Pharmaceutically acceptable salts of benz[c]chroman compounds, as well as polymorphs and uses of pharmaceutically acceptable salts
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- REISTONE BIOPHARMA CO LTD
- Filing Date
- 2023-06-05
- Publication Date
- 2026-06-11
Smart Images
Figure 2023236877000001 
Figure 2023236877000002 
Figure 2023236877000003
Abstract
Description
【Technical Field】 【0001】 The present disclosure belongs to the field of pharmaceutical technology and relates to pharmaceutically acceptable salts of benzoc[c]chroman compounds, as well as their polymorphs and uses. 【Background Art】 【0002】 Cathepsin is a kind of protease widely present in lysosomes of various tissue cells. Depending on their structures and types of catalysis, cathepsins are classified into three classes: serine proteases (cathepsin A and G), aspartic proteases (cathepsin D and E), and cysteine proteases. Among them, cysteine proteases are the largest family of cathepsins and include 11 proteases: cathepsin B, C, F, H, K, L, O, S, W, V, and Z. 【0003】 Cathepsin C is also known as dipeptidyl peptidase I or "DPP1". DPP1 is constitutively expressed in many tissues and is constitutively expressed at the highest levels in the lung, kidney, liver, and spleen. Several recently published studies have described the role of cathepsin C in specific inflammatory processes. For example, from Adkison et al., J Clin Invest. 2002 Feb;109(3):363 - 71; Tinh et al., Archives of Biochemistry and Biophysics. 2002 403:160 - 170, it can be seen from these studies that cathepsin C co - expresses with specific serine proteases in granules and has the function of converting these protease precursors into the active form, and then is released from the inflammatory cell granules collected at the inflammatory site. These proteases, when activated, have many functions including the degradation of various extracellular matrix components, and together they can propagate tissue damage and chronic inflammation. 【0004】 WO 2004 / 110988 relates to certain nitrile derivatives and their use as DPP1 inhibitors. 【0005】 International Publication No. 2009 / 074829 relates to peptidyl nitriles and their use as DPP1 inhibitors. 【0006】 International Publication No. 2010 / 128324 relates to α-aminoamidonitriles and their use as DPP1 inhibitors. 【0007】 International Publication No. 2012 / 119941 relates to peptidyl nitrile compounds and their use as DPP1 inhibitors. 【0008】 International Publication No. 2013 / 041497 relates to N-[1-cyano-2-(phenyl)ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide and its use as a DPP1 inhibitor. 【0009】 International Publication Nos. 2001 / 096285 and 2003 / 048123 relate to β-aminoamidonitriles having inhibitory activity against cysteine proteases. 【0010】 International Publication No. 2015 / 110826 relates to α-aminoamidonitriles and their use as DPP1 inhibitors. 【0011】 International Publication No. 2022 / 117059 provides a cathepsin C inhibitor named with the chemical name (S)-N-((S)-1-cyano-2-(8-cyano-2-fluoro-6H-benzo[c]chromen-3-yl)ethyl)-1,4-oxazepane-2-carboxamide and having the structure shown in Formula I: 【Chemical formula】 as shown. 【0012】 The crystal form of a pharmaceutical active ingredient often affects the chemical stability of the drug, and different crystallization and storage conditions can change the crystal structure of the compound and sometimes lead to the formation of other crystal forms. Generally, amorphous pharmaceuticals do not have a regular crystal structure and may have other defects such as low product stability, fine precipitation, difficult filtration, easy aggregation, and poor fluidity. The requirements for product storage, manufacturing, and scale-up vary depending on the polymorphism of the drug. Therefore, it is necessary to conduct a detailed study on the crystal form of the aforementioned compound in order to improve the various properties of the compound. 【Summary of the Invention】 【0013】 The present invention relates to a pharmaceutically acceptable salt of a compound of formula I: 【Chemical Formula】 which is a pharmaceutically acceptable salt of the compound of formula I, wherein the pharmaceutically acceptable salt is an acid addition salt selected from the group consisting of hydrochloride, methanesulfonate, phosphate, L-tartrate, maleate, p-toluenesulfonate, sulfate, fumarate, succinate, citrate, malate, and hydrobromide, and preferably is in crystalline form, and provides a pharmaceutically acceptable salt of the compound of formula I. 【0014】 In some embodiments, there is provided a pharmaceutically acceptable salt of the compound of formula I, wherein the stoichiometric ratio of the compound of formula I to the acid molecule or acid group is 1:0.5 to 1:3, preferably 1:0.5, 1:1, 1:1.2, 1:2, or 1:3, and more preferably 1:1. 【0015】 In some embodiments, there is provided a pharmaceutically acceptable salt of the compound of formula I, wherein the pharmaceutically acceptable salt of the compound of formula I is hydrochloride, and the stoichiometric ratio of the compound of formula I to the hydrochloride group is 1:1. 【0016】 The present disclosure also provides a method for producing the pharmaceutically acceptable salts as described above, which includes a step of converting a compound of formula I into a salt with an acid. In some embodiments, the step of converting a compound of formula I into a salt with an acid is carried out in a solvent selected from one or more of dichloromethane, N,N-dimethylformamide, acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, 1,4-dioxane, water, dimethyl sulfoxide and ethyl acetate, preferably in a solvent selected from acetone, methanol, ethanol, ethanol / water, isopropanol / water, ethyl acetate, acetonitrile, tetrahydrofuran, dimethyl sulfoxide / water, 1,4-dioxane, methanol / water, N,N-dimethylformamide and dichloromethane. 【0017】 The present disclosure also provides crystalline form A of the hydrochloride salt of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 7.043, 12.430, 14.356, 14.840 and 15.250, and the error range of the 2θ angle is ±0.20. 【0018】 In some embodiments, the present disclosure provides crystalline form A of the hydrochloride salt of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 7.043, 8.719, 10.737, 12.430, 14.356, 14.840, 15.250 and 17.686, and the error range of the 2θ angle is ±0.20. 【0019】 In some embodiments, the present disclosure provides crystalline form A of the hydrochloride salt of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 7.043, 8.719, 10.737, 12.430, 14.356, 14.840, 15.250, 17.686, 21.697, 22.305, 25.635 and 27.433, and the error range of the 2θ angle is ±0.20. 