Medicinal salts of triazole compounds, crystalline forms and methods for preparing same

Abstract

The present disclosure relates to medicinal salts, crystalline forms and preparation methods of triazole compounds. Specifically, the present disclosure provides medicinal salts, crystalline forms and preparation methods of the compound of Formula I (1S,3aS,5S,6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydrocyclopentadiene-1-carboxylic acid, the corresponding salts have good stability and can be used in clinical treatment. [Formula 1] TIFF2026505734000034.tif41168

Description

[Technical Field]

[0001] This application claims priority from Chinese Patent Application No. 2023100662824, filed on January 19, 2023. The above Chinese patent application is incorporated herein by reference in its entirety.

[0002] The present disclosure is in the pharmaceutical field and relates to medicinal salts, crystalline forms of triazole compounds and methods for their preparation. [Background technology]

[0003] Serum phospholipids are membrane-derived bioactive lipid mediators, of which lysophosphatidic acid (LPA) is of greatest medical importance. Lysophospholipids influence fundamental cellular functions, including proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis. These functions influence many biological processes, including, but not limited to, neurogenesis, angiogenesis, wound healing, fibrosis, immunity, and carcinogenesis.

[0004] LPA is not a single molecular entity but a group of endogenous structural variants with fatty acids of varying lengths and saturations. The structural backbone of LPA is derived from glycerol-based phospholipids such as phosphatidylcholine (PC) or phosphatidic acid (PA). Lysophosphatidic acid (LPA) is a lysophospholipid that acts in autocrine and paracrine ways via specific G-protein-coupled receptors (GPCRs). LPA binds to its homologous GPCRs (LPA1, LPA2, LPA3, LPA4, LPA5, and LPA6) and activates intracellular signaling pathways, thereby producing various biological responses. LPA receptor antagonists have been found to be applicable to the treatment of diseases, disorders, or conditions affected by LPA.

[0005] PCT / CN2022 / 106706 discloses a class of novel triazole derivatives having the chemical name (1S,3aS,5S,6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydrocyclopentadiene-1-carboxylic acid, as shown in Formula I, and indicates their use as LPA1 inhibitors. This disclosure incorporates PCT / CN2022 / 106706 in its entirety. [ka]

[0006] The crystalline structure of a pharmaceutical active ingredient often affects the chemical and physical stability of the drug, and the crystallization and storage conditions can change the crystalline structure of the compound, sometimes resulting in the formation of other crystalline forms. Generally, amorphous drug products do not have a regular crystalline structure and often have other defects, such as relatively poor product stability, relatively difficult filtration, prone to caking, and poor flowability. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] PCT / CN2022 / 106706 Summary of the Invention [Problem to be solved by the invention]

[0008] Therefore, studying the medicinal salts and crystalline forms of (1S,3aS,5S,6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydrocyclopentadiene-1-carboxylic acid, whose chemical name is shown in Formula I, is of great significance in developing pharmaceuticals that are suitable for industrial production and have good biological activity. [Means for solving the problem]

[0009] (Summary of the Invention) One aspect of the present disclosure provides crystalline Form A of the compound of Formula I, (1S,3aS,5S,6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydrocyclopentadiene-1-carboxylic acid.

[0010] [ka] In some embodiments, the A-type crystal has characteristic peaks at 7.534, 10.223, 14.364, 17.269, 18.495, and 19.553 in a powder X-ray diffraction spectrum expressed in terms of diffraction angles 2θ.

[0011] In some other embodiments, the A-type crystal has characteristic peaks at 7.534, 10.223, 14.364, 15.816, 16.678, 17.269, 18.495, and 19.553 in a powder X-ray diffraction spectrum expressed in terms of diffraction angles 2θ.

[0012] In some other embodiments, the A-type crystal has a powder X-ray diffraction spectrum expressed in terms of diffraction angles 2θ, which has characteristic peaks at 7.534, 10.223, 14.364, 15.816, 16.678, 17.269, 18.495, 19.553, 21.043, 21.342, 23.647, and 25.965.

[0013] Most preferably, the powder X-ray diffraction spectrum expressed in terms of diffraction angle 2θ is as shown in FIG.

[0014] According to another aspect, the present disclosure provides a method for preparing crystalline Form A of the compound of formula I, comprising dissolving the compound of formula I in propylene glycol methyl ether, further adding n-heptane, and stirring to cause crystallization.

[0015] In some other embodiments, the method for preparing Form A crystals of the compound of Formula I includes dissolving the compound of Formula I in solvent (1), adding solvent (2), further adding solvent (3), and stirring to cause crystallization, wherein solvent (1) is at least one solvent selected from propylene glycol methyl ether, 1,4-dioxane, 10% water / acetone, N,N-dimethylformamide, N,N-dimethylacetamide, 50% methanol / chloroform, and 67% tetrahydrofuran / ethanol, solvent (2) is selected from methyl tert-butyl ether, and solvent (3) is selected from n-heptane.

[0016] In some other embodiments, the method for preparing crystalline Form A of the compound of formula I comprises dissolving the compound of formula I in acetone and stirring to cause crystallization.

[0017] According to another aspect, the present disclosure provides Form B crystals of compound Formula I, (1S,3aS,5S,6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydrocyclopentadiene-1-carboxylic acid.

[0018] [ka] In some embodiments, the B-type crystal has characteristic peaks at 7.437, 10.381, 14.955, and 17.513 in a powder X-ray diffraction spectrum expressed in terms of diffraction angles 2θ.

[0019] In some other embodiments, the B-type crystal has characteristic peaks at 7.437, 10.381, 14.717, 14.955, 17.513, 21.395, 22.607, and 23.221 in a powder X-ray diffraction spectrum expressed in terms of diffraction angles 2θ.

[0020] In some other embodiments, the B-type crystal has a powder X-ray diffraction spectrum expressed in terms of diffraction angles 2θ, which has characteristic peaks at 7.437, 10.381, 14.717, 14.955, 17.513, 18.466, 21.395, 21.692, 22.607, 23.221, and 25.972.

[0021] In some other embodiments, the powder X-ray diffraction spectrum of the B-type crystals, expressed in terms of diffraction angle 2θ angles, is as shown in FIG.

[0022] According to another aspect, the present disclosure provides a method for preparing Type B crystals of the compound of Formula I, comprising dissolving the compound of Formula I in solvent (A), adding solvent (B), and further adding solvent (C), followed by stirring to allow crystallization, wherein solvent (A) is at least one solvent selected from tetrahydrofuran, dichloromethane, 10% water / isopropanol, and trichloromethane; solvent (B) is selected from methyl tert-butyl ether; and solvent (C) is selected from n-heptane.

[0023] In some other embodiments, the method for preparing Form B crystals of the compound of Formula I comprises dissolving the compound of Formula I in water, methanol, ethanol, isopropanol, n-propanol, ethyl acetate, acetonitrile, isopropyl acetate, methyl tert-butyl ether, 2-butanone, methyl isobutyl ketone, n-heptane, isopropyl ether, isoamyl alcohol, 10% water / methanol, 7% water / ethanol, 50% methanol / water, 50% ethyl acetate / ethanol, 50% ethyl acetate / n-heptane, cyclohexane, n-hexane, or toluene, and stirring to cause crystallization.

[0024] According to another aspect, the present disclosure provides crystalline Form C of the compound of Formula I, (1S,3aS,5S,6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydrocyclopentadiene-1-carboxylic acid.

