Crystal form of LPAR1 inhibitor, pharmaceutical composition comprising crystal form, and use thereof

Abstract

Disclosed in the present invention are a crystal form of an LPAR1 inhibitor, a pharmaceutical composition comprising the crystal form, and use thereof. The LPAR1 inhibitor is compound I or a stereoisomer thereof, and the crystal form thereof comprises crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, or crystal form F. All the crystal forms exhibit stable physical and chemical properties, good formulation process processability, good biological performance in vivo and in vitro, and wide application prospects.

Description

A crystal form of an LPAR1 inhibitor, pharmaceutical compositions comprising the crystal form, and their uses.

[0001] This application claims priority to Chinese Patent Application No. 2025101207695, filed on January 24, 2025; Chinese Patent Application No. 2025113224776, filed on September 16, 2025; and Chinese Patent Application No. 2026100768663, filed on January 20, 2026. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to the field of medicinal chemistry, and more specifically to a crystal form of an LPAR1 inhibitor, a pharmaceutical composition comprising the crystal form, and the use thereof. Background Technology

[0003] Lysophosphatidic acid (monoacyl-glycerol-3-phosphate, LPA) is a class of bioactive phospholipids produced by lysophosphatidylcholine (LPC) and exerts a wide range of cellular responses, such as proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis, through a family of 7-membrane domain G protein-coupled receptors (GPCRs). These receptors are collectively referred to as LPA receptors (LPARs). LPA receptor-mediated signaling has been shown to influence many biological processes, such as wound healing, immunity, oncogenesis, angiogenesis, and neurogenesis. Aberrant upregulation of the LPA pathway has been associated with a variety of diseases. Therefore, LPA receptors may be drug targets for various diseases, including cancer, fibrosis, inflammation, pain, and cardiovascular disease.

[0004] Currently identified LPA receptors include LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, and LPAR6. Characterization of these six LPA receptors reveals differences in their tissue distribution and downstream signaling pathways. Lysophosphatidylcholine receptor 1 (LPAR1) is a G protein-coupled receptor that mediates the growth factor-like activity of LPA, playing a crucial role in the development of cancer, inflammation, fibrosis, neurological disorders, and urinary tract diseases. For example, silencing LPA1 with siRNA or using LPA1 antagonists can reduce tumor burden in bone and soft tissues; LPA promotes the migration of human monocytes and is associated with T cell proliferation and infiltration; LPA receptor antagonists can protect individuals from infection-induced inflammation; and upregulation of LPAR1 activity is associated with fibrosis observed in systemic scleroderma. Previous studies have shown that in mice with unilateral ureteral ligation, a model of renal fibrosis, LPA production and LPA1 expression are increased, and administration of LPA1-deficient or LPA receptor antagonist drugs can inhibit renal fibrosis. In bronchoalveolar lavage fluid from patients with idiopathic pulmonary fibrosis, LPA concentrations are elevated, and LPA1 is most abundant in fibroblasts, which play an important role in pulmonary fibrosis; LPA induces fibroblast migration. In mice with scleroderma and subcutaneous bleomycin administration, administration of LPA1-deficient or LPA receptor antagonist drugs can inhibit skin fibrosis. LPA and LPA1 are also associated with neuropathic pain. LPA1 can also participate in urinary system diseases by causing contraction of urethral resection specimens and prostate specimens and increasing intraurethral pressure.

[0005] Recently, LPAR1 inhibitors have been clinically studied for their association with fibrotic diseases such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis, but no small molecule inhibitors of LPAR1 have yet been marketed. Therefore, developing small molecule LPAR1 inhibitors with the desired selectivity, good biological activity, and strong metabolic stability is of great significance for the treatment of these diseases. Simultaneously, developing suitable drug formulations for these compounds, such as those that improve stability, hygroscopicity, and / or efficacy, to achieve good results in both the manufacturing and administration stages, has become an urgent technical challenge. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a drug form of LPAR1 small molecule inhibitor suitable for drug development.

[0007] This invention provides the crystal form of compound I or its stereoisomers:

[0008] According to the technical solution of the present invention, the stereoisomer of compound I is compound IR:

[0009] According to the technical solution of the present invention, the crystal form is the crystal form of compound IR.

[0010] According to the technical solution of the present invention, the crystal form is crystal form A, crystal form B, crystal form C, crystal form D, crystal form E or crystal form F.

[0011] According to the technical solution of the present invention, the crystal form is crystal form A, crystal form B or crystal form C.

[0012] According to the technical solution of the present invention, the crystal form is crystal form A; the crystal form A has characteristic peaks at 6.9±0.2°, 9.9±0.2°, 13.7±0.2°, 14.5±0.2° and 15.4±0.2° when X-ray powder diffraction is expressed in 2θ angle using Cu-Kα radiation.

[0013] According to the technical solution of the present invention, the crystal form A, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 5.1±0.2°, 6.9±0.2°, 7.0±0.2°, 9.9±0.2°, 10.2±0.2°, 12.9±0.2°, 13.7±0.2°, 14.5±0.2°, 15.4±0.2°, and 19.5±0.2° in 2θ angles.

[0014] According to the technical solution of the present invention, the crystal form A, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 5.1±0.2°, 6.9±0.2°, 7.0±0.2°, 9.9±0.2°, 10.2±0.2°, 12.9±0.2°, 13.7±0.2°, 14.2±0.2°, 14.5±0.2°, 15.4±0.2°, 19.5±0.2°, 20.7±0.2°, 23.0±0.2°, 24.6±0.2°, and 28.2±0.2° in terms of 2θ angle.

[0015] According to the technical solution of the present invention, the crystal form A is subjected to Cu-Kα radiation, and X-ray powder diffraction, expressed in 2θ angles, is performed at 5.1±0.2°, 6.9±0.2°, 7.0±0.2°, 9.9±0.2°, 10.2±0.2°, 12.9±0.2°, 13.7±0.2°, 14.2±0.2°, 14.5±0.2°, 15.4±0.2°, 16.3±0.2°, 16.7±0.2°, 19.5±0.2°, 20.7±0.2°, 21.3±0.2°, and 22. Characteristic peaks are present at 7±0.2°, 23.0±0.2°, 24.0±0.2°, 24.2±0.2°, 24.6±0.2°, 25.0±0.2°, 25.7±0.2°, 25.9±0.2°, 26.3±0.2°, 26.6±0.2°, 27.7±0.2°, 28.2±0.2°, 28.9±0.2°, 29.9±0.2°, 30.8±0.2°, 33.3±0.2°, 34.1±0.2°, 34.8±0.2°, and 36.3±0.2°.

[0016] According to the technical solution of the present invention, the crystal form A has an X-ray powder diffraction pattern as shown in Figure 3.

[0017] According to the technical solution of the present invention, the crystal form A, when subjected to Cu-Kα radiation and X-ray powder diffraction with an angle of 2θ, exhibits diffraction peaks as shown in Table 1-2, with an error range of ±0.2°.

[0018] According to the technical solution of the present invention, the crystal form A has diffraction peaks as shown in Table 1-3 when X-ray powder diffraction is performed using Cu-Kα radiation and expressed in terms of 2θ angle, with an error range of ±0.2°.

[0019] According to the technical solution of the present invention, the differential scanning calorimetry curve of the crystal form A has an endothermic peak at a peak temperature of approximately 154.2℃±3℃.

[0020] According to the technical solution of the present invention, the thermogravimetric analysis curve of crystal form A shows a weight loss of 0.22% in the temperature range of 28.7℃±3℃ to 140℃±3℃. For example, the weight loss is 0.22% in the temperature range of 28.7℃ to 140℃.

[0021] According to the technical solution of the present invention, the crystal form A has a DSC-TGA spectrum as shown in Figure 4.

[0022] According to the technical solution of the present invention, the crystal form A is a long rod-shaped crystal. For example, in one embodiment, the crystal form A has a polarized light micrograph as shown in FIG6.

[0023] According to the technical solution of the present invention, the crystal form A has the basic characteristics shown in Figure 5. 1 H-NMR spectrum.

[0024] According to the technical solution of the present invention, the crystal form A does not contain organic solvents. Preferably, the organic solvent is one, two or more of the following: isopropanol (IPA), isopropyl acetate (IPAc), methyl tert-butyl ether (MTBE), n-heptane, acetone, methanol, ethanol, 2-butanone, ethyl acetate, methyl acetate, 4-methyl-2-pentanone, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, n-hexane, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, or N-methylpyrrolidone; for example, n-heptane and / or dichloromethane.

[0025] According to the technical solution of the present invention, the crystal form A is amorphous.

[0026] According to the technical solution of the present invention, the crystal form is crystal form B; the crystal form B, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 8.5±0.2°, 10.5±0.2°, 12.6±0.2° and 13.5±0.2° in 2θ angles.

[0027] According to the technical solution of the present invention, the crystal form B, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 8.5±0.2°, 10.5±0.2°, 12.6±0.2°, 13.5±0.2°, 16.8±0.2°, 21.1±0.2°, and 28.9±0.2° when expressed in 2θ angles.

[0028] According to the technical solution of the present invention, the crystal form B, using Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at angles of 2θ at 8.5±0.2°, 10.5±0.2°, 12.6±0.2°, 13.5±0.2°, 16.8±0.2°, 17.2±0.2°, 20.0±0.2°, 20.6±0.2°, 21.1±0.2°, 23.8±0.2°, 24.1±0.2°, 25.9±0.2°, 27.0±0.2°, 28.9±0.2°, and 29.3±0.2°.

[0029] According to the technical solution of the present invention, the crystal form B is subjected to Cu-Kα radiation, and X-ray powder diffraction, expressed in 2θ angles, is performed at 8.5±0.2°, 10.5±0.2°, 12.6±0.2°, 13.5±0.2°, 16.8±0.2°, 17.2±0.2°, 18.5±0.2°, 20.0±0.2°, 20.6±0.2°, and 21.1±0.2°. Characteristic peaks are present at 2°, 22.4±0.2°, 23.8±0.2°, 24.1±0.2°, 24.6±0.2°, 25.4±0.2°, 25.9±0.2°, 26.7±0.2°, 27.0±0.2°, 28.9±0.2°, 29.3±0.2°, 31.2±0.2°, 33.2±0.2°, and 33.7±0.2°.

[0030] According to the technical solution of the present invention, the crystal form B has an X-ray powder diffraction pattern as shown in Figure 7.

[0031] According to the technical solution of the present invention, the crystal form B, when subjected to Cu-Kα radiation and X-ray powder diffraction with an angle of 2θ, exhibits diffraction peaks as shown in Table 2-3, with an error range of ±0.2°.

[0032] According to the technical solution of the present invention, the crystal form B, when subjected to Cu-Kα radiation and X-ray powder diffraction with an angle of 2θ, exhibits diffraction peaks as shown in Table 2-4, with an error range of ±0.2°.

[0033] According to the technical solution of the present invention, the differential scanning calorimetry (DSC) curve of crystal form B has an endothermic peak at a peak temperature of approximately 145.8℃ ± 3℃. For example, it has an endothermic peak at 145.8℃. Another example is an endothermic peak at 146.1℃. Yet another example is an endothermic peak at 147.4℃.

[0034] According to the technical solution of the present invention, the thermogravimetric analysis curve of crystal form B shows a weight loss of 2.35% in the temperature range of 29.2℃±3℃ to 140℃±3℃. For example, a weight loss of 2.35% in the temperature range of 29.2℃ to 140℃.

[0035] According to the technical solution of the present invention, the crystal form B has a DSC-TGA spectrum as shown in Figure 8.

[0036] According to the technical solution of the present invention, the crystal form B is a needle-like crystal. For example, in one embodiment, the crystal form B has a polarized light micrograph as shown in FIG10.

[0037] According to the technical solution of the present invention, the crystal form B does not contain organic solvents. Preferably, the organic solvent is one, two or more of the following: IPA, IPAc, MTBE, n-heptane, acetone, methanol, ethanol, 2-butanone, ethyl acetate, methyl acetate, 4-methyl-2-pentanone, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, n-hexane, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, or N-methylpyrrolidone; for example, MTBE.

[0038] According to the technical solution of the present invention, the crystal form B is an amorphous form.

[0039] According to the technical solution of the present invention, the crystal form B has the basic characteristics shown in Figure 9. 1 H-NMR spectrum.

[0040] According to the technical solution of the present invention, the crystal form is crystal form C; the crystal form C, when subjected to Cu-Kα radiation, exhibits characteristic peaks at 4.4±0.2°, 12.4±0.2° and 14.5±0.2° in X-ray powder diffraction at an angle of 2θ.

[0041] According to the technical solution of the present invention, the crystal form C is subjected to Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angle, has characteristic peaks at 4.4±0.2°, 12.4±0.2°, 14.5±0.2°, 17.5±0.2°, 20.4±0.2° and 24.5±0.2°.

[0042] According to the technical solution of the present invention, the crystal form C has an X-ray powder diffraction pattern as shown in Figure 11;

[0043] According to the technical solution of the present invention, the crystal form C, when subjected to Cu-Kα radiation and X-ray powder diffraction with an angle of 2θ, exhibits diffraction peaks as shown in Table 3-2, with an error range of ±0.2°.

[0044] According to the technical solution of the present invention, the crystal form C, when subjected to Cu-Kα radiation and X-ray powder diffraction with an angle of 2θ, exhibits diffraction peaks as shown in Table 3-3, with an error range of ±0.2°.

[0045] According to the technical solution of the present invention, the crystal form C contains an organic solvent. Preferably, the organic solvent is one, two or more of the following: IPA, IPAc, MTBE, n-heptane, acetone, methanol, ethanol, 2-butanone, ethyl acetate, methyl acetate, 4-methyl-2-pentanone, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, n-hexane, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, or N-methylpyrrolidone; for example, IPA or IPAc. Preferably, the molar ratio of the organic solvent to compound IR is (0.1-1):1, more preferably (0.3-0.5):1, for example, 0.3:1 or 0.5:1.

[0046] For example, in one embodiment, the crystal form C contains IPA, and the molar ratio of IPA to compound IR is (0.3-0.5):1, for example, 0.3:1 or 0.5:1.

[0047] According to the technical solution of the present invention, the crystal form C is a solvate, such as an organic solvate, preferably an IPA solvate or an IPAc solvate. For example, the molar ratio of the organic solvent to the compound IR in the solvate is (0.1-1):1, preferably (0.3-0.5):1, for example, 0.3:1 or 0.5:1.

