A pharmaceutical salt of a triazole compound, a crystal form thereof, and a preparation method thereof

Abstract

The present disclosure relates to a pharmaceutically acceptable salt of a triazole compound, a crystal form and a preparation method thereof. Specifically, the present disclosure provides a pharmaceutically acceptable salt of a compound of formula (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)octahydrocyclopenta[c]pyrrole-1-carboxylic acid, a crystal form and a preparation method thereof, and the corresponding salt has good stability and can be better used for clinical treatment.

Description

[0001] This application claims priority to Chinese patent application 2023100662824, filed on January 19, 2023. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This disclosure pertains to the pharmaceutical field and relates to a pharmaceutically acceptable salt, crystal form, and preparation method of a triazole compound. Background Technology

[0003] Phospholipids are mesangial-derived bioactive lipid mediators, among which lysophosphatidic acid (LPA) is the most important in medicine. Lysophospholipids influence fundamental cellular functions including proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis. These functions affect 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 rather a group of endogenous structural variants of fatty acids with varying lengths and saturation levels. The backbone of LPA is derived from glycerol-based phospholipids, such as phosphatidylcholine (PC) or phosphatidic acid (PA). Lysophosphatidic acid (LPA) is a lysophosphatidylcholine that functions via a specific set of G-protein-coupled receptors (GPCRs) in both autocrine and paracrine modes. LPA binds to its homologous GPCRs (LPA1, LPA2, LPA3, LPA4, LPA5, LPA6), activating intracellular signaling pathways to produce various biological responses. Antagonists of LPA receptors have been found to treat diseases, disorders, or conditions in which LPA is involved.

[0005] PCT / CN2022 / 106706 discloses a novel class of triazole derivatives, with 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)octahydrocyclopentadien-1-carboxylic acid as shown in Formula I, demonstrating its application as an LPA1 inhibitor. This disclosure incorporates the entire contents of PCT / CN2022 / 106706.

[0006]

[0007] The crystal structure of a pharmaceutically active ingredient often affects its chemical and physical stability. Different crystallization and storage conditions can lead to changes in the crystal structure of the compound, sometimes even resulting in other crystal forms. Generally, amorphous drug products lack regular crystal structures and often have other defects, such as poor product stability, difficulty in filtration, easy agglomeration, and poor flowability. Therefore, studying the pharmaceutically usable salt and crystal form of the chemically named (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)octahydrocyclopentadien-1-carboxylic acid (Formula I) is of great significance for developing drugs suitable for industrial production and with good biological activity. Summary of the Invention

[0008] This disclosure provides, in one aspect, the A crystal form of 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)octahydrocyclopentadien-1-carboxylic acid.

[0009]

[0010] In some embodiments, the A crystal form, in X-ray powder diffraction patterns expressed as diffraction angle 2θ, has characteristic peaks at 7.534, 10.223, 14.364, 17.269, 18.495, and 19.553.

[0011] In other embodiments, the A crystal form, in X-ray powder diffraction patterns expressed as diffraction angle 2θ, has characteristic peaks at 7.534, 10.223, 14.364, 15.816, 16.678, 17.269, 18.495, and 19.553.

[0012] In other embodiments, the A crystal form, in X-ray powder diffraction patterns expressed as diffraction angles 2θ, 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] The optimal X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is as follows: Figure 2 As shown.

[0014] On the other hand, this disclosure provides a method for preparing the A crystal form of a compound of formula I, comprising: dissolving the compound of formula I in propylene glycol methyl ether, then adding n-heptane, and stirring to precipitate crystals.

[0015] In some other embodiments, the method for preparing the A crystal form of the compound of formula I includes: dissolving the compound of formula I in solvent (1), adding solvent (2), adding solvent (3), and stirring to crystallize; wherein solvent (1) is selected from 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 other embodiments, the method for preparing the A crystal form of the compound of formula I includes: dissolving the compound of formula I in acetone and stirring to crystallize.

[0017] On the other hand, this disclosure provides the B crystal form of 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)octahydrocyclopentadien-1-carboxylic acid.

[0018]

[0019] In some embodiments, the B crystal form, in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ, has characteristic peaks at 7.437, 10.381, 14.955, and 17.513.

[0020] In other embodiments, the B crystal form, in X-ray powder diffraction patterns expressed as diffraction angle 2θ, has characteristic peaks at 7.437, 10.381, 14.717, 14.955, 17.513, 21.395, 22.607, and 23.221.

[0021] In other embodiments, the B crystal form, in X-ray powder diffraction patterns expressed as diffraction angles 2θ, 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.

[0022] In other embodiments, the X-ray powder diffraction pattern of the B crystal form, expressed in terms of a diffraction angle 2θ, is as follows: Figure 3 As shown.

[0023] On the other hand, this disclosure provides a method for preparing the B crystal form of a compound of formula I, comprising: dissolving the compound of formula I in solvent (A), adding solvent (B), adding solvent (C), and stirring to crystallize; wherein solvent (A) is selected from at least one solvent selected from tetrahydrofuran, dichloromethane, 10% water / isopropanol, and chloroform; solvent (B) is selected from methyl tert-butyl ether; and solvent (C) is selected from n-heptane.

[0024] In some other embodiments, the method for preparing the B crystal form of the compound of formula I includes: 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 induce crystallization.

[0025] On the other hand, this disclosure provides the C-crystal form of 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)octahydrocyclopentadien-1-carboxylic acid.

[0026]

[0027] In some embodiments, the C-type crystal form, in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ, has characteristic peaks at 5.702, 10.643, 17.229, 18.213, 18.666, and 20.900.

[0028] In other embodiments, the C-type crystal form, in X-ray powder diffraction patterns expressed as diffraction angles 2θ, 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.

[0029] In other embodiments, the C-type crystal form, in X-ray powder diffraction patterns expressed as diffraction angles 2θ, 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.

[0030] In other embodiments, the X-ray powder diffraction pattern of the C-type, expressed in terms of a diffraction angle 2θ, is as follows: Figure 4 As shown.

[0031] On the other hand, this disclosure also 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)octahydrocyclopentadien-1-carboxylic acid, said pharmaceutically acceptable salt being selected from sodium salts or ethanolamine salts.

[0032]

[0033] In an optional embodiment, the chemical ratio of compound 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)octahydrocyclopentadien-1-carboxylic acid to sodium ions is 1:1.