[0025] [ka] In some embodiments, the C-type crystal has a powder X-ray diffraction spectrum expressed in terms of diffraction angles 2θ, which has characteristic peaks at 5.702, 10.643, 17.229, 18.213, 18.666, and 20.900.

[0026] In some other embodiments, the C-type crystal has a powder X-ray diffraction spectrum expressed in terms of diffraction angles 2θ, which has characteristic peaks at 5.702, 10.074, 10.643, 11.463, 17.229, 18.213, 18.666, 20.900, 22.422, and 23.968.

[0027] In some other embodiments, the C-type crystal has a powder X-ray diffraction spectrum expressed in terms of diffraction angles 2θ, which has characteristic peaks at 5.702, 10.074, 10.643, 11.463, 16.738, 17.229, 18.213, 18.666, 20.900, 22.057, 22.422, 23.397, and 23.968.

[0028] In some other embodiments, the C-type crystal has a powder X-ray diffraction spectrum, expressed in terms of diffraction angle 2θ, as shown in FIG.

[0029] According to another aspect, the present disclosure further provides a pharmaceutically acceptable salt of the compound (1S,3aS,5S,6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydrocyclopentadiene-1-carboxylic acid as shown in Formula I, wherein the pharmaceutically acceptable salt is selected from the sodium salt or the ethanolamine salt.

[0030] [ka] In an alternative embodiment, the chemical composition of the compound of formula I, (1S,3aS,5S,6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydrocyclopentadiene-1-carboxylic acid, and sodium ions is 1:1.

[0031] The present disclosure further provides a process for preparing a pharmaceutically acceptable salt of a compound of formula I, (1S,3aS,5S,6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydrocyclopentadiene-1-carboxylic acid, comprising reacting a compound of formula I with a base selected from sodium hydroxide or ethanolamine.

[0032] The solvent used in the salt formation of the present disclosure is one or more solvents selected from, but not limited to, acetonitrile, ethanol / ethyl acetate, methanol / acetonitrile, 2-butanone, isopropanol, isopropyl acetate, n-propanol, n-heptane, acetone, tetrahydrofuran, ethanol, methanol, 1,4-dioxane, dichloromethane / methanol, water / isopropanol, tetrahydrofuran / ethanol.

[0033] Furthermore, in an optional embodiment, the method for preparing the above pharmaceutically acceptable salt further comprises steps such as crystallization, filtering, washing or drying.

[0034] According to another aspect, the present disclosure further provides Form I crystals of the sodium salt of the compound of Formula I, (1S,3aS,5S,6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydrocyclopentadiene-1-carboxylic acid, wherein the powder X-ray diffraction spectrum, expressed in 2θ angles, has characteristic peaks at 6.446, 8.350, 8.847, 9.335, 12.845, 16.901, and 17.874.

[0035] In some other embodiments, the Form I crystal of the sodium salt has characteristic peaks at 6.446, 8.350, 8.847, 9.335, 9.807, 12.845, 13.328, 13.739, 15.728, 16.901, and 17.874 in a powder X-ray diffraction spectrum expressed in terms of diffraction angles 2θ.

[0036] In some other embodiments, the Form I crystal of the sodium salt has a powder X-ray diffraction spectrum expressed in terms of diffraction angles 2θ, which has characteristic peaks at 4.741, 6.446, 8.350, 8.847, 9.335, 9.807, 12.845, 13.328, 13.739, 15.728, 16.901, 17.874, 19.059, and 19.805.

[0037] In some other embodiments, the Form I crystal of the sodium salt has a powder X-ray diffraction spectrum expressed in terms of diffraction angles 2θ, which has characteristic peaks at 4.741, 6.446, 8.350, 8.847, 9.335, 9.807, 12.845, 13.328, 13.739, 15.728, 16.901, 17.874, 19.059, 19.805, 21.490, 23.607, 25.460, and 25.773.

[0038] In some other embodiments, the powder X-ray diffraction spectrum of the sodium salt type I crystals, expressed in terms of diffraction angle 2θ angles, is as shown in FIG.

[0039] According to another aspect, the present disclosure provides a method for preparing Form I crystals of the sodium salt of the compound of Formula I, comprising dissolving the compound of Formula I in 50% ethanol / ethyl acetate, 50% methanol / acetonitrile, or tetrahydrofuran, adding sodium hydroxide solution, further adding methyl tert-butyl ether, and stirring to cause crystallization.

[0040] According to another aspect, the present disclosure provides a method for preparing Form I crystals of the sodium salt of the compound of Formula I, comprising dissolving the compound of Formula I in 2-butanone or acetonitrile, adding an ethanolic sodium hydroxide solution, and stirring to cause crystallization.

[0041] According to another aspect, the present disclosure further provides Form II crystals of the sodium salt of the compound of Formula I, (1S,3aS,5S,6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydrocyclopentadiene-1-carboxylic acid, wherein the powder X-ray diffraction spectrum, expressed in 2θ angles, has characteristic peaks at 6.771, 13.464, 14.419, and 15.593.

[0042] In some other embodiments, the type II crystal of the sodium salt has characteristic peaks at 6.771, 13.464, 13.970, 14.419, 15.593, 18.044, and 19.952 in a powder X-ray diffraction spectrum expressed in terms of diffraction angles 2θ.

[0043] In some other embodiments, the powder X-ray diffraction spectrum of the sodium salt crystal form II, expressed in terms of diffraction angle 2θ angles, is as shown in FIG.

[0044] According to another aspect, the present disclosure provides a method for preparing crystalline Form II of the sodium salt of the compound of Formula I, comprising dissolving the compound of Formula I in isopropanol or 1,4-dioxane, adding an ethanolic solution of sodium hydroxide, and stirring to cause crystallization.

[0045] According to another aspect, the present disclosure provides a method for preparing Form II crystals of the sodium salt of the compound of Formula I, comprising dissolving Form I crystals of the sodium salt of the compound of Formula I in isopropanol or isopropyl acetate and stirring to cause crystallization.

[0046] According to another aspect, the present disclosure provides a method for preparing Form II crystals of the sodium salt of the compound of Formula I, comprising dissolving Form I crystals of the sodium salt of the compound of Formula I in ethanol or n-propanol, adding n-heptane, and stirring to cause crystallization.

[0047] According to another aspect, the present disclosure further provides Form III crystals of the sodium salt of the compound of Formula I, (1S,3aS,5S,6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydrocyclopentadiene-1-carboxylic acid, wherein the powder X-ray diffraction spectrum expressed in 2θ angles has characteristic peaks at 6.605, 18.597, 20.094, and 26.882.

[0048] In some other embodiments, the type III crystal of the sodium salt has characteristic peaks at 5.639, 6.605, 10.311, 13.323, 18.597, 20.094, and 26.882 in a powder X-ray diffraction spectrum expressed in terms of diffraction angle 2θ.

[0049] In some other embodiments, the powder X-ray diffraction spectrum of the sodium salt crystal form III, expressed in terms of diffraction angle 2θ angles, is as shown in FIG.

[0050] According to another aspect, the present disclosure provides a method for preparing Form III crystals of the sodium salt of the compound of Formula I, comprising dissolving Form I crystals of the sodium salt of the compound of Formula I in 1,4-dioxane and stirring to cause crystallization.