[0048] For example, in one embodiment, the crystal form C is an IPA solvate. In the IPA solvate, the molar ratio of IPA to compound IR is (0.3-0.5):1, for example, 0.3:1 or 0.5:1.

[0049] According to the technical solution of the present invention, the crystal form C contains an acid. Preferably, the acid is hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, or benzenesulfonic acid; for example, sulfuric acid or benzenesulfonic acid. Preferably, the molar ratio of the acid to compound IR is (0.5-1):1, more preferably (0.7-0.8):1, for example, 0.7:1 or 0.8:1.

[0050] For example, in one embodiment, the crystal form C contains sulfuric acid, and the molar ratio of the sulfuric acid to compound IR is 0.7:1.

[0051] For example, in one embodiment, the crystal form C contains benzenesulfonic acid, and the molar ratio of benzenesulfonic acid to compound IR is 0.8:1.

[0052] According to the technical solution of the present invention, the crystal form is crystal form D, crystal form E or crystal form F.

[0053] According to the technical solution of the present invention, the crystal form is crystal form D; the crystal form D, when subjected to Cu-Kα radiation, exhibits characteristic peaks at 7.5±0.2°, 7.7±0.2° and 14.2±0.2° in X-ray powder diffraction at an angle of 2θ.

[0054] According to the technical solution of the present invention, the crystal form D is subjected to Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, has characteristic peaks at 7.5±0.2°, 7.7±0.2°, 8.9±0.2°, 12.4±0.2°, 13.4±0.2°, 14.2±0.2° and 15.2±0.2°.

[0055] According to the technical solution of the present invention, the crystal form D is subjected to Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, has characteristic peaks at 7.5±0.2°, 7.7±0.2°, 8.9±0.2°, 12.4±0.2°, 13.4±0.2°, 14.2±0.2°, 15.2±0.2°, 16.1±0.2°, 17.9±0.2°, 21.7±0.2°, and 24.3±0.2°.

[0056] According to the technical solution of the present invention, the crystal form D has an X-ray powder diffraction pattern as shown in Figure 12.

[0057] According to the technical solution of the present invention, the crystal form D, when subjected to Cu-Kα radiation and X-ray powder diffraction with an angle of 2θ, exhibits diffraction peaks as shown in Table 4-2, with an error range of ±0.2°.

[0058] According to the technical solution of the present invention, the crystal form D, when subjected to Cu-Kα radiation and X-ray powder diffraction with an angle of 2θ, exhibits diffraction peaks as shown in Table 4-3, with an error range of ±0.2°.

[0059] According to the technical solution of the present invention, the differential scanning calorimetry curve of the crystal form D has endothermic peaks at peak temperatures of approximately 61.8℃±5℃ and 149.7℃±5℃.

[0060] According to the technical solution of the present invention, the differential scanning calorimetry curve of the crystal form D further exhibits an exothermic peak at a peak temperature of approximately 101.7℃ ± 5℃. For example, it further exhibits an exothermic peak at 101.7℃.

[0061] According to the technical solution of the present invention, the thermogravimetric analysis curve of the crystal D shows a weight loss of 2.07% ± 0.5% in the temperature range of 26.8℃ ± 3℃ to 120.0℃ ± 3℃; for example, a weight loss of 2.07% in the temperature range of 26.8℃ to 120.0℃.

[0062] According to the technical solution of the present invention, the crystal form D has a DSC-TGA pattern as shown in Figure 13.

[0063] According to the technical solution of the present invention, the crystal form D has the basic characteristics shown in Figure 14. 1 H-NMR spectrum.

[0064] According to the technical solution of the present invention, the crystal form D contains an organic solvent. Preferably, the organic solvent is one or both of dichloromethane and n-heptane. More preferably, the mass fraction of the organic solvent in crystal form D is 0.1%-1.0%; for example, 0.2%.

[0065] According to the technical solution of the present invention, the crystal form D is a hydrate.

[0066] According to the technical solution of the present invention, the crystal form is crystal form E; the crystal form E has characteristic peaks at 13.5±0.2°, 14.1±0.2° and 17.0±0.2° when X-ray powder diffraction is performed using Cu-Kα radiation and expressed in 2θ angle.

[0067] According to the technical solution of the present invention, the crystal form E is irradiated with Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angle, has characteristic peaks at 5.4±0.2°, 8.2±0.2°, 11.4±0.2°, 13.5±0.2°, 14.1±0.2°, 14.7±0.2°, 17.0±0.2° and 21.7±0.2°.

[0068] According to the technical solution of the present invention, the crystal form E is irradiated with Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, has characteristic peaks at 5.4±0.2°, 8.2±0.2°, 9.0±0.2°, 10.9±0.2°, 11.4±0.2°, 13.5±0.2°, 14.1±0.2°, 14.7±0.2°, 17.0±0.2°, 21.3±0.2°, 21.7±0.2°, and 23.4±0.2°.

[0069] According to the technical solution of the present invention, the crystal form E is subjected to Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, has characteristic peaks at 5.4±0.2°, 8.2±0.2°, 9.0±0.2°, 10.9±0.2°, 11.4±0.2°, 13.5±0.2°, 14.1±0.2°, 14.7±0.2°, 16.4±0.2°, 17.0±0.2°, 18.1±0.2°, 20.0±0.2°, 21.3±0.2°, 21.7±0.2°, 23.4±0.2°, 24.4±0.2°, 25.1±0.2°, 28.9±0.2°, 29.9±0.2°, and 32.6±0.2°.

[0070] According to the technical solution of the present invention, the crystal form E has an X-ray powder diffraction pattern as shown in Figure 15.

[0071] According to the technical solution of the present invention, the crystal form E, when subjected to Cu-Kα radiation and X-ray powder diffraction with an angle of 2θ, exhibits diffraction peaks as shown in Table 5-2, with an error range of ±0.2°.

[0072] According to the technical solution of the present invention, the crystal form E, when subjected to Cu-Kα radiation and X-ray powder diffraction with an angle of 2θ, exhibits diffraction peaks as shown in Table 5-3, with an error range of ±0.2°.

[0073] According to the technical solution of the present invention, the differential scanning calorimetry curve of the crystal form E has endothermic peaks at peak temperatures of approximately 59.1℃±5℃ and 95.4℃±5℃.

[0074] According to the technical solution of the present invention, the thermogravimetric analysis curve of the crystal form E shows a weight loss of 15.87% ± 3% in the temperature range of 18.4℃ ± 3℃ to 120.0℃ ± 3℃; for example, a weight loss of 15.87% in the temperature range of 18.4℃ to 120.0℃.

[0075] According to the technical solution of the present invention, the crystal form E has a DSC-TGA pattern as shown in Figure 16.

[0076] According to the technical solution of the present invention, the crystal form E has the basic characteristics shown in Figure 17. 1 H-NMR spectrum.

[0077] According to the technical solution of the present invention, the crystal form E contains an organic solvent; preferably, the organic solvent is dimethyl sulfoxide. More preferably, the mass fraction of the organic solvent in crystal form E is 15%-20%; for example, 18.6%.

[0078] According to the technical solution of the present invention, the crystal form E is a solvate, such as an organic solvate. Preferably, crystal form E is a dimethyl sulfoxide solvate. More preferably, the organic solvent accounts for 15%-20% by mass in the organic solvate; for example, 18.6%.

[0079] According to the technical solution of the present invention, the crystal form is crystal form F; the crystal form F has characteristic peaks at 4.5±0.2°, 12.5±0.2°, 14.8±0.2° and 17.9±0.2° when X-ray powder diffraction is performed using Cu-Kα radiation and expressed in 2θ angle.

[0080] According to the technical solution of the present invention, the crystal form F is subjected to Cu-Kα radiation, and the X-ray powder diffraction, expressed in 2θ angles, has characteristic peaks at 4.5±0.2°, 6.9±0.2°, 10.0±0.2°, 12.5±0.2°, 13.9±0.2°, 14.8±0.2°, 17.9±0.2°, 20.5±0.2°, and 24.7±0.2°.

[0081] According to the technical solution of the present invention, the crystal form F has an X-ray powder diffraction pattern as shown in Figure 18.

[0082] According to the technical solution of the present invention, the crystal form F has diffraction peaks as shown in Table 6-2 when X-ray powder diffraction is performed using Cu-Kα radiation and expressed in terms of 2θ angle, with an error range of ±0.2°.

[0083] According to the technical solution of the present invention, the crystal form F, when subjected to Cu-Kα radiation and X-ray powder diffraction with an angle of 2θ, exhibits diffraction peaks as shown in Table 6-3, with an error range of ±0.2°.

[0084] According to the technical solution of the present invention, the differential scanning calorimetry curve of the crystal form F has endothermic peaks at peak temperatures of approximately 67.3℃±5℃, 126.2℃±5℃ and 148.5℃±5℃; for example, it has endothermic peaks at peak temperatures of approximately 67.3℃, 126.2℃ and 148.5℃.

[0085] According to the technical solution of the present invention, the thermogravimetric analysis curve of the crystal form F shows a weight loss of 7.32% ± 3% in the temperature range of 27.9℃ ± 3℃ to 110.0℃ ± 3℃; for example, a weight loss of 7.32% in the temperature range of 27.9℃ to 110.0℃.

[0086] According to the technical solution of the present invention, the crystal form F has a DSC-TGA pattern as shown in Figure 19.

[0087] According to the technical solution of the present invention, the crystal form F has the basic characteristics shown in Figure 20. 1 H-NMR spectrum.

[0088] According to the technical solution of the present invention, the crystal form F contains an organic solvent. Preferably, the organic solvent is n-heptane. More preferably, the mass fraction of the organic solvent in crystal form F is 1%-5%; for example, 1.7%.

[0089] The present invention also provides a method for preparing a crystal form of compound I or its stereoisomer, wherein the preparation method is selected from any of the following methods:

[0090] Method 1: Mix compound I or its stereoisomer with solvent A and stir until a precipitate forms; if no precipitate forms, add the antisolvent to the system and continue stirring until a precipitate forms to obtain the crystal form described above.

[0091] Method 2: Mix compound I or its stereoisomer with an acid, and stir in solvent B until a precipitate forms to obtain the crystal form described above; if no precipitate forms during stirring, add solvent C to the system and continue stirring until a precipitate forms.

[0092] Method 3: Dissolve compound I or its stereoisomer in solvent D, and allow the solvent to evaporate slowly to obtain the crystal form;

[0093] Method 4: Place the open device containing compound I or its stereoisomer into a sealed device containing solvent E, so that compound I or its stereoisomer does not come into direct contact with solvent E, and then let it stand to obtain the crystal form.

[0094] According to the technical solution of the present invention, method one: mix compound I or its stereoisomer with solvent A, stir until precipitation occurs, and obtain the crystal form.

[0095] According to the technical solution of the present invention, solvent A is selected from one, two or more of the following: isopropanol (IPA), isopropyl acetate (IPAc), methyl tert-butyl ether (MTBE), n-heptane, acetone, methanol, ethanol, 2-butanone, ethyl acetate, methyl acetate, 4-methyl-2-pentanone, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, n-hexane, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, toluene, dimethylacetamide, cyclopentyl methyl ether, toluene, methyl isobutyl ketone, and water; or a mixture of any one or two of the above solvents with any one of n-heptane, n-hexane, toluene, or water.

[0096] According to the technical solution of the present invention, solvent A is IPA, IPAc, MTBE, acetone, dichloromethane, ethanol, ethyl acetate, tetrahydrofuran, or acetonitrile, or a mixture of any one of the above solvents with any one of n-heptane, n-hexane, toluene, or water. Preferably, in the mixed solvent, the volume ratio of any one of IPA, IPAc, MTBE, acetone, dichloromethane, ethanol, ethyl acetate, tetrahydrofuran, or acetonitrile to any one of n-heptane, n-hexane, toluene, or water is 1:(1-10); more preferably 1:(1-5); more preferably 1:(2-4); for example, 1:2, 1:3, 1:4, 1:5, or 1:9.

[0097] According to the technical solution of the present invention, solvent A is a mixture of IPA, IPAc, MTBE, IPA and n-heptane, a mixture of acetone and n-heptane, a mixture of IPAc and n-heptane, a mixture of dichloromethane and n-heptane, a mixture of ethanol and n-heptane, a mixture of ethyl acetate and n-heptane, a mixture of methyl tert-butyl ether and toluene, a mixture of tetrahydrofuran and n-hexane, a mixture of acetonitrile and n-hexane, or a mixture of tetrahydrofuran and n-hexane.

[0098] Preferably, the volume ratio of IPA to n-heptane in the mixed solvent of IPA and n-heptane is 1:2 or 1:9.

[0099] Preferably, the volume ratio of IPAc to n-heptane in the mixed solvent of IPAc and n-heptane is 1:2.

[0100] Preferably, the volume ratio of acetone to n-heptane in the mixed solvent of acetone and n-heptane is 1:4 or 1:3.

[0101] Preferably, the volume ratio of dichloromethane to n-heptane in the mixed solvent of dichloromethane and n-heptane is 1:2.

[0102] Preferably, the volume ratio of ethanol to n-heptane in the mixed solvent of ethanol and n-heptane is 1:4.

[0103] Preferably, the volume ratio of ethyl acetate to n-heptane in the mixed solvent of ethyl acetate and n-heptane is 1:3.

[0104] Preferably, the volume ratio of MTBE to toluene in the mixed solvent of methyl tert-butyl ether and toluene is 1:4.

[0105] Preferably, the volume ratio of tetrahydrofuran to n-hexane in the mixed solvent of tetrahydrofuran and n-hexane is 1:4.

[0106] Preferably, the volume ratio of acetonitrile to hexane in the mixed solvent of acetonitrile and n-hexane is 1:4.

[0107] Preferably, the volume ratio of tetrahydrofuran to n-hexane in the mixed solvent of tetrahydrofuran and n-hexane is 1:4.

[0108] According to the technical solution of the present invention, when the solvent A is a mixed solvent of dichloromethane and n-heptane, the crystal form A is obtained.