[0034] This disclosure also provides a method for preparing a pharmaceutically acceptable salt of compound 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)octahydrocyclopentadien-1-carboxylic acid, comprising the step of reacting the compound of formula I with a base, wherein the base is selected from sodium hydroxide or ethanolamine.

[0035] The solvents used in the salt formation of this disclosure are selected from, but are 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, or one or more solvents.

[0036] Furthermore, in an optional embodiment, the method for preparing the aforementioned pharmaceutically usable salt also includes steps such as crystallization, filtration, washing, or drying.

[0037] On the other hand, this disclosure also provides the X-ray powder diffraction pattern of sodium salt I 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)octahydrocyclopentadien-1-carboxylic acid, expressed as a diffraction angle 2θ, with characteristic peaks at 6.446, 8.350, 8.847, 9.335, 12.845, 16.901 and 17.874.

[0038] In other embodiments, the sodium salt I crystal form, as expressed in X-ray powder diffraction patterns at diffraction angles of 2θ, 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.

[0039] In other embodiments, the sodium salt I crystal form, as expressed in X-ray powder diffraction patterns at diffraction angles of 2θ, 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.

[0040] In other embodiments, the sodium salt I crystal form, as expressed in X-ray powder diffraction patterns at diffraction angles of 2θ, exhibits 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.

[0041] In other embodiments, the sodium salt I crystal form, as shown in the X-ray powder diffraction pattern expressed in diffraction angle 2θ, is as follows: Figure 5 As shown.

[0042] On the other hand, this disclosure provides a method for preparing the sodium salt I crystal form of a 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, then adding methyl tert-butyl ether, and stirring to precipitate crystals.

[0043] On the other hand, this disclosure provides a method for preparing the sodium salt I crystal form of a compound of formula I, comprising: dissolving the compound of formula I in 2-butanone or acetonitrile, adding sodium hydroxide ethanol solution, and stirring to precipitate crystals.

[0044] On the other hand, this disclosure also provides the X-ray powder diffraction pattern of sodium salt II 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)octahydrocyclopentadien-1-carboxylic acid, expressed as a diffraction angle 2θ, with characteristic peaks at 6.771, 13.464, 14.419 and 15.593.

[0045] In other embodiments, the sodium salt II crystal form, as expressed in X-ray powder diffraction patterns at diffraction angles of 2θ, has characteristic peaks at 6.771, 13.464, 13.970, 14.419, 15.593, 18.044, and 19.952.

[0046] In other embodiments, the sodium salt II crystal form, as shown in the X-ray powder diffraction pattern expressed in diffraction angle 2θ, is as follows: Figure 6 As shown.

[0047] On the other hand, this disclosure provides a method for preparing the sodium salt II crystal form of a compound of formula I, comprising: dissolving the compound of formula I in isopropanol or 1,4-dioxane, adding a sodium hydroxide ethanol solution, and stirring to induce crystallization.

[0048] On the other hand, this disclosure provides a method for preparing the sodium salt II crystal form of a compound of formula I, comprising: dissolving the sodium salt I crystal form of the compound of formula I in isopropanol or isopropyl acetate, and stirring to precipitate crystals.

[0049] On the other hand, this disclosure provides a method for preparing the sodium salt II crystal form of a compound of formula I, comprising: dissolving the sodium salt I crystal form of the compound of formula I in ethanol or n-propanol, then adding n-heptane and stirring to precipitate crystals.

[0050] On the other hand, this disclosure also provides the X-ray powder diffraction pattern of sodium salt 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)octahydrocyclopentadien-1-carboxylic acid III crystal form, expressed as diffraction angle 2θ, with characteristic peaks at 6.605, 18.597, 20.094, and 26.882.

[0051] In other embodiments, the sodium salt III crystal form, as expressed in X-ray powder diffraction patterns at diffraction angles of 2θ, has characteristic peaks at 5.639, 6.605, 10.311, 13.323, 18.597, 20.094, and 26.882.

[0052] In other embodiments, the sodium salt III crystal form, as shown in the X-ray powder diffraction pattern expressed in diffraction angle 2θ, is as follows: Figure 7 As shown.

[0053] On the other hand, this disclosure provides a method for preparing the sodium salt III crystal form of a compound of formula I, comprising: dissolving the sodium salt I crystal form of the compound of formula I in 1,4-dioxane and stirring to crystallize.

[0054] On the other hand, this disclosure also provides the X-ray powder diffraction pattern of sodium salt 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)octahydrocyclopentadien-1-carboxylic acid IV crystal form, expressed as diffraction angle 2θ, with characteristic peaks at 7.078, 14.227, 15.004, 18.812, and 20.081.

[0055] In other embodiments, the sodium salt IV crystal form, as expressed in X-ray powder diffraction patterns at diffraction angles of 2θ, has characteristic peaks at 5.078, 7.078, 10.670, 13.231, 14.227, 15.004, 18.812, 20.081, and 24.018.

[0056] In other embodiments, the sodium salt IV crystal form, as shown in the X-ray powder diffraction pattern expressed in diffraction angle 2θ, is as follows: Figure 8 As shown.

[0057] On the other hand, this disclosure provides a method for preparing the sodium salt IV crystal form of a compound of formula I, comprising: heating the sodium salt I crystal form of the compound of formula I to 180°C or above.

[0058] On the other hand, this disclosure also provides the X-ray powder diffraction pattern of compound 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)octahydrocyclopentadien-1-carboxylic acid ethanolamine salt I crystal form, expressed as diffraction angle 2θ, with characteristic peaks at 5.343, 9.612, 10.751, 16.737, and 19.178.

[0059] In other embodiments, the X-ray powder diffraction pattern of ethanolamine salt I, expressed as a diffraction angle 2θ, 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.

[0060] In other embodiments, the X-ray powder diffraction pattern of ethanolamine salt I crystal form, expressed as a diffraction angle 2θ, is as follows: Figure 10 As shown.

[0061] On the other hand, this disclosure provides a method for preparing the ethanolamine salt I crystal form of a compound of formula I, comprising: dissolving the compound of formula I in tetrahydrofuran, adding an ethanolamine ethanol solution, and adding methyl tert-butyl ether and stirring to induce crystallization.

[0062] Furthermore, the disclosed 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)octahydrocyclopentadien-1-carboxylic acid, wherein the error range of the 2θ angle is ±0.2.

[0063] In some embodiments, the method for preparing the crystal form described in this disclosure further includes crystallization, filtration, washing, or drying steps.

