferably, the molar ratio of the compound represented by Formula (I) to the potassium ions, water being 1:1:1; or The salt is a second potassium salt crystal form, the second potassium salt crystal form comprising a compound represented by Formula (I), potassium ions, and 1,4-dioxane, the molar ratio of the compound represented by Formula (I) to the potassium ions, 1,4-dioxane being (0.5-2):(0.5-2):(0.5-2); preferably, the molar ratio of the compound represented by Formula (I) to the potassium ions, 1,4-dioxane being (0.9-1.1):(0.9-1.1):(0.9-1.1); preferably, the molar ratio of the compound represented by Formula (I) to the potassium ions, 1,4-dioxane being 1:1:1; or The salt is a first tris salt crystal form, the molar ratio of the compound represented by Formula (I) to tris being (0.5-2):(0.5-2); preferably, the molar ratio of the compound represented by Formula (I) to tris being (0.9-1.1):(0.9-1.1); preferably, the molar ratio of the compound represented by Formula (I) to the tris being 1:1; or The salt is a second tris salt crystal form, the molar ratio of the compound represented by Formula (I) to tris being (0.5-2):( 0.5-2); preferably, the molar ratio of the compound represented by Formula ( I) to tris being (0.9-1.1):(0.9-1.1); preferably, the molar ratio of the compound represented by Formula (I) to tris is 1:1; or The salt is an ethanolamine salt crystal form, the molar ratio of the compound represented by Formula (I) to ethanolamine being (0.5-2):(0.5-2); preferably, the molar ration of the compound represented by Formula (I) to ethanolamine being (0.9-1.1):(0.9-1.1); preferably the molar ratio of the compound represented by Formula (I) to ethanolamine is 1:1; or the salt is a first imidazole salt crystal form, the molar ratio of the compound of formula (I) to imidazole is (0.5-2):(0.5-2); preferably, the molar ratio of the compound of formula (I) to imidazole is (0.9-1.1):(0.9-1.1); preferably, the molar ratio of the compound of formula (I) to imidazole is 1:1; or the salt is a second imidazole salt crystal form, the molar ratio of the compound of formula (I) to imidazole is (0.5-2):(0.5-2); preferably, the molar ratio of the compound of formula (I) to imidazole is (0.9-1.1):(0.9-1.1); preferably, the molar ratio of the compound of formula (I) to imidazole is 1:1; or the salt is a sodium salt amorphous, the molar ratio of the compound of formula (I) to sodium ion is (0.5-2):(0.5-2):(0.5-2); preferably, the molar ratio of the compound of formula (I) to sodium ion is (0.9-1.1):(0.9-1.1):(0.9-1.1); preferably, the molar ratio of the compound of formula (I) to sodium ion is 1:1; or the salt is a calcium salt amorphous, the molar ratio of the compound of formula (I) to calcium ion is (0.5-2):(0.5-2); preferably, the molar ratio of the compound of formula (I) to calcium ion is (0.9-2):(0.9-1.1); preferably, the molar ratio of the compound of formula (I) to calcium ion is 2:1; or the salt is a magnesium salt crystal form, the molar ratio of the compound of formula (I) to magnesium ion is (0.5-2):(0.5-2); preferably, the molor ratio of the compound of formula (I) to magnesium ion is (0.9-2):(0.9-1.1); preferably, molar ratio of the compound of formula (I) to magnesium ion is 2:

1.