[0109] According to the technical solution of the present invention, when the solvent A is a mixed solvent of MTBE, IPA and n-heptane, a mixed solvent of acetone and n-heptane, a mixed solvent of IPAc and n-heptane, a mixed solvent of ethanol and n-heptane, a mixed solvent of ethyl acetate and n-heptane, a mixed solvent of methyl tert-butyl ether and toluene, a mixed solvent of tetrahydrofuran and n-hexane, a mixed solvent of acetonitrile and n-hexane, or a mixed solvent of tetrahydrofuran and n-hexane, the crystal form B is obtained.

[0110] According to the technical solution of the present invention, when the solvent A is a mixed solvent of dimethyl sulfoxide and water, the crystal form E is obtained.

[0111] According to the technical solution of the present invention, solvent A is dimethyl sulfoxide, a mixed solvent of dimethyl sulfoxide and water, or a mixed solvent of dimethyl sulfoxide and toluene.

[0112] Preferably, the solvent is a mixture of dimethyl sulfoxide and water, wherein the volume ratio of dimethyl sulfoxide to water is 1:9.

[0113] Preferably, the solvent is a mixture of dimethyl sulfoxide and toluene, wherein the volume ratio of dimethyl sulfoxide to toluene is 1:9.

[0114] According to the technical solution of the present invention, the antisolvent is water, n-heptane, or toluene.

[0115] According to the technical solution of the present invention, when the solvent A is dichloromethane and the antisolvent is n-heptane, the crystal form D is obtained.

[0116] According to the technical solution of the present invention, solvent B and solvent C are each independently selected from one, two or more of the following: isopropanol, isopropyl acetate, methyl tert-butyl ether, n-heptane, acetone, methanol, ethanol, 2-butanone, ethyl acetate, methyl acetate, 4-methyl-2-pentanone, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, n-hexane, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, and water.

[0117] According to the technical solution of the present invention, the solvent B is selected from one, two or more of the following: IPA, IPAc, MTBE, n-heptane, acetone, methanol, ethanol, 2-butanone, ethyl acetate, methyl acetate, 4-methyl-2-pentanone, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, n-hexane, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, and water. For example, it is IPA or IPAc. Another example is a mixed solvent of any one of IPA, IPAc, or ethanol with n-heptane. Preferably, in the mixed solvent, the volume ratio of any one of IPA, IPAc, or ethanol to n-heptane is 1:(1-5); more preferably, it is 1:2.

[0118] According to the technical solution of the present invention, the solvent C is selected from one, two or more of the following: IPA, IPAc, MTBE, n-heptane, acetone, methanol, ethanol, 2-butanone, ethyl acetate, methyl acetate, 4-methyl-2-pentanone, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, n-hexane, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, and water. For example, n-heptane.

[0119] According to the technical solution of the present invention, the solvent D is a mixed solvent of dichloromethane, methanol, IPAc, acetonitrile, and water, or a mixed solvent of acetone and water. Preferably, in the mixed solvent of acetonitrile and water, the volume ratio of acetonitrile to water is 4:1. Preferably, in the mixed solvent of acetone and water, the volume ratio of acetone to water is 4:1.

[0120] According to the technical solution of the present invention, the solvent E is any one of dimethyl sulfoxide, acetone or 2-methyltetrahydrofuran.

[0121] According to the technical solution of the present invention, in method one, the stirring temperature is 5-50℃; preferably 10-30℃; for example, 10-15℃, 20-25℃ or 50℃.

[0122] According to the technical solution of the present invention, in method two, the temperature during stirring in solvent B is 5-50℃.

[0123] According to the technical solution of the present invention, in method two, the temperature for continued stirring is -20 to 50°C.

[0124] According to the technical solution of the present invention, the mass ratio of compound I or its stereoisomer to the volume of solvent A is 1g:(5-50)mL. For example, it is 1g:6.7mL, 1g:15mL, 1g:25mL or 1g:50mL.

[0125] According to the technical solution of the present invention, the mass ratio of compound I or its stereoisomer to the volume of the antisolvent is 1g:(15-500)mL. For example, it is 1g:16.7mL, 1g:100mL, 1g:200mL, 1g:450mL or 1g:500mL.

[0126] According to the technical solution of the present invention, the mass ratio of compound I or its stereoisomer to the volume of solvent B is 1 g:(5-50) mL. For example, it is 1 g:25 mL.

[0127] According to the technical solution of the present invention, the mass ratio of compound I or its stereoisomer to the volume of solvent C is 1 g:(5-50) mL. For example, it is 1 g:25 mL.

[0128] According to the technical solution of the present invention, in method two, the acid is hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, or benzenesulfonic acid.

[0129] According to the technical solution of the present invention, the molar ratio of compound I or its stereoisomer to acid is 1:(0.5-2). For example, it is 1:1.

[0130] According to the technical solution of the present invention, the mass-volume ratio of compound I or its stereoisomer to solvent D is 1g:(10-100)mL, for example 1g:14.7mL, 1g:25mL, 1g:50mL or 1g:100mL.

[0131] According to the technical solution of the present invention, when the acid is sulfuric acid, p-toluenesulfonic acid or methanesulfonic acid, the solvent B is IPA or IPAc, and the solvent C is n-heptane, the crystal form C is obtained.

[0132] According to the technical solution of the present invention, when the acid is benzenesulfonic acid, the solvent B is IPA, and the solvent C is n-heptane, the crystal form C is obtained.

[0133] According to the technical solution of the present invention, when the acid is hydrochloric acid and the solvent B is a mixed solvent of ethanol and n-heptane, the crystal form F is obtained.

[0134] According to the technical solution of the present invention, when the solvent D is dichloromethane, the crystal form D is obtained.

[0135] According to the technical solution of the present invention, when the solvent E is dimethyl sulfoxide, the crystal form E is obtained.

[0136] According to the technical solution of the present invention, in method three, the slow evaporation is natural evaporation at room temperature.

[0137] According to the technical solution of the present invention, the mass-volume ratio of compound I or its stereoisomer to solvent E is 1g:(50-500)mL, for example 1g:150mL.

[0138] According to the technical solution of the present invention, in method four, the settling time is 5-10 days; for example, 7 days.

[0139] According to the technical solution of the present invention, in method four, the temperature of the static settling is 20-30℃.

[0140] The present invention also provides a pharmaceutical composition comprising the crystal form described above.

[0141] In one embodiment, the pharmaceutical composition contains one, two or more of the crystal forms A, B, C, D, E or F described above.

[0142] In one embodiment, the pharmaceutical composition contains one, two, or three of the crystal form A, crystal form B, or crystal form C described above.

[0143] According to the technical solution of the present invention, the pharmaceutical composition further contains a pharmaceutically acceptable carrier.

[0144] According to the technical solution of the present invention, the pharmaceutical composition may further contain a second active ingredient, such as one, two or more of the following: LPAR1 inhibitor, LPAR2 inhibitor, LPAR3 inhibitor, ROCK inhibitor, FAAH inhibitor, TGF-β inhibitor, ACC inhibitor, ASK-1 inhibitor, FXR agonist, GLP-1 agonist, PPARα agonist, VEGFR inhibitor, FGFR inhibitor, PDGFR inhibitor, ATX inhibitor, GPR84 agonist, PASK inhibitor, CFTR agonist, JAK1 inhibitor, ADAMTS5 inhibitor, TOL2 / 3 inhibitor, CTGF inhibitor, αv-β6 / αv-β1 antagonist, JNK1 inhibitor, mineralocorticoid receptor antagonist, Nrf2 activator, chymotrypsin inhibitor, PDE inhibitor, NOX1 / 4 inhibitor, leukotriene receptor antagonist, thromboxane receptor antagonist, SLC22A12 inhibitor, sGC inhibitor, xanthine oxidase inhibitor, or TGFP antagonist.

[0145] The present invention also provides the use of the above-described crystal form or pharmaceutical composition in formulation preparation.

[0146] The present invention also provides a formulation comprising the above-described crystal form or pharmaceutical composition.

[0147] According to the technical solution of the present invention, the formulation is an LPAR1 inhibitor.

[0148] The present invention also provides the use of the above-described crystal form, pharmaceutical composition, and formulation in the preparation of a medicament for the prevention and / or treatment of LPAR1-mediated diseases or conditions.

[0149] Preferably, the drug is an LPAR1 inhibitor.

[0150] According to the technical solution of the present invention, the disease is selected from fibrotic diseases, respiratory diseases, pain, nervous system diseases, cardiovascular and cerebrovascular diseases, inflammatory diseases, kidney diseases, liver diseases, eye diseases, cancer, gastrointestinal diseases, urinary system diseases, metabolic diseases, or transplant rejection.

[0151] Preferably, the fibrotic diseases include, but are not limited to: pulmonary fibrosis (especially idiopathic pulmonary fibrosis and progressive pulmonary fibrosis), renal fibrosis, liver fibrosis, skin fibrosis, intestinal fibrosis, ocular fibrosis, cardiac fibrosis, and pancreatic fibrosis.

[0152] Preferably, the respiratory diseases include, but are not limited to: interstitial lung disease (ILD), idiopathic interstitial pneumonia (IIP), asthma, chronic obstructive pulmonary disease (COPD), bronchospasm, cough, chronic cough, respiratory failure, silicosis, acute lung injury, and acute respiratory distress.

[0153] Preferably, the kidney disease includes, but is not limited to: acute kidney injury, chronic kidney disease, and diabetic nephropathy.

[0154] Preferably, the liver diseases include, but are not limited to: alcoholic steatohepatitis, non-alcoholic fatty liver disease (NAFLD), acute hepatitis, chronic hepatitis, cirrhosis, impaired liver function, primary biliary cirrhosis, etc.; the non-alcoholic fatty liver disease (NAFLD) may be non-alcoholic steatohepatitis (NASH).

[0155] Preferably, the inflammatory diseases include, but are not limited to: autoimmune diseases, inflammation, arthritis, rheumatoid arthritis, scleroderma, Raynaud's phenomenon, chronic pruritus, lupus, cryptogenic fibrotic alveolitis, psoriasis, systemic sclerosis, and collagen vascular diseases.

[0156] Preferably, the neurological diseases include, but are not limited to: Alzheimer's disease, Parkinson's disease, neurodegenerative diseases, traumatic brain injury, epilepsy, mental illness, and sleep disorders.

[0157] Preferably, the cardiovascular and cerebrovascular diseases include, but are not limited to: collagen vascular diseases, myocardial infarction, stroke, thrombosis, arteriosclerosis, heart failure, and hypertension.

[0158] Preferably, the gastrointestinal diseases include, but are not limited to: colitis, inflammatory bowel disease, digestive tract diseases, and gastrointestinal dysfunction.

[0159] Preferably, the pain includes, but is not limited to: cancer pain, neuropathic pain, inflammatory pain, surgical pain, visceral pain, toothache, premenstrual pain, central pain, pain caused by burns, migraine, cluster headache, and chronic pain.

[0160] Preferably, the urinary system diseases include urinary incontinence, dysuria, cystitis, benign prostatic hyperplasia, urinary disorders associated with benign prostatic hyperplasia, bladder neck sclerosis, and hypoactive bladder.

[0161] Preferably, the eye disease includes macular degeneration and diabetic retinopathy.

[0162] Preferably, the cancers include, but are not limited to: breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioblastoma, bone cancer, colon cancer, intestinal cancer, liver cancer, head and neck cancer, melanoma, multiple myeloma, chronic lymphocytic leukemia, and tumor metastasis.

[0163] Preferably, the metabolic disease includes, but is not limited to, osteoporosis.

[0164] According to the technical solution of the present invention, the disease or condition is interstitial lung disease, pulmonary fibrosis (especially idiopathic pulmonary fibrosis), liver fibrosis, kidney fibrosis, non-alcoholic fatty liver disease (e.g., non-alcoholic steatohepatitis), psoriasis, or scleroderma.

[0165] The present invention also provides a method for preventing and / or treating LPAR1-mediated diseases or conditions, comprising administering a therapeutically effective amount of the above-described compound I or its stereoisomer crystal form, pharmaceutical composition or formulation to a subject.

[0166] According to the technical solution of the present invention, a method for preventing and / or treating LPAR1-mediated diseases or conditions includes administering a therapeutically effective amount of one, two or more of the above-mentioned crystal form A, crystal form B, crystal form C, crystal form D, crystal form E or crystal form F, the above-mentioned pharmaceutical composition or preparation, to a subject.

[0167] According to the technical solution of the present invention, a method for preventing and / or treating LPAR1-mediated diseases or conditions includes administering a therapeutically effective amount of one, two, or three of the above-mentioned crystal form A, crystal form B, or crystal form C, the above-mentioned pharmaceutical composition or preparation, to a subject.

[0168] The positive and progressive effects of this invention are as follows: the crystal form of this invention has stable physical and chemical properties, good processability in formulation manufacturing, and superior in vitro and in vivo biological performance, with broad application prospects. Specifically, the above-mentioned compound I and its stereoisomers and crystal forms exhibit strong selectivity, good biological activity, and strong metabolic stability; the preparation method of the above-mentioned crystal form is simple, suitable for industrial production, and is not easily hygroscopic, possessing good stability and solubility, which is of great value for drug optimization and development.

[0169] Terminology Definitions and Explanations

[0170] Unless otherwise stated, the following terms appearing in this specification and claims have the following meanings:

[0171] The terms “including,” “comprising,” “having,” “containing,” or “involving,” as used herein, and their other variations thereof, are inclusive or open-ended and do not exclude other unlisted elements or method steps.

[0172] As used herein, the term “about” means that a person skilled in the art would consider the value to be within an acceptable standard error, such as ±0.05, ±0.1, ±0.2, ±0.3, ±1, ±2, or ±3.

[0173] Unless otherwise stated, the numerical ranges described in this specification and claims are equivalent to describing at least each of the specific numerical values. For example, the numerical range "1-10" is equivalent to describing each of the numerical values ​​in the range "1-10".

[0174] Unless otherwise stated, "more" means 3 or more, such as 3, 4, 5, 6, 7, 8 or 9.

[0175] The term "crystal form" refers to a crystal form that has the same chemical composition but a different spatial arrangement of molecules and / or ions that form crystals. In some cases, crystal forms can be characterized by known techniques, including XRPD crystallography, solid-state nuclear magnetic resonance (ssNMR) spectroscopy, DSC, or some combination of these techniques. Crystal forms produce characteristic XRPD spectra with well-defined peaks.