[0051] According to another aspect, the present disclosure further provides a Form IV crystal of the sodium salt of the compound of Formula I, (1S,3aS,5S,6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydrocyclopentadiene-1-carboxylic acid, wherein the powder X-ray diffraction spectrum, expressed in diffraction angles 2θ, has characteristic peaks at 7.078, 14.227, 15.004, 18.812, and 20.081.

[0052] In some other embodiments, the type IV crystal of the sodium salt has characteristic peaks at 5.078, 7.078, 10.670, 13.231, 14.227, 15.004, 18.812, 20.081, and 24.018 in a powder X-ray diffraction spectrum expressed in terms of diffraction angles 2θ.

[0053] In some other embodiments, the type IV crystal of the sodium salt has a powder X-ray diffraction spectrum, expressed in terms of diffraction angle 2θ, as shown in FIG.

[0054] According to another aspect, the present disclosure provides a method for preparing Form IV crystalline form of the sodium salt of the compound of Formula I, comprising heating Form I crystalline form of the sodium salt of the compound of Formula I to 180° C. or greater.

[0055] According to another aspect, the present disclosure further provides Form I crystals of the compound of Formula I, (1S,3aS,5S,6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydrocyclopentadiene-1-carboxylic acid ethanolamine salt, wherein the powder X-ray diffraction spectrum, expressed in 2θ angles, has characteristic peaks at 5.343, 9.612, 10.751, 16.737, and 19.178.

[0056] In some other embodiments, the type I crystal of the ethanolamine salt has characteristic peaks at 5.343, 9.612, 10.751, 12.023, 14.613, 16.737, 17.886, 19.178, 20.434, and 21.788 in a powder X-ray diffraction spectrum expressed in terms of diffraction angles 2θ.

[0057] In some other embodiments, the type I crystal of the ethanolamine salt has a powder X-ray diffraction spectrum, expressed in terms of diffraction angle 2θ angles, as shown in FIG.

[0058] According to another aspect, the present disclosure provides a method for preparing Form I crystals of the ethanolamine salt of the compound of Formula I, comprising dissolving the compound of Formula I in tetrahydrofuran, adding an ethanolamine ethanol solution, adding methyl tert-butyl ether, and stirring to cause crystallization.

[0059] Further disclosed is a crystalline form of the compound of Formula I, (1S,3aS,5S,6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydrocyclopentadiene-1-carboxylic acid, wherein the error range of the 2θ angle is ±0.2.

[0060] In certain embodiments, the method for preparing the crystalline forms described herein further comprises a crystallization, filtration, washing, or drying step.

[0061] According to another aspect, the present disclosure further provides a pharmaceutical composition comprising Type A crystalline, Type B crystalline, Type C crystalline, amorphous, sodium salt, Type I crystalline of the sodium salt, Type II crystalline of the sodium salt, Type III crystalline of the sodium salt, Type IV crystalline of the sodium salt, amorphous, ethanolamine salt, or Type I crystalline of the ethanolamine salt of the compound of Formula I above, (1S,3aS,5S,6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydrocyclopentadiene-1-carboxylic acid, and optionally a pharmaceutically acceptable excipient.

[0062] The present disclosure further provides a method for preparing a pharmaceutical composition, the method comprising the step of mixing Type A crystals, Type B crystals, Type C crystals, amorphous, sodium salt, Type I crystals of the sodium salt, Type II crystals of the sodium salt, Type III crystals of the sodium salt, Type IV crystals of the sodium salt, amorphous, ethanolamine salt, or Type I crystals of the ethanolamine salt of the compound of Formula I (1S,3aS,5S,6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydrocyclopentadiene-1-carboxylic acid, as described above, with a pharmaceutically acceptable excipient.

[0063] The present disclosure further provides use of the Type A crystal, Type B crystal, Type C crystal, amorphous, sodium salt, Type I crystal of the sodium salt, Type II crystal of the sodium salt, Type III crystal of the sodium salt, Type IV crystal of the sodium salt, amorphous, ethanolamine salt, Type I crystal of the ethanolamine salt of the compound of Formula I (1S,3aS,5S,6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydrocyclopentadiene-1-carboxylic acid as an LPA1 inhibitor.

[0064] The present disclosure further provides use of the Type A crystal, Type B crystal, Type C crystal, amorphous, sodium salt, Type I crystal of the sodium salt, Type II crystal of the sodium salt, Type III crystal of the sodium salt, Type IV crystal of the sodium salt, amorphous sodium salt, ethanolamine salt, Type I crystal of the ethanolamine salt, or the pharmaceutical composition of the compound of Formula I, (1S,3aS,5S,6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydrocyclopentadiene-1-carboxylic acid, for the prevention and / or treatment of organ fibrotic and degenerative diseases, respiratory diseases, kidney diseases, liver diseases, inflammatory diseases, nervous system diseases, cardiovascular and cerebrovascular diseases, gastrointestinal diseases, pain, urinary system diseases, eye diseases, metabolic diseases, cancer, and transplant organ rejection.

[0065] The present disclosure further provides use of the Type A crystal, Type B crystal, Type C crystal, amorphous, sodium salt, Type I crystal of the sodium salt, Type II crystal of the sodium salt, Type III crystal of the sodium salt, Type IV crystal of the sodium salt, amorphous sodium salt, ethanolamine salt, Type I crystal of the ethanolamine salt of the compound of Formula I, (1S,3aS,5S,6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydrocyclopentadiene-1-carboxylic acid, or the pharmaceutical composition, in the preparation of a medicament for preventing and / or treating organ fibrotic and degenerative diseases, respiratory diseases, kidney diseases, liver diseases, inflammatory diseases, nervous system diseases, cardiovascular and cerebrovascular diseases, gastrointestinal diseases, pain, urinary system diseases, eye diseases, metabolic diseases, cancer, and transplant organ rejection.

[0066] The term "2θ or 2θ angle" used in the present disclosure refers to the diffraction angle, where θ is the Bragg angle and is expressed in ° or degrees. The error range of 2θ for each characteristic peak is ±0.20 (including rounding to the nearest decimal place), and specifically includes -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, - 0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.

[0067] In the present disclosure, there is a certain degree of error in the measurement of the chemical ratio of the compound and the acid molecule, and generally, ±10% is within a reasonable error range. Depending on the context of use, there is a certain degree of error variation, and the variation of the error does not exceed ±10%, and may be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, and preferably ±5%. In the present disclosure, numerical values ​​indicated by "about" are within the above reasonable error range.

[0068] "Crystallization" or "crystallization" as referred to in this disclosure includes, but is not limited to, stirred crystallization, slurry crystallization, cooling crystallization, and volatile crystallization.

[0069] "Differential scanning calorimetry or DSC" as used herein refers to the measurement of temperature and heat flow differences between a sample and a reference during a heating or isothermal process of the sample to characterize all physical and chemical changes associated with thermal effects and obtain information on the phase transitions of the sample.

[0070] The drying temperature described in the present disclosure is generally 25°C to 100°C, preferably 40°C to 70°C, and drying may be performed under normal pressure or reduced pressure.