5. The crystalline form of the compound as shown in formula (I) or a salt thereof according to claim 1, characterized in that, the X-ray powder diffraction pattern of the free form crystal form has diffraction peaks at the following 2θ angles: 4.9±0.2°, 9.7±0.2°, 18.7±0.2°, 19.4±0.2°; the inorganic base salt is a sodium salt, a potassium salt, a calcium salt and a magnesium salt; the organic base salt is a tris-hydroxymethyl aminomethane salt, an ethanolamine salt and an imidazole salt; or, the sodium salt of the compound of formula (I) is a first sodium salt crystal form, a second sodium salt crystal form, a third sodium salt crystal form or a fourth sodium salt crystal form of the compound of formula (I); the X-ray powder diffraction pattern of the first sodium salt crystal form has diffraction peaks at the following 2θ angles: 6.7±0.2°, 7.2±0.2°, 14.9±0.2°, 18.1±0.2°; the salt is a second sodium salt crystal form, characterized in that the X-ray powder diffraction pattern of the second sodium salt crystal form has diffraction peaks at the following 2θ angles: 6.1±0.2°, 10.6±0.2°, 19.9±0.2°, 23.2±0.2°; the salt is a third sodium salt crystalline form, characterized in that the X-ray powder diffraction pattern of the third sodium salt crystalline form has diffraction peaks at the following 2θ angles: 5.9±0.2°, 10.6±0.2°, 18.3±0.2°; the salt is a fourth sodium salt crystalline form, characterized in that the X-ray powder diffraction pattern of the fourth sodium salt crystalline form has diffraction peaks at the following 2θ angles: 6.8±0.2°, 7.7±0.2°, 17.2±0.2°; or, the potassium salt of the compound of formula (I) is a first potassium salt crystalline form, a second potassium salt crystalline form of the compound of formula (I); the first potassium salt crystalline form has an X-ray powder diffraction pattern with diffraction peaks at the following 2θ angles: 6.8±0.2 °, 7.7±0.2 °, 10.9±0.2 °, 15.4±0.2 °; the second potassium salt crystalline form has an X-ray powder diffraction pattern with diffraction peaks at the 2θ angles: 6.4±0.2 °, 10.8±0.2 °, 21.0±0.2 °, 25.7±0.2 °; or, the tris-hydroxymethylaminomethane salt of the compound of formula (I) is a first tris-hydroxymethylaminomethane salt crystalline form, a second tris-hydroxymethylaminomethane salt crystalline form of the compound of formula (I); the first tris-hydroxymethylaminomethane salt crystalline form has an X-ray powder diffraction pattern with diffraction peaks at the following2θ angles: 6.5±0.2 °, 9.5±0.2 °, 14.3±0.2 °, 17.7±0.2 °; the second tris-hydroxymethylaminomethane salt crystalline form has an X-ray power diffraction pattern with diffraction peaks at the following 2θ angles: 6.5±0.2 °, 7.3±0.2 °, 9.9±0.2 °; or, the ethanolamine salt of the compound of formula (I) is an ethanolamine salt crystalline form of the compound of formula (I); the ethanolamine salt crystalline form has an X-ray powder diffraction pattern with diffraction peaks at the following: 9.4±0.2 °, 19.5±0.2 °, 20.2±0.2 °, 22.9±0.2 °; or, the imidazole salt of the compound of formula (I) is a first imidazole salt crystalline form, a second imidazole salt crystalline form of the compound of formula (I); the first imidazole salt crystalline form has an X-ray powder diffraction pattern with diffraction peaks at the following : 7.4±0.2 °, 14.7±0.2 °, 18.7±0.2 °, 19.9±0.2 °; the second imidazole salt crystalline form has an X-ray powder diffraction pattern with diffraction peaks the following 2θ angles: 4.6±0.2 °, 9.3±0.2 °, 13.0±0.2 °, 28.0±0.2 °; or, the calcium salt of the compound of formula (I) is amorphous; or, the sodium salt of the compound of formula (I) is amorphous; or, the magnesium salt of the compound of formula (I) is a magnesium salt crystalline form of the compound of formula (I); the magnesium salt crystalline form has an X-ray powder diffraction pattern with diffraction peaks at the following angles: 5.6±0.2 °, 11.2±0.2 °, 16.8±0.2 °.