[0176] The term "amorphous" refers to a solid form that is not crystalline and consists of molecules and / or ions. Amorphous solids do not exhibit definite X-ray powder diffraction patterns with clear maximum values.

[0177] The term "basically as shown in the figure X-ray powder diffraction pattern" 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 major peaks shown in the X-ray powder diffraction pattern appear in the X-ray powder diffraction pattern; the major peaks refer to the peaks with a relative intensity greater than 10%, preferably greater than 20%, and more preferably greater than 30%, with the highest peak as a reference (the relative intensity of the highest peak is specified as 100%).

[0178] The term "room temperature" refers to a temperature of 20-30°C.

[0179] The term "solvate" refers to a substance formed by combining the compound of this invention with a stoichiometric or non-stoichiometric solvent. The solvent molecules in the solvate can exist in an ordered or disordered arrangement. The solvents include, but are not limited to, water, methanol, ethanol, and dimethyl sulfoxide. For example, the solvate can be a hydrate or a dimethyl sulfoxide solvate.

[0180] The terms "carrier" and "pharmaceutically acceptable carrier" refer to a diluent, adjuvant, excipient, or medium that is administered or formulated with a compound for administration. Non-limiting examples of such pharmaceutically acceptable carriers include liquids such as water, saline, and oils; and solids such as gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. Additionally, auxiliaries, stabilizers, thickeners, lubricants, flavoring agents, and coloring agents may be used. The corresponding stable isomers can be separated by known methods, such as extraction, filtration, or column chromatography.

[0181] The term "patient" or "subject" refers to a living organism that suffers from or is susceptible to a disease or symptom that can be treated by application of the drug or drug composition provided by the present invention, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cattle, sheep, horse or primate, and most preferably a human.

[0182] The term "disease" or "symptom" refers to a state or health condition in which a patient or subject can be treated with the medicine, pharmaceutical composition, preparation or method provided by the present invention.

[0183] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0184] The term "treatment" refers to preventing, halting, or slowing the progression of a subject's disease or ailment, or eliminating a subject's disease or ailment. In some embodiments, "treatment" means halting or slowing the progression of a subject's disease or ailment, or eliminating a subject's disease or ailment. In one embodiment, "treatment" means reducing at least one objective manifestation of a subject's disease or ailment.

[0185] The term "effective amount" refers to an amount sufficient to produce the desired biological effect.

[0186] The term “therapeutic effective amount” refers to an amount sufficient to produce the desired therapeutic effect, which includes one or more of the following: (1) prevention of disease: for example, prevention of disease, disorder or condition in an individual who is susceptible to disease, disorder or condition but has not yet experienced or developed the pathology or symptoms of the disease. (2) suppression of disease: for example, suppression of disease, disorder or condition in an individual who is experiencing or developing the pathology or symptoms of the disease (i.e., preventing the further development of the pathology and / or symptoms). (3) relief of disease: for example, relief of disease, disorder or condition in an individual who is experiencing or developing the pathology or symptoms of the disease (i.e., reversal of the pathology and / or symptoms).

[0187] The compounds described herein may include all stereoisomers of the compound. The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including enantiomers, diastereomers, cis-trans isomers, and conformational isomers. Unless otherwise specified, wedge-shaped solid lines are used. and wedge-shaped dashed key The absolute configuration representing the center of a solid.

[0188] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0189] Those skilled in the art can determine, using conventional methods, the appropriate amounts of salts, any one or a mixture of two salt crystal forms or free base crystal forms in a pharmaceutical composition, as well as various pharmaceutically acceptable carriers and / or other active ingredients.

[0190] The reagents and raw materials used in this invention are all commercially available. Attached Figure Description

[0191] Figure 1 shows the atomic thermal vibration ellipsoids of two crystallographically independent compound IR molecules in an asymmetric unit (Note: the atomic thermal vibration ellipsoids in the figure are drawn at a 50% probability level).

[0192] Figure 2 shows the atomic thermal vibration ellipsoids of two crystallographically independent compound IR molecules in an asymmetric unit (Note: the second conformational position of the disordered group on the second crystallographically independent compound IR molecule has been omitted).

[0193] Figure 3 shows the XRPD pattern of crystal form A;

[0194] Figure 4 shows the DSC-TGA spectrum of crystal form A;

[0195] Figure 5 shows crystal form A. 1 H-NMR spectrum;

[0196] Figure 6 shows the PLM diagram of crystal form A;

[0197] Figure 7 shows the XRPD pattern of crystal form B;

[0198] Figure 8 shows the DSC-TGA spectrum of crystal form B;

[0199] Figure 9 shows crystal form B. 1 H-NMR spectrum;

[0200] Figure 10 shows the PLM diagram of crystal form B;

[0201] Figure 11 shows the XRPD pattern of crystal form C;

[0202] Figure 12 shows the XRPD pattern of crystal form D;

[0203] Figure 13 shows the DSC-TGA spectrum of crystal form D;

[0204] Figure 14 shows crystal form D. 1 H-NMR spectrum;

[0205] Figure 15 shows the XRPD pattern of crystal form E;

[0206] Figure 16 shows the DSC-TGA spectrum of crystal form E;

[0207] Figure 17 shows crystal form E. 1 H-NMR spectrum;

[0208] Figure 18 shows the XRPD pattern of crystal form F;

[0209] Figure 19 shows the DSC-TGA spectrum of crystal form F;

[0210] Figure 20 shows crystal form F. 1 H-NMR spectrum;

[0211] Figure 21 shows the DVS pattern of crystal form A;

[0212] Figure 22 shows the XRPD overlay images of crystal form A before and after DVS testing;

[0213] Figure 23 shows the DVS diagram of crystal form B.

[0214] Figure 24 shows the XRPD overlay images of crystal form B before and after DVS testing. Detailed Implementation

[0215] The following detailed description, in conjunction with specific embodiments, illustrates the general formula compounds of the present invention, their preparation methods, and applications in further detail. The following embodiments are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0216] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0217] Abbreviations:

[0218] THF: Tetrahydrofuran; n-BuLi: n-Butyllithium; TBDMSCl: Tert-Butyldimethylchlorosilane; IPA: Isopropanol; IPAc: Isopropyl acetate; MTBE: Methyl tert-Butyl ether; ACN: Acetonitrile; DMSO: Dimethyl sulfoxide; EtOH: Ethanol; EtOAc: Ethyl acetate; DMAc: Dimethylacetamide; DCM: Dichloromethane; PTFE: Polytetrafluoroethylene.

[0219] Instrumentation and Methods:

[0220] 1. X-ray powder diffraction (XRPD)

[0221] The XRPD test was performed using an X-ray powder diffractometer manufactured by PANalytical, and the test parameters are shown in the table below.

[0222] 2. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)

[0223] The TGA analysis was performed using a Discovery TA5500 / TA550 thermogravimetric analyzer, and the DSC analysis was performed using a Discovery TA2500 / TA250 differential scanning calorimeter. The test parameters are shown in the table below:

[0224] 3. Dynamic Moisture Adsorption (DVS)

[0225] The DVS test used SMS (Surface Measurement Systems)'s DVS Intrinsic or Intrinsic Plus. The relative humidity at 25°C was corrected for using the deliquescence points of LiCl, Mg(NO3)2, and KCl. The test parameters are shown in the table below:

[0226] 4. Liquid NMR (Solution NMR)

[0227] 1H NMR (1H NMR) spectrum 1 H NMR was acquired on a Bruker 400M NMR spectrometer, using DMSO-d6 and deuterated methanol as solvents.

[0228] 5. Polarizing microscope (PLM)

[0229] PLM data were acquired at room temperature using an Axio Lab.A1 upright microscope.

[0230] 6. High-performance liquid chromatography (HPLC)

[0231] The purity of the samples was tested using an Agilent high-performance liquid chromatograph or a Waters ultra-high-performance liquid chromatograph, and the analytical conditions are shown in the table below:

[0232] ①High-performance liquid chromatography (HPLC) test conditions:

[0233] ②Ultra-high performance liquid chromatography test conditions:

[0234] 7. Variable Temperature X-ray Powder Diffraction (VT-XRPD)

[0235] The VT-XRPD test was conducted using an X-ray powder diffractometer manufactured by PANalytical, and the test parameters are shown in the table below.

[0236] 8. Single-crystal X-ray diffraction (SCXRD)

[0237] Single-crystal X-ray diffraction data were collected using a Rigaku XtaLAB Synergy R-type single-crystal X-ray diffractometer. Instrument parameters are as follows:

[0238] Example 1: Preparation of (R)-2-(1-((6-(5-(((((3,3-difluoropentan-2-yl)oxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)ethynyl)cyclopropyl)acetic acid (compound IR)

[0239] (1) Preparation of compound IN-01

[0240] Compound SM01 (60 g, 907.7 mmol) was dissolved in THF (240 mL), and the resulting solution was cooled to -78 °C (dry ice-ethyl acetate bath), followed by the dropwise addition of n-BuLi (399.4 mL, 998.5 mmol, 2.5 M n-hexane solution). After the addition was complete, the reaction mixture was stirred at -78 °C for 1 hour. Then, a THF (300 mL) solution of TBDMSCl (136.81 g, 907.7 mmol) was added dropwise, and the reaction mixture was stirred at -78 °C for 0.5 hours, followed by stirring at room temperature for 1 hour. The reaction mixture was cooled to 0 °C, and the reaction was quenched by adding saturated ammonium chloride solution (480 mL) and water (120 mL). The aqueous phase was extracted with ethyl acetate (300 mL × 2), the organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0) to give compound IN-01 (308 g), LC-MS: [M+H] + =181.36.

[0241] (2) Preparation of compound IN-02

[0242] IN-01 (150 g, 831.7 mmol) was dissolved in methyl tert-butyl ether (1500 mL). The resulting solution was cooled to -78 °C (dry ice-ethyl acetate bath), and then n-BuLi (366 mL, 914.8 mmol, 2.5 M hexane solution) was added dropwise. The reaction solution was stirred at -78 °C for 1 hour, and then stirred for another 3 hours after the solution naturally warmed to room temperature. The reaction solution was then cooled to 0 °C, and ethylene oxide (360.4 mL, 1.08 mol, 3 M diethyl ether solution) was added dropwise, maintaining this temperature while stirring for 1 hour. The reaction was quenched by adding saturated ammonium chloride solution (1200 mL) and water (300 mL). The aqueous phase was extracted with ethyl acetate (750 mL × 2), the organic phases were combined, washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound IN-02 (104 g), LC-MS: [M+H] + =225.1.

[0243] (3) Preparation of compound IN-03

[0244] IN-02 (84.0 g, 374.3 mmol) was dissolved in acetonitrile (840 mL) and water (840 mL). Sodium bicarbonate (94.34 g, 1122.9 mmol) and 2,2,6,6-tetramethylpiperidine oxide (11.7 g, 74.9 mmol) were added, followed by the addition of iodophenyldiacetic acid (301.4 g, 935.8 mmol) in portions. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding saturated sodium sulfite solution (420 mL). The aqueous phase was extracted with ethyl acetate (600 mL × 3). The combined organic phases were washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound IN-03 (62 g). LC-MS: [M+H] + =239.40.

[0245] (4) Preparation of compound IN-04

[0246] IN-03 (67 g, 281.1 mmol) was dissolved in N,N-dimethylformamide (420 mL), and iodomethane (48.3 g, 340.1 mmol) was added. After cooling the reaction solution to 0–5 °C, potassium carbonate (42.7 g, 309.0 mmol) was added. The reaction solution was stirred at this temperature for 0.5 h, then heated to room temperature and stirred for another 2 h. The reaction solution was poured into water (1.1 L) and extracted with ethyl acetate (670 mL × 2). The combined organic phases were washed with water (670 mL × 2), washed with saturated brine (670 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 40) to give compound IN-04 (129 g). LC-MS: [M+H] + =253.42.

[0247] (5) Preparation of compound IN-05

[0248] Compound SM02 (50 g, 277.47 mmol) was dissolved in dichloromethane (500 mL), and dimethylhydroxylamine hydrochloride (32.48 g, 332.96 mmol), N,N-diisopropylethylamine (107.58 g, 832.41 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (158.25 g, 416.21 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched in water (500 mL) and extracted with dichloromethane (500 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound IN-05 (60 g). LC-MS: [M+H] + =224.05.

[0249] (6) Preparation of compound IN-06

[0250] IN-05 (60 g, 268.73 mmol) was dissolved in THF (600 mL). The resulting solution was cooled to 0 °C, and ethyl magnesium bromide solution (201.55 mL, 403.10 mmol, 2 M THF solution) was added dropwise. The reaction mixture was heated to room temperature and stirred for 2 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (500 mL) and extracted with ethyl acetate (500 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound IN-06 (45 g). LC-MS: [M+H] + =193.25.

[0251] (7) Preparation of compound IN-07

[0252] IN-06 (55 g, 286.07 mmol) was dissolved in dichloromethane (550 mL). The resulting solution was cooled to 0 °C, and diethylaminotrifluoride (184.44 g, 1.14 mol) was added dropwise. The reaction mixture was heated to 30 °C and stirred for 48 hours. The reaction mixture was then quenched by slowly pouring in a saturated sodium bicarbonate aqueous solution (2000 mL), and extracted with dichloromethane (500 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound IN-07 (60 g crude). The crude compound was dissolved in THF (500 mL), activated carbon (5.5 g) was added, and the solution was heated to 50 °C and stirred for decolorization for 0.5 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound IN-07 (55 g). LC-MS: [M+H] + =215.25.

[0253] (8) Preparation of compound IN-08

[0254] IN-07 (50 g, 233.37 mmol) was dissolved in THF (500 mL), and wet palladium on carbon (5.0 g, 10%) and wet palladium hydroxide on carbon (2.0 g, 20%) were added. Under hydrogen protection, the reaction solution was heated to 50 °C and stirred for 24 hours. After cooling to room temperature, the reaction solution was filtered under reduced pressure. The filtrate was dried with molecular sieves, filtered again, and concentrated under reduced pressure to obtain a THF solution (186 g) of compound IN-08. LC-MS: [M+H] + =125.13.