【0020】 In some embodiments, the present disclosure provides crystalline form A of the hydrochloride salt of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ is as shown in Figure 1. 【0021】 In some embodiments, a crystalline form A of the hydrochloride salt of the compound of formula I is provided, which has an endothermic peak at 268 °C in a differential scanning calorimetry (DSC) spectrum with an error range of ±2 °C. 【0022】 The present disclosure also provides a) a step of dissolving the hydrochloride salt of the compound of formula I in solvent A; b) a step of performing stirring. A method for producing crystalline form A of the hydrochloride salt of the compound of formula I is provided, which method comprises the above steps. 【0023】 In some embodiments, the production method further comprises a step of performing centrifugation, washing and / or drying. 【0024】 In some embodiments, in the method for producing crystalline form A of the hydrochloride salt of the compound of I, solvent A is selected from the group consisting of water, C 1-4 ketone solvents, C 1-4 alcohol solvents, a mixed solvent of water and C 1-4 alcohol solvents, C 1-4 ester solvents, C 1-4 nitrile solvents, tetrahydrofuran, a mixed solvent of dimethyl sulfoxide and water, and 1,4-dioxane, and is preferably selected from the group consisting of acetone, methanol, ethanol, ethanol / water, isopropanol / water, ethyl acetate, acetonitrile, tetrahydrofuran, dimethyl sulfoxide / water, 1,4-dioxane, and methanol / water. 【0025】 In some embodiments, in the method for producing crystalline form A of the hydrochloride salt of the compound of formula I, it is dissolved in 0.01 to 0.05 ml of solvent A per milligram of the compound of formula I, and more preferably, it is dissolved in 0.01 to 0.03 ml of solvent A per milligram of the compound of formula I. 【0026】 In some embodiments, in the method for producing crystalline form A of the hydrochloride salt of the compound of formula I, the mixed solvent of water and an alcohol solvent is a mixed solvent of water and methanol, and the molar ratio of water to methanol is 0.10 to 0.95, preferably 0.14, 0.26, 0.37, 0.47, 0.57, 0.66, 0.74, 0.82 and 0.90. 【0027】 The present disclosure also provides crystalline form A' of the hydrochloride salt of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 8.452, 12.476, 15.884, 17.037, 17.227, 22.328 and 23.566, and the error range of the 2θ angle is ±0.20. 【0028】 In some embodiments, the present disclosure provides crystalline form A' of the hydrochloride salt of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 8.452, 10.537, 12.476, 15.884, 17.037, 17.227, 20.784, 22.328, 23.566 and 27.567, and the error range of the 2θ angle is ±0.20. 【0029】 In some embodiments, the present disclosure provides crystalline form A' of the hydrochloride salt of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 8.452, 10.537, 12.476, 13.296, 14.332, 15.884, 17.037, 17.227, 20.784, 22.328, 23.566 and 27.567, and the error range of the 2θ angle is ±0.20. 【0030】 In some embodiments, the present disclosure provides crystalline form A' of the hydrochloride salt of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 8.452, 10.537, 12.476, 13.296, 14.332, 15.884, 17.037, 17.227, 20.784, 21.329, 22.328, 23.566, 24.497, 25.221 and 27.567, and the error range of the 2θ angle is ±0.20. 【0031】 In some embodiments, there is provided crystalline form A' of the hydrochloride salt of the compound of formula I having an endothermic peak at 161° C. in the DSC spectrum with an error range of ±2° C. 【0032】 The present disclosure also provides crystalline form B of the methanesulfonate salt of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 6.717, 8.783, 13.969, 15.902, 16.647 and 17.515, and the error range of the 2θ angle is ±0.20. 【0033】 In some embodiments, there is provided crystalline form B of the methanesulfonate salt of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 6.717, 8.105, 8.783, 13.969, 15.902, 16.647 and 17.515, and the error range of the 2θ angle is ±0.20. 【0034】 In some embodiments, there is provided crystalline form B of the methanesulfonate salt of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 6.717, 8.105, 8.783, 13.969, 15.902, 16.647, 17.515, 20.446, 21.069, 21.645 and 24.665, and the error range of the 2θ angle is ±0.20. 【0035】 In some embodiments, there is provided crystalline form B of the methanesulfonate salt of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 6.717, 8.105, 8.783, 13.969, 15.902, 16.647, 17.515, 20.446, 21.069, 21.645, 23.549, 24.665, 26.284, 27.289 and 27.667, and the error range of the 2θ angle is ±0.20. 【0036】 In some embodiments, there is provided crystalline form B of the methanesulfonate salt of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ is as shown in FIG. 6. 【0037】 In some embodiments, provided is crystalline Form B of the methanesulfonate salt of the compound of Formula I, which has an endothermic peak at 161 °C in the DSC spectrum with an error range of ±2 °C. 【0038】 The present disclosure also provides crystalline Form C of the methanesulfonate salt of the compound of Formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 7.747, 11.163, 12.676, 15.268, 16.824, 18.549 and 19.759, and the error range of the 2θ angle is ±0.20. 【0039】 In some embodiments, provided is crystalline Form C of the methanesulfonate salt of the compound of Formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 4.522, 7.747, 11.163, 12.676, 15.268, 16.824, 18.549 and 19.759, and the error range of the 2θ angle is ±0.20. 【0040】 In some embodiments, provided is crystalline Form C of the methanesulfonate salt of the compound of Formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 4.522, 7.747, 11.163, 12.676, 15.268, 16.824, 18.549, 19.759, 21.460, 24.637 and 25.497, and the error range of the 2θ angle is ±0.20. 【0041】 In some embodiments, provided is crystalline Form C of the methanesulfonate salt of the compound of Formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 4.522, 7.747, 11.163, 12.676, 15.268, 16.824, 18.549, 19.759, 21.460, 22.539, 24.637 and 25.497, and the error range of the 2θ angle is ±0.20. 【0042】 In some embodiments, provided is crystalline Form C of the methanesulfonate salt of the compound of Formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ is as shown in FIG. 9. 【0043】 In some embodiments, there is provided a crystalline form C of the methanesulfonate salt of the compound of formula I that has an endothermic peak at 194 °C in the DSC spectrum with an error range of ±2 °C. 