Pharmaceutical salts of benzo [c] chroman compounds, polymorphs and uses thereof
Patent Information
- Application Number
- CN202380039466.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2022-06-07
- Filing Date
- 2023-06-05
- Publication Date
- 2024-12-17
AI Technical Summary
Polymorphic forms of drugs have different requirements for product storage, production and amplification, and amorphous drug products have poor stability, fine crystallization, difficulty in filtration, easy agglomeration, and poor fluidity, which affects the chemical stability and storage conditions of the compounds.
Provides a pharmaceutically acceptable salt of benzo[c]chroman compound, including acid addition salts such as hydrochloride, methanesulfonate, phosphate, etc., which can form a stable salt through specific chemical proportions and preparation methods. Polymorphic forms, such as hydrochloride A crystal form, mesylate B crystal form, etc., optimize the physical properties of the compound.
It improves the chemical stability and storage conditions of the compound, improves the convenience of production and scale-up, enhances the fluidity and filterability of the drug, and meets the diverse needs of polymorphic products.
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Abstract
Description
Pharmaceutically acceptable salts of benzo[c]chroman compounds, their polymorphs and uses Technical Field
[0001] The present disclosure belongs to the field of medical technology and relates to a pharmaceutically acceptable salt of a benzo[c]chroman compound, its polymorphic form and use. Background Art
[0002] Cathepsins are a class of proteolytic enzymes found widely within the lysosomes of various tissue cells. Based on their structure and catalytic activity, cathepsins are divided into three categories: serine proteases (cathepsins A and G), aspartic proteases (cathepsins D and E), and cysteine proteases. Cysteine proteases are the largest family of cathepsins and include 11 proteases: cathepsins B, C, F, H, K, L, O, S, W, V, and Z.
[0003] Cathepsin C, also known as dipeptidyl peptidase I or "DPP1," is constitutively expressed in many tissues, with the highest levels in the lung, kidney, liver, and spleen. Recently published studies have begun to describe the role of cathepsin C in certain inflammatory processes. For example, Adkison et al., J Clin Invest. 2002 Feb;109(3):363-71; Tinh et al., Archives of Biochemistry and Biophysics. 2002 403:160-170. These studies suggest that cathepsin C is co-expressed with certain serine proteases in granules and functions to process the precursor forms of these proteases into active forms, which are then released from inflammatory cell granules recruited to sites of inflammation. Once activated, these proteases have many functions, including the degradation of various extracellular matrix components, which together can propagate tissue damage and chronic inflammation.
[0004] WO 2004 / 110988 relates to certain nitrile derivatives and their use as DPP1 inhibitors.
[0005] WO 2009 / 074829 relates to peptidyl nitriles and their use as DPP1 inhibitors.
[0006] WO 2010 / 128324 relates to α-aminoamide nitriles and their use as DPP1 inhibitors.
[0007] WO 2012 / 119941 relates to peptidyl nitrile compounds and their use as DPP1 inhibitors.
[0008] WO 2013 / 041497 relates to N-[1-cyano-2-(phenyl)ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamides and their use as DPP1 inhibitors.
[0009] WO 2001 / 096285 and WO 2003 / 048123 relate to β-aminoamide nitriles having inhibitory activity against cysteine proteases.
[0010] WO 2015 / 110826 relates to α-aminoamide nitriles and their use as DPP1 inhibitors.
[0011] WO 2022 / 117059 provides a cathepsin C inhibitor, whose chemical name is (S)-N-((S)-1-cyano-2-(8-cyano-2-fluoro-6H-benzo[c]chroman-3-yl)ethyl)-1,4-oxazepane-2-carboxamide, and has the structure shown in Formula I.
[0012] The crystal form of a pharmaceutically active ingredient often affects the chemical stability of the drug. Differences in crystallization and storage conditions can lead to variations in the compound's crystal structure, sometimes resulting in the formation of alternative morphologies. Generally speaking, amorphous pharmaceutical products lack a regular crystal structure and often exhibit other drawbacks, such as poor product stability, fine crystallization, difficulty in filtration, susceptibility to agglomeration, and poor flowability. Polymorphic drug forms impose varying requirements on product storage, production, and scale-up. Therefore, in-depth research into the crystal forms of these compounds is essential to improve their various properties.