[0255] (9) Preparation of compound IN-09

[0256] Compound SM03 (50 g, 199.27 mmol) and 2-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran (41.9 g, 298.9 mmol) were dissolved in acetonitrile (500 mL), and bis(triphenylphosphine)palladium dichloride (7.0 g, 9.96 mmol), cuprous iodide (2.0 g, 9.96 mmol), and triethylamine (60.0 g, 597.8 mmol) were added. Under nitrogen protection, the reaction mixture was heated to 50 °C and stirred for 1.5 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound IN-09 (60.0 g). LC-MS: [M+H] + =311.95.

[0257] (10) Preparation of compound IN-10

[0258] IN-09 (60.0 g, 0.19 mol) and trimethylsilylmethyl azide (50 g, 0.38 mol) were dissolved in THF (600 mL). Pentamethylcyclopentadienylbis(triphenylphosphine)ruthenium chloride (15 g, 0.019 mol), tetrabutylammonium iodide (7.0 g, 0.019 mol), and cuprous iodide (3.6 g, 0.019 mol) were added. Under nitrogen protection, the reaction mixture was heated to 40 °C and stirred for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound IN-10 (68.0 g). LC-MS: [M+H] + =439.00.

[0259] (11) Preparation of compound IN-11

[0260] IN-10 (68.0 g, 155.21 mmol) was dissolved in THF (600 mL), and tetrabutylammonium fluoride (48.7 g, 186.26 mmol) was added in portions. The reaction mixture was stirred at room temperature for 1 hour. The solution was then concentrated under reduced pressure, and the residue was diluted with water (120 mL), extracted with ethyl acetate (60 mL), and the combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound IN-11 (42.2 g). LC-MS: [M+H] + =367.00.

[0261] (12) Preparation of compound IN-12

[0262] IN-11 (5 g, 13.6 mmol) and N,N'-dimethylethylenediamine (720 mg, 8.2 mmol) were dissolved in 1,4-dioxane (50 mL), and sodium iodide (10.3 g, 68.7 mmol) and cuprous iodide (260 mg, 1.4 mmol) were added. Under nitrogen protection, the reaction mixture was heated to 100 °C and stirred for 24 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound IN-12 (5.5 g). LC-MS: [M+H] + =415.00.

[0263] (13) Preparation of compound IN-13

[0264] IN-12 (5.5 g, 13.3 mmol) was dissolved in methanol (60 mL), and pyridine 4-methylbenzenesulfonic acid (3.3 g, 13.3 mmol) was added. The reaction mixture was heated to 60 °C and stirred for 16 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound IN-13 (4.5 g). LC-MS: [M+H] + =330.95.

[0265] (14) Preparation of compound IN-14

[0266] IN-13 (4.5 g, 13.6 mmol) was dissolved in acetonitrile (50 mL) and water (35 mL), and potassium permanganate (4.3 g, 27.2 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. Sodium hydroxide aqueous solution (2 M, 50 mL) was added to the reaction mixture, and the mixture was filtered under reduced pressure. The filtrate was extracted with ethyl acetate (50 mL), and the aqueous phases were combined. The pH was adjusted to 3 with dilute hydrochloric acid (1 M), and the mixture was filtered under reduced pressure. The filter cake was washed with pure water (30 mL) and dried under reduced pressure to give compound IN-14 (2.8 g). LC-MS: [M+H] + =344.95.

[0267] (15) Preparation of compound IN-15

[0268] IN-14 (16 g, 46.50 mmol), triethylamine (16.94 g, 167.39 mmol), and azidotrimethylsilane (10.71 g, 92.99 mmol) were dissolved in THF (160 mL). 1-Propylphosphine (44.38 g, 69.74 mmol, 50% ethyl acetate solution) was added dropwise with stirring. The reaction mixture was stirred at room temperature for 0.5 hours, and then a THF solution of compound IN-08 (74 g, 92.99 mmol) was added. The reaction mixture was heated to 80 °C and stirred for another 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound IN-15 (17 g). LC-MS: [M+H] + =466.20.

[0269] (16) Preparation of compound IN-16

[0270] IN-04 (16.28 g, 64.48 mmol) was dissolved in THF (170 mL), and a THF solution of tetrabutylammonium fluoride (1 M, 64.48 mL, 64.48 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 0.5 h. Anhydrous magnesium sulfate (30 g) was added to the reaction mixture and dried for 1 h. The mixture was filtered, and IN-15 (15 g, 32.24 mmol), bis(triphenylphosphine)palladium dichloride (2.26 g, 3.22 mmol), cuprous iodide (614 mg, 3.22 mmol), and triethylamine (9.79 g, 96.72 mmol) were added to the filtrate. The reaction mixture was stirred at room temperature for 16 h under nitrogen protection, then diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound IN-16 (12 g, crude product), which was then preparatively separated by high performance liquid chromatography (0.1% trifluoroacetic acid) to obtain compound IN-16 (10 g). LC-MS: [M+H] + =476.20.

[0271] (17) Preparation of compound IR

[0272] IN-16 (3.00 g, 6.43 mmol) was dissolved in THF (45 mL), and a solution of lithium hydroxide monohydrate (0.80 g, 18.88 mmol) in water (15 mL) was added. The reaction mixture was stirred at room temperature. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and water (15 mL) and dichloromethane (15 mL) were added. The mixture was then concentrated again under reduced pressure to further remove THF. The mixture was extracted with dichloromethane (60 mL) and water (30 mL). The aqueous phase was adjusted to pH 1-2 with dilute hydrochloric acid (1 M) and then extracted once with dichloromethane (60 mL). The organic phases were combined, washed with saturated brine (350 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then dichloromethane (15 mL) was added. Heptane (30 mL) was slowly added dropwise at 10-15 °C, and the mixture was stirred for 1 hour to crystallize. The crystals were filtered, and the filter cake was dried under vacuum at 45 °C to obtain compound IR (2.3 g, purity 96.18%). Its chirality was confirmed by single-crystal characterization. LC-MS: [M+H] + =462.15.

[0273] 1H NMR (400MHz, DMSO-d6): δ12.23(s,1H),9.89(s,1H),7.75(d,J=8.4Hz,1H),7.70(d,J=8.4Hz,1H),4.90-5. 10(m,1H),3.90(s,3H),2.51(s,3H),2.46(s,2H),2.14-1.77(m,2H),1.52-1.13(m,3H),1.10-0.78(m,7H).

[0274] Single crystal characterization:

[0275] Approximately 20 mg of compound IR was weighed into a 3 mL glass bottle, and 0.5 mL of solvent 1,4-dioxane was added. If the solid was not completely dissolved, it was filtered using a 0.45 μm PTFE filter membrane. The 3 mL glass bottle containing the solution was placed openly into a 20 mL bottle containing 3 mL of the antisolvent cyclohexane. The 20 mL bottle was sealed with a cap and allowed to stand at room temperature for a certain period of time to allow the solvent vapor to interact with the solution and separate the precipitated solid. A single crystal of compound IR (crystal form A) with suitable size and high diffraction quality was selected from the obtained solid and characterized by room temperature single-crystal X-ray diffraction (SCXRD). The single-crystal structure analysis showed that the asymmetric unit of the crystal structure was composed of two compound IR molecules, and the structure did not contain any water of crystallization or other crystallizing solvent molecules, which confirmed that compound IR (crystal form A) was an amorphous form. Based on the single-crystal structure data obtained from the analysis (as shown in Table 1, Figure 1, and Figure 2 below), the absolute configuration of the chiral center (C18) in the compound IR molecule was confirmed to be the R configuration.

[0276] Table 1: Crystallographic data and structural refinement parameters of compound IR (crystal form A) single crystals

[0277] Example 2 Preparation of 2-(1-((6-(5-(((((3,3-difluoropentan-2-yl)oxy)carbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)ethynyl)cyclopropyl)acetic acid (compound I)

[0278] Compound I was prepared using the same method as Compound IR in Example 1, except that the starting material SM02 was replaced with SM04. LC-MS: [M+H] + =462.05.

[0279] 1H NMR (400MHz, DMSO-d6): δ7.74(d,J=8.2Hz,1H),7.65(d,J=8.2Hz,1H),5.04-4.91(m,1H), 3.85(s,3H),2.51(s,3H),2.26(s,2H),2.05-1.78(m,2H),1.23(s,3H),0.96-0.88(m,7H).

[0280] Example 3 Preparation of crystal form A

[0281] Take an appropriate amount of the compound obtained in Example 1 and perform XRPD, VT-XRPD, TGA, DSC, 1 H NMR and PLM characterization. Specific results are shown in Tables 1-1 to 1-3 and Figures 3 to 6.

[0282] XRPD results (Figure 3) show that the compound is in crystalline form (IR), named crystal form A. TGA and DSC results (Figure 4) show that crystal form A experiences a 0.22% weight loss when heated to 140℃, and has an endothermic peak at 154.2℃ (peak temperature). PLM results (Figure 6) show that crystal form A consists of long rod-shaped crystals of varying sizes. VT-XRPD results show that crystal form A remains unchanged after purging with nitrogen for 20 minutes, and no transformation occurs after heating to 130℃ under a nitrogen atmosphere and then cooling to 25℃ under a nitrogen atmosphere. It is speculated that crystal form A is an amorphous form.

[0283] Table 1-1 Characterization results of crystal form A

[0284] Table 1-2 XRPD diffraction peak analysis data for crystal form A

[0285] Table 1-3 XRPD pattern analysis data for crystal form A

[0286] Example 4: Preparation of Crystal Form B

[0287] The compound IR (20 mg) obtained in Example 1 was stirred for 2 days in the solvent (0.5 mL) and temperature corresponding to Table 2-1, centrifuged, and the precipitate was vacuum dried at 50 °C for 6 hours. The results of XRPD characterization of the obtained solid are shown in Table 2-1.

[0288] Table 2-1 Preparation of Crystal Form B

[0289] This embodiment yielded a new crystal form of compound IR, named crystal form B. Crystal form B (group 3) was subjected to XRPD, VT-XRPD, TGA, DSC, and other assays. 1H NMR and PLM characterization. Specific results are shown in Tables 2-2 to 2-4 and Figures 7 to 10.

[0290] TGA and DSC results (Figure 8) show that crystal form B loses 2.35% of its weight when heated to 140°C, and has an endothermic peak at 145.8°C (peak temperature). 1 ¹H NMR results (Figure 9) show no MTBE residue in crystal form B. PLM results (Figure 10) show that crystal form B consists of needle-like crystals of varying sizes. VT-XRPD results show that crystal form B remains unchanged after purging with nitrogen for 20 minutes, and does not undergo a crystal form transformation after heating to 130°C and then cooling to 25°C under nitrogen atmosphere. It is speculated that crystal form B is an amorphous form.

[0291] Table 2-2 Characterization results of crystal form B

[0292] Table 2-3 XRPD diffraction peak analysis data for crystal form B

[0293] Table 2-4 XRPD pattern analysis data for crystal form B

[0294] Example 5 Preparation of Crystal Form C

[0295] Approximately 20 mg of compound IR obtained in Example 1 and the acid corresponding to it in Table 3-1 (molar ratio of 1:1 with compound IR) were weighed and added to 0.5 mL of the solvent corresponding to it in Table 3-1. The mixture was stirred at room temperature for 2 hours, then suspended and stirred at 5°C for 2 days. The mixture was then stirred for 9 days under temperature cycling (50°C–5°C, 0.1°C / min), and then transferred to room temperature for open evaporation to obtain a gel. 0.5 mL of n-heptane was added to the gel, and the mixture was stirred at room temperature for 1 day. After stirring under temperature cycling (50°C–5°C, 0.1°C / min, 2 cycles), the mixture was cooled to -20°C and stirred for 1 day, precipitating a solid. The obtained solid was dried at 50°C for 6 hours and then characterized by XRPD. Specific information and results are summarized in Table 3-1.

[0296] Table 3-1 Preparation of Crystal Form C

[0297] This embodiment yielded a new crystal form of compound IR, named crystal form C. Crystal forms C (groups 2 and 8) were subjected to XRPD, TGA, DSC, and other assays. 1 Characterization was performed using ¹H NMR and PLM. Specific results are shown in Tables 3-2 to 3-3 and Figure 11.

[0298] 1¹H NMR results showed that crystal form C (group 2) contained sulfuric acid, and the molar ratio of sulfuric acid to compound IR was 0.7:1. Crystal form C (group 8) also contained IPA, and the molar ratio of IPA to compound IR was 0.3:1 (4.2 wt%).

[0299] 1 ¹H NMR results showed that crystal form C (group 8) contained benzenesulfonic acid, and the molar ratio of benzenesulfonic acid to compound IR was 0.8:1. Crystal form C (group 8) also contained IPA, and the molar ratio of IPA to compound IR was 0.5:1 (6.1 wt%).

[0300] Table 3-2 XRPD diffraction peak analysis data for crystal form C

[0301] Table 3-3 XRPD pattern analysis data of crystal form C

[0302] Example 6 Preparation of crystal form D

[0303] Method 1: At room temperature, weigh 20 mg of compound IR obtained in Example 1 into a glass bottle, add 1.0 mL of DCM to dissolve it, filter through a 0.45 μm PTFE membrane to obtain a clear solution. Then use... The container was sealed with sealing film, punctured with four small holes, and placed in a fume hood to evaporate naturally at room temperature. The resulting solid was collected and characterized by XRPD.

[0304] Method 2: At room temperature, 60 mg of compound IR obtained in Example 1 was weighed into a glass bottle, and 0.4 mL of DCM was added to obtain a clear solution. Then, 1.0 mL of n-heptane solvent was slowly added dropwise, and a solid precipitated out. The solid was separated by centrifugation and characterized by XRPD.

[0305] This embodiment yielded a new crystal form of compound IR, named crystal form D. Crystal form D (method 1) was subjected to XRPD, VT-XRPD, TGA, DSC, and... 1 Characterization was performed using ¹H NMR and other methods. Specific results are shown in Tables 4-1 to 4-3 and Figures 12 to 14.

[0306] Table 4-1 Characterization results of crystal form D

[0307] The TGA / DSC results (Figure 13) show that crystal form D loses approximately 2.07% of its weight when heated to 120°C, with two endothermic peaks at 61.8°C and 149.7°C (peak temperatures) and one exothermic peak at 101.7°C (peak temperature). 1¹H NMR results (Figure 14) show that crystal form D contains approximately 0.2% (mass fraction) of DCM. VT-XRPD results show that crystal form D remains essentially unchanged after purging with nitrogen for 20 minutes, with only a slight shift. After heating to 80°C in a nitrogen atmosphere and then cooling to 25°C in a nitrogen atmosphere, crystal form D partially transforms into crystal form A. After exposure to air for 20 minutes, the crystal form does not change significantly. It is speculated that crystal form D is a hydrate.