[0071] "Pharmaceutically acceptable excipients" as referred to in this disclosure include, but are not limited to, any auxiliary agent, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, or emulsifier that has already been approved by the U.S. Food and Drug Administration and is acceptable for use in humans or domestic animals. [Brief explanation of the drawings]

[0072] [Figure 1] 1 is an amorphous XRPD spectrum of the compound of formula I. [Figure 2] 1 is an XRPD spectrum of crystalline form A of compound of formula I. [Figure 3] 1 is an XRPD spectrum of crystalline form B of compound of formula I. [Figure 4] 1 is an XRPD spectrum of crystalline form C of the compound of formula I. [Figure 5] 1 is an XRPD spectrum of crystalline Form I of the sodium salt of the compound of Formula I. [Figure 6] 1 is an XRPD spectrum of crystalline Form II of the sodium salt of the compound of Formula I. [Figure 7] 1 is an XRPD spectrum of crystalline Form III of the sodium salt of the compound of Formula I. [Figure 8] 1 is an XRPD spectrum of crystalline Form IV of the sodium salt of the compound of Formula I. [Figure 9] 1 is an amorphous XRPD spectrum of the sodium salt of the compound of formula I. [Figure 10] 1 is an XRPD spectrum of crystalline form I of the ethanolamine salt of the compound of formula I. DETAILED DESCRIPTION OF THE INVENTION

[0073] The present disclosure is further illustrated by the following examples and experimental examples, which are for illustrative purposes only and are not intended to limit the scope of the disclosure.

[0074] Test conditions for the equipment used in the experiment: The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shift (δ) is 10 -6 The NMR data are shown in ppm. A Bruker AVANCE-400 nuclear magnetic resonance spectrometer was used for the NMR measurements. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0075] For MS analysis, an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatograph mass spectrometer (manufacturer: Agilent, MS model number: 6110 / 6120 Quadrupole MS) was used. A Waters ACQuity UPLC-QD / SQD (manufacturer: Waters, MS model number: Waters ACQuity Qda Detector / Waters SQ Detector) and a Thermo Ultimate 3000-Q Exactive (manufacturer: Thermo, MS model number: Thermo Q 15 Exactive) were used. For HPLC analysis, an Agilent 1260DAD high-performance liquid chromatograph (Sunfire C18 150 × 4.6 mm column) and a Thermo U3000 high-performance liquid chromatograph (Gimini C18 150 × 4.6 mm column) were used. XRPD is a method of detecting powder X-ray diffraction. A BRUKER D8 X-ray diffractometer is used for the measurement. The specific collected information is a Cu anode (40 kV, 40 mA), radiation: monochromatic Cu-Ka radiation (l = 1.5418 Å), scanning method: θ / 2θ, scanning range: 3 to 48 oDSC is differential scanning calorimetry (DSC). Measurements were performed using a METTLER TOLEDO DSC 3+ differential scanning calorimeter with a heating rate of 10°C / min. The specific temperature range was determined by reference to the corresponding spectrum (mainly 25°C to 300°C). The nitrogen gas purge rate was 50mL / min. TGA is thermogravimetric analysis (TGA). Detection was performed using a METTLER TOLEDO TGA 2 thermogravimetric analyzer with a heating rate of 10°C / min. The specific temperature range was determined by reference to the corresponding spectrum (mainly 30°C to 400°C). The nitrogen gas purge rate was 50mL / min. DVS is dynamic moisture sorption (DVS). Surface Measurement Systems instrinsic was used. The humidity range was measured from 0% to 95% starting from 50% in 10% increments. The criterion was a mass change per gradient (dM / dT) of ≤ 0.002%. TMAX was 360 min, and two cycles were repeated.

[0076] Known starting materials of the present disclosure may be synthesized by or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical 30 Technology (Accela ChemBio Inc.), and Darui Chemical.

[0077] In the examples, thin layer chromatography (TLC) was used to monitor the reaction process. The developing solvents used in the reactions, the column chromatographic eluent system used to purify the compounds, and the developing solvent system for thin layer chromatography included A: dichloromethane / methanol system and B: n-hexane / ethyl acetate system. The volume ratio of the solvents may be adjusted according to the polarity of the compounds, and may be adjusted by adding small amounts of basic or acidic reagents such as triethylamine and acetic acid.

[0078] Example 1: Preparation of Compound I (Compound 1-P1 is prepared as described in Example 3 of the application with application number PCT / CN2022 / 106706) [ka] [ka]

[0079] Step 1: 5-Hydroxyhexahydrocyclopentadien-2(1H)-one (1b) The starting material, cis-tetrahydrocyclopentadiene-2,5(1H,3H)-dione 1a (24 g, 173.7 mmol), was dissolved in ethanol (500 mL) and cooled to 0° C. Sodium borohydride (1.47 g, 43.4 mmol) was added and the mixture was stirred at 0° C. for 2 hours. The reaction mixture was quenched with acetic acid (10 mL), concentrated, and the residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate) to give the title product 1b (9 g, 37.0% yield). 1 H NMR: (400 MHz, CDCl3) δ 4.55 - 4.37 (m, 1H), 2.90 - 2.75 (m, 2H), 2.64 - 2.48 (m, 2H), 2.36 - 2.14 (m, 4H), 1.65 - 1.49 (m, 3H).

[0080] Step 2: 5-((tert-butyldiphenylsilyl)oxy)hexahydrocyclopentadien-2(1H)-one (1c) 1b (15 g, 107.0 mmol) was dissolved in dichloromethane (150 mL), imidazole (21.8 g, 321.0 mmol) was added, and the mixture was cooled to 0 °C. tert-Butyldiphenylchlorosilane (30.5 mL, 117.7 mmol) was added, and the reaction was stirred at 0 °C for 1 hour. The reaction mixture was washed with 1 M hydrochloric acid solution (150 mL × 3), saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate) to give the title product 1c (41 g, crude product), which was used directly in the next reaction without further purification.

[0081] Step 3: Methyl 5-((tert-butyldiphenylsilyl)oxy)-2-oxooctahydrocyclopentadiene-1-carboxylate (1d) A solution of 1c (41 g, 108.3 mmol) in tetrahydrofuran (500 mL) was cooled to 0 °C, and 60% sodium hydride (17.3 g, 433.2 mmol) was added, followed by dimethyl carbonate (19.5 g, 216.6 mmol). The mixture was heated to 60 °C and stirred for 3 hours. Water (150 mL) was added to quench the reaction. Extraction was performed with ethyl acetate (100 mL × 3). The combined organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate) to give the title product 1d (25 g, 52.9% yield). MS (ESI): m / z = 459.1 [M+Na] + .

[0082] Step 4: Methyl 5-((tert-butyldiphenylsilyl)oxy)-2-hydroxyoctahydrocyclopentadiene-1-carboxylate (1e) 1d (32 g, 73.3 mmol) was dissolved in tetrahydrofuran (350 mL) and cooled to 0 °C. Sodium borohydride (2.48 g, 73.3 mmol) was added and the mixture was stirred at 0 °C for 3 hours. The reaction was quenched with 0.5 M hydrochloric acid solution (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate) to give the title product 1e (9 g, 28.0% yield). MS (ESI): m / z = 461.2 [M+Na] + .

[0083] Step 5: Methyl 5-((tert-butyldiphenylsilyl)oxy)-2-((methylsulfonyl)oxy)octahydrocyclopentadiene-1-carboxylate (1f) 1e (9 g, 20.5 mmol) was dissolved in dichloromethane (20 mL), triethylamine (5.19 g, 51.3 mmol) was added, and the mixture was cooled to 0 °C. Methanesulfonic anhydride (5.36 g, 30.8 mmol) was added, and the reaction mixture was allowed to warm to room temperature and react for 3 hours with stirring. The reaction mixture was washed with water (25 mL × 2), saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate) to give the title product 1f (9 g, 84.9% yield). MS (ESI): m / z = 539.1 [M+Na] + .