【0044】 The present disclosure also provides a crystalline form D of the phosphate salt of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 9.593, 12.831, 13.464, 15.666, 18.161 and 19.245, and the error range of the 2θ angle is ±0.20. 【0045】 In some embodiments, there is provided a crystalline form D of the phosphate salt of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 8.491, 9.593, 12.831, 13.464, 13.954, 14.943, 15.666, 16.616, 17.259, 18.161 and 19.245, and the error range of the 2θ angle is ±0.20. 【0046】 In some embodiments, there is provided a crystalline form D of the phosphate salt of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 4.213, 6.650, 8.491, 9.593, 10.897, 12.831, 13.464, 13.954, 14.943, 15.666, 16.616, 17.259, 18.161 and 19.245, and the error range of the 2θ angle is ±0.20. 【0047】 In some embodiments, there is provided a crystalline form D of the phosphate salt of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 4.213, 6.650, 8.491, 9.593, 10.897, 12.831, 13.464, 13.954, 14.943, 15.666, 16.616, 17.259, 18.161, 19.245, 24.822, 25.665 and 26.618, and the error range of the 2θ angle is ±0.20. 【0048】 In some embodiments, there is provided a crystalline form D of the phosphate salt of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ is as shown in FIG. 12. 【0049】 In some embodiments, there is provided crystalline form D of a phosphate of a compound of formula I that has endothermic peaks at 130 °C and 143 °C in a DSC spectrum, with an error range of ±2 °C. 【0050】 The present disclosure also provides crystalline form E of an L-tartrate of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 6.383, 9.081, 12.936, 16.161, and 18.397, with an error range of ±0.20 for the 2θ angle. 【0051】 In some embodiments, there is provided crystalline form E of an L-tartrate of a compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 6.383, 9.081, 12.936, 14.400, 16.161, 18.397, and 19.489, with an error range of ±0.20 for the 2θ angle. 【0052】 In some embodiments, there is provided crystalline form E of an L-tartrate of a compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 6.383, 9.081, 12.936, 14.400, 16.161, 18.397, 19.489, 23.786, 24.536, and 26.203, with an error range of ±0.20 for the 2θ angle. 【0053】 In some embodiments, there is provided crystalline form E of an L-tartrate of a compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ is as shown in FIG. 15. 【0054】 In some embodiments, there is provided crystalline form E of an L-tartrate of a compound of formula I that has an endothermic peak at 132 °C in a DSC spectrum, with an error range of ±2 °C. 【0055】 The present disclosure also provides crystalline form F of the hydrobromide salt of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 7.133, 12.485, 14.422, 17.721 and 18.823, and the error range of the 2θ angle is ±0.20. 【0056】 In some embodiments, there is provided crystalline form F of the hydrobromide salt of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 6.152, 7.133, 10.827, 12.485, 14.422, 17.721 and 18.823, and the error range of the 2θ angle is ±0.20. 【0057】 In some embodiments, there is provided crystalline form F of the hydrobromide salt of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 6.152, 7.133, 10.827, 12.485, 14.422, 17.721, 18.823, 20.738, 21.656, 22.309, 23.238, 25.116, 25.672 and 27.416, and the error range of the 2θ angle is ±0.20. 【0058】 In some embodiments, there is provided crystalline form F of the hydrobromide salt of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ is as shown in FIG. 18. 【0059】 In some embodiments, there is provided crystalline form F of the hydrobromide salt of the compound of formula I, which has endothermic peaks at 99 °C and 216 °C in the DSC spectrum, and the error range is ±2 °C. 【0060】 The term "2θ or 2θ angle" in the present disclosure refers to the diffraction angle, where θ is the Bragg angle, and its unit is ° or degree. The error range of 2θ for each characteristic peak is ±0.20 (including the case where the numerical value above the second decimal place is rounded off), 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 and 0.20. 【0061】 The present disclosure also provides a pharmaceutical composition comprising a pharmaceutically acceptable salt of the compound of formula I, crystalline form A of the hydrochloride salt of the compound of formula I, crystalline form B of the methanesulfonate salt of the compound of formula I, crystalline form C of the methanesulfonate salt of the compound of formula I, crystalline form D of the phosphate salt of the compound of formula I, crystalline form E of the L-tartrate salt of the compound of formula I, or crystalline form F of the hydrobromide salt of the compound of formula I, and a pharmaceutically acceptable excipient. 【0062】 The present disclosure also provides a method for manufacturing a pharmaceutical composition, which includes the step of mixing crystalline form A of the hydrochloride salt of the compound of formula I, crystalline form B of the methanesulfonate salt of the compound of formula I, crystalline form C of the methanesulfonate salt of the compound of formula I, crystalline form D of the phosphate salt of the compound of formula I, crystalline form E of the L-tartrate salt of the compound of formula I, or crystalline form F of the hydrobromide salt of the compound of formula I with a pharmaceutically acceptable excipient. 【0063】 The present disclosure also relates to the use of a pharmaceutically acceptable salt of the compound of formula I, crystalline form A of the hydrochloride salt of the compound of formula I, crystalline form B of the methanesulfonate salt of the compound of formula I, crystalline form C of the methanesulfonate salt of the compound of formula I, crystalline form D of the phosphate salt of the compound of formula I, crystalline form E of the L-tartrate salt of the compound of formula I, crystalline form F of the hydrobromide salt of the compound of formula I, or the composition in the manufacture of a medicament for the prevention and / or treatment of asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, α1-antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease, rheumatoid arthritis, rhinosinusitis, hidradenitis suppurativa, or cancer. 【0064】 The present disclosure also relates to a method for preventing and / or treating asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, α1-antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease, rheumatoid arthritis, rhinosinusitis, hidradenitis suppurativa, or cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of the compound of formula I, crystalline form A of the hydrochloride salt of the compound of formula I, crystalline form B of the methanesulfonate salt of the compound of formula I, crystalline form C of the methanesulfonate salt of the compound of formula I, crystalline form D of the phosphate salt of the compound of formula I, crystalline form E of the L-tartrate salt of the compound of formula I, crystalline form F of the hydrobromide salt of the compound of formula I, or the composition. 