6. The crystalline form or salt thereof of the compound as shown in formula (I) according to claim 5, characterized in that, the X-ray powder diffraction pattern of said free form satisfies one or more of the following conditions: (1a) it has diffraction peaks at 4.9±0.2°, 9.7±0.2°, 16.9±0.2°, 18.7±0.2°, 19.4±0.2°, 24.2±0.2°; (1b) it has diffraction peaks at one or more of the following 2θ angles: 12.0±0.2°, 14.5±0.2°, 18.4±0.2°, 18.0±0.2°, 27.7±0.2°; (1c) it has diffraction peaks at 4.9±0.2°, 9.7±0.2°, 16.9±0.2°, 18.0±0.2°, 18.4±0.2°, 18.7±0.2°, 19.4±0.2°, 24.2±0.2°; (1d) it has diffraction peaks at 4.9±0.2°, 9.7±0.2°, 12.0±0.2°, 14.5±0.2°, 16.9±0.2°, 18.0±0.2°, 18.4±0.2°, 18.7±0.2°, 19.4±0.2°, 24.2±0.2°, 27.7±0.2°; (1e) it contains diffraction peak positions as shown in Table 13: Table 13 ; or, the X-ray powder diffraction pattern of said first sodium salt form satisfies one or more of the following conditions: (2a) it has diffraction peaks at 6.7±0.2°, 7.2±0.2°, 14.2±0.2°, 14.9±0.2°, 18.1±0.2°; (2b) it has diffraction peaks at one or more of the following 2θ angles: 9.0±0.2°, 16.9±0.2°, 23.8±0.2°, 24.1±0.2°, 26.8±0.2°, 27.4±0.2°; (2c) it has diffraction peaks at 6.7±0.2°, 7,2±0.2°, 9.0±0.2°, 14.2±0.2°, 14. 9±0.2°, 18.1±0.2°, 24.1±0.2°, 27.4±0.2°; (2d) it has diffraction peaks at 6.7±0.2°, 7 2±0.2°, 9.0±0.2°, 14 2±0.2°, 14.9±0.2°, 16.9±0.2°, 18.1±0.2°, 23.8±0.2°, 24. 1±0.2°, 26.8±0.2°, 27 4±0.2°; (2e) it contains diffraction peak positions as shown in Table 1: Table 1 ; or, the X-ray powder diffraction pattern of said second sodium salt form satisfies one or more of the following conditions: (3a) it has diffraction peaks at 6.1±0.2°, 7.4±0.2°, 10.6±0.2°, 19.9±0.2°, 23.2±0.2°; (3b) having diffraction peaks at one or more of the following 2Q angles: 6.7±0.2°, 8.6±0.2°, 14.5±0.2°, 15.5±0.2°, 17.2±0.2°, 18.1±0.2°, 18.3±0.2°, 25.9±0.2°; (3c) having diffraction peaks at 6.1±0.2°, 6.7±0.2°, 7.4±0.2°, 8.6±0.2°, 10.6±0.2°, 18.1±0.2°, 19.9±0.2°, 23.2±0.2°; (3d) having diffraction peaks at 6.1±0.2°, 6.7±0.2°, 7.4±0.2°, 8.6±0.2°, 10.6±0.2°, 15.5±0.2°, 17.2±0.2°, 18.1±0.2°, 19.9±0.2°, 23.2±0.2°; (3e) having diffraction peaks at 6.1±0.2°, 6.7±0.2°, 7.4±0.2°, 8.6±0.2°, 10.6±0.2°, 14.5±0.2°, 15.5±0.2°, 17.2±0.2°, 18.1±0.2°, 19.9±0.2°, 23.2±0.2°, 25.9±0.2°; (3f) comprising diffraction peaks at positions as shown in Table 2: Table 2 ; or, the X-ray powder diffraction pattern of the third sodium salt crystal form meets one or more of the following conditions: (4a) having diffraction peaks at 5.9±0.2°, 10.6±0.2°, 18.3±0.2°, 23.4±0.2°; (4b) having diffraction peaks at one or more of the following 2Q angles: 7.6±0.2°, 14.7±0.2°, 15.6±0.2°, 25.9±0.2°; (4c) having diffraction peaks at 5.9±0.2°, 7.6±0.2°, 10.6±0.2°, 15.6±0.2°, 18.3±0.2°, 23.4±0.2°; (4d) having diffraction peaks at 5.9±0.2°, 7.6 ±0.2°, 10.6±0.2°, 14.7±0.2°, 1 5.6±0.2°, 18.3±0.2°, 2 3.4±0.2°, 25.9±0.2°; (4e) comprising diffraction peaks at positions as shown in Table 3: Table 3 ; or, the X-ray powder diffraction pattern of the fourth sodium salt crystal form meets one or more of the following conditions: (5a) having diffraction peaks at 6.8±0.2°, 7.7±0.2°, 13.7±0.2°, 15.1±0.2°, 17.2±0.2°; (5b) having diffraction peaks at one or more of the following 2Q angles: 9.9±0.2°, 1 1.2±0.2°, 14.4±0.2°, 15.6±0.2°, 20.2±0.2°, 20.5±0.2°, 21.3±0.2°, 22.5±0.2°, 27.9±0.2°; (5c) having diffraction peaks at 6.8±0.2°, 7.7±0.2°, 9.9±0.2°, 11.2±0.2°, 13.7±0.2°, 15.1±0.2°, 15.6±0.2°, 17.2±0.2°, 20.2±0.2°; (5d) having diffraction peaks at 6.8±0.2°, 7.7±0.2°, 9.9±0.2°, 11.2±0.2°, 13.7±0.2°, 14.4±0.2°, 15.1±0.2°, 15.6±0.2°, 17.2±0.2°, 20.2±0.2°, 20.5±0.2°, 21.3±0.2°, 22.5±0.2°, 27.9±0.2°; (5e) comprising the diffraction peaks positions as shown in Table 4: Table 4 ; or the X-ray powder diffraction spectrum of the first potassium salt crystal form meets one or more of the following conditions: (6a) having diffraction peaks at 6.8±0.2°, 7.7±0.2°, 10.9±0.2°, 15.4±0.2°, 20.2±0.2°; (6b) having diffraction peaks at one or more of the following 2θ angles: 9.9±0.2°, 13.6±0.2°, 14.2±0.2°, 15.1±0.2°, 17.4±0.2°, 22.9±0.2°, 23.3±0.2°, 24.7±0.2°, 24.9±0.2°; (6c) having diffraction peaks at 6.8±0.2°, 7,7±0.2°, 10.9±0.2°, 15,4±0.2°, 17.4±0.2°, 20.2±0.2°, 24.9±0.2°; (6d) having diffraction peaks at 6.8±0.2°, 7, 7±0.2°, 9.9±0.2°, 10.9±0.2°, 14.2±0.2°, 15. l±0.2°, 15.4±0.2°, 17.4±0.2°, 20,2±0.2°, 23.3±0.2°, 24. 7±0.2°, 24.9±0.2°; (6e) having diffraction peaks at 6.8±0.2°, 7. 7±0.2°, 9.9±0.2°, 1 0.9±0.2°, 13.6±0.2°, 1 4.2±0.2°, 15.1±0.2°, 15.4±0.2°, 17. 4±0.2°, 20.2±0.2°, 22.9±0.2°, 23. 3±0.2°, 24.7±0.2°, 24,9±0.2°; (6f) comprising the diffraction peaks positions as shown in Table 5: Table 5 ; or the X-ray powder diffraction spectrum of the second potassium salt crystal form meets one or more of the following conditions: (7a) having diffraction peaks at 6.4±0.2°, 10.8±0.2°, 18.9±0.2°, 21.0±0.2°, 25.7±0.2°; (7b) having diffraction peaks at one or more of the following 2Q angles: 7.0±0.2°, 10.5±0.2°, 13.1±0.2°, 16.7±0.2°, 17.7±0.2°, 18.4±0.2°, 19.5±0.2°, 20.7±0.2°, 23.0±0.2°, 32.8±0.2°; (7c) having diffraction peaks at 6.4±0.2°, 10.5±0.2°, 10.8±0.2°, 18.4±0.2°, 18.9±0.2°, 21.0±0.2°, 25.7±0.2°; (7d) having diffraction peaks at 6.4±0.2°, 7.0±0.2°, 10.5±0.2°, 10.8±0.2°, 13.1±0.2°, 16.7±0.2°, 18.4±0.2°, 18.9±0.2°, 19.5±0.2°, 21.0±0.2°, 23.0±0.2°, 25.7±0.2°; (7e) having diffraction peaks at 6.4±0.2°, 7.0±0.2°, 10.5±0.2°, 10.8±0.2°, 13.1±0.2°, 16.7±0.2°, 17.7±0.2°, 18.4±0.2°, 18.9±0. 2°, 19.5±0.2°, 20.7±0 2°, 21.0±0.2°, 23.0±0 2°, 25.7±0.2°, 32.8±0.2°; (7f) comprising diffraction peaks at positions as shown in Table 6: Table 6 ; or, the X-ray powder diffraction pattern of the first tris-hydroxymethylaminomethane salt crystalline form satisfies one or more of the following conditions: (8a) having diffraction peaks at 6.5±0.2°, 9.5±0.2°, 14.3±0.2°, 17.7±0.2°, 30.0±0.2°; (8b) having diffraction peaks at one or more of the following 2Q angles: 14.9±0.2°, 17.0±0.2°, 17.4±0.2°, 18.2±0.2°, 20.0±0.2°, 20.7±0.2°, 21.1±0.2°, 21.6±0.2°, 22.5±0.2°, 23.1±0.2°, 23.5±0.2°, 24.2±0.2°, 26.2±0.2°, 28.7±0.2°, 31.8±0.2°; (8c) having diffraction peaks at 6.5±0.2°, 9. 5±0.2°, 14.3±0.2°, 17 0±0.2°, 17.7±0.2°, 18.2±0.2°, 21.6±0.2°, 22. 