[0084] Step 6: Methyl 5-((tert-butyldiphenylsilyl)oxy)-3,3a,4,5,6,6a-hexahydrocyclopentadiene-1-carboxylate (1g) 1f (9 g, 17.4 mmol) was dissolved in toluene (100 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (5.3 g, 34.8 mmol) was added, and the mixture was heated to 90 °C and stirred for 2 hours. The reaction mixture was concentrated, and the residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate) to give the title product 1g (6.5 g, 88.7% yield). MS (ESI): m / z = 443.2 [M+Na] + .

[0085] Step 7: Methyl 5-((tert-butyldiphenylsilyl)oxy)octahydrocyclopentadiene-1-carboxylate (1h) 1g (6.5g, 15.5mmol) was dissolved in methanol (65mL), and 10% Pd / C (600mg) was added under a nitrogen atmosphere. After purging with hydrogen gas several times, the reaction mixture was stirred under a hydrogen atmosphere (15psi) at room temperature for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated to give the crude product 1h (6.5g), which was directly used in the next reaction. MS (ESI): m / z = 445.2 [M+Na] + .

[0086] Step 8: Methyl 5-hydroxyoctahydrocyclopentadiene-1-carboxylate (1i) 1h (6.3 g, 14.9 mmol) was dissolved in tetrahydrofuran (60 mL), and 1 M tetrabutylammonium fluoride tetrahydrofuran solution (16.4 mL, 16.4 mmol) was added. The mixture was allowed to react at room temperature for 3 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate) to give the title product 1i (2.1 g, 76.5% yield). 1 H NMR (400 MHz, CDCl3) δ 4.03 (tt, J = 9.8, 6.1 Hz, 1H), 3.65 (s, 3H), 2.75 - 2.61 (m, 2H), 2.50 - 2.38 (m, 1H), 2.26 - 2.15 (m, 1H), 2.02 - 1.88 (m, 2H), 1.83 - 1.74 (m, 2H), 1.66 - 1.49 (m, 2H), 1.22 - 1.07 (m, 2H).

[0087] Step 9: 2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-ol (1k) 3-Bromo-2-methyl-6-(1-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridine 1j (2.5 g, 6.81 mmol, prepared according to the method disclosed in Example 1 of patent application WO2017223016A1), bis(dibenzylideneacetone)palladium (391 mg, 0.68 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (578 mg, 1.36 mmol), and potassium hydroxide (1.15 g, 20.44 mmol) were dissolved in 1,4-dioxane (50 mL) and water (10 mL), and the mixture was reacted at 100°C for 2 hours under a nitrogen atmosphere. The pH was adjusted to 6-7 with 1 M hydrochloric acid solution, water (10 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by diphenyl flash column chromatography (ethyl acetate / petroleum ether) to give the title product 1k (1.9 g, 92% yield). MS (ESI) m / z = 305.6 [M+H] + .

[0088] Step 10: Methyl 5-((2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)octahydrocyclopentadiene-1-carboxylate (1l) 1k (1 g, 3.29 mmol), triphenylphosphine (2.59 g, 9.86 mmol), and 1i (605 mg, 3.29 mmol) were dissolved in tetrahydrofuran (50 mL) and heated to 50 °C. A solution of di-tert-butyl azodicarboxylate (2.25 g, 9.86 mmol) dissolved in tetrahydrofuran (10 mL) was slowly added dropwise, and the mixture was stirred at 50 °C for 2 hours. The mixture was concentrated under reduced pressure to give the crude product, which was purified using a reverse-phase C18 column (acetonitrile / water) to give the title product 1l (1.2 g, 77% yield). MS (ESI) m / z = 471.8 [M+H] + .

[0089] Step 11: Methyl 5-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydrocyclopentadiene-1-carboxylate (1m) 1L (1.2 g, 2.55 mmol) was dissolved in methanol (30 mL), p-toluenesulfonic acid hydrate (194 mg, 1.02 mmol) was added, and the reaction mixture was heated to 70°C and reacted under a nitrogen atmosphere for 2 hours. The mixture was cooled and concentrated under reduced pressure to obtain the title product, crude product 1M (900 mg), which was used directly in the next reaction. MS (ESI) m / z = 387.7 [M+H] + .

[0090] Step 12: 5-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydrocyclopentadiene-1-carboxylic acid (1n) 1m (900 mg, 2.33 mmol) was dissolved in tetrahydrofuran (10 mL), methanol (10 mL), and water (10 mL). Lithium hydroxide (536 mg, 23.29 mmol) was added and the mixture was allowed to react at room temperature for 3 hours. The pH was adjusted to 5-6 with 1M hydrochloric acid, water (10 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title product 1n (800 mg, 82% yield). MS (ESI) m / z = 373.6 [M+H] + .

[0091] Step 13: (1S,3aS,5S,6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydrocyclopentadiene-1-carboxylic acid (1) 1n (350 mg, 0.94 mmol) was dissolved in N,N-dimethylacetamide (20 mL), 60% sodium hydride (180 mg, 7.52 mmol) was added in an ice bath, and the mixture was incubated for 30 minutes. 2-Chloro-4-(methoxymethyl)pyrimidine (179 mg, 1.13 mmol) was added and the mixture was incubated at room temperature for 30 minutes. The mixture was diluted with water (10 mL), adjusted to pH 4-5 with 1 M hydrochloric acid, and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by reverse-phase flash column chromatography (acetonitrile / water) and then lyophilized to give compound 1 (200 mg, 43% yield). MS (ESI) m / z = 495.5 [M+H] + Compound 1 was subjected to SFC chiral preparative separation (separation conditions: SFC chiral preparative column DAICEL CHIRALPAK AS (250 mm × 30 mm, 10 μm), mobile phase: A was CO2, B was ethanol (0.1% aqueous ammonia)), and the corresponding components were collected and concentrated under reduced pressure to give compounds 1-P1 and 1-P2.

[0092] Compound 1-P1 has a relatively short retention time: MS m / z (ESI): 495.2 [M+H] + Chiral SFC analysis: retention time 2.717 min, chiral purity 100% (column: Chiralpak AS-3, 0.46 cm ID x 100 mm, 3 μm, mobile phase: A is CO2, B is ethanol (0.05% diethylamine)). 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 5.0 Hz, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.13 (d, J = 6.6 Hz, 2H), 6.16 - 6.01 (m, 2H), 4.86 (s, 1H), 4.36 (s, 2H), 4.18 (s, 3H), 3.45 (s, 3H), 3.15 - 2.98 (m, 1H), 2.91 - 2.77 (m, 2H), 2.34 (s, 3H), 2.30 - 2.21 (m, 1H), 2.09 - 2.00 (m, 1H), 1.87 - 1.77 (m, 2H), 1.75 - 1.64 (m, 1H), 1.57 - 1.40 (m, 3H). Compound 1-P2 has a relatively long retention time: MS m / z (ESI): 495.2 [M+H] + Chiral SFC analysis: retention time 3.031 min, chiral purity 97.4% (column: Chiralpak AS-3, 0.46 cm ID x 100 mm, 3 μm, mobile phase: A is CO2, B is ethanol (0.05% diethylamine)). 1 H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 5.0 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.16 - 7.10 (m, 2H), 6.17 - 6.01 (m, 2H), 4.87 (s, 1H), 4.36 (s, 2H), 4.18 (s, 3H), 3.45 (s, 3H), 3.14 - 3.00 (m, 1H), 2.91 - 2.78 (m, 2H), 2.35 (s, 3H), 2.31 - 2.21 (m, 1H), 2.11 - 2.02 (m, 1H), 1.89 - 1.78 (m, 2H), 1.75 - 1.63 (m, 1H), 1.58 - 1.39 (m, 3H). The compound 1-P1 product was detected as amorphous by powder X-ray diffraction, and the XRPD spectrum is shown in FIG.