【0065】 The present disclosure also relates to a pharmaceutically acceptable salt of the compound of formula I, crystalline form A of the hydrochloride salt of the compound of formula I, crystalline form B of the methanesulfonate salt of the compound of formula I, crystalline form C of the methanesulfonate salt of the compound of formula I, crystalline form D of the phosphate salt of the compound of formula I, crystalline form E of the L-tartrate salt of the compound of formula I, crystalline form F of the hydrobromide salt of the compound of formula I, or the composition for use in the prevention and / or treatment of asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, α1-antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease, rheumatoid arthritis, rhinosinusitis, hidradenitis suppurativa, or cancer. 【0066】 As used herein, the term "excipient" includes, but is not limited to, any adjuvant, carrier, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent or emulsifying agent approved by the US Food and Drug Administration and acceptable for use in humans or domestic animals. 【0067】 The starting material used in the method for producing the crystalline form of the present disclosure can be a compound in any form, and specific forms include, but are not limited to, amorphous form, any crystalline form, hydrate, solvate, etc. 【0068】 As used herein, the term "differential scanning calorimetry or DSC" means measuring the temperature difference and heat flow difference between a sample and a reference during the heating or isothermal process of the sample, characterizing all physical and chemical changes related to the thermal effect, and obtaining the phase change information of the sample. 【0069】 In the present disclosure, the values related to the determination and calculation of the substance content inevitably have a certain degree of error. Generally, ±10% belongs to a reasonable error range. The degree of error varies depending on the situation used, and the error is 10% or less, and may be 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1%, preferably 5%. 【Brief Description of the Drawings】 【0070】 【Figure 1】 Figure 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form A of the hydrochloride salt of the compound of formula I; 【Figure 2】 Figure 2 is a DSC spectrum of crystalline form A of the hydrochloride salt of the compound of formula I; 【Figure 3】 Figure 3 is a thermogravimetric analysis (TGA) spectrum of crystalline form A of the hydrochloride salt of the compound of formula I; 【Figure 4】 Figure 4 is a dynamic vapor sorption (DVS) plot of crystalline form A of the hydrochloride salt of the compound of formula I; 【Figure 5】Figure 5 shows the XRPD patterns before and after DVS of crystalline form A of the hydrochloride salt of the compound of formula I, where the upper XRPD pattern is the pattern before DVS and the lower XRPD pattern is the pattern after DVS; 【Figure 6】 Figure 6 shows the XRPD pattern of crystalline form B of the methanesulfonate salt of the compound of formula I; 【Figure 7】 Figure 7 shows the DSC spectrum of crystalline form B of the methanesulfonate salt of the compound of formula I; 【Figure 8】 Figure 8 shows the TGA spectrum of crystalline form B of the methanesulfonate salt of the compound of formula I; 【Figure 9】 Figure 9 shows the XRPD pattern of crystalline form C of the methanesulfonate salt of the compound of formula I; 【Figure 10】 Figure 10 shows the DSC spectrum of crystalline form C of the methanesulfonate salt of the compound of formula I; 【Figure 11】 Figure 11 shows the TGA spectrum of crystalline form C of the methanesulfonate salt of the compound of formula I; 【Figure 12】 Figure 12 shows the XRPD pattern of crystalline form D of the phosphate salt of the compound of formula I; 【Figure 13】 Figure 13 shows the DSC spectrum of crystalline form D of the phosphate salt of the compound of formula I; 【Figure 14】 Figure 14 shows the TGA spectrum of crystalline form D of the phosphate salt of the compound of formula I; 【Figure 15】 Figure 15 shows the XRPD pattern of crystalline form E of the L-tartrate salt of the compound of formula I; 【Figure 16】 Figure 16 shows the DSC spectrum of crystalline form E of the L-tartrate salt of the compound of formula I; 【Figure 17】 Figure 17 shows the TGA spectrum of crystalline form E of the L-tartrate salt of the compound of formula I; 【Figure 18】 Figure 18 shows the XRPD pattern of crystalline form F of the hydrobromide salt of the compound of formula I; 【Figure 19】 Figure 19 shows the DSC spectrum of crystalline form F of the hydrobromide salt of the compound of formula I; 【Figure 20】Figure 20 is the TGA spectrum of crystalline form F of the hydrobromide salt of the compound of formula I; 【Figure 21】 Figure 21 is the nuclear magnetic resonance (NMR) spectrum of crystalline form F of the hydrobromide salt of the compound of formula I; 【Figure 22】 Figure 22 is the XRPD pattern of crystalline form A' of the hydrochloride salt of the compound of formula I; 【Figure 23】 Figure 23 is the DSC spectrum of crystalline form A' of the hydrochloride salt of the compound of formula I; 【Figure 24】 Figure 24 is the TGA spectrum of crystalline form A' of the hydrochloride salt of the compound of formula I. 【Mode for Carrying Out the Invention】 【0071】 The present disclosure will be described in more detail through the following examples or experimental examples. The examples or experimental examples of the present disclosure are only intended to explain the technical solutions of the present disclosure and should not be regarded as limiting the spirit and scope of the present disclosure. 