5±0.2°, 30.0±0.2°; (8d) which has diffraction peaks at 6.5±0.2°, 9.5±0.2°, 14.3±0.2°, 17.0±0.2°, 17.4±0.2°, 17.7±0.2°, 18.2±0.2°, 20.7±0.2°, 21.6±0.2°, 22.5±0.2°, 23.1±0.2°, 24.2±0.2°, 26.2±0.2°, 28.7±0.2°, 30.0±0.2°; (8e) which has diffraction peaks at 6.5±0.2°, 9.5±0.2°, 14.3±0.2°, 14.9±0.2°, 17.0±0.2°, 17.4±0.2°, 17.7±0.2°, 18.2±0.2°, 20.0±0.2°, 20.7±0.2°, 21.1±0.2°, 21.6±0.2°, 22.5±0.2°, 23.1±0.2°, 23.5±0.2°, 24.2±0.2°, 26.2±0.2°, 28.7±0.2°, 30.0±0.2°, 31.8±0.2°; (8f) which comprises diffraction peaks at positions as shown in Table 7: Table 7 ; or, the X-ray powder diffraction pattern of the second tris-hydroxymethylaminomethane salt crystal form satisfies one or more of the following conditions: (9a) which has diffraction peaks at 6.5±0.2°, 7.3±0.2°, 9.9±0.2°, 17.6±0.2°, 20.3±0.2°; (9b) which has diffraction peaks at one or more of the following 2θ angles: 6.9±0.2°, 10.2±0.2°, 14.7±0.2°, 14.9±0.2°, 15.0±0.2°, 15.5±0.2°, 16.0±0.2°, 17.9±0.2°, 19.5±0.2°, 26.0±0.2°; (9c) which has diffraction peaks at 6.5±0.2°, 6.9±0.2°, 7.3±0.2°, 9. 9±0.2°, 14.9±0.2°, 16.0±0.2°, 17.6±0.2°, 19.5±0.2°, 20.3±0.2°; (9d) which has diffraction peaks at 6.5±0.2°, 6 9±0.2°, 7.3±0.2°, 9 9±0.2°, 14.7±0.2°, 14. 9±0.2°, 15.0±0.2°, 15 5±0.2°, 16.0±0.2°, 17 6±0.2°, 17.9±0.2°, 19. 5±0.2°, 20.3±0.2°, 26.0±0.2°; (9e) which comprises diffraction peaks at positions as shown in Table 8: Table 8 ; or, the X-ray powder diffraction pattern of the ethanolamine salt crystal form satisfies one or more of the following conditions: (10a) which has diffraction peaks at 9.4±0.2°, 17.9±0.2°, 19. (10b) It has diffraction peaks at one or more of the following 2θ angles: 10.1±0.2°, 11.9±0.2°, 12.3±0.2°, 14.2±0.2°, 14.5±0.2°, 16.7±0.2°, 17.6±0.2°, 20.5±0.2°, 27.4±0.2°, 28.0±0.2°, 28.4±0.2°; (10c) It has diffraction peaks at 9.4±0.2°, 10.1±0.2°, 11.9±0.2°, 14.5±0.2°, 17.6±0.2°, 17.9±0.2°, 19.5±0.2°, 20.2±0.2°, and 22.9±0.2°; (10d) It has diffraction peaks at 9.4±0.2°, 10.1±0.2°, 11.9±0.2°, 12.3±0.2°, 14.2±0.2°, 14.5±0.2°, 16.7±0.2°, 17.6±0.2°, 17.9±0.2°, 19.5±0.2°, 20.2±0.2°, 20.5±0.2°, 22.9±0.2°, 27.4±0.2°, 28.0±0.2°, and 28.4±0.2°; (10e) The positions of its diffraction peaks are shown in Table 9: Table 9 Alternatively, the X-ray powder diffraction pattern of the first imidazole salt crystal form satisfies one or more of the following conditions: (11a) It has diffraction peaks at 6.2±0.2°, 6.9±0.2°, 7.4±0.2°, 14.7±0.2°, 18.7±0.2°, and 19.9±0.2°; (11b) It has diffraction peaks at one or more of the following 2θ angles: 10.8±0.2°, 12.4±0.2°, 12.9±0.2°, 16.3±0.3°, 19.3±0.2°, 22.1±0.2°, 23.3±0.2°, and 27.1±0.2°; (11c) It has diffraction peaks at 6.2±0.2°, 6.9±0.2°, 7.4±0.2°, 12.9±0.2°, 14.7±0.2°, 16.3±0.2°, 18.7±0.2°, 19.3±0.2°, and 19.9±0.2°; (11d) It has diffraction peaks at 6.2±0.2°, 6.9±0.2°, 7.4±0.2°, 10.8±0.2°, 12.4±0.2°, 12.9±0.2°, 14.7±0.2°, 16.3±0.2°, 18.7±0.2°, 19.3±0.2°, 19.9±0.2°, 22.1±0.2°, 23.3±0.2°, and 27.1±0.2°; (11e) The positions of its diffraction peaks are shown in Table 10: Table 10 Alternatively, the X-ray powder diffraction pattern of the second imidazole salt crystal form satisfies one or more of the following conditions: (12a) It has diffraction peaks at 4.6±0.2°, 9.3±0.2°, 13.0±0.2°, 23.3±0.2°, and 28.0±0.2°; (12b) It has diffraction peaks at one or more of the following 2θ angles: 11.1±0.2°, 12.2±0.2°, 14.0±0.2°, 15.8±0.2°, 17.8±0.2°, 23.3±0.2°; (12c) It has diffraction peaks at 4.6±0.2°, 9.3±0.2°, 11.1±0.2°, 13.0±0.2°, 23.3±0.2°, and 28.0±0.2°; (12d) It has diffraction peaks at 4.6±0.2°, 9.3±0.2°, 11.1±0.2°, 13.0±0.2°, 17.8±0.2°, 23.3±0.2°, and 28.0±0.2°; (12e) The positions of its diffraction peaks are shown in Table 11: Table 11 Alternatively, the X-ray powder diffraction pattern of the magnesium salt crystal form satisfies one or more of the following conditions: (13a) It has diffraction peaks at 5.6±0.2°, 11.2±0.2°, 16.8±0.2°, and 22.4±0.2°; (13b) It has diffraction peaks at one or more of the following 2θ angles: 12.3±0.2°, 17.1±0.2°, 17.5±0.2°, 27.6±0.2°, 28.1±0.2°, 28.6±0.2°; (13c) It has diffraction peaks at 5.6±0.2°, 11.2±0.2°, 16.8±0.2°, 17.5±0.2°, 22.4±0.2°, and 27.6±0.2°; (13d) It has diffraction peaks at 5.6±0.2°, 11.2±0.2°, 12.3±0.2°, 16.8±0.2°, 17.1±0.2°, 17.5±0.2°, 22.4±0.2°, 27.6±0.2°, 28.1±0.2°, and 28.6±0.2°; (13e) The positions of its diffraction peaks are shown in Table 12: Table 12 7. The crystalline form of the compound of formula (I) or a salt thereof according to claim 1, wherein, The differential scanning calorimetry (DSC) of the free crystal form contains an endothermic peak at 157.48℃ ± 10℃; or The salt is a first sodium salt crystal form, and the differential scanning calorimetry (DSC) curve of the first sodium salt crystal form contains an endothermic peak at 127.86℃±10℃; or The salt is a second sodium salt crystal form, and the differential scanning calorimetry (DSC) of the second sodium salt crystal form contains an endothermic peak at 125.50℃ ± 10℃; or The salt is in the third sodium salt crystal form, and the differential scanning calorimetry (DSC) curve of the third sodium salt crystal form contains one or more endothermic peaks at 57.44℃±10℃, 102.84℃±10℃, and 141.86℃±10℃; or The salt is a fourth sodium salt crystal form, and the differential scanning calorimetry (DSC) curve of the fourth sodium salt crystal form contains an endothermic peak at 129.81℃±10℃; or The salt is a first potassium salt crystal form, and the differential scanning calorimetry (DSC) curve of the first potassium salt crystal form contains one or more endothermic peaks at 127.94℃±10℃ and 137.15℃±10℃; or The salt is a second potassium salt crystal form, and the differential scanning calorimetry (DSC) curve of the second potassium salt crystal form contains one or more endothermic peaks at 120.94℃±10℃ and 136.50℃±10℃; or The salt is in the first tris(hydroxymethyl)aminomethane salt crystal form, and the differential scanning calorimetry (DSC) curve of the first tris(hydroxymethyl)aminomethane salt crystal form contains one or more endothermic peaks at 135.07℃±10℃ and 203.43℃±10℃; or The salt is a second tris(hydroxymethyl)aminomethane salt crystal form, and the differential scanning calorimetry (DSC) curve of the second tris(hydroxymethyl)aminomethane salt crystal form contains one or more endothermic peaks at 143.28℃±10℃ and 203.19℃±10℃; or The salt is in the ethanolamine salt crystal form, and the differential scanning calorimetry (DSC) of the ethanolamine salt crystal form contains an endothermic peak at 134.61℃±10℃; or The salt is a first imidazole salt crystal form, and the differential scanning calorimetry (DSC) curve of the first imidazole salt crystal form contains one or more endothermic peaks at 154.65℃±10℃, 162.92℃±10℃, 177.76℃±10℃, and 200.00℃±10℃; or The salt is a second imidazole salt crystal form, and the differential scanning calorimetry (DSC) curve of the second imidazole salt crystal form contains one or more endothermic peaks at 85.33℃±10℃, 143.11℃±10℃, and 162.71℃±10℃, and an exothermic peak at 147.45℃±10℃; or The salt is a magnesium salt crystal form, and the differential scanning calorimetry (DSC) of the magnesium salt crystal form contains one or more endothermic peaks at 65.43℃±10℃ and 115.89℃±10℃.