[0064] On the other hand, this disclosure also provides a pharmaceutical composition comprising a crystal form A, crystal form B, crystal form C, amorphous form, sodium salt, sodium salt I crystal form II crystal form III crystal form IV crystal form IV crystal form, sodium salt amorphous form, ethanolamine salt, ethanolamine salt I crystal form, and optionally a pharmaceutically acceptable excipient.

[0065] This disclosure also provides a method for preparing a pharmaceutical composition, comprising the step of mixing the aforementioned 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)octahydrocyclopentadien-1-carboxylic acid in crystal form A, crystal form B, crystal form C, amorphous form, sodium salt, sodium salt I crystal form, sodium salt II crystal form, sodium salt III crystal form, sodium salt IV crystal form, sodium salt amorphous form, ethanolamine salt, or ethanolamine salt I crystal form with a pharmaceutically acceptable excipient.

[0066] This disclosure also provides the use of the aforementioned 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)octahydrocyclopentadien-1-carboxylic acid in crystal form A, crystal form B, crystal form C, amorphous form, sodium salt, sodium salt I crystal form, sodium salt II crystal form, sodium salt III crystal form, sodium salt IV crystal form, sodium salt amorphous form, ethanolamine salt, ethanolamine salt I crystal form, or the aforementioned pharmaceutical composition as an LPA1 inhibitor.

[0067] This disclosure also provides the use of the aforementioned 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)octahydrocyclopentadien-1-carboxylic acid in crystal forms A, B, C, amorphous, sodium salt, sodium salt I, sodium salt II, sodium salt III, sodium salt IV, sodium salt amorphous, ethanolamine salt, ethanolamine salt I, or the aforementioned pharmaceutical composition for the prevention and / or treatment of organ fibrosis, respiratory diseases, kidney diseases, liver diseases, inflammatory diseases, nervous system diseases, cardiovascular diseases, gastrointestinal diseases, pain, urinary system diseases, eye diseases, metabolic diseases, cancer, and transplant rejection.

[0068] This disclosure also provides the use of the aforementioned 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)octahydrocyclopentadien-1-carboxylic acid in crystal forms A, B, C, amorphous, sodium salt, sodium salt I, sodium salt II, sodium salt III, sodium salt IV, sodium salt amorphous, ethanolamine salt, ethanolamine salt I, or the aforementioned pharmaceutical composition in the preparation of medicaments for the prevention and / or treatment of organ fibrosis, respiratory diseases, kidney diseases, liver diseases, inflammatory diseases, nervous system diseases, cardiovascular diseases, gastrointestinal diseases, pain, urinary system diseases, eye diseases, metabolic diseases, cancer, and transplant rejection.

[0069] The "2θ or 2θ angle" mentioned in this disclosure refers to the diffraction angle, where θ is the Bragg angle, and the unit is ° or degree; the error range of 2θ for each characteristic peak is ±0.20 (including the case where the number has more than one decimal place after rounding), specifically -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.

[0070] The determination of the stoichiometry of compounds and acid molecules in this disclosure is subject to a certain degree of error. Generally, ±10% is within the reasonable error range. The error may vary to a certain extent depending on the context in which it is used, but this variation shall not exceed ±10%, and may be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%. The values ​​indicated by "about" in this disclosure are within the aforementioned reasonable error range.

[0071] The “crystallization” or “precipitation” described in this disclosure includes, but is not limited to, stirring crystallization, pulping crystallization, cooling crystallization, and volatilization crystallization.

[0072] The “differential scanning calorimetry or DSC” described in this disclosure refers to measuring the temperature difference and heat flow difference between the sample and the reference material during the sample heating or isothermal process, in order to characterize all physical and chemical changes related to thermal effects and obtain phase transition information of the sample.

[0073] The drying temperature described in this disclosure is generally 25℃-100℃, preferably 40℃-70℃, and can be dried under normal pressure or reduced pressure.

[0074] The “pharmaceuticalally acceptable excipients” described in this disclosure include, but are not limited to, any adjuvant, carrier, flow aid, sweetener, diluent, preservative, dye / coloring agent, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, or emulsifier that has been approved by the U.S. Food and Drug Administration for use in humans or livestock. Attached Figure Description

[0075] Figure 1 The image shows the amorphous XRPD spectrum of compound I.

[0076] Figure 2 The image shows the XRPD spectrum of compound A of formula I.

[0077] Figure 3 The image shows the XRPD spectrum of compound B of formula I.

[0078] Figure 4 The image shows the XRPD spectrum of compound C of formula I.

[0079] Figure 5 The image shows the XRPD spectrum of sodium salt I of compound formula I.

[0080] Figure 6 The image shows the XRPD spectrum of sodium salt II of compound I.

[0081] Figure 7 The image shows the XRPD spectrum of sodium salt III of compound I.

[0082] Figure 8 The image shows the XRPD spectrum of sodium salt of compound I in crystal form IV.

[0083] Figure 9 The image shows the amorphous XRPD spectrum of the sodium salt of compound I.

[0084] Figure 10 The image shows the XRPD spectrum of ethanolamine salt I of compound formula I. Detailed Implementation

[0085] This disclosure is further described in detail through the following embodiments and experimental examples. These embodiments and experimental examples are for illustrative purposes only and are not intended to limit the scope of this disclosure.

[0086] Test conditions of the instruments used in the experiment:

[0087] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0088] MS determinations were performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometry system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS). Other instruments used included waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector) and THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q 15 Exactive). HPLC determinations were performed using an Agilent 1260DAD high-performance liquid chromatograph (Sunfire C18 150×4.6mm column) and a Thermo U3000 high-performance liquid chromatograph (Gimini C18 150×4.6mm column). XRPD (X-ray Powder Diffraction) was used for analysis. Measurements were performed using a BRUKER D8 X-ray diffractometer. Specific data acquisition information included: Cu anode (40 kV, 40 mA), and the radiation source was monochromatic Cu-Ka rays. Scanning method: θ / 2θ, scanning range: 3-48°. DSC (Differential Scanning Calorimetry): Measurements were performed using a METTLERTOLEDO DSC 3+ differential scanning calorimeter, with a heating rate of 10℃ / min. Specific temperature ranges were referenced from relevant spectra (mostly 25℃-300℃), and nitrogen purging was performed at a rate of 50 mL / min. TGA (Thermogravimetric Analysis): Detection was performed using a METTLERTOLEDO TGA 2 thermogravimetric analyzer, with a heating rate of 10℃ / min. Specific temperature ranges were referenced from relevant spectra (mostly 30℃-400℃), and nitrogen purging was performed at a rate of 50 mL / min. DVS (Dynamic Moisture Adsorption): Surface Measurement Systems instrument was used. Humidity was measured from 50%, with a range of 0%-95% in 10% increments. The judgment criterion was a mass change of dM / dT ≤ 0.002% for each gradient. TMAX was 360 min, with two cycles.