[0093] Example 2: Testing the antagonist properties of compounds In the present disclosure, the antagonist properties of the compounds were measured by FLIPR (Fluorescence Imaging Plate Reader) method, and the compounds are inhibitors of intracellular calcium elevation induced by hLPAR1 (human lysophosphatidic acid receptor 1) activation expressed in CHO-K1 cells (Chinese hamster ovary cells K1, HDB).

[0094] 1. Experimental reagents and equipment consumables

[0095] [Table 1]

[0096] 2. Preparation of reagents 2.1. Reaction buffer: HBSS + 20 mM HEPES + 0.1% fatty acid-free BSA + 0.001% F-127 2.2. 50x Red dye: (red dye for blocking background signals in cells) was prepared by weighing 4 g of tartrazine and 10.2 g of acid red and dissolving them in 100 mL of H2O.

[0097] 2.3. Fluo-8 staining mixture: 4 mL of reaction buffer, 32 μL of fluo-8, 320 μL of 50× Red dye, and 40 μL of probenecid.

[0098] 3. Preparation of Compounds 3.1. LPA: Dissolved in DPBS (containing 0.1% fatty acid-free BSA) to prepare a mother solution with a concentration of 0.8 μM, which was then dispensed and stored at −20°C.

[0099] 3.2 Preparation of compounds for measurement: Compounds for measurement were dissolved in DMSO to prepare a 10 mM stock solution and stored at -20°C. During the experiment, the compounds were first gradient diluted with DMSO (initial concentration 50 μM, 3-fold dilution, 10 points) to prepare a 200x concentrated compound solution. Then, the compound was diluted with reaction buffer to a 5x concentrated compound solution and transferred to a 384-well plate (product number #6008590) using a Bravo.

[0100] 4. Experimental Procedure 4.1. CHO-K1 / LPA1R cells were cultured in cell culture medium (F-12 + 10% FBS + 400 μg / mL hygromycin B).

[0101] 4.2. When the cell fusion rate reached 80%, the cells were digested with 0.25% pancreatin.

[0102] 4.3 When the cells became round, the digestion was stopped with medium F-12 (10% FBS) and the cells were counted. After that, the density was increased to 6.7 × 10 in F-12 (10% FBS). 5 cells / mL of cell suspension.

[0103] 4.4 Cells were added to a 384-well black cell culture plate using a Multidrop automatic dispenser, with 30 μL of cell suspension per well, and cultured for 20–24 hours in a 37°C, 5% CO2 incubator. The medium was then replaced with serum-free F-12 medium and the cells were starved for 24 hours.

[0104] 4.5. LPA dose measurement experiment. A 6x LPA gradient dilution solution was prepared using reaction buffer (initial concentration 60 μM, 3-fold dilution, 10 points). The medium in a 384-well black cell culture plate was discarded and replaced with reaction buffer. 10 μL of 5% DMSO reaction buffer was added, followed by 10 μL of Fluo-8 staining mixture. The plate was then incubated in a dark place at 37°C in a 5% CO2 incubator for 0.5 hours.

[0105] 4.6. Set the corresponding program on the FLIPR to add the 6x LPA gradient solution and take readings. Data was collected for 2 minutes.

[0106] 4.7, the response curve is obtained from the LPA value, and EC 80 The LPA concentration was calculated. A 6x LPA solution was prepared and placed in a 384-well plate (product number #6008590), and HPE and ZPE were added to the corresponding wells. HPE (100% effective) was 60 μM LPA, and ZPE (0% effective) was reaction buffer.

[0107] 4.8. Compound Testing. The medium in the 384-well black cell culture plate was discarded and replaced with reaction buffer. 10 μL of 5× compound solution was transferred using a Bravo, followed immediately by the addition of 10 μL of Fluo-8 staining mixture. The plate was then incubated in the dark at 37°C in a 5% CO2 incubator for 0.5 hours.

[0108] 4.9. Set the corresponding program on the FLIPR to add 6x LPA solution and take a reading. Data was collected for 2 minutes.

[0109] 4.10. Finally, the output fluorescence counts were analyzed to calculate the IC50 of the compound.

[0110] 5. Experimental results

[0111] [Table 2]

[0112] Conclusion: The results show that the above compounds have excellent LPAR1 inhibitory activity and can be used as LPAR1 antagonists to treat LPAR1 target-related diseases.

[0113] Example 3: Preparation of Crystalline Form A of the Compound of Formula I Approximately 300 mg of the compound of formula I was weighed and dissolved in 7 mL of propylene glycol methyl ether, and 21 mL of n-heptane was added. The reaction solution was stirred for 1 day, and the solid was suction filtered and dried to obtain type A crystals of the compound of formula I.

[0114] The XRPD spectrum was detected by powder X-ray diffraction and is shown in Figure 2, and the positions of its characteristic peaks are listed in Table 2. The TGA spectrum showed a weight loss of 1.55% by 100°C. The DSC spectrum showed an endothermic peak at 183.35°C.

[0115] The DVS detection results showed that the sample had a moisture-induced weight gain of approximately 0.17% under normal storage conditions (i.e., 25°C, 60% RH), a moisture-induced weight gain of approximately 0.20% under accelerated storage conditions (i.e., 70% RH), and a moisture-induced weight gain of approximately 0.37% under extreme storage conditions (i.e., 90% RH). Re-measurement of the crystal form after DVS detection showed no conversion of the crystal form.

[0116] [Table 3]

[0117] Example 4: Preparation of crystalline form A of compound of formula I Approximately 5 mg of the compound of formula (I) was weighed out, dissolved in solvent A to clarify, solvent B was added, and then solvent C was further added, followed by stirring for 3 days. The precipitated solid was centrifuged and dried to obtain type A crystals of the compound of formula (I).

[0118] [Table 4]

[0119] Example 5: Preparation of Crystalline Form B of Compound of Formula I Approximately 5 mg of the compound represented by formula (I) was weighed out and dissolved in 0.1 mL of tetrahydrofuran (solvent A) to clarify the solution. 0.2 mL of methyl tert-butyl ether (solvent B) was added, and 0.2 mL of n-heptane (solvent C) was further added. The mixture was stirred for 1 day, and the precipitated solid was centrifuged and dried to obtain type B crystals of the compound of formula I.

[0120] [Table 5]

[0121] The XRPD spectrum was detected by powder X-ray diffraction and is shown in Figure 3, with the characteristic peak positions listed in Table 5. The TGA spectrum showed a weight loss of 1.66% up to 100°C. The DSC spectrum showed endothermic peaks at 163.19°C and 182.43°C, and an exothermic peak at 164.04°C.

[0122] The DVS detection results showed that the sample had a moisture weight gain of approximately 0.25% under normal storage conditions (i.e., 25°C, 60% RH), a moisture weight gain of approximately 0.31% under accelerated storage conditions (i.e., 70% RH), and a moisture weight gain of approximately 0.64% under extreme storage conditions (i.e., 90% RH). The crystal form was re-measured after DVS detection, and no conversion of the crystal form was observed.