【0072】 The abbreviations used in the present disclosure are explained below: XRPD X-ray powder diffraction DSC Differential scanning calorimetry TGA Thermogravimetric analysis DVS Dynamic vapor sorption 1 1H-NMR Solution nuclear magnetic resonance hydrogen spectroscopy DMF N,N-Dimethylformamide MEK Butanone MTBE Methyl tert-butyl ether THF Tetrahydrofuran IPA Isopropanol ACN Acetonitrile MeOH Methanol EOH Ethanol ACT Acetone PA Phosphoric acid TA Tartaric acid HBr Hydrobromic acid HCl Hydrochloric acid DCM Dichloromethane 【0073】 Test conditions of the equipment used in the experiments of the present disclosure: 1. X-ray powder diffraction, XRPD Equipment type: Malver Panalytical Aeris X-ray powder diffractometer Radiation: Monochromatic Cu-Kα ray (λ = 1.54188) Scan mode: θ / 2θ, Scan range (2θ range): 3.5 - 50° Voltage: 40 kV, Current: 15 mA 【0074】 2. Differential scanning calorimetry, DSC Equipment type: TA DSC250 Purge gas: Nitrogen; Nitrogen purge rate: 50 mL / min Heating rate: 10 °C / min Temperature range: 25 °C - 250 °C 【0075】 3. Thermogravimetric analysis, TGA Equipment type: TA TGA550 Purge gas: Nitrogen; Nitrogen purge rate: 20 ml / min Scan rate: 10 °C / min Temperature range: 30 °C - 350 °C 【0076】 4. Dynamic vapor sorption (DVS) Using SMS Intrinsic PLUS, at 25 °C, with a humidity change of 50% - 0% - 90% and a step width of 10%, detection is performed, and the criteria are that the mass change dM / dT of each gradient is less than 0.002%, TMAX is 360 minutes, and 2 cycles are performed. 【0077】 5. The high performance liquid chromatography (HPLC) described in the stability test of crystalline form A of the present disclosure is determined by Agilent 1260 Infinity II. 【0078】 In the content detection method by high performance liquid chromatography described in the present disclosure, the HPLC conditions are as follows: chromatography column, Agilent Eclipse Plus C18 4.6 mm × 150 mm, 3.5 μm; mobile phase, A - 10 mmol / L sodium dihydrogen phosphate solution (pH 8.0) and B - ACN; flow rate, 1.0 ml / min; wavelength, 210 nm. 【0079】 In the related substance detection method by high performance liquid chromatography described in the present disclosure, the HPLC conditions are as follows: chromatography column, Agilent Eclipse Plus C18 4.6 mm × 150 mm, 3.5 μm; mobile phase, A - 10 mmol / L ammonium acetate solution and B - ACN; flow rate, 1.0 ml / min; wavelength, 210 nm. 【Example】 【0080】 Example 1: (S)-N-((S)-1-cyano-2-(8-cyano-2-fluoro-6H-benzo[c]chromen-3-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound of formula I): 【Chemical formula】 Production 【Chemical formula】 【0081】 Synthesis of compound I-2 Methyl 2-fluoro-5-hydroxybenzoate (4.30 g, 25.29 mmol), 4-bromo-3-(bromomethyl)benzonitrile (Compound I-1) (7.72 g, 25.30 mmol), and potassium carbonate (6.99 g, 50.58 mmol) were dissolved in N,N-dimethylformamide (50 mL) at room temperature, and the reaction mixture was heated to 40 °C and stirred for 12 hours. Water (300 mL) was added thereto, and the mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 9 / 1) to obtain Compound I-2. 1 1H NMR (400 MHz, CDCl 3 ) δ 7.87 (d, 1H), 7.73 (d, 1H), 7.55 - 7.48 (m, 2H), 7.18 - 7.09 (m, 2H), 5.11 (s, 2H), 3.95 (s, 3H). 【0082】 Synthesis of Compound I-3 Compound I-2 (2.90 g, 6.37 mmol), palladium(II) acetate (0.14 g, 0.64 mmol), potassium carbonate (1.76 g, 12.73 mmol), and tricyclohexylphosphine tetrafluoroborate (0.23 g, 0.64 mmol) were dissolved in N,N-dimethylformamide (30 mL) at room temperature under a nitrogen atmosphere, and the reaction mixture was heated to 120 °C and stirred for 1.5 hours. After completion of the reaction, the resulting mixture was cooled to room temperature, and then water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 4 / 1) to obtain Compound I-3. 1 1H NMR (400 MHz, CDCl 3 ) δ 7.80 - 7.72 (m, 2H), 7.60 (d, 1H), 7.52 - 7.49 (m, 2H), 5.18 (s, 2H), 3.98 (s, 3H). 【0083】 Synthesis of Compound I-4 Compound I-3 (1.20 g, 3.81 mmol) and lithium borohydride (0.25 g, 11.47 mmol) were dissolved in tetrahydrofuran (25 mL) at room temperature, and the reaction mixture was heated to 55 °C and stirred for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, followed by addition of water (200 mL), and the mixture was extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 9 / 1) to obtain Compound I-4. 1 H NMR (400 MHz, CDCl 3 ) δ 7.67 (s, 2H), 7.47 (s, 1H), 7.38 (d, 1H), 7.12 (d, 1H), 5.11 (s, 2H), 4.77 (s, 2H). 【0084】 Synthesis of Compound I-5 Compound I-3 (450 mg, 1.59 mmol) was dissolved in dichloromethane (15 mL), and then phosphorus tribromide (520 mg, 1.92 mmol) was added dropwise at room temperature, and the reaction mixture was stirred at room temperature for 20 minutes. After completion of the reaction, water (100 mL) was added, and the obtained mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 9 / 1) to obtain Compound I-5. 1 H NMR (300 MHz, CDCl 3 ) δ 7.73 (s, 2H), 7.52 (s, 1H), 7.45 (d, 1H), 7.10 (d, 1H), 5.17 (s, 2H), 4.53 (s, 2H). 【0085】 Synthesis of Compound I-6 N-(Diphenylmethylene)aminoacetonitrile (250 mg, 1.14 mmol), Compound I-5 (470 mg, 1.26 mmol), benzyltrimethylammonium chloride (22 mg, 0.12 mmol) and sodium hydroxide (91 mg, 2.3 mmol) were dissolved in a mixed solvent of dichloromethane (6 mL) and water (6 mL) at room temperature, and the reaction mixture was heated to 35 °C and stirred for 24 hours. Water (30 mL) was added thereto, and the resulting mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 4 / 1) to obtain Compound I-6. MS-ESI: m / z 458.4 [M+1] + . 【0086】 Synthesis of Compound I-7 Compound I-6 (520 mg, 0.90 mmol) was dissolved in tetrahydrofuran (10 mL), and then 1 M aqueous hydrochloric acid solution (4 mL) was added dropwise at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, saturated aqueous sodium bicarbonate solution (30 mL) was added, and the resulting mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 2 / 1) to obtain Compound I-7. MS-ESI: m / z 293.9 [M+1] + . 【0087】 Synthesis of Compound I-8 Compound I-7 (220 mg, 0.68 mmol), compound a (170 mg, 0.69 mmol), N,N,N’,N’-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (360 mg, 0.95 mmol) and N,N-diisopropylethylamine (250 mg, 1.93 mmol) were dissolved in N,N-dimethylformamide (5 mL) at room temperature, and the reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, the resulting mixture was purified by preparative liquid chromatography (C18, acetonitrile / water system) to obtain compound I-8. MS-ESI: m / z 465.1 [M-56+1] + . 【0088】 Synthesis of compound I-9 Compound I-8 (280 mg, 0.51 mmol) was subjected to chiral resolution (column: chiralpak IE, 250×25 mm, 5 μm, mobile phase: n-hexane, ethanol, gradient: 30% n-hexane phase, flow rate: 15 mL / min, column temperature: 30 °C) to obtain compound I-9 (a total of two diastereomeric peaks, with compound I-9 being the first eluted peak). 1 1H NMR (300 MHz, DMSO-d 6 ) δ 8.89 (d, 1H), 8.08 (d, 1H), 7.94 - 7.89 (m, 2H), 7.83 (s, 1H), 7.07 (d, 1H), 5.24 - 5.14 (m, 2H), 5.09 - 5.07 (m, 1H), 4.15 - 4.12 (m, 1H), 3.99 - 3.87 (m, 2H), 3.63 - 3.56 (m, 2H), 3.29 - 3.02 (m, 4H), 1.89 - 1.79 (m, 2H), 1.41 - 1.36 (m, 9H). 