[0089] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, and Darui Chemicals.

[0090] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0091] Example 1: Preparation of compound I (compound 1-P1, according to the preparation method in Example 3 of application application number PCT / CN2022 / 106706)

[0092]

[0093]

[0094] Step 1: 5-Hydroxyhexahydrocyclopentadien-2(1H)-one (1b)

[0095] The starting material cis-tetrahydrocyclopentadien-2,5(1H,3H)-dione 1a (24 g, 173.7 mmol) was dissolved in ethanol (500 mL), cooled to 0 °C, and sodium borohydride (1.47 g, 43.4 mmol) was added. The mixture was stirred at 0 °C for 2 hours. The reaction solution was quenched with acetic acid (10 mL), concentrated, and the residue was purified by silica gel rapid column chromatography (petroleum ether / ethyl acetate) to give the title product 1b (9 g, yield 37.0%). 1 H NMR: (400MHz, CDCl3) δ4.55-4.37(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).

[0096] Step 2: 5-((tert-butyldiphenylsilyl)oxy)hexahydrocyclopentadien-2(1H)-one (1c)

[0097] 1b (15 g, 107.0 mmol) was dissolved in dichloromethane (150 mL), and imidazole (21.8 g, 321.0 mmol) was added. The mixture was cooled to 0 °C, and tert-butyldiphenylchlorosilane (30.5 mL, 117.7 mmol) was added. The mixture was stirred at 0 °C for 1 hour. The reaction solution was washed with 1 M hydrochloric acid solution (150 mL × 3), washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to rapid silica gel 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.

[0098] Step 3: Methyl 5-((tert-butyldiphenylsilyl)oxy)-2-oxooctahydrocyclopentadien-1-carboxylic acid (1d)

[0099] A 41 g (108.3 mmol) tetrahydrofuran solution (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. The reaction was quenched with water (150 mL). The mixture was extracted with ethyl acetate (100 mL × 3), the organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to rapid silica gel 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] + .

[0100] Step 4: Methyl 5-((tert-butyldiphenylsilyl)oxy)-2-hydroxyoctahydrocyclopentadien-1-carboxylic acid (1e)

[0101] 1d (32 g, 73.3 mmol) was dissolved in tetrahydrofuran (350 mL), cooled to 0 °C, and sodium borohydride (2.48 g, 73.3 mmol) was added. The mixture was stirred at 0 °C for 3 hours. The reaction was quenched with 0.5 M hydrochloric acid solution (30 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to rapid silica gel column chromatography (petroleum ether / ethyl acetate) to give the title product 1e (9 g, yield 28.0%). MS (ESI): m / z = 461.2 [M + Na] + .

[0102] Step 5: Methyl 5-((tert-butyldiphenylsilyl)oxy)-2-((methanesulfonyl)oxy)octahydrocyclopentadien-1-carboxylic acid (1f)

[0103] 1e (9 g, 20.5 mmol) was dissolved in dichloromethane (20 mL), and triethylamine (5.19 g, 51.3 mmol) was added. The mixture was cooled to 0 °C, and methanesulfonic anhydride (5.36 g, 30.8 mmol) was added. The reaction mixture was then brought to room temperature and stirred for 3 hours. The reaction mixture was washed with water (25 mL × 2), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to rapid silica gel column chromatography (petroleum ether / ethyl acetate) to give the title product 1f (9 g, yield 84.9%). MS (ESI): m / z = 539.1 [M + Na] + .

[0104] Step 6: Methyl 5-((tert-butyldiphenylsilyl)oxy)-3,3a,4,5,6,6a-hexahydrocyclopentadiene-1-carboxylic acid (1g)

[0105] 1 f (9 g, 17.4 mmol) was dissolved in toluene (100 mL), and 1,8-diazabicyclo[5.4.0]undec-7-ene (5.3 g, 34.8 mmol) was added. The mixture was heated to 90 °C and stirred for 2 hours. The reaction solution was concentrated, and the residue was subjected to rapid silica gel column chromatography (petroleum ether / ethyl acetate) to give 1 g (6.5 g, yield 88.7%) of the title product. MS (ESI): m / z = 443.2 [M + Na] + .

[0106] Step 7: Methyl 5-((tert-butyldiphenylsilyl)oxy)octahydrocyclopentadien-1-carboxylate (1h)

[0107] 1 g (6.5 g, 15.5 mmol) was dissolved in methanol (65 mL). Under a nitrogen atmosphere, 10% Pd / C (600 mg) was added, and the mixture was purged with hydrogen several times. The reaction solution was then stirred at room temperature (15 psi) for 3 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain the title product 1 h crude product (6.5 g), which was directly used for the next reaction. MS (ESI): m / z = 445.2 [M + Na] + .

[0108] Step 8: Methyl 5-hydroxyoctahydrocyclopentadien-1-carboxylate (1i)

[0109] 1 h (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 reaction mixture was reacted 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 organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to rapid silica gel column chromatography (petroleum ether / ethyl acetate) to give the title product 1i (2.1 g, yield 76.5%). 1 H NMR (400MHz, CDCl3) δ4.03 (tt, J=9.8, 6.1Hz, 1H), 3.65 (s, 3H), 2.75-2.61 (m, 2H), 2.50-2.38 (m, 1 H), 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).

[0110] 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)

[0111] 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 by 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 reaction was carried out at 100 °C for 2 hours under a nitrogen atmosphere. The pH was adjusted to 6-7 with 1M 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 obtain the crude product. The crude product was purified by silica-based rapid column chromatography (ethyl acetate / petroleum ether) to give the title product 1k (1.9 g, 92% yield). MS (ESI) m / z = 305.6 [M + H₂) + .

[0112] Step 10: 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)octahydrocyclopentadien-1-carboxylic acid methyl ester (11)

[0113] 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), heated to 50 °C, and a solution of di-tert-butyl azodicarbonate (2.25 g, 9.86 mmol) dissolved in tetrahydrofuran (10 mL) was slowly added dropwise. The mixture was stirred at 50 °C for 2 hours. The solution was concentrated under reduced pressure to obtain the crude product, which was purified by 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] + .