[0123] [Table 6]

[0124] Example 6: Preparation of Crystalline Form B of the Compound of Formula I Approximately 5 mg of the compound represented by formula (I) was weighed and dissolved in 0.25 mL of water (solvent A). The reaction solution was stirred for 1 day, and the solid was centrifuged and dried to obtain type B crystals of the compound of formula I.

[0125] [Table 7]

[0126] Example 7: Preparation of crystalline form C of compound of formula I Approximately 10 mg of the compound represented by formula (I) was weighed out, and 0.2 mL of 50% methanol / acetonitrile or 0.2 mL of tetrahydrofuran was added, followed by the addition of an ethanolamine ethanol solution (2 mol / L, 10 μL). 0.4 mL of methyl tert-butyl ether was added to the reaction solution, and the mixture was stirred for 2 days. 0.8 mL of methyl tert-butyl ether was further added, and the mixture was heated and cooled from 50°C to 5°C (heating and cooling rate: 45°C / h), stirred for 1 day, and then stirred at 25°C for 2 days. The mixture was centrifuged and dried to obtain type C crystals of the compound of formula I.

[0127] The XRPD spectrum was detected by powder X-ray diffraction and is shown in Figure 4, and the positions of its characteristic peaks are listed in Table 7. The TGA spectrum showed a weight loss of 4.34% up to 110°C and a weight loss of 8.22% from 110°C to 195°C. The DSC spectrum showed endothermic peaks at 106.12°C and 177.29°C.

[0128] [Table 8]

[0129] Example 8: Preparation of Form I Crystals of the Sodium Salt of the Compound of Formula I Approximately 10 mg of the compound of formula (I) was weighed, and 0.2 mL of a 50% ethanol / ethyl acetate solution (solvent A) was added, followed by the addition of a sodium hydroxide solution (2 mol / L, 10.5 μL) and 0.8 mL of methyl tert-butyl ether. The reaction solution was stirred for 2 days, centrifuged, and dried to obtain type I crystals of the sodium salt of the compound of formula I.

[0130] [Table 9]

[0131] The XRPD spectrum was detected by powder X-ray diffraction and is shown in Figure 5, with the characteristic peak positions listed in Table 9. The sodium ion content was determined to be 4.85% by ion chromatography. The TGA spectrum showed a weight loss of 7.36% between 30 and 110°C. The DSC spectrum showed endothermic peaks at 90.11, 122.09, and 210.70°C, and an exothermic peak at 145.47°C.

[0132] DVS detection showed that the sample exhibited a moisture weight gain of approximately 6.31% under normal storage conditions (i.e., 25°C, 60% RH), a moisture weight gain of approximately 7.08% under accelerated storage conditions (i.e., 70% RH), and a moisture weight gain of approximately 42.38% under extreme storage conditions (i.e., 90% RH).

[0133] [Table 10]

[0134] Example 9: Preparation of Form I Crystals of the Sodium Salt of the Compound of Formula I Approximately 10 mg of the compound of formula (I) was weighed, and 0.2 mL of 2-butanone or 0.2 mL of acetonitrile was added thereto. Then, an ethanolic solution of sodium hydroxide (1 mol / L, 21 μL) was added thereto. The reaction solution was stirred for 1 day, centrifuged, and dried to obtain type I crystals of the sodium salt of the compound of formula I.

[0135] Example 10: Preparation of Crystalline Form II of the Sodium Salt of the Compound of Formula I Approximately 10 mg of the compound represented by formula (I) was weighed, and 0.2 mL of isopropanol or 0.2 mL of 1,4-dioxane was added thereto. Then, an ethanolic solution of sodium hydroxide (1 mol / L, 21 μL) was added thereto. The reaction solution was stirred for 1 day, centrifuged, and dried to obtain Form II crystals of the sodium salt of the compound of formula I.

[0136] The XRPD spectrum was detected by powder X-ray diffraction as shown in Figure 6, and the positions of its characteristic peaks are listed in Table 10. The sodium ion content was determined to be 4.75% by ion chromatography. The TGA spectrum showed a weight loss of 2.18% between 30 and 120°C. The DSC spectrum showed endothermic peaks at 179.08 and 223.40°C.

[0137] DVS detection showed that the sample exhibited a moisture weight gain of approximately 6.35% under normal storage conditions (i.e., 25°C, 60% RH), a moisture weight gain of approximately 22.41% under accelerated storage conditions (i.e., 70% RH), and a moisture weight gain of approximately 56.98% under extreme storage conditions (i.e., 90% RH).

[0138] [Table 11]

[0139] Example 11: Preparation of Form II Crystals of the Sodium Salt of the Compound of Formula I Approximately 5 mg of type I crystals of the sodium salt of the compound of formula (I) were weighed, and 0.2 mL of isopropanol or 0.2 mL of isopropyl acetate was added. The reaction solution was stirred for 2 days, centrifuged, and dried to obtain type II crystals of the sodium salt of the compound of formula I.

[0140] Example 12: Preparation of Crystalline Form II of the Sodium Salt of the Compound of Formula I Approximately 5 mg of type I crystals of the sodium salt of the compound of formula (I) were weighed and dissolved in 0.2 mL of ethanol or 0.2 mL of n-propanol, and 1 mL of n-heptane was added. The reaction solution was stirred for 5 days, centrifuged, and dried to obtain type II crystals of the sodium salt of the compound of formula I.

[0141] Example 13: Preparation of Form III Crystals of the Sodium Salt of the Compound of Formula I Approximately 5 mg of the type I crystals of the sodium salt of the compound of formula (I) were weighed, and 0.2 mL of 1,4-dioxane was added. The reaction solution was stirred for 2 days, centrifuged, and dried to obtain type III crystals of the sodium salt of the compound of formula (I).

[0142] It was detected by powder X-ray diffraction, and the XRPD spectrum is shown in FIG. 7, and the positions of its characteristic peaks are shown in Table 11.

[0143] [Table 12]

[0144] Example 14: Preparation of Form IV Crystals of the Sodium Salt of the Compound of Formula I Approximately 2 mg of the type I crystals of the sodium salt of the compound of formula (I) were weighed and heated to 180°C to obtain type IV crystals of the sodium salt of the compound of formula I. The crystals were detected by powder X-ray diffraction, and the XRPD spectrum is shown in Figure 8, and the positions of their characteristic peaks are shown in Table 12.

[0145] [Table 13]

[0146] Example 15: Amorphous Preparation of the Sodium Salt of the Compound of Formula I Approximately 2 mg of the type I crystals of the sodium salt of the compound of formula (I) was weighed and heated to 130°C to obtain the title product. The product was found to be an amorphous sodium salt by powder X-ray diffraction, and the XRPD spectrum was as shown in Figure 9.

[0147] Example 16: Preparation of Form I Crystals of the Ethanolamine Salt of the Compound of Formula I Approximately 30 mg of the compound represented by formula (I) was weighed, and 0.6 mL of tetrahydrofuran was added, followed by the addition of an ethanolamine ethanol solution (2 mol / L, 31.5 μL), and then 3.6 mL of methyl tert-butyl ether. The reaction solution was subjected to a temperature increase / decrease cycle from 50°C to 5°C (temperature increase / decrease rate: 45°C / h), stirred for 3 days, centrifuged, and dried to obtain type I crystals of the ethanolamine salt of the compound of formula I.