[0308] Table 4-2 XRPD diffraction peak analysis data for crystal form D

[0309] Table 4-3 XRPD pattern analysis data for crystal form D

[0310] Example 7 Preparation of crystal form E

[0311] Method 1:

[0312] The compound IR (20 mg) obtained in Example 1 was stirred at 50 °C for 2 days in a DMSO / H2O solvent system (0.5 mL, v / v = 1 / 9), centrifuged, and the resulting solid was characterized by XRPD.

[0313] Method 2:

[0314] At room temperature, 20 mg of compound IR obtained in Example 1 was weighed into a glass bottle (3 mL), 3 mL of DMSO was measured into a small bottle (20 mL), and the glass bottle containing compound IR was placed open into the small bottle (20 mL). The small bottle (20 mL) was then sealed and left to stand at room temperature for about one week. The solid obtained was collected and characterized by XRPD.

[0315] This embodiment yielded a new crystal form of compound IR, named crystal form E. Crystal form E was subjected to XRPD, TGA, DSC, and other assays. 1 Characterization was performed using HNMR and other methods. Specific results are shown in Tables 5-1 to 5-3 and Figures 15 to 17.

[0316] Table 5-1 Characterization results of crystal form E

[0317] The TGA / DSC results (Figure 16) show that crystal form E loses approximately 15.87% of its weight when heated to 120°C, and has two endothermic peaks at 59.1°C and 95.4°C (peak temperatures). 1 The 1H NMR results (Figure 17) show that crystal form E contains approximately 18.6% (mass fraction) DMSO. Crystal form E was heated to 70°C and then subjected to... 1¹H NMR analysis showed that crystal form E contained approximately 18.6% DMSO. Crystal form E was then heated to 120°C for further analysis. 1 ¹H NMR analysis showed that crystal form E contained approximately 6.8% DMSO. It is speculated that crystal form E is a DMSO solvate.

[0318] Table 5-2 XRPD diffraction peak analysis data for crystal form E

[0319] Table 5-3 XRPD spectrum analysis data for crystal form E

[0320] Example 8 Preparation of crystal form F

[0321] The compound IR (20 mg) obtained in Example 1 was suspended in hydrochloric acid (molar ratio of IR to compound IR was 1:1) in an EtOH / n-heptane (0.5 mL, v / v = 1 / 2) system and stirred at room temperature for 1 day. After centrifugation, the precipitate was dried under vacuum at room temperature for 6 hours, and the obtained solid was characterized by XRPD.

[0322] This embodiment yielded a new crystal form of compound IR, named crystal form F. Crystal form F was subjected to XRPD, TGA, DSC, and other assays. 1 Characterization was performed using HNMR and other methods. Specific results are shown in Tables 6-1 to 6-3 and Figures 18 to 20.

[0323] Table 6-1 Characterization results of crystal form F

[0324] The TGA / DSC results (Figure 19) show that crystal form F loses 7.32% of its weight when heated to 110°C, and has three endothermic peaks at 67.3°C, 126.2°C and 148.5°C (peak temperatures). 1 The H NMR results (Figure 20) show that there is no EtOH residue in crystal form F, but it contains about 1.7% (mass fraction) of n-heptane.

[0325] Table 6-2 XRPD diffraction peak analysis data for crystal form F

[0326] Table 6-3 XRPD spectrum analysis data for crystal form F

[0327] Example 9 Performance Test

[0328] 1. Hygroscopicity test

[0329] Hygroscopicity of crystal form A and crystal form B was evaluated using a dynamic moisture adsorption analyzer (DVS). Starting at 0% relative humidity (0%RH), the percentage change in sample mass was collected under constant temperature of 25°C as humidity changed (0%RH-95%RH-0%RH).

[0330] The results showed that the water adsorption of crystal form A and crystal form B at 25℃ / 80%RH was 0.1261% (Figure 21) and 0.0776% (Figure 23), respectively. No crystal form transformation occurred in crystal form A and crystal form B after DVS testing (Figures 22 and 24).

[0331] 2. Solid stability test

[0332] Solid-state stability of crystal form A was assessed under conditions of 25℃ / 60%RH / 1 week and 40℃ / 75%RH / 1 week, while the solid-state stability of free crystal form B was assessed under conditions of 60℃ / 1 week, 25℃ / 60%RH / 1 week, and 40℃ / 75%RH / 1 week. Physical and chemical stability were tested by XRPD and HPLC, respectively. The results are shown in Table 7-1. Neither crystal form A nor crystal form B underwent crystal transformation under any conditions, and the purity of both crystal forms A and B did not change significantly under any conditions.

[0333] Table 7-1 Results of Solid Stability Assessment

[0334] 3. Solubility test

[0335] (1) Dynamic solubility test

[0336] The dynamic solubility of crystal form A in pure water and three biosolvents was evaluated. The dynamic solubility of the sample in pure water, FaSGF, FaSSIF, and FeSSIF was determined at 37°C using a rotary mixer (25 rpm) at a feed concentration of 5 mg / mL for 0.5, 2, 4, and 24 hours. Samples at each time point were centrifuged and filtered (using a 0.22 μm PTFE filter), and the HPLC concentration and pH of the filtrate were measured. The XRPD of the solid samples after centrifugation was tested. The solubility test results are summarized in Table 7-2. The crystal form of compound I, crystal form A, did not change in any of the systems.

[0337] Table 7-2 Results of dynamic solubility test for crystal form A

[0338] (2) Equilibrium solubility test

[0339] The equilibrium solubility of crystal form B in three different pH buffer solutions was evaluated. Using a feed concentration of 5 mg / mL at 37°C and magnetic stirring (500 rpm), the equilibrium solubility of the sample was determined in three solutions: pH 1.2 (aqueous solution of 3.725 g / L KCl and 0.085 mol / L HCl, endpoint pH = 1.2), pH 4.5 (aqueous solution of 4.49 g / L citric acid and 6.90 g / L sodium citrate, endpoint pH = 4.5), and pH 6.8 (aqueous solution of 6.78 g / L potassium dihydrogen phosphate and 0.022 mol / L NaOH, endpoint pH = 6.8). After 24 hours, the sample was centrifuged and filtered (using a 0.22 μm PTFE filter). The HPLC concentration and pH value of the filtrate were measured, and the XRPD of the centrifuged solid sample was tested. The solubility test results are summarized in Table 7-3.

[0340] Table 7-3 Equilibrium solubility test results of crystal form B

[0341] 4. Mechanical stability test

[0342] The mechanical stability of crystal form A and crystal form B was evaluated by manual grinding. Approximately 20 mg of crystal form A and crystal form B were weighed into a mortar and manually ground for 3 minutes. The solids were then collected for XRPD testing.

[0343] The results showed that the crystal forms of crystal form A and crystal form B did not change significantly after manual grinding.

[0344] Example 7 Biological Activity Test

[0345] 1. Evaluation of LPAR1 in vitro bioactivity

[0346] The inhibitory properties of the compounds and their crystal forms in this invention were determined using the FLIPR (fluorescence imaging plate reader) method in CHO-K1 cells (Chinese hamster ovary cells K1, ATCC) that highly expressed hLPAR1 (human lysophosphatidic acid receptor 1, accession number NM_001401.4).

[0347] CHO-K1 cells stably expressing hLPAR1 were placed in a cell culture incubator at 37°C and 5% CO2, and cultured in F-12 medium containing 10% FBS (fetal bovine serum, Gibco, 10099-141), 1% penicillin-streptomycin (Gibco, 15140-122), and 0.4 mg / mL Hygromycin B (Gibco, 10687010). 18–24 hours before the FLIPR assay, cells were seeded at a density of 250,000 cells / mL into 96-well plates and incubated overnight in a cell culture incubator. On the day of the experiment, the culture medium was discarded, and the cells were washed in FLIPR buffer (2.5 mM probenecid (Thermo, P36400), 1.3 mM CaCl2, 3.3 mM Na2CO3, 1 mM MgSO4, 20 mM HEPES (Invitrogen, 15630080), 1×HBSS (Invitrogen, 14065056), 0.1% BSA (BioSharp, 70080030)). 75 μL of 1 mM Fluo-4 AM fluorescent dye (Thermo, F14202) was added to each well, and the cells were incubated at 37°C for 1.0 h. Subsequently, the 96-well plate was washed once with buffer, and 50 μL of buffer containing the test compound or its crystal form or solvent was added to each well, and the cells were incubated at room temperature for 30 min. The cell plate was then placed in a FLIPR apparatus for baseline fluorescence measurement (excitation wavelength 485 nm, emission wavelength 525-535 nm). Subsequently, agonist (1 μM sodium oleoyl-L-α-lysophosphate (Sigma, L7260)) or solvent (ultrapure water) was added at 50 μL / well, and fluorescence values ​​were measured at 1-second intervals for 2 min. Finally, the output fluorescence counts were analyzed, and the IC50 was calculated using the log(inhibitor) vs. response-variable slope (four parameters) equation in GraphPad Prism 9.0 software. 50 value.

[0348] In vitro bioactivity evaluation results showed that the compounds and their crystal forms of the present invention have excellent LPAR1 inhibitory activity, and the IR of the compounds and their crystal forms showed an IC50 value for LPAR1 inhibitory activity. 50 <25nM, specifically 20.2nM.

[0349] 2. Pharmacokinetic Study in Rats

[0350] Male SPF-grade SD rats (Beijing Vital River Laboratory Animal Technology Co., Ltd.), weighing 200-250g, were administered a 1mg / kg clear solution of the compound or its crystal form of this invention via oral gavage (Po, fasting overnight but allowing free water, and food returned 4 hours after administration) and tail vein bolus injection (Iv, fasting and allowing free water throughout the administration). The solvent for the Po group was 5% DMSO + 5% ethanol + 60% PEG400 + 30% physiological saline; the solvent for the IV group was 10% ethanol + 20% pure water + 70% PEG400 solution. Blood was collected from the orbital venous plexus / jugular vein of rats at specific time points after drug administration (0.167, 0.5, 1, 2, 4, 6, 8, and 24 h for the Po group; and 0.033, 0.167, 1, 2, 4, 6, 8, and 24 h for the IV group). The concentration of compounds in plasma was detected by LC-MS / MS (AB SCIEX Qtrap4500). Data were analyzed using a non-compartmental model with WinNonlin (version 5.2.1 Pharsight, Mountain View, CA) to obtain pharmacokinetic parameters (including Cp). max C0, T max AUC last AUC inf T 1 / 2 (e.g., parameters). In the table: ***: 5000 ng / mL * hr ≤ AUC last <10000ng / mL*hr; **:800ng / mL≤C max <5000ng / mL; *: 200ng / mL≤C max <800ng / mL;

[0351] Pharmacokinetic studies in rats showed that the compounds and their crystal forms of this invention exhibited good pharmacokinetic properties in rats, achieving high in vivo exposure and high oral bioavailability (>120%) at low doses, and possessing a long half-life (6h < T). 1 / 2 <12h).

[0352] 3. Pharmacokinetics in monkeys

[0353] Crab-eating macaques (Suzhou Xishan Zhongke Experimental Animal Co., Ltd.), aged 3-5 years and weighing 3-5 kg, were administered the compound or crystal form of this invention in a clear solution via oral gavage (Po, fasting before administration but water allowed) and intravenous bolus injection (Iv, fasting and water allowed throughout the administration) after acclimatization. The solvent for the Po group was 5% DMSO + 5% ethanol + 60% PEG400 + 30% physiological saline, and the solvent for the IV group was 10% ethanol + 20% ultrapure water + 70% PEG400 solution. At specific time points after drug administration (0.167, 0.5, 1, 2, 3, 4, 6, 9, 12, 24, 32, and 48 h for the Po group; and 0.083, 0.25, 1, 2, 3, 4, 6, 9, 12, 24, 32, and 48 h for the IV group), approximately 1 mL of whole blood was collected from the peripheral blood vessels of the non-drug-treated limb of each cynomolgus monkey. The concentration of compounds in plasma was detected by LC-MS / MS (AB SCIEX Qtrap4500). Data were analyzed using a non-compartmental model with WinNonlin (version 5.2.1 Pharsight, Mountain View, CA) to obtain the pharmacokinetic parameters (including Cp) of the cynomolgus monkeys. max C0, T max AUC last AUC inf T 1 / 2 (e.g., parameters).

[0354] The pharmacokinetic studies in cynomolgus monkeys showed that the compounds and their crystal forms of the present invention have superior pharmacokinetic properties in cynomolgus monkeys, achieving higher in vivo exposure at lower doses, and also have the advantages of higher bioavailability, longer half-life, higher clearance rate, and larger volume of distribution.

[0355] 4. Study on the metabolic stability of human primary hepatocytes

[0356] Frozen human hepatocytes were suspended in culture medium to reach a density of 1.5 × 10⁻⁶. 6 Cells / mL were counted and viable cell density was determined using AO / PI staining, and then the cells were diluted with culture medium to a density of 0.5 × 10⁶ cells / mL. 6 Cells / mL were used for the following experiments under these conditions: Cells were added to 96-well plates and pre-incubated in a 37°C water bath for 10 min. The compound of this invention was added to a final concentration of 0.5 μM to initiate the reaction. Samples were taken at 0.5 min, 30 min, 60 min, 90 min, 120 min, and 240 min. The reaction was then terminated, the cells were vortexed, centrifuged at 3220 × g for 45 min, and the supernatant was collected for LC-MS / MS analysis. T was calculated according to the following formula. 1 / 2 CL:

[0357] T 1 / 2 = -0.693 / slope, CLint = -slope * incubation volume / number of cells.

[0358] The results show that the compounds of this invention have good metabolic stability in human primary hepatocytes.