【0089】 Synthesis of compound I Compound I-9 (85 mg, 0.16 mmol) was dissolved in formic acid (1 mL) at room temperature, and the reaction mixture was heated to 40 °C and stirred for 1 hour. After completion of the reaction, the resulting mixture was purified by preparative liquid chromatography (C18, ammonium bicarbonate / acetonitrile / water system) to obtain compound I. The obtained compound was determined to be amorphous by XRPD. MS-ESI: m / z 421.2 [M+1]+ . 1 1H NMR(400MHz,DMSO-d 6 )δ8.69(d,1H), 8.05(d,1H), 7.89 - 7.86(m,2H), 7.80(s,1H), 7.03(d,1H), 5.20 - 5.12(m,2H), 5.09 - 5.02(m,1H), 4.00 - 3.97(m,1H), 3.88 - 3.83(m,1H), 3.77 - 3.68(m,1H), 3.25 - 3.14(m,2H), 3.05 - 2.98(m,1H), 2.82 - 2.72(m,1H), 2.62 - 2.53(m,2H), 1.80 - 1.66(m,2H). 【0090】 Example 2: Biological Evaluation of the Compound of Formula I - In vitro CatC Cell Activity Experiment 1. Experimental Materials [Table 1] 【0091】 2. Experimental Procedures Complete culture medium RPMI 1640 + 10% FBS was prepared and mixed well. The U937 cell line was revived and subcultured about twice, and a cell line in good growth condition was selected. The cell suspension was transferred to a centrifuge tube and centrifuged at 800 - 1000 rpm for 3 - 5 minutes. The supernatant was discarded. An appropriate amount of culture medium was added to the centrifuge tube and gently transferred with a pipette to resuspend the cells uniformly. The cells were counted using a Vi-Cell XR cell counter. The cell suspension was adjusted to an appropriate concentration. The cell suspension was added to a 384-well plate at 25000 μL / well. The compound was prepared as a 10 mM solution in DMSO, diluted with DMSO to obtain a 1 mM solution, and subjected to a logarithmic dilution with HPD300 in DMSO to obtain 10 concentrations. Gly-Phe-AFC was formulated as a 35 mM solution in DMSO and divided. Gly-Phe-AFC was formulated to 1.75 mM in serum-free medium. After adding the compound and incubating in an incubator for 1 hour, the substrate-AFC was added (12.5 μL was added to the plate). After incubating the plate for 30 minutes, it was measured. The plate was placed on an EnSpire for reading, and the fluorescence values were recorded at Ex 400 nm and Em 505 nm. The inhibition rate was calculated according to the following formula: Inhibition rate (%) = (1 - (RFU compound - RFU blank) / (RFU DMSO - RFU blank)) × 100%. XLFit was used to draw a drug efficacy inhibition rate curve and calculate the IC 50 value. A 4-parameter model [Fit = (A + ((B - A) / (1 + ((C / x)^D))))] was used. 【0092】 By the above test, the in vitro inhibition of the compound of formula I of the present disclosure on CatC cell activity was determined, and the determined IC 50 value was 6.1 nM, indicating that the inhibitory effect on CatC cell activity is significant. 【0093】 Example 3: Preparation of Crystal Form A of the Hydrochloride Salt of the Compound of Formula I Method 1: The compound of formula I (1.01 g) was added to 76 mL of acetone and stirred at 60 °C. After the solution became clear, 586.0 μL of dilute hydrochloric acid solution (500 μL of hydrochloric acid and 500 μL of purified water were measured and mixed well before use) was added. After dropping the hydrochloric acid, a precipitation phenomenon occurred. The heating was stopped and the mixture was stirred overnight. The next day, the sample was poured onto filter paper, air-dried in a draft, collected, and 960 mg of the hydrochloride salt of the compound of formula I (off-white solid, yield: 95%) was obtained and stored in a sealed manner. 【Chemical formula】 【0094】 The product was detected by X-ray powder diffraction and determined to be crystalline form A of the hydrochloride salt of the compound of formula I. The XRPD pattern is shown in Figure 1, and the positions of the characteristic peaks are shown in Table 1. The DSC spectrum has an endothermic peak at about 268 °C as shown in Figure 2. As shown in Figure 3, the TGA spectrum shows a sharp weight loss at 200 °C or higher. 【0095】 The chloride ion content of the sample of crystalline form A was determined by ion chromatography. The result was 7.64%, which was substantially consistent with the theoretical value of 7.7% for 1 mole of hydrochloride salt, confirming that hydrochloric acid and the free base of the compound of formula I formed a salt in a molar ratio of 1:1. 【0096】 As shown in Figure 4, DVS detection shows that the weight increase due to moisture absorption under accelerated experimental conditions (i.e., 80% RH) is about 1.1%. During the change of humidity from 0% to 90% RH, the desorption process of the sample is consistent with its adsorption process. After DVS detection, the crystal form was redetermined, and the XRPD pattern is shown in Figure 5, indicating that the crystal form did not change before and after DVS detection. 【0097】 【Table 2】 【0098】 Method 2: 30 mg of the free base of the compound of formula I was added to 0.3 mL of the solvent in Table 2, and a suspension was obtained under stirring conditions. 4 mol / L aqueous hydrochloric acid was added to the suspension at a molar ratio of 1.2:1 with respect to the free base, and the volume of the liquid was supplemented to 1.2 mL. The mixture was stirred at 50 °C for 3 hours, then cooled to 25 °C and kept at this temperature with stirring overnight. The solid precipitated from the system was centrifuged and dried at 60 °C under reduced pressure for 6 hours to obtain a solid. The obtained solid was determined to be crystalline form A by XRPD detection. 【0099】 【Table 3】 【0100】 Method 3: 10 mg of the hydrochloride salt of the compound of formula I was added to 0.2 ml of the solvent as shown in Table 3, kept in a fine powder state in the solvent, and stirred for 1 week. The solvent was quickly removed using filter paper, and the obtained solid was determined to be crystalline form A by XRPD detection. 【0101】 【Table 4】 【0102】 Example 4: Preparation of Crystalline Form B of the Methanesulfonate Salt of the Compound of Formula I 15 mg of the compound of formula I was dissolved in 1 ml of DMF, and methanesulfonic acid (4.1 mg) was added. The solution was heated to 50 °C, stirred at a constant temperature of 50 °C for 4 hours, then cooled to 0 °C, and the reaction was continued with stirring at a controlled temperature for 2 days or more. After vacuum drying, a solid was obtained as crystalline form B of the methanesulfonate salt of the compound of formula I. The XRPD pattern is shown in Figure 6, and the positions of the characteristic peaks are shown in Table 4. The DSC spectrum is shown in Figure 7, having an endothermic peak at 161 °C, indicating low crystallinity. The TGA spectrum is shown in Figure 8. 