[0114] Step 11: Methyl 5-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydrocyclopentadien-1-carboxylic acid (1m)

[0115] 1 L (1.2 g, 2.55 mmol) was dissolved in methanol (30 mL), and p-toluenesulfonic acid hydrate (194 mg, 1.02 mmol) was added. The reaction solution was heated to 70 °C and reacted under a nitrogen atmosphere for 2 hours. After cooling, the solution was concentrated under reduced pressure to obtain 1 M (900 mg) of the crude title product, which was used directly in the next reaction. MS (ESI) m / z = 387.7 [M+H] + .

[0116] Step 12: 5-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydrocyclopentadien-1-carboxylic acid (1n)

[0117] 1 M (900 mg, 2.33 mmol) was dissolved in tetrahydrofuran (10 mL), methanol (10 mL), and water (10 mL), then lithium hydroxide (536 mg, 23.29 mmol) was added, and the reaction was carried out at room temperature for 3 hours. The pH was adjusted to 5-6 with 1 M hydrochloric acid solution, water (10 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, 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) + .

[0118] 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)octahydrocyclopentadien-1-carboxylic acid (1)

[0119] 1n (350 mg, 0.94 mmol) was dissolved in N,N-dimethylacetamide (20 mL), and 60% sodium hydride (180 mg, 7.52 mmol) was added under ice bath conditions. The reaction was allowed to proceed for 30 minutes, followed by the addition of 2-chloro-4-(methoxymethyl)pyrimidine (179 mg, 1.13 mmol), and the reaction was allowed to proceed for another 30 minutes at room temperature. The mixture was diluted with water (10 mL), and the pH was adjusted to 4–5 with 1 M hydrochloric acid. Extraction was performed with ethyl acetate (20 mL × 2). The organic phases were combined, 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 reversed-phase rapid column chromatography (acetonitrile / water) and then lyophilized to give compound 1 (200 mg, 43% yield). MS (ESI) m / z = 495.5 [M + H) +

[0120] Compound 1 was prepared by SFC chirality (separation conditions: SFC chirality preparation column DAICEL CHIRALPAK AS (250mm*30mm, 10um); mobile phase: A is CO2, B is ethanol (0.1% ammonia)), and its corresponding components were collected and concentrated under reduced pressure to obtain compounds 1-P1 and 1-P2.

[0121] Compound 1-P1 has a shorter 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, 0.46cm ID*100mm, 3um; mobile phase: A is CO2, B is ethanol (0.05% diethylamine). 1 H NMR (400MHz, CDCl3) δ8.50 (d, J=5.0Hz, 1H), 7.90 (d, J=8.5Hz, 1H), 7.13 (d, J =6.6Hz, 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).

[0122] Compound 1-P2 exhibits the longest 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 I.D. * 100 mm, 3 μm; mobile phase: A is CO2, B is ethanol (0.05% diethylamine). 1H NMR (400MHz, CDCl3) δ8.50 (d, J=5.0Hz, 1H), 7.91 (d, J=8.5Hz, 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).

[0123] The product of compound 1-P1 was found to be amorphous by X-ray powder diffraction, and its XRPD spectrum is shown below. Figure 1 As shown

[0124] Example 2: Antagonistic Properties Test of Compounds

[0125] The antagonistic properties of the compounds in this disclosure were determined using the FLIPR (fluorescence imaging plate reader) method. The compounds are inhibitors of intracellular calcium elevation induced by activation of hLPAR1 (human lysophosphatidic acid receptor 1) expressed in CHO-K1 cells (Chinese hamster ovary cells K1, HDB).

[0126] 1. Experimental reagents and instruments / consumables

[0127]

[0128]

[0129] 2. Reagent preparation

[0130] 2.1 Reaction buffer: HBSS + 20mM HEPES + 0.1% fatty acid-free BSA + 0.001% F-127

[0131] 2.2 50x Red dye: (a red dye used to mask background signals in cells), prepared by dissolving 4g of tartrazine and 10.2g of acid red in 100mL of H2O.

[0132] 2.3 Fluo-8 staining mixture: 4 mL reaction buffer, 32 μL fluo-8, 320 μL 50x Red dye, 40 μL probenecid.

[0133] 3. Compound preparation

[0134] 3.1 LPA: Dissolve in DPBS (containing 0.1% fatty acid-free BSA) to prepare a stock solution with a concentration of 0.8 μM, aliquot and store at -20℃.

[0135] 3.2 Preparation of the test compound: The test compound was dissolved in DMSO to prepare a 10 mM stock solution, which was stored at -20℃. During the experiment, the compound was first serially diluted with DMSO (initial concentration 50 μM, 3-fold dilution, 10 spots) to prepare a 200-fold concentration solution. Then, it was diluted with reaction buffer to a 5-fold concentration solution and transferred to a 384-well plate (catalog number #6008590) using Bravo.

[0136] 4. Experimental Procedure

[0137] 4.1. CHO-K1 / LPA1R cells were cultured in cell culture medium (F-12 + 10% FBS + 400 μg / ml hygromycin B).

[0138] 4.2 When the cell confluence reaches 80%, digest with 0.25% trypsin.

[0139] 4.3. Once the cells become rounded, stop the digestion with F-12 culture medium (10% FBS) and count the cells. Then dilute with F-12 (10% FBS) to a density of 6.7 × 10⁻⁶. 5 Cells / ml of cell suspension.

[0140] 4.4. Using the Multidrop automated dispensing device, add 30 μL of cell suspension to each well of a 384-well black cell culture plate and incubate at 37°C in a 5% CO2 incubator for 20-24 hours. Then, replace the culture medium with serum-free F-12 medium and starve the cells for 24 hours.

[0141] 4.5. LPA Dosage Test. Prepare 6x LPA solution using reaction buffer, serially diluting (starting concentration 60 μM, 3-fold dilution, 10 spots). Discard the culture medium in the 384-well black cell culture plate and replace it with reaction buffer. Add 10 μL of 5% DMSO reaction buffer, then add 10 μL of Fluo-8 staining mixture, and incubate at 37°C in a 5% CO2 incubator in the dark for 0.5 hours.

[0142] 4.6. Set up the FLIPR program to add a 6x LPA gradient solution and take readings. Collect data for 2 minutes.