[0359] 5. Study on the permeability of Caco-2 cells

[0360] Caco-2 cells were fed at a rate of 6.86 × 10⁻⁶. 5 10 cells / mL were seeded into 96-well Transwell plates, and the culture medium was changed every other day. After 14-18 days of culture, the cell electrical resistance (TEER) was measured to determine the integrity of the monolayer cell membrane. A TEER value greater than 230 ohms·cm⁻¹ was acceptable. 2 This indicates that the Caco-2 monolayer membrane is qualified. Transport experiments were conducted under intact cell membrane conditions: In groups A to B, the compounds of this invention (final concentrations of 10 μM and 243 μM) were added to the drug-feeding side of a Transwell plate, and buffer was added to the receiving side. The plate was then incubated at 37°C and 5% CO2 for 2 hours. After incubation, samples were taken from both the drug-feeding and receiving sides and added to a stop agent containing an internal standard. The plates were vortexed at 1000 rpm for 10 min, then centrifuged at 4000 rpm and 4°C for 30 min. The supernatant was collected and analyzed using LC-MS / MS. Groups B to A were analyzed under the same conditions. Finally, Papp(10) was calculated according to the following formula. -6 cm / sec), outflow rate:

[0361] Apparent permeability coefficient (Papp) = (receiver side volume / (membrane area * incubation time)) * (receiver side drug concentration at the end of incubation) / (drug concentration on the dosing side at the beginning of incubation);

[0362] Escape rate (ER) = Papp(BA) / Papp(AB).

[0363] Experimental results show that the compounds of this invention have high permeability and no significant efflux.

[0364] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the concept and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. Crystal form of compound I or its stereoisomers:

2. The crystal form as described in claim 1, characterized in that, The stereoisomer of compound I is compound IR:

3. The crystal form as described in claim 1, characterized in that, It is selected from one or more of the following conditions: (1) The crystal form is that of compound IR: (2) The crystal form is crystal form A, crystal form B, crystal form C, crystal form D, crystal form E or crystal form F, wherein, The crystal form A, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 6.9±0.2°, 9.9±0.2°, 13.7±0.2°, 14.5±0.2°, and 15.4±0.2° in 2θ angles. The crystal form B, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 8.5±0.2°, 10.5±0.2°, 12.6±0.2°, and 13.5±0.2° when expressed in 2θ angles. The crystal form C, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 4.4±0.2°, 12.4±0.2°, and 14.5±0.2°, expressed in 2θ angles. The crystal form D, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 7.5±0.2°, 7.7±0.2°, and 14.2±0.2°, expressed in 2θ angles. The crystal form E, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 13.5±0.2°, 14.1±0.2°, and 17.0±0.2°, expressed in 2θ angles. The crystal form F, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 4.5±0.2°, 12.5±0.2°, 14.8±0.2°, and 17.9±0.2° when expressed in 2θ angles.

4. The crystal form as described in claim 3, characterized in that, It is selected from one or more of the following conditions: (1) The crystal form A, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 5.1±0.2°, 6.9±0.2°, 7.0±0.2°, 9.9±0.2°, 10.2±0.2°, 12.9±0.2°, 13.7±0.2°, 14.5±0.2°, 15.4±0.2°, and 19.5±0.2° in 2θ angles. (2) The crystal form B, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 8.5±0.2°, 10.5±0.2°, 12.6±0.2°, 13.5±0.2°, 16.8±0.2°, 21.1±0.2° and 28.9±0.2° in 2θ angles. (3) The crystal form C, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 4.4±0.2°, 12.4±0.2°, 14.5±0.2°, 17.5±0.2°, 20.4±0.2° and 24.5±0.2° in 2θ angles. (4) The crystal form D, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 7.5±0.2°, 7.7±0.2°, 8.9±0.2°, 12.4±0.2°, 13.4±0.2°, 14.2±0.2° and 15.2±0.2° in 2θ angles. (5) The crystal form E, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 5.4±0.2°, 8.2±0.2°, 11.4±0.2°, 13.5±0.2°, 14.1±0.2°, 14.7±0.2°, 17.0±0.2°, and 21.7±0.2° in 2θ angles. (6) The crystal form F, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 4.5±0.2°, 6.9±0.2°, 10.0±0.2°, 12.5±0.2°, 13.9±0.2°, 14.8±0.2°, 17.9±0.2°, 20.5±0.2° and 24.7±0.2° in 2θ angles.

5. The crystal form as described in claim 3, characterized in that, It is selected from one or more of the following conditions: (1) The crystal form A, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 5.1±0.2°, 6.9±0.2°, 7.0±0.2°, 9.9±0.2°, 10.2±0.2°, 12.9±0.2°, 13.7±0.2°, 14.2±0.2°, 14.5±0.2°, 15.4±0.2°, 19.5±0.2°, 20.7±0.2°, 23.0±0.2°, 24.6±0.2°, and 28.2±0.2° in terms of 2θ angles. (2) The crystal form B, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at angles of 2θ at 8.5±0.2°, 10.5±0.2°, 12.6±0.2°, 13.5±0.2°, 16.8±0.2°, 17.2±0.2°, 20.0±0.2°, 20.6±0.2°, 21.1±0.2°, 23.8±0.2°, 24.1±0.2°, 25.9±0.2°, 27.0±0.2°, 28.9±0.2°, and 29.3±0.2°. (3) The crystal form C has diffraction peaks as shown in Table 3-2 when subjected to Cu-Kα radiation and X-ray powder diffraction with an angle of 2θ, with an error range of ±0.2°. (4) The crystal form C contains an organic solvent; (5) The crystal form C is a solvate; (6) The crystal form C contains an acid; (7) The crystal form D, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 7.5±0.2°, 7.7±0.2°, 8.9±0.2°, 12.4±0.2°, 13.4±0.2°, 14.2±0.2°, 15.2±0.2°, 16.1±0.2°, 17.9±0.2°, 21.7±0.2°, and 24.3±0.2° in 2θ angles. (8) The crystal form D has the basic characteristics shown in Figure 14. 1 H-NMR spectrum; (9) The crystal form D contains an organic solvent; (10) The crystal form E, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 5.4±0.2°, 8.2±0.2°, 9.0±0.2°, 10.9±0.2°, 11.4±0.2°, 13.5±0.2°, 14.1±0.2°, 14.7±0.2°, 17.0±0.2°, 21.3±0.2°, 21.7±0.2°, and 23.4±0.2° in terms of 2θ angles. (11) The crystal form E is a solvate; (12) The crystal form F has diffraction peaks as shown in Table 6-2 when X-ray powder diffraction is performed using Cu-Kα radiation and expressed in 2θ angle, with an error range of ±0.2°.

6. The crystal form as described in claim 3, characterized in that, It is selected from one or more of the following conditions: (1) The crystal form A was subjected to Cu-Kα radiation, and X-ray powder diffraction, expressed in 2θ angles, was performed at 5.1±0.2°, 6.9±0.2°, 7.0±0.2°, 9.9±0.2°, 10.2±0.2°, 12.9±0.2°, 13.7±0.2°, 14.2±0.2°, 14.5±0.2°, 15.4±0.2°, 16.3±0.2°, 16.7±0.2°, 19.5±0.2°, 20.7±0.2°, 21.3±0.2°, and 22.7±0.2°. Characteristic peaks are present at 2°, 23.0±0.2°, 24.0±0.2°, 24.2±0.2°, 24.6±0.2°, 25.0±0.2°, 25.7±0.2°, 25.9±0.2°, 26.3±0.2°, 26.6±0.2°, 27.7±0.2°, 28.2±0.2°, 28.9±0.2°, 29.9±0.2°, 30.8±0.2°, 33.3±0.2°, 34.1±0.2°, 34.8±0.2°, and 36.3±0.2°. (2) The thermogravimetric analysis curve of the crystal form A shows a weight loss of 0.22% in the temperature range of 28.7℃±3℃ to 140℃±3℃; (3) The crystal form B was subjected to Cu-Kα radiation, and X-ray powder diffraction, expressed in 2θ angles, was performed at 8.5±0.2°, 10.5±0.2°, 12.6±0.2°, 13.5±0.2°, 16.8±0.2°, 17.2±0.2°, 18.5±0.2°, 20.0±0.2°, 20.6±0.2°, 21.1±0.2°, and 2 Characteristic peaks are present at 2.4±0.2°, 23.8±0.2°, 24.1±0.2°, 24.6±0.2°, 25.4±0.2°, 25.9±0.2°, 26.7±0.2°, 27.0±0.2°, 28.9±0.2°, 29.3±0.2°, 31.2±0.2°, 33.2±0.2°, and 33.7±0.2°. (4) The differential scanning calorimetry curve of the crystal form B has an endothermic peak at a peak temperature of about 145.8℃±3℃. (5) The thermogravimetric analysis curve of the crystal form B shows a weight loss of 2.35% in the temperature range of 29.2℃±3℃ to 140℃±3℃; (6) The crystal form C has diffraction peaks as shown in Table 3-3 when subjected to Cu-Kα radiation and X-ray powder diffraction with an angle of 2θ, with an error range of ±0.2°. (7) The crystal form C contains an organic solvent, which is one, two or more of the following: IPA, IPAc, MTBE, n-heptane, acetone, methanol, ethanol, 2-butanone, ethyl acetate, methyl acetate, 4-methyl-2-pentanone, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, n-hexane, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidone; (8) The crystal form C contains an organic solvent, and the molar ratio of the organic solvent to compound IR is (0.1-1):1; (9) The crystal form C is an organic solvate; for example, the crystal form C is an IPA solvate or an IPAc solvate; (10) The crystal form C is an organic solvate; wherein the molar ratio of the organic solvent to compound IR is (0.1-1):1; (11) The crystal form C contains an acid; the acid is hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid or benzenesulfonic acid; for example, sulfuric acid or benzenesulfonic acid; (12) The crystal form C contains an acid; the molar ratio of the acid to compound IR is (0.5-1):1; (13) The crystal form D has diffraction peaks as shown in Table 4-2 when using Cu-Kα radiation and X-ray powder diffraction with an angle of 2θ, with an error range of ±0.2°; for example, the crystal form D has diffraction peaks as shown in Table 4-3 when using Cu-Kα radiation and X-ray powder diffraction with an angle of 2θ, with an error range of ±0.2°. (14) The differential scanning calorimetry curve of the crystal form D has endothermic peaks at peak temperatures of approximately 61.8℃±5℃ and 149.7℃±5℃. (15) The differential scanning calorimetry curve of the crystal form D has an exothermic peak at a peak temperature of about 101.7℃±5℃; (16) The thermogravimetric analysis curve of the crystal D shows a weight loss of 2.07% ± 0.5% in the temperature range of 26.8℃ ± 3℃ to 120.0℃ ± 3℃; (17) The crystal form D contains an organic solvent; the organic solvent is one or both of dichloromethane or n-heptane; (18) The crystal form D contains an organic solvent; the mass fraction of the organic solvent in the crystal form D is 0.1%-1.0%; (19) The crystal form E, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at 5.4±0.2°, 8.2±0.2°, 9.0±0.2°, 10.9±0.2°, 11.4±0.2°, 13.5±0.2°, 14.1±0.2°, 14.7±0.2°, 16.4±0.2°, 17.0±0.2°, 18.1±0.2°, 20.0±0.2°, 21.3±0.2°, 21.7±0.2°, 23.4±0.2°, 24.4±0.2°, 25.1±0.2°, 28.9±0.2°, 29.9±0.2°, and 32.6±0.2° in terms of 2θ angles. (20) The differential scanning calorimetry curve of the crystal form E has endothermic peaks at peak temperatures of approximately 59.1℃±5℃ and 95.4℃±5℃. (21) The thermogravimetric analysis curve of the crystal form E shows a weight loss of 15.87% ± 3% in the temperature range of 18.4℃ ± 3℃ to 120.0℃ ± 3℃; (22) The crystal form E contains an organic solvent; (23) The crystal form E is an organic solvate; for example, crystal form E is a dimethyl sulfoxide solvate; (24) The crystal form F has diffraction peaks as shown in Table 6-3 when X-ray powder diffraction is performed using Cu-Kα radiation and expressed in terms of 2θ angle, with an error range of ±0.2°. (25) The differential scanning calorimetry curve of the crystal form F has endothermic peaks at peak temperatures of approximately 67.3℃±5℃, 126.2℃±5℃ and 148.5℃±5℃; (26) The thermogravimetric analysis curve of the crystal form F shows a weight loss of 7.32% ± 3% in the temperature range of 27.9℃ ± 3℃ to 110.0℃ ± 3℃; (27) The crystal form F contains an organic solvent.