[0013] Summary of the Invention
[0014] The present disclosure provides a pharmaceutically acceptable salt of a compound of formula I, wherein the pharmaceutically acceptable salt is an acid addition salt selected from hydrochloride, methanesulfonate, phosphate, L-tartrate, maleate, p-toluenesulfonate, sulfate, fumarate, succinate, citrate, malate and hydrobromide. Preferably, the pharmaceutically acceptable salt is in a crystalline form.
[0015] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula I, wherein the chemical ratio of the compound of Formula I to the acid molecule or acid radical is 1:0.5 to 1:3, preferably 1:0.5, 1:1, 1:1.2, 1:2 or 1:3; more preferably 1:1.
[0016] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula I, wherein the pharmaceutically acceptable salt of the compound of Formula I is hydrochloride, the chemical ratio of the compound of Formula I to hydrochloride is 1:1.
[0017] The present disclosure also provides a method for preparing the above-mentioned pharmaceutically acceptable salt, which comprises the step of forming a salt with an acid. In certain embodiments, the step of forming 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 acetone, methanol, ethanol, ethanol / water, isopropanol / water, ethyl acetate, acetonitrile, tetrahydrofuran, dimethyl sulfoxide / water, 1,4-dioxane, methanol / water, N,N-dimethylformamide and dichloromethane.
[0018] The present disclosure also provides a hydrochloride salt form A of the compound represented by 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.
[0019] In some embodiments, the hydrochloride salt form A of the compound represented by Formula I has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, which has characteristic peaks at 7.043, 8.719, 10.737, 12.430, 14.356, 14.840, 15.250 and 17.686, and the 2θ angle error range is ±0.20.
[0020] In some embodiments, the hydrochloride salt form A of the compound represented by Formula I has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and 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 2θ angle error range is ±0.20.
[0021] In some embodiments, the hydrochloride salt form A of the compound represented by Formula I has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in FIG1 .
[0022] In some embodiments, the hydrochloride form A of the compound represented by Formula I has an endothermic peak at 268° C. in the DSC spectrum, and the error range of the endothermic peak is ±2° C.
[0023] The present disclosure also provides a method for preparing the hydrochloride crystal form A of the compound represented by the above formula I, comprising:
[0024] a) dissolving the hydrochloride of the compound represented by formula I in solvent A;
[0025] b) stirring;
[0026] In some embodiments, the preparation method further comprises centrifugation, washing and / or drying steps.
[0027] In some embodiments, the preparation method of the hydrochloride A crystal form of the compound represented by formula I, the solvent A is selected from water, C 1-4 Ketone solvents, C 1-4 Alcohol solvents, water and C 1-4 Mixed solvents of 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; the alcohol solvents are preferably acetone, methanol, ethanol, ethanol / water, isopropanol / water, ethyl acetate, acetonitrile, tetrahydrofuran, dimethyl sulfoxide / water, 1,4-dioxane, and methanol / water.
[0028] In some embodiments, in the preparation method of the hydrochloride form A of the compound represented by Formula I, each milligram of the compound represented by Formula I is dissolved in 0.01-0.05 ml of solvent A; more preferably, each milligram of the compound represented by Formula I is dissolved in 0.01-0.03 ml of solvent A.
[0029] In some embodiments, in the preparation method of the hydrochloride form A of the compound represented by Formula I, the mixed solvent of water and an alcohol solvent is a mixed solvent of water and methanol, wherein the molar ratio of water to the methanol is 0.10-0.95, preferably 0.14, 0.26, 0.37, 0.47, 0.57, 0.66, 0.74, 0.82, and 0.90.
[0030] The present disclosure also provides a hydrochloride A' crystal form of the compound represented by the above 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.
[0031] In some embodiments, the hydrochloride A' form of the compound represented by Formula I has an X-ray powder diffraction pattern represented by a diffraction angle 2θ 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, and the 2θ angle error range is ±0.20.
[0032] In some embodiments, the hydrochloride A' form of the compound represented by Formula I has an X-ray powder diffraction pattern represented by a diffraction angle 2θ having 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 2θ angle error range is ±0.20.
[0033] In some embodiments, the hydrochloride A' form of the compound represented by 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.
[0034] In some embodiments, the hydrochloride A' crystal form of the compound represented by Formula I has an endothermic peak at 161°C in the DSC spectrum, and the error range of the endothermic peak is ±2°C.
[0035] The present disclosure also provides a mesylate salt crystalline form