8. The crystalline form of the compound as represented by formula (I) or a salt thereof according to claim 1, wherein, The thermogravimetric analysis of the free crystal form showed a weight loss of 0.02±1% at initial heating to 113±10℃; or The salt is a first sodium salt crystal form, and the thermogravimetric analysis of the first sodium salt crystal form shows a weight loss of 3.4 ± 1% when initially heated to 139 ± 10 °C; or The salt is a second sodium salt crystal form, and the thermogravimetric analysis of the second sodium salt crystal form shows a weight loss of 12.2 ± 1% when initially heated to 153 ± 10 °C; or The salt is a third sodium salt crystal form, characterized in that the thermogravimetric analysis of the third sodium salt crystal form shows a weight loss of 1±1% when initially heated to 74±10℃, and a weight loss of 7.7±1% when heated from 74±10℃ to 139±10℃; or The salt is a fourth sodium salt crystal form, and the thermogravimetric analysis of the fourth sodium salt crystal form shows a weight loss of 3.7±1% when initially heated to 110±10℃; or The salt is a first potassium salt crystal form, and the thermogravimetric analysis of the first potassium salt crystal form shows a weight loss of 3.2 ± 1% when initially heated to 120 ± 10 °C; or The salt is a second potassium salt crystal form, and the thermogravimetric analysis of the second potassium salt crystal form shows a weight loss of 8.2 ± 1% when initially heated to 130 ± 10 °C; or The salt is in the form of tris(hydroxymethyl)aminomethane salt, and the thermogravimetric analysis of the first tris(hydroxymethyl)aminomethane salt crystal form shows a weight loss of 6.9±1% when initially heated to 175±10℃; or The salt is in the form of tris(hydroxymethyl)aminomethane salt, and the thermogravimetric analysis of the second tris(hydroxymethyl)aminomethane salt crystal form shows a weight loss of 0.4±1% when initially heated to 105±10℃, and a weight loss of 8.0±1% when heated from 105±10℃ to 175±10℃; or The salt is in the ethanolamine salt crystal form, and the thermogravimetric analysis of the ethanolamine salt crystal form shows a weight loss of 7.6±1% when initially heated to 175±10℃; or The salt is a first imidazole salt crystal form, and the thermogravimetric analysis of the first imidazole salt crystal form shows a weight loss of 4.3±1% when initially heated to 150±10℃, and a weight loss of 16.4±1% when heated from 150±10℃ to 220±10℃; or The salt is a second imidazole salt crystal form. The thermogravimetric analysis of the second imidazole salt crystal form shows a weight loss of 1.2±1% at initial heating to 80±10℃, 3.3±1% from 80±10℃ to 140±10℃, and 17.2±1% from 140±10℃ to 210±10℃; or The salt is a magnesium salt crystal form. The thermogravimetric analysis of the magnesium salt crystal form shows a weight loss of 1.9±1% when initially heated to 75±10℃, a weight loss of 7.8±1% when heated from 75±10℃ to 150±10℃, and a weight loss of 11.7±1% when heated from 150±10℃ to 250±10℃.