7. The crystal form as described in claim 3, characterized in that, It is selected from one or more of the following conditions: (1) The X-ray powder diffraction of crystal form A satisfies one of the following conditions: (i) The crystal form A has a basic X-ray powder diffraction pattern as shown in Figure 3; (ii) The crystal form A, when subjected to Cu-Kα radiation and X-ray powder diffraction with an angle of 2θ, exhibits diffraction peaks as shown in Table 1-2, with an error range of ±0.2°. (iii) The crystal form A exhibits diffraction peaks as shown in Table 1-3 using Cu-Kα radiation and X-ray powder diffraction with an angle of 2θ, with an error range of ±0.2°. (2) The differential scanning calorimetry curve of the crystal form A has an endothermic peak at a peak temperature of about 154.2℃±3℃; (3) The thermogravimetric analysis curve of the crystal form A shows a weight loss of 0.22% in the temperature range of 28.7℃ to 140℃; preferably, the crystal form A has a DSC-TGA spectrum as shown in Figure 4. (4) The crystal form A has a basic polarized light microstructure as shown in Figure 6; (5) The crystal form A has the basic characteristics shown in Figure 5. 1 H-NMR spectrum; (6) Crystal form A does not contain organic solvents; (7) Crystal form A is amorphous; (8) The X-ray powder diffraction of crystal form B satisfies one of the following conditions: (i) The crystal form B has a basic X-ray powder diffraction pattern as shown in Figure 7; (ii) The crystal form B, when subjected to Cu-Kα radiation and X-ray powder diffraction with an angle of 2θ, exhibits diffraction peaks as shown in Table 2-3, with an error range of ±0.2°. (iii) The crystal form B exhibits diffraction peaks as shown in Table 2-4 using Cu-Kα radiation and X-ray powder diffraction with an angle of 2θ, with an error range of ±0.2°. (9) The differential scanning calorimetry curve of the crystal form B has an endothermic peak at a peak temperature of 145.8℃; or, an endothermic peak at 146.1℃; or, an endothermic peak at 147.4℃. (10) The thermogravimetric analysis curve of the crystal form B shows a weight loss of 2.35% in the temperature range of 29.2℃ to 140℃; preferably, the crystal form B has a DSC-TGA spectrum as shown in Figure 8. (11) The crystal form B has a basic polarized light microstructure as shown in Figure 10; (12) Crystal form B does not contain organic solvents; (13) Crystal form B is amorphous; (14) The crystal form B has the basic characteristics shown in Figure 9. 1 H-NMR spectrum; (15) The crystal form C has a basic X-ray powder diffraction pattern as shown in Figure 11; (16) The crystal form D has a basic X-ray powder diffraction pattern as shown in Figure 12; (17) The crystal form D has a basic DSC-TGA pattern as shown in Figure 13; (18) The crystal form D is a hydrate; (19) The X-ray powder diffraction of the crystal form E satisfies one of the following conditions: (i) The crystal form E has a basic X-ray powder diffraction pattern as shown in Figure 15; (ii) The crystal form E, when subjected to Cu-Kα radiation and X-ray powder diffraction with an angle of 2θ, exhibits diffraction peaks as shown in Table 5-2, with an error range of ±0.2°. (iii) The crystal form E, when subjected to Cu-Kα radiation and X-ray powder diffraction with an angle of 2θ, exhibits diffraction peaks as shown in Table 5-3, with an error range of ±0.2°. (20) The crystal form E has a basic DSC-TGA pattern as shown in Figure 16; (21) The crystal form E has the basic characteristics shown in Figure 17. 1 H-NMR spectrum; (22) The crystal form E contains an organic solvent; the organic solvent is dimethyl sulfoxide; (23) The crystal form E contains an organic solvent; the mass fraction of the organic solvent in the crystal form E is 15%-20%; for example, 18.6%; (24) The crystal form E is an organic solvate; the organic solvent in the organic solvate has a mass percentage of 15%-20%; for example, 18.6%; (25) The crystal form F has a basic X-ray powder diffraction pattern as shown in Figure 18; (26) The crystal form F has a basic DSC-TGA spectrum as shown in Figure 19; (27) The crystal form F has the basic characteristics shown in Figure 20. 1 H-NMR spectrum; (28) The crystal form F contains an organic solvent; the organic solvent is n-heptane; (29) The crystal form F contains an organic solvent; the mass fraction of the organic solvent in the crystal form F is 1%-5%; for example, 1.7%.

8. The method for preparing the crystal form according to any one of claims 1-7, characterized in that, The preparation method is selected from any of the following methods: Method 1: Mix compound I or its stereoisomer with solvent A and stir until a precipitate forms; if no precipitate forms, add the antisolvent to the system and continue stirring until a precipitate forms to obtain the crystal form described above. Method 2: Mix compound I or its stereoisomer with an acid, and stir in solvent B until a precipitate forms to obtain the crystal form described above; If no precipitate forms after stirring, add solvent C to the system and continue stirring until a precipitate forms. Method 3: Dissolve compound I or its stereoisomer in solvent D, and allow the solvent to evaporate slowly to obtain the crystal form; Method 4: Place the open device containing compound I or its stereoisomer into a sealed device containing solvent E, so that compound I or its stereoisomer does not come into direct contact with solvent E, and then let it stand to obtain the crystal form.

9. The preparation method according to claim 8, characterized in that, It is selected from one or more of the following conditions: (1) Solvent A is selected from one, two or more of the following: isopropanol (IPA), isopropyl acetate (IPAc), methyl tert-butyl ether (MTBE), n-heptane, acetone, methanol, ethanol, 2-butanone, ethyl acetate, methyl acetate, 4-methyl-2-pentanone, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, n-hexane, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, toluene, dimethylacetamide, cyclopentyl methyl ether, toluene, methyl isobutyl ketone, and water; or a mixture of any one or two of the above solvents with any one of the solvents n-heptane, n-hexane, toluene, or water. For example, solvent A is a mixture of IPA, IPAc, MTBE, IPA and n-heptane, a mixture of acetone and n-heptane, a mixture of IPAc and n-heptane, a mixture of dichloromethane and n-heptane, a mixture of ethanol and n-heptane, a mixture of ethyl acetate and n-heptane, a mixture of methyl tert-butyl ether and toluene, a mixture of tetrahydrofuran and n-hexane, a mixture of acetonitrile and n-hexane, or a mixture of tetrahydrofuran and n-hexane. Preferably, the volume ratio of IPA to n-heptane in the mixed solvent of IPA and n-heptane is 1:2 or 1:9; Preferably, the volume ratio of IPAc to n-heptane in the mixed solvent of IPAc and n-heptane is 1:2; Preferably, the volume ratio of acetone to n-heptane in the mixed solvent of acetone and n-heptane is 1:4 or 1:3; Preferably, the volume ratio of dichloromethane to n-heptane in the mixed solvent of dichloromethane and n-heptane is 1:2; Preferably, the volume ratio of ethanol to n-heptane in the mixed solvent of ethanol and n-heptane is 1:4; Preferably, the volume ratio of ethyl acetate to n-heptane in the mixed solvent of ethyl acetate and n-heptane is 1:3; Preferably, the volume ratio of MTBE to toluene in the mixed solvent of methyl tert-butyl ether and toluene is 1:4; Preferably, the volume ratio of tetrahydrofuran to n-hexane in the mixed solvent of tetrahydrofuran and n-hexane is 1:4; Preferably, the volume ratio of acetonitrile to n-hexane in the mixed solvent of acetonitrile and n-hexane is 1:4; Preferably, the volume ratio of tetrahydrofuran to n-hexane in the mixed solvent of tetrahydrofuran and n-hexane is 1:4; (2) The antisolvent is water, n-heptane, or toluene; (3) Solvent B and solvent C are each independently selected from one, two or more of the following: isopropanol, isopropyl acetate, methyl tert-butyl ether, n-heptane, acetone, methanol, ethanol, 2-butanone, ethyl acetate, methyl acetate, 4-methyl-2-pentanone, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, n-hexane, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, and water. Preferably, solvent B is a mixture of any one of IPA, IPAc, or ethanol with n-heptane; preferably, the volume ratio of any one of IPA, IPAc, or ethanol to n-heptane in the mixed solvent is 1:(1-5); more preferably 1:

2. Preferably, solvent C is n-heptane; (4) The solvent D is a mixed solvent of dichloromethane, methanol, IPAc, acetonitrile and water or a mixed solvent of acetone and water; preferably, in the mixed solvent of acetonitrile and water, the volume ratio of acetonitrile to water is 4:1; preferably, in the mixed solvent of acetone and water, the volume ratio of acetone to water is 4:

1. (5) The solvent E is any one of dimethyl sulfoxide, acetone or 2-methyltetrahydrofuran; (6) In method one, the stirring temperature is 5-50℃; preferably 10-30℃; for example, 10-15℃, 20-25℃ or 50℃. (7) In Method 2, the temperature during stirring in solvent B is 5-50℃; (8) In Method 2, the temperature for continued stirring is -20 to 50℃; (9) The mass ratio of compound I or its stereoisomer to the volume of solvent A is 1 g: (5-50) mL; for example, 1 g: 6.7 mL, 1 g: 15 mL, 1 g: 25 mL or 1 g: 50 mL; (10) The mass ratio of compound I or its stereoisomer to the volume of the antisolvent is 1 g:(15-500) mL; for example, 1 g:16.7 mL, 1 g:100 mL, 1 g:200 mL, 1 g:450 mL or 1 g:500 mL; (11) The mass ratio of compound I or its stereoisomer to the volume of solvent B is 1 g:(5-50) mL; for example, 1 g:25 mL; (12) The mass ratio of compound I or its stereoisomer to the volume of solvent C is 1 g:(5-50) mL; for example, 1 g:25 mL; (13) In Method 2, the acid is hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid or benzenesulfonic acid; (14) The molar ratio of compound I or its stereoisomer to acid is 1:(0.5-2); for example, 1:1; (15) The mass-volume ratio of compound I or its stereoisomer to solvent D is 1 g:(10-100) mL, for example 1 g:14.7 mL, 1 g:25 mL, 1 g:50 mL or 1 g:100 mL; (16) In Method 3, the slow evaporation is natural evaporation at room temperature; (17) The mass-volume ratio of compound I or its stereoisomer to solvent E is 1 g:(50-500) mL, for example 1 g:150 mL; (18) In Method 4, the settling time is 5-10 days; for example, 7 days. (19) In Method 4, the temperature for standing is 20-30℃.

10. The preparation method according to claim 8, characterized in that, It is selected from one or more of the following conditions: (1) When the solvent A is a mixed solvent of dichloromethane and n-heptane, the crystal form A is obtained; (2) When the solvent A is a mixed solvent of MTBE, IPA and n-heptane, a mixed solvent of acetone and n-heptane, a mixed solvent of IPAc and n-heptane, a mixed solvent of ethanol and n-heptane, a mixed solvent of ethyl acetate and n-heptane, a mixed solvent of methyl tert-butyl ether and toluene, a mixed solvent of tetrahydrofuran and n-hexane, a mixed solvent of acetonitrile and n-hexane, or a mixed solvent of tetrahydrofuran and n-hexane, the crystal form B is obtained; (3) When the solvent A is a mixed solvent of dimethyl sulfoxide and water, the crystal form E is obtained; (4) When the solvent A is dichloromethane and the antisolvent is n-heptane, the crystal form D is obtained; (5) When the acid is sulfuric acid, p-toluenesulfonic acid or methanesulfonic acid, the solvent B is IPA or IPAc, and the solvent C is n-heptane, the crystal form C is obtained; (6) When the acid is benzenesulfonic acid, the solvent B is IPA, and the solvent C is n-heptane, the crystal form C is obtained; (7) When the acid is hydrochloric acid and the solvent B is a mixed solvent of ethanol and n-heptane, the crystal form F is obtained; (8) When the solvent D is dichloromethane, the crystal form D is obtained; (9) When the solvent E is dimethyl sulfoxide, the crystal form E is obtained.

11. A pharmaceutical composition, characterized in that, The pharmaceutical composition contains the crystal form according to any one of claims 1-7.

12. The pharmaceutical composition according to claim 11, characterized in that, It is selected from one or more of the following conditions: (1) The pharmaceutical composition further contains a pharmaceutically acceptable carrier; (2) The pharmaceutical composition further contains a second active ingredient, such as one, two or more of the following: other LPAR1 inhibitors, LPAR2 inhibitors, LPAR3 inhibitors, ROCK inhibitors, FAAH inhibitors, TGF-β inhibitors, ACC inhibitors, ASK-1 inhibitors, FXR agonists, GLP-1 agonists, PPARα agonists, VEGFR inhibitors, FGFR inhibitors, PDGFR inhibitors, ATX inhibitors, GPR84 agonists, PASK inhibitors, CFTR agonists, JAK1 inhibitors, ADAMTS5 inhibitors, TOL2 / 3 inhibitors, CTGF inhibitors, αv-β6 / αv-β1 antagonists, JNK1 inhibitors, mineralocorticoid receptor antagonists, Nrf2 activators, chymotrypsin inhibitors, PDE inhibitors, NOX1 / 4 inhibitors, leukotriene receptor antagonists, thromboxane receptor antagonists, SLC22A12 inhibitors, sGC inhibitors, xanthine oxidase inhibitors, or TGFP antagonists.

13. A formulation, characterized in that, The formulation contains the crystal form according to any one of claims 1-7 or the pharmaceutical composition according to any one of claims 11-12; preferably, the formulation is an LPAR1 inhibitor.

14. The use of the crystal form according to any one of claims 1-7, the pharmaceutical composition according to any one of claims 11-12, or the formulation according to claim 13 in the preparation of a medicament for the prevention and / or treatment of LPAR1-mediated diseases or conditions; Preferably, the drug is an LPAR1 inhibitor; Preferably, the disease or symptom is a fibrotic disease, a respiratory disease, pain, a nervous system disease, a cardiovascular disease, an inflammatory disease, a kidney disease, a liver disease, an eye disease, cancer, a gastrointestinal disease, a urinary system disease, a metabolic disease, or transplant rejection; Preferably, the disease or condition is pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis, progressive pulmonary fibrosis), renal fibrosis, liver fibrosis, skin fibrosis, intestinal fibrosis, ocular fibrosis, cardiac fibrosis, pancreatic fibrosis, interstitial lung disease, idiopathic interstitial pneumonia, asthma, chronic obstructive pulmonary disease, bronchospasm, cough, chronic cough, respiratory failure, silicosis, acute lung injury, acute respiratory distress syndrome, acute kidney injury, chronic kidney disease, diabetic nephropathy, alcoholic steatohepatitis, non-alcoholic fatty liver disease (e.g., non-alcoholic steatohepatitis), acute hepatitis, chronic hepatitis, cirrhosis, impaired liver function, primary biliary cirrhosis, autoimmune diseases, inflammation, arthritis, rheumatoid arthritis, scleroderma, Raynaud's phenomenon, chronic pruritus, lupus, cryptogenic fibrotic alveolitis, psoriasis, systemic sclerosis, collagen vascular disease, Alzheimer's disease, Parkinson's disease, etc. Neurodegenerative diseases, traumatic brain injury, epilepsy, mental illness, sleep disorders, collagen vascular diseases, myocardial infarction, stroke, thrombosis, atherosclerosis, heart failure, hypertension, colitis, inflammatory bowel disease, digestive tract diseases, gastrointestinal dysfunction, cancer pain, neuropathic pain, inflammatory pain, surgical pain, visceral pain, toothache, premenstrual pain, central pain, pain caused by burns, migraine, cluster headache, chronic pain, urinary incontinence, dysuria, cystitis, benign prostatic hyperplasia, urinary disorders associated with benign prostatic hyperplasia, bladder neck sclerosis, hypoactive bladder, macular degeneration, diabetic retinopathy, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioblastoma, bone cancer, colon cancer, intestinal cancer, liver cancer, head and neck cancer, melanoma, multiple myeloma, chronic lymphocytic leukemia, tumor metastasis or osteoporosis; More preferably, the disease or condition is interstitial lung disease, pulmonary fibrosis (especially idiopathic pulmonary fibrosis), liver fibrosis, kidney fibrosis, non-alcoholic fatty liver disease (e.g., non-alcoholic steatohepatitis), psoriasis, or scleroderma.

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