【0103】 【Table 5】 【0104】 Example 5: Preparation of Crystal Form C of Methanesulfonate Salt of the Compound of Formula I 15 mg of the compound of Formula I was dissolved in 1 ml of DCM, and methanesulfonic acid (4.1 mg) was added. The solution was heated to 50 °C and stirred at a constant temperature of 50 °C for 4 hours, then cooled to 0 °C and stirred at a controlled temperature for more than 2 days to continue the reaction. After vacuum drying, the obtained solid was determined to be Crystal Form C of the methanesulfonate salt of the compound of Formula I by XRPD. The XRPD detection data of Crystal Form C of the methanesulfonate salt of the compound of Formula I are shown in Table 5, and the XRPD pattern is shown in Figure 9. The DSC spectrum is shown in Figure 10 and has an endothermic peak at about 194 °C. The TGA spectrum is shown in Figure 11. 【0105】 [Table 6] 【0106】 Example 6: Preparation of Crystal Form D of Phosphate Salt of the Compound of Formula I 15 mg of the compound of Formula I was dissolved in 1 ml of DCM, and phosphoric acid (4.2 mg) was added. The solution was heated to 50 °C and stirred at a constant temperature of 50 °C for 4 hours, then cooled to 0 °C and stirred at a controlled temperature for more than 2 days to continue the reaction. After vacuum drying, the obtained solid was determined to be Crystal Form D of the phosphate salt of the compound of Formula I by XRPD. The XRPD detection data of Crystal Form D of the phosphate salt of the compound of Formula I are shown in Table 6, and the XRPD pattern is shown in Figure 12. The DSC spectrum is shown in Figure 13 and has endothermic peaks at 130 °C and 143 °C. The TGA spectrum is shown in Figure 14. As a result of ion chromatography detection, the phosphate group content was 24.18%, indicating that a salt was formed with a ratio of phosphoric acid to free base of about 1:1. 【0107】 [Table 7] 【0108】 Example 7: Preparation of Crystal Form E of L-Tartrate Salt of the Compound of Formula I 15 mg of the compound of formula I was dissolved in 1 ml of DMF, and L-tartaric acid (6.4 mg) was added. The solution was heated to 50 °C and stirred at a constant temperature of 50 °C for 4 hours, then cooled to 0 °C and stirred at a controlled temperature for more than 2 days to continue the reaction. After vacuum drying, the obtained solid was determined to be crystalline form E of the L-tartrate salt of the compound of formula I by XRPD. The XRPD detection data of crystalline form E of the L-tartrate salt of the compound of formula I are shown in Table 7, and the XRPD pattern is shown in Figure 15. The DSC spectrum is shown in Figure 16 and has an endothermic peak at 132 °C. The TGA spectrum is shown in Figure 17. 【0109】 【Table 8】 【0110】 Example 8: Preparation of Crystalline Form F of the Hydrobromide Salt of the Compound of Formula I 80 mg of the compound of formula I was dissolved in 1 ml of dioxane, and hydrobromic acid was added at a molar ratio of acid to API of 1.2:1. When stirred at room temperature for 12 hours, a solid precipitated. After vacuum drying, the obtained solid was determined to be crystalline form F of the hydrobromide salt of the compound of formula I by XRPD. The XRPD detection data are shown in Table 8, and the XRPD pattern is shown in Figure 18. The DSC spectrum is shown in Figure 19 and has endothermic peaks at 99 °C and 216 °C. The TGA spectrum is shown in Figure 20. The NMR results (Figure 21) showed that the ratio of compound I to hydrobromic acid was about 1:1 to form a salt. 【0111】 【Table 9】 【0112】 Example 9: Stability Test of Crystalline Form A of the Hydrochloride Salt of the Compound of Formula I Determine whether light, temperature, and humidity affect the stability of crystalline form A of the hydrochloride salt of the compound of formula I. Crystalline form A of the hydrochloride salt was placed in a stabilization chamber in the dark and subjected to stress tests using a series of temperature and humidity combinations. After being placed under light and various temperature and humidity conditions for different numbers of days, the samples were taken out and compared with the original crystalline form A of the hydrochloride salt. According to the determination by high-performance liquid chromatography, as shown in Table 9, no significant increase in the isomers of the compound of formula I was observed in any of the samples. When the samples taken out on the last day were subjected to XRPD detection under light and various temperature and humidity conditions, there was no change in crystalline form A of the hydrochloride salt, indicating good stability. 【0113】 【Table 10】 【0114】 Example 10: Preparation of Crystalline Form A’ of the Hydrochloride Salt of the Compound of Formula I Weighed 0.42 g (0.1 mmol) of the compound of formula I, added it to 25 ml of ethanol, stirred at 70 °C, filtered after the solution became clear. A white solid precipitated from the filtrate. The bottle containing the filtrate was transferred to an oil bath at 70 °C, and after the solution became clear, 2 ml of a solution of hydrochloric acid and ethanol (1:1) was added to precipitate a large amount of solid. The mixture was cooled to room temperature, crystallized for 4 hours, and filtered. The filter cake was dried at 50 °C for 12 hours to obtain 0.39 g of crystalline form A’ with a yield of 85.5%. The XRPD pattern is shown in Figure 22, and the positions of the characteristic peaks are shown in Table 10. The DSC spectrum is shown in Figure 23, having an endothermic peak at 161 °C, indicating low crystallinity. The TGA spectrum is shown in Figure 24. 【0115】 【Table 11】
Claims
[Claim 1] Formula I: 【Chemistry 1】 A pharmaceutically acceptable salt of the compound, The pharmaceutically acceptable salt is an acid addition salt selected from the group consisting of hydrochloride, methanesulfonate, phosphate, L-tartrate, maleate, p-toluenesulfonate, sulfate, fumarate, succinate, citrate, malate, and hydrobromide, and is preferably in crystalline form, and is a pharmaceutically acceptable salt of the compound of formula I. [Claim 2] The stoichiometric ratio of the compound of formula I to the acid molecule or acid group is 1:0.5 to 1:3, preferably 1:0.5, 1:1, 1:1.2, 1:2, or 1:3; especially, The pharmaceutically acceptable salt of the compound of formula I according to claim 1, wherein the pharmaceutically acceptable salt of the compound of formula I is a hydrochloride salt, and the stoichiometric ratio of the compound of formula I to the hydrochloric acid group is 1:
1. [Claim 3] A method for producing a pharmaceutically acceptable salt of a compound of formula I according to claim 1 or 2, The process includes the step of chlorinating the compound of formula I with an acid; especially, A method for producing a pharmaceutically acceptable salt of a compound of formula I, wherein the step of chlorinating the compound of formula I with an acid is carried out in a solvent selected from one or more of dichloromethane, N,N-dimethylformamide, acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, 1,4-dioxane, water, dimethyl sulfoxide, and ethyl acetate, preferably in a solvent selected from acetone, methanol, ethanol, ethanol / water, isopropanol / water, ethyl acetate, acetonitrile, tetrahydrofuran, dimethyl sulfoxide / water, 1,4-dioxane, methanol / water, N,N-dimethylformamide, and dichloromethane. [Claim 4] The X-ray powder diffraction pattern, represented by a diffraction angle of 2θ, has characteristic peaks at 7.043, 12.430, 14.356, 14.840, and 15.250, preferably at 7.043, 8.719, 10.737, 12.430, 14.356, 14.840, 15.250, and 17.686, more preferably at 7.043, 8.719, 10.737, 12.430, 14.356, 14.840, 15.250, 17.686, 21.697, 22.305, 25.635, and 27.433, with an error range of ±0.20 for 2θ, Equation I: 【Chemistry 2】 Crystalline form A of the hydrochloride salt of the compound. [Claim 5] Crystalline form A of the hydrochloride salt of the compound of formula I according to claim 4, having an endothermic peak at 268°C and an error range of ±2°C in differential scanning calorimetry (DSC) spectra. [Claim 6] The X-ray powder diffraction pattern, represented by a diffraction angle of 2θ, has characteristic peaks at 8.452, 12.476, 15.884, 17.037, 17.227, 22.328 and 23.566, preferably having characteristic peaks at 8.452, 10.537, 12.476, 15.884, 17.037, 17.227, 20.784, 22.328, 23.566 and 27.567, more preferably at 8.452, 10.537, 12.476, 13.296 and 14.3 The formula has characteristic peaks at 32, 15.884, 17.037, 17.227, 20.784, 22.328, 23.566 and 27.567, most preferably at 8.452, 10.537, 12.476, 13.296, 14.332, 15.884, 17.037, 17.227, 20.784, 21.329, 22.328, 23.566, 24.497, 25.221 and 27.567, and the error range of the 2θ angle is ±0.20, Equation I: 【Transformation 3】 Crystalline form A' of the hydrochloride salt of the compound. [Claim 7] Crystalline form A' of the hydrochloride salt of the compound of formula I according to claim 6, having an endothermic peak at 263°C in the DSC spectrum and an error range of ±2°C. [Claim 8] The X-ray powder diffraction pattern, represented by a diffraction angle of 2θ, has characteristic peaks at 6.717, 8.783, 13.969, 15.902, 16.647 and 17.515, preferably at 6.717, 8.105, 8.783, 13.969, 15.902, 16.647 and 17.515, and more preferably at 6.717, 8.105, 8.783, 13.969, 15.902, 16.647 and 17. The formula has characteristic peaks at 515, 20.446, 21.069, 21.645 and 24.665, most preferably at 6.717, 8.105, 8.783, 13.969, 15.902, 16.647, 17.515, 20.446, 21.069, 21.645, 23.549, 24.665, 26.284, 27.289 and 27.667, with an error range of ±0.20 for the 2θ angle, formula I: 【Chemistry 4】 The crystalline form B of the compound methanesulfonate. [Claim 9] Crystalline form B of the methanesulfonate of the compound of formula I according to claim 8, having an endothermic peak at 161°C in the DSC spectrum and an error range of ±2°C. [Claim 10] The X-ray powder diffraction pattern, represented by a diffraction angle of 2θ, has characteristic peaks at 7.747, 11.163, 12.676, 15.268, 16.824, 18.549 and 19.759, preferably having characteristic peaks at 4.522, 7.747, 11.163, 12.676, 15.268, 16.824, 18.549 and 19.759, more preferably at 4.522, 7.747, 11.163, and 12.67 The formula has characteristic peaks at 6, 15.268, 16.824, 18.549, 19.759, 21.460, 24.637 and 25.497, most preferably having characteristic peaks at 4.522, 7.747, 11.163, 12.676, 15.268, 16.824, 18.549, 19.759, 21.460, 22.539, 24.637 and 25.497, with an error range of ±0.20 for the 2θ angle, Equation I: 【Transformation 5】 The crystalline form C of the compound methanesulfonate. [Claim 11] Crystalline form C of the methanesulfonate of the compound of formula I according to claim 10, having an endothermic peak at 194°C in the DSC spectrum and an error range of ±2°C. [Claim 12] The X-ray powder diffraction pattern, represented by a diffraction angle of 2θ, has characteristic peaks at 9.593, 12.831, 13.464, 15.666, 18.161, and 19.245, preferably at 8.491, 9.593, 12.831, 13.464, 13.954, 14.943, 15.666, 16.616, 17.259, 18.161, and 19.245, and more preferably at 4.213, 6.650, 8.491, 9.593, 10.897, 12.831, and 13.46 The formula has characteristic peaks at 4, 13.954, 14.943, 15.666, 16.616, 17.259, 18.161 and 19.245, most preferably at 4.213, 6.650, 8.491, 9.593, 10.897, 12.831, 13.464, 13.954, 14.943, 15.666, 16.616, 17.259, 18.161, 19.245, 24.822, 25.665 and 26.618, and the error range of 2θ angle is ±0.20, Equation I: 【Transformation 6】 The crystalline form D of the compound phosphate. [Claim 13] Crystalline form D of the phosphate of the compound of formula I according to claim 12, having endothermic peaks at 130°C and 143°C in the DSC spectrum, with an error range of ±2°C. [Claim 14] The X-ray powder diffraction pattern, represented by a diffraction angle of 2θ, has characteristic peaks at 6.383, 9.081, 12.936, 16.161, and 18.397, preferably at 6.383, 9.081, 12.936, 14.400, 16.161, 18.397, and 19.489, more preferably at 6.383, 9.081, 12.936, 14.400, 16.161, 18.397, 19.489, 23.786, 24.536, and 26.203, and the error range of 2θ is ±0.20, Equation I: 【Transformation 7】 Crystal form E of the L-tartrate salt of the compound. [Claim 15] Crystal form E of the L-tartrate of the compound of formula I according to claim 14, having an endothermic peak at 132°C in the DSC spectrum and an error range of ±2°C. [Claim 16] The X-ray powder diffraction pattern, represented by a diffraction angle of 2θ, has characteristic peaks at 7.133, 12.485, 14.422, 17.721, and 18.823, preferably at 6.152, 7.133, 10.827, 12.485, 14.422, 17.721, and 18.823, more preferably at 6.152, 7.133, 10.827, 12.485, 14.422, 17.721, 18.823, 20.738, 21.656, 22.309, 23.238, 25.116, 25.672, and 27.416, and the error range of 2θ is ±0.20, Equation I: 【Transformation 8】 The crystalline form F of the compound hydrobromide salt. [Claim 17] Crystalline form F of the hydrobromide salt of the compound of formula I according to claim 16, having endothermic peaks at 99°C and 216°C in the DSC spectrum, with an error range of ±2°C. [Claim 18] A pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of formula I as described in claim 1 or 2, or a crystalline form as described in any one of claims 4 to 17, and a pharmaceutically acceptable excipient. [Claim 19] The pharmaceutical composition according to claim 18 for the prevention and / or treatment of asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, α1-antitrypsin deficiency, lupus nephritis, diabetes mellitus, inflammatory bowel disease, rheumatoid arthritis, sinusitis, hidradenitis suppurativa, or cancer.