9. The crystalline form of the compound of formula (I) or a salt thereof according to claim 5, wherein, The free state crystal form is free state crystal form A, and free state crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 2; or The first sodium salt is sodium salt crystal form A, which has an X-ray powder diffraction pattern substantially as shown in Figure 9; or The sodium salt is an amorphous sodium salt, which has an X-ray powder diffraction pattern substantially as shown in Figure 13; or The second sodium salt is sodium salt crystal form B, which has an X-ray powder diffraction pattern substantially as shown in Figure 14; or The third sodium salt is sodium salt crystal form C, which has an X-ray powder diffraction pattern substantially as shown in Figure 18; or The fourth sodium salt is sodium salt crystal form D, which has an X-ray powder diffraction pattern substantially as shown in Figure 22; or The first potassium salt is potassium salt crystal form A, which has an X-ray powder diffraction pattern substantially as shown in Figure 26; or The second potassium salt is potassium salt crystal form B, which has an X-ray powder diffraction pattern substantially as shown in Figure 30; or The first trihydroxymethylaminomethane salt is trihydroxymethylaminomethane salt crystal form A, which has an X-ray powder diffraction pattern substantially as shown in Figure 34; or The second tris(hydroxymethyl)aminomethane salt is tris(hydroxymethyl)aminomethane salt crystal form B, which has an X-ray powder diffraction pattern substantially as shown in Figure 38; or The ethanolamine salt is ethanolamine salt crystal form A, and ethanolamine salt crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 42; or The first imidazole salt is imidazole salt crystal form A, characterized in that the imidazole salt crystal form A has an X-ray powder diffraction pattern substantially as shown in FIG46; or The second imidazole salt is imidazole salt crystal form B, which has an X-ray powder diffraction pattern substantially as shown in FIG50; or The calcium salt is an amorphous calcium salt, which has an X-ray powder diffraction pattern substantially as shown in Figure 54; or The magnesium salt is magnesium salt crystal form A, which has an X-ray powder diffraction pattern substantially as shown in Figure 56.