[0143] 4.7. Based on the LPA values, obtain its reaction curve and calculate the EC. 80The concentration of LPA was determined. A 6x LPA solution was prepared in a 384-well plate (catalog number #6008590), and HPE and ZPE were added to the corresponding positions. HPE (100% effect) was 60 μL LPA, and ZPE (0% effect) was the reaction buffer.

[0144] 4.8 Compound Assay. Discard the culture medium in the 384-well black cell culture plate and replace it with reaction buffer. Transfer 10 μL of 5X compound solution to Bravo, and immediately add 10 μL of Fluo-8 staining mixture. Incubate at 37°C in a 5% CO2 incubator in the dark for 0.5 hours.

[0145] 4.9. Set the appropriate FLIPR program to add 6x LPA solution and take readings. Collect data for 2 minutes.

[0146] 4.10 Finally, the output fluorescence counts are analyzed to calculate the IC50 of the compound.

[0147] 5. Experimental Results

[0148] Table 1 shows the IC50 values ​​obtained by the disclosed compounds against the LPAR1 receptor. 50

[0149]

[0150] Conclusion: The results show that the above compounds have excellent LPAR1 inhibitory activity and can be used as LPAR1 antagonists.

[0151] Treatment of target-related diseases.

[0152] Example 3: Preparation of crystal form A of compound I

[0153] Weigh about 300 mg of the compound shown in Formula I, dissolve it in 7 ml of propylene glycol methyl ether, add 21 ml of n-heptane, stir the reaction solution for 1 day, filter the solid and dry it to obtain the crystal form of compound A of Formula I.

[0154] X-ray powder diffraction analysis showed the following XRPD spectrum: Figure 2 As shown in Table 2, the positions of its characteristic peaks are as follows. The TGA spectrum shows a weight loss of 1.55% before 100℃. The DSC spectrum shows that the endothermic peak reaches a value of 183.35℃.

[0155] DVS test results showed that under normal storage conditions (i.e., 25°C, 60% RH), the sample's moisture absorption weight gain was approximately 0.17%; under accelerated testing conditions (i.e., 70% RH), the moisture absorption weight gain was approximately 0.20%; and under extreme conditions (90% RH), the moisture absorption weight gain was approximately 0.37%. Retesting of the crystal form after DVS testing showed no change in crystal form.

[0156] Table 2

[0157]

[0158]

[0159] Example 4: Preparation of crystal form A of compound I

[0160] Weigh about 5 mg of the compound shown in formula (I), dissolve it in solvent A, add solvent B, then add solvent C, stir for 3 days, centrifuge and dry the precipitated solid to obtain the crystal form of compound A of formula (I).

[0161] Table 3 Preparation of Crystal Form A of Compound I

[0162]

[0163] Example 5: Preparation of crystal form B of compound of formula I

[0164] Weigh about 5 mg of the compound shown in formula (I), dissolve it in 0.1 ml of tetrahydrofuran (solvent A), add 0.2 ml of methyl tert-butyl ether (solvent B), then add 0.2 ml of n-heptane (solvent C), stir for 1 day, centrifuge the precipitated solid, and dry it to obtain the crystal form of compound B of formula I.

[0165] Table 4. Preparation of crystal form B of compound I.

[0166]

[0167] X-ray powder diffraction analysis showed the following XRPD spectrum: Figure 3 As shown in Table 5, the characteristic peak positions are as follows. The TGA spectrum shows a weight loss of 1.66% before 100℃. The DSC spectrum shows that the endothermic peaks are at 163.19℃ and 182.43℃, and the exothermic peak is at 164.04℃.

[0168] DVS test results showed that under normal storage conditions (i.e., 25°C, 60% RH), the sample's moisture absorption weight gain was approximately 0.25%; under accelerated testing conditions (i.e., 70% RH), the moisture absorption weight gain was approximately 0.31%; and under extreme conditions (90% RH), the moisture absorption weight gain was approximately 0.64%. Retesting of the crystal form after DVS testing showed no change in crystal form.

[0169] Table 5

[0170]

[0171] Example 6: Preparation of crystal form B of compound I

[0172] Weigh about 5 mg of the compound shown in formula (I), dissolve it in 0.25 ml of water (solvent A), stir the reaction solution for 1 day, centrifuge and dry the solid to obtain the crystal form of compound B of formula I.

[0173] Table 6 Preparation of Crystal Form B of Compound I

[0174]

[0175]

[0176] Example 7: Preparation of the C crystal form of compound I

[0177] Weigh approximately 10 mg of the compound shown in formula (I), add 0.2 ml of 50% methanol / acetonitrile or 0.2 ml of tetrahydrofuran, add an ethanol solution of ethanolamine (2 mol / L, 10 μL), add 0.4 ml of methyl tert-butyl ether to the reaction solution, stir for 2 days, then add 0.8 ml of methyl tert-butyl ether, and stir for 1 day at a temperature of 50℃-5℃ (heating rate of 45℃ / h), then stir at 25℃ for 2 days, centrifuge and dry to obtain the C crystal form of compound I.

[0178] X-ray powder diffraction analysis showed the following XRPD spectrum: Figure 4 As shown in Table 7, the characteristic peak positions are as follows. The TGA spectrum shows a weight loss of 4.34% before 110℃ and 8.22% between 110℃ and 195℃. The DSC spectrum shows that the endothermic peaks are at 106.12℃ and 177.29℃.

[0179] Table 7

[0180]

[0181]

[0182] Example 8: Preparation of the sodium salt I crystal form of compound I

[0183] Weigh about 10 mg of the compound shown in formula (I), add 0.2 ml of 50% ethanol / ethyl acetate to dissolve it (solvent A), add sodium hydroxide solution (2 mol / L, 10.5 μL), add 0.8 ml of methyl tert-butyl ether, stir the reaction solution for 2 days, centrifuge and dry to obtain sodium salt I crystal form of compound I.

[0184] Table 8 Preparation of Sodium Salt I Crystal Form of Compound I (Formula I)

[0185]

[0186] X-ray powder diffraction analysis showed the following XRPD spectrum: Figure 5The positions of its characteristic peaks are shown in Table 9. Ion chromatography analysis revealed a sodium ion content of 4.85%. TGA chromatograms showed a weight loss of 7.36% between 30℃ and 110℃. DSC chromatograms showed endothermic peaks at 90.11℃, 122.09℃, and 210.70℃, and an exothermic peak at 145.47℃.