[0148] The XRPD spectrum was detected by powder X-ray diffraction and is shown in Figure 10, and the positions of its characteristic peaks are listed in Table 13. The TGA spectrum showed a weight loss of 13.57% between 30 and 190 °C. The DSC spectrum showed endothermic peaks at 59.63 and 148.77 °C.

[0149] [Table 14]

[0150] Example 17, Stability Study of Influencing Factors: Free-form crystals of the compound of formula I, type A and type B, were opened and spread flat, and the stability of the samples was examined under light irradiation (4500 Lux), high temperature (40°C, 60°C), and high humidity (RH 75%, RH 93%) conditions with a sampling observation period of one month.

[0151] [Table 15]

[0152] Conclusion: The free-form A crystals and the free-form B crystals of the compound of formula I were left for one month and showed good physical and chemical stability.

[0153] Form I crystals of the sodium salt of the compound of formula I and Form II crystals of the sodium salt were opened and spread out flat, and the stability of the samples was examined under conditions of light irradiation (4500 Lux), high temperature (40°C, 60°C), and high humidity (RH 75%) with a sampling observation period of one month.

[0154] [Table 16]

[0155] Conclusion: After leaving the sodium salt type I crystals for one month, the physical and chemical stability was good, and the sodium salt type II crystals had good physical and chemical stability except at high humidity.

[0156] Example 18, Long-Term / Accelerated Stability: The stability of free-form A crystals and free-form B crystals of the compound of formula I was examined under conditions of 25°C / 60% RH and 40°C / 75% RH, respectively.

[0157] [Table 17]

[0158] Conclusion: Free-form A crystals and free-form B crystals were left under long-term accelerated conditions for 6 months and showed good physical and chemical stability.

[0159] The stability of the sodium salt type I crystals and sodium salt type II crystals of the compound of formula I was examined under conditions of 25°C / 60% RH and 40°C / 75% RH, respectively.

[0160] [Table 18]

[0161] Conclusion: Form I and II crystals of the sodium salt were left under long-term accelerated conditions for 3 months and showed good physical and chemical stability.

Claims

1. A crystal of Form A of the compound of formula I, 【Chemistry 1】 the powder X-ray diffraction spectrum, expressed in terms of diffraction angle 2θ angles, has characteristic peaks at 7.534, 10.223, 14.364, 17.269, 18.495 and 19.553, preferably has characteristic peaks at 7.534, 10.223, 14.364, 15.816, 16.678, 17.269, 18.495 and 19.553, more preferably has characteristic peaks at 7.534, 10.223, 14.364, 15.816, 16.678, 17.269, 18.495, 19.553, 21.043, 21.342, 23.647 and 25.965, and most preferably has characteristic peaks as shown in FIG. 2 ; A type crystal.

2. A B-type crystal of the compound of formula I, 【Chemistry 2】 the powder X-ray diffraction spectrum, expressed in terms of diffraction angle 2θ angles, has characteristic peaks at 7.437, 10.381, 14.955 and 17.513, preferably has characteristic peaks at 7.437, 10.381, 14.717, 14.955, 17.513, 21.395, 22.607 and 23.221, more preferably has characteristic peaks at 7.437, 10.381, 14.717, 14.955, 17.513, 18.466, 21.395, 21.692, 22.607, 23.221 and 25.972, and most preferably has a powder X-ray diffraction spectrum, expressed in terms of diffraction angle 2θ angles, as shown in FIG. B type crystal.

3. Pharmaceutically acceptable salts of compounds of formula I, 【Transformation 3】 The pharmaceutically acceptable salt is selected from the group consisting of sodium salts and ethanolamine salts. Medicinal salt.

4. The chemical composition of the compound of formula I and the base ion is 1:1 or 1:2, preferably 1:

1.

4. The medicinal salt of claim 3.

5. 1. A process for preparing a pharmaceutically acceptable salt of a compound of formula I, comprising: 【Chemistry 4】 reacting a compound of formula I with a base selected from sodium hydroxide or ethanolamine, method.

6. Form I crystals of the sodium salt of the compound of formula I, 【Transformation 5】 The powder X-ray diffraction spectrum, expressed in terms of diffraction angles (2θ), has characteristic peaks at 6.446, 8.350, 8.847, 9.335, 12.845, 16.901 and 17.874, preferably at 6.446, 8.350, 8.847, 9.335, 9.807, 12.845, 13.328, 13.739, 15.728, 16.901 and 17.874, more preferably at 4.741, 6.446, 8.350, 8.847, 9.335, 9.807, 12.845, 13.328, 13.739, 15.728, 16.901 and 17.

874. and more preferably has characteristic peaks at 4.741, 6.446, 8.350, 8.847, 9.335, 9.807, 12.845, 13.328, 13.739, 15.728, 16.901, 17.874, 19.059, 19.805, 21.490, 23.607, 25.460, and 25.773, and most preferably has characteristic peaks at diffraction angles 2θ as shown in FIG. 5 . Type I crystal.

7. Crystalline Form II of the sodium salt of the compound of formula I, 【Transformation 6】 The powder X-ray diffraction spectrum expressed as a diffraction angle 2θ angle has characteristic peaks at 6.771, 13.464, 13.970, 14.419, 15.593, 18.044 and 19.952, preferably at 6.771, 11.446, 13.464, 13.970, 14.419, 15.593, 18.044, 19.952 and 24.

260. and most preferably has characteristic peaks at 6.771, 8.505, 11.446, 13.464, 13.970, 14.419, 15.593, 18.044, 19.952, 20.313, 22.868, 24.260 and 32.304, and its powder X-ray diffraction spectrum, expressed as diffraction angles 2θ angles, is as shown in FIG. 6 . Type II crystal.

8. A crystalline form of a compound of formula I or a crystalline form of a pharmaceutically acceptable salt of a compound of formula I, 【Transformation 7】 The error range of the 2θ angle is ±0.

2. Crystalline form.

9. A pharmaceutical composition comprising the following ingredients: i) a crystalline form of the compound of formula I as defined in any one of claims 1 or 2, or a pharmaceutically acceptable salt of the compound of formula I as defined in any one of claims 3 or 4, or a crystalline form as defined in claim 6 or 7; ii) one or more pharmaceutically acceptable excipients; Pharmaceutical compositions.

10. 1. A method for preparing a pharmaceutical composition, comprising:

10. A method for producing a pharmaceutical composition comprising the steps of: mixing a crystalline form of the compound of formula I according to claim 1 or 2, or a pharmaceutically acceptable salt of the compound of formula I according to claim 3 or 4, or a crystalline form according to claim 6 or 7, with a pharmaceutically acceptable excipient; method.

11. A crystalline form of the compound of formula I according to any one of claims 1 or 2, or a pharmaceutically acceptable salt of the compound of formula I according to any one of claims 3 or 4, or a crystalline form according to claim 6 or 7, or a composition according to claim 9, in the preparation of an LPA1 inhibitor. use.

12. a crystalline form of the compound of formula I according to claim 1 or 2, or a pharmaceutical salt of the compound of formula I according to claim 3 or 4, or a crystalline form of claim 6 or 7, or a composition according to claim 9, in the preparation of a medicament for the treatment and / or prevention of patients with organ fibrotic and degenerative diseases, respiratory diseases, kidney diseases, liver diseases, inflammatory diseases, nervous system diseases, cardiovascular and cerebrovascular diseases, gastrointestinal diseases, pain, urinary system diseases, eye diseases, metabolic diseases, cancer, transplant organ rejection, use.

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