10. A method for preparing a crystalline form of a compound represented by formula (I) or a salt thereof, characterized by, Includes at least one of the following methods: Method 1 includes the following steps: the compound shown in formula (I) or the free crystal form of the compound shown in formula (I) and the salt-forming reagent are stirred in a first solvent at 50°C for 1-4 hours, then cooled to room temperature for a first pulping to obtain a solid, the solid is separated and a first drying is performed; The first solvent is selected from one or a mixture of several of the following: alcohols, MEK, acetonitrile, IPAc, EA, Acetone, 1,4-dioxane, THF, DMSO, DMF, heptane, MTBE, NMP, Toluene, and water. The alcohols are selected from methanol and ethanol; The first drying process is selected from vacuum drying, and the first drying temperature is 20-50℃, preferably 30℃; The first pulping time is 1-3 days; Method 2 includes the following steps: The compound shown in Formula (I) or the free crystal form of the compound shown in Formula (I) is stirred with a salt-forming reagent (e.g., an organic base or an inorganic base) in a second solvent at 50°C for 1-4 hours, and then cooled to room temperature and stirred for 1-3 days; the mixture is placed in an ice bath to precipitate a solid. If no solid precipitates, the clear solution is placed at room temperature to slowly evaporate and obtain a solid. The solid is then separated and subjected to a second drying process. The second solvent is selected from one or a mixture of several of the following: alcohols, MEK, acetonitrile, IPAc, EA, Acetone, 1,4-dioxane, THF, DMSO, DMF, heptane, MTBE, NMP, Toluene, and water. The alcohols are selected from methanol and ethanol; The second drying is selected from vacuum drying, and the second drying temperature is 20-50℃, preferably 30℃ or 50℃; Method 3 includes the following steps: the compound shown in formula (I) or the free crystal form of the compound shown in formula (I) and a salt-forming reagent (e.g., an organic or inorganic base) are stirred in a third solvent at 50°C for 1-4 hours, then cooled to room temperature and stirred for 1-3 days; an antisolvent is added to obtain a solid, the solid is separated and subjected to a third drying process; The third solvent is selected from one or a mixture of several of the following: alcohols, MEK, acetonitrile, IPAc, EA, Acetone, 1,4-dioxane, THF, DMSO, DMF, heptane, MTBE, NMP, Toluene, and water. The alcohols are selected from methanol and ethanol; The third drying process is selected from vacuum drying, and the third drying temperature is 20-50℃, preferably 30℃ or 50℃. The antisolvent is selected from heptane, MTBE, and toluene; Method 4 includes the following steps: Stir the compound shown in Formula (I) or the free crystal form of the compound shown in Formula (I) in a fourth solvent for about 10-30 min to obtain a suspension, add the salt-forming reagent to the above suspension, add seed crystals, stir for 10-30 min until clear, stir at 50℃ for 1-4 h, then cool to room temperature for a second pulping to obtain a solid, separate the solid and perform a fourth drying; The fourth solvent is selected from one or a mixture of alcohols, acetonitrile, and Acetone; The alcohols are selected from methanol and ethanol; The fourth drying process is selected from vacuum drying, and the drying temperature is 20-50℃, preferably 50℃; The second pulping time is 1-3 days.

11. A pharmaceutical composition, characterized by, It comprises the crystal form of the compound according to any one of claims 1 to 9 or a salt thereof.

12. Use of the crystal form of the compound of any one of claims 1 to 9 or a salt thereof, or the pharmaceutical composition of claim 11, in the preparation of a medicament for the prevention and / or treatment of diseases with insufficient endogenous production of Ang II; And / or, the drug is used for the prevention and / or treatment of diseases for which an increased effect of Ang II is desired or required; And / or, the drug is used to prevent and / or treat diseases in which AT2R is expressed and which are desired or necessary to be stimulated; And / or, the use of the crystal form of the compound of any one of claims 1 to 9 or a salt thereof, or the use of the pharmaceutical composition of claim 11 in the preparation of an AT2R agonist.

13. Use according to claim 12, characterized in that, The diseases mentioned include at least one of asthma, obstructive pulmonary disease, pneumonia, pulmonary hypertension, adult respiratory distress syndrome, and idiopathic pulmonary fibrosis.

14. A method for preventing and / or treating a disease in which endogenous production of Ang II is insufficient, comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt thereof according to claim 1. include; The patient is given a pharmaceutically acceptable dose of the crystal form of the compound of any one of claims 1 to 9 or a salt thereof, or the pharmaceutical composition of claim 11.

15. A method for preventing and / or treating a disease in which an increase in the action of Ang II is desired or required, characterized by, include; The patient is given a pharmaceutically acceptable dose of the crystal form of the compound of any one of claims 1 to 9 or a salt thereof, or the pharmaceutical composition of claim 11.

16. A method of preventing and / or treating a disease in which AT2R is expressed and stimulation thereof is desired or necessary, characterized in that, include; The patient is given a pharmaceutically acceptable dose of the crystal form of the compound of any one of claims 1 to 9 or a salt thereof, or the pharmaceutical composition of claim 11.

17. The method according to any one of claims 13 to 16, characterized in that, The diseases mentioned include at least one of asthma, obstructive pulmonary disease, pneumonia, pulmonary hypertension, adult respiratory distress syndrome, and idiopathic pulmonary fibrosis.

18. The crystal form of the compound according to any one of claims 1 to 9 or a salt thereof, or the pharmaceutical composition according to claim 11, for the prevention and / or treatment of diseases with insufficient endogenous production of Ang II; or Used for the prevention and / or treatment of diseases for which an increased effect of Ang II is desired or required; or For the prevention and / or treatment of diseases in which AT2R is expressed and which are expected or necessary to be stimulated; or Used to prepare AT2R agonists.

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