[0187] DVS testing showed that under normal storage conditions (i.e., 25°C, 60% RH), the sample's moisture absorption weight gain was approximately 6.31%; under accelerated testing conditions (i.e., 70% RH), the moisture absorption weight gain was approximately 7.08%; and under extreme conditions (90% RH), the moisture absorption weight gain was approximately 42.38%.

[0188] Table 9

[0189]

[0190]

[0191] Example 9: Preparation of the sodium salt I crystal form of compound I

[0192] Weigh about 10 mg of the compound shown in formula (I), add 0.2 ml of 2-butanone or 0.2 ml of acetonitrile, add sodium hydroxide ethanol solution (1 mol / L, 21 μL), stir the reaction solution for 1 day, centrifuge and dry to obtain sodium salt I crystal form of compound I.

[0193] Example 10: Preparation of the sodium salt II crystal form of compound I

[0194] Weigh about 10 mg of the compound shown in formula (I), add 0.2 ml of isopropanol or 0.2 ml of 1,4-dioxane, add sodium hydroxide ethanol solution (1 mol / L, 21 μL), stir the reaction solution for 1 day, centrifuge and dry to obtain sodium salt II crystal form of the compound of formula I.

[0195] X-ray powder diffraction analysis showed the following XRPD spectrum: Figure 6 The positions of its characteristic peaks are shown in Table 10. Ion chromatography analysis revealed a sodium ion content of 4.75%. TGA chromatograms showed a weight loss of 2.18% between 30℃ and 120℃. DSC chromatograms showed endothermic peaks at 179.08℃ and 223.40℃.

[0196] DVS testing showed that under normal storage conditions (i.e., 25°C, 60% RH), the sample's moisture absorption weight gain was approximately 6.35%; under accelerated testing conditions (i.e., 70% RH), the moisture absorption weight gain was approximately 22.41%; and under extreme conditions (90% RH), the moisture absorption weight gain was approximately 56.98%.

[0197] Table 10

[0198]

[0199]

[0200] Example 11: Preparation of the sodium salt II crystal form of compound I

[0201] Weigh about 5 mg of sodium salt I crystal form of the compound shown in formula (I), add 0.2 ml of isopropanol or 0.2 ml of isopropyl acetate, stir the reaction solution for 2 days, centrifuge and dry to obtain sodium salt II crystal form of the compound shown in formula (I).

[0202] Example 12: Preparation of the sodium salt II crystal form of compound I

[0203] Weigh about 5 mg of sodium salt I crystal form of the compound shown in formula (I), dissolve it in 0.2 ml of ethanol or 0.2 ml of n-propanol, add 1 ml of n-heptane, stir the reaction solution for 5 days, centrifuge and dry to obtain sodium salt II crystal form of the compound of formula I.

[0204] Example 13: Preparation of the III crystal form of the sodium salt of Formula I

[0205] Weigh about 5 mg of sodium salt I crystal form of the compound shown in formula (I), add 0.2 ml of 1,4-dioxane, stir the reaction solution for 2 days, centrifuge and dry to obtain sodium salt III crystal form of the compound shown in formula (I).

[0206] X-ray powder diffraction analysis showed the following XRPD spectrum: Figure 7 The positions of its characteristic peaks are shown in Table 11.

[0207] Table 11

[0208]

[0209]

[0210] Example 14: Preparation of the IV crystal form of the sodium salt of compound I

[0211] Approximately 2 mg of sodium salt I crystal form of compound (I) was weighed and heated to 180 °C to obtain sodium salt IV crystal form of compound (I). The XRPD spectrum obtained by X-ray powder diffraction is shown below. Figure 8 The positions of its characteristic peaks are shown in Table 12.

[0212] Table 12

[0213]

[0214] Example 15: Preparation of the amorphous sodium salt of Formula I

[0215] Approximately 2 mg of sodium salt I crystal form of the compound shown in formula (I) was weighed and heated to 130 °C to obtain the title product. X-ray powder diffraction analysis showed that the product was an amorphous sodium salt, and the XRPD spectrum is shown below. Figure 9 .

[0216] Example 16: Preparation of the I crystal form of ethanolamine salt of Formula I

[0217] Weigh approximately 30 mg of the compound shown in formula (I), add 0.6 ml of tetrahydrofuran, add ethanolamine ethanol solution (2 mol / L, 31.5 μl), add 3.6 ml of methyl tert-butyl ether, and stir the reaction solution for 3 days by cycling the temperature from 50℃ to 5℃ (temperature cycling rate of 45℃ / h). After centrifugation and drying, the ethanolamine salt I crystal form of compound formula I is obtained.

[0218] X-ray powder diffraction analysis showed the following XRPD spectrum: Figure 10 The positions of its characteristic peaks are shown in Table 13. The TGA spectrum shows a weight loss of 13.57% between 30℃ and 190℃. The DSC spectrum shows endothermic peaks at 59.63℃ and 148.77℃.

[0219] Table 13

[0220]

[0221] Example 17: Stability Study of Influencing Factors

[0222] The free A-type and B-type crystals of the compound described in Formula I were laid out in an open manner, and the stability of the samples was investigated under light (4500 Lux), high temperature (40℃, 60℃), and high humidity (RH 75%, RH 93%) conditions. The sampling and investigation period was 1 month.

[0223] Table 14 Influencing Factors

[0224]

[0225] Conclusion: The compounds shown in Formula I exhibit good physical and chemical stability in both free crystal form A and free crystal form B after being stored for one month.

[0226] The sodium salt I and sodium salt II crystal forms of the compound shown in Formula I were laid out in an open position, and the stability of the samples was investigated under light (4500 Lux), high temperature (40℃, 60℃), and high humidity (RH 75%) conditions. The sampling period was one month.

[0227] Table 15 Influencing Factors

[0228]

[0229] Conclusion: Sodium salt I crystal form exhibits good physical and chemical stability after one month of storage; sodium salt II crystal form is physically and chemically stable except under high humidity.

[0230] Good sexual function.

[0231] Example 18, Long-term / Accelerated Stability:

[0232] The stability of the compound shown in Formula I in its free crystal form A and free crystal form B was investigated under conditions of 25℃ / 60%RH and 40℃ / 75%RH, respectively.

[0233] Table 16 Long-term Acceleration

[0234]

[0235]

[0236] Conclusion: Both free A-form and free B-form crystals exhibit good physical and chemical stability after being placed under long-term accelerated conditions for 6 months.

[0237] The stability of sodium salt I and sodium salt II of the compound shown in Formula I was investigated under conditions of 25℃ / 60%RH and 40℃ / 75%RH, respectively.

[0238] Table 17 Long-term Acceleration

[0239]

[0240] Conclusion: Sodium salts in crystal form I and II exhibit good physical and chemical stability after being placed under long-term accelerated conditions for 3 months.

Claims

1. A crystal form A of the compound shown in Formula I, ， With diffraction angle 2 θ The X-ray powder diffraction pattern, expressed as an angle, shows characteristic peaks at 7.534, 10.223, 14.364, 17.269, 18.495, and 19.

553. θ The angle error range is ±0.

2.

2. A crystal form A of the compound shown in Formula I, ， With diffraction angle 2 θ The X-ray powder diffraction pattern, expressed as an angle, shows characteristic peaks at 7.534, 10.223, 14.364, 15.816, 16.678, 17.269, 18.495, and 19.

553. θ The angle error range is ±0.

2.

3. A crystal form A of the compound shown in Formula I, ， With diffraction angle 2 θ The X-ray powder diffraction pattern, expressed as an angle, shows 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. θ The angle error range is ±0.

2.

4. A crystal form A of the compound shown in Formula I, ， With diffraction angle 2 θ The X-ray powder diffraction pattern expressed in terms of angle is shown in Figure 2.

5. A B-crystal form of the compound shown in Formula I, ， With diffraction angle 2 θ The X-ray powder diffraction pattern, expressed as an angle, shows characteristic peaks at 7.437, 10.381, 14.717, 14.955, 17.513, 21.395, 22.607, and 23.

221. θ The angle error range is ±0.

2.

6. A B-crystal form of the compound shown in Formula I, ， With diffraction angle 2 θ The X-ray powder diffraction pattern, expressed as an angle, shows 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. θ The angle error range is ±0.

2.

7. A B-crystal form of the compound shown in Formula I, ， With diffraction angle 2 θ The X-ray powder diffraction pattern expressed in terms of angle is shown in Figure 3.

8. A pharmaceutically acceptable salt of a compound of formula I, said pharmaceutically acceptable salt being selected from sodium salts or ethanolamine salts. 。 9. The medicinal salt according to claim 8, characterized in that, The chemical ratio of the compound shown in Formula I to the base ion is 1:1 or 1:

2.

10. The medicinal salt according to claim 9, characterized in that, The chemical ratio of the compound shown in Formula I to the base ion is 1:

1.

11. A method for preparing a pharmaceutically acceptable salt of a compound of Formula I, comprising the step of reacting the compound of Formula I with a base, wherein the base is selected from sodium hydroxide or ethanolamine. 。 12. A sodium salt of the compound shown in Formula I, crystal form I. ， With diffraction angle 2 θ The X-ray powder diffraction pattern, expressed as an angle, shows characteristic peaks at 6.446, 8.350, 8.847, 9.335, 12.845, 16.901, and 17.

874. θ The angle error range is ±0.

2.

13. A sodium salt of the compound shown in Formula I, crystal form I. ， With diffraction angle 2 θ The X-ray powder diffraction pattern, expressed as an angle, shows 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. θ The angle error range is ±0.

2.

14. A sodium salt of the compound shown in Formula I, crystal form I. ， With diffraction angle 2 θ The X-ray powder diffraction pattern, expressed as an angle, shows 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. θ The angle error range is ±0.

2.

15. A sodium salt of the compound shown in Formula I, crystal form I. ， With diffraction angle 2 θ The X-ray powder diffraction pattern, expressed as an angle, shows 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. θ The angle error range is ±0.

2.

16. A sodium salt of the compound shown in Formula I, crystal form I. ， With diffraction angle 2 θ The X-ray powder diffraction pattern expressed in terms of angle is shown in Figure 5.

17. A sodium salt II crystal form of the compound shown in Formula I, ， With diffraction angle 2 θ The X-ray powder diffraction pattern, expressed as an angle, shows characteristic peaks at 6.771, 13.464, 13.970, 14.419, 15.593, 18.044, and 19.

952. θ The angle error range is ±0.

2.

18. A sodium salt II crystal form of the compound shown in Formula I, ， With diffraction angle 2 θ The X-ray powder diffraction pattern, expressed as an angle, shows characteristic peaks at 6.771, 11.446, 13.464, 13.970, 14.419, 15.593, 18.044, 19.952, and 24.

260. θ The angle error range is ±0.

2.

19. A sodium salt II crystal form of the compound shown in Formula I, ， With diffraction angle 2 θ The X-ray powder diffraction pattern, expressed in terms of angle, shows 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. θ The angle error range is ±0.

2.

20. A sodium salt II crystal form of the compound shown in Formula I, ， With diffraction angle 2 θ The X-ray powder diffraction pattern expressed in terms of angle is shown in Figure 6.

21. A pharmaceutical composition comprising the following components: i) the crystal form of the compound of formula I according to any one of claims 1 to 7, or a pharmaceutically acceptable salt of the compound of formula I according to claim 8, or the crystal form according to any one of claims 12 to 20; and ii) One or more pharmaceutically acceptable excipients.

22. A method for preparing a pharmaceutical composition, comprising the steps of: mixing a crystal form of the compound of formula I according to any one of claims 1 to 7, or a pharmaceutically acceptable salt of the compound of formula I according to claim 8, or a crystal form according to any one of claims 12 to 20, with a pharmaceutically acceptable excipient.

23. Use of the crystal form of the compound of formula I according to any one of claims 1 to 7, or the pharmaceutically acceptable salt of the compound of formula I according to claim 8, or the crystal form of any one of claims 12 to 20, or the composition according to claim 21 in the preparation of an LPA1 inhibitor.

24. The use of the crystal form of the compound of formula I according to any one of claims 1 to 7, or the pharmaceutically acceptable salt of the compound of formula I according to claim 8, or the crystal form of any one of claims 12 to 20, or the composition according to claim 21, in the preparation of a medicament for treating and / or preventing organ fibrosis, respiratory diseases, kidney diseases, liver diseases, inflammatory diseases, nervous system diseases, cardiovascular diseases, gastrointestinal diseases, pain, urinary system diseases, eye diseases, metabolic diseases, cancer, and transplant rejection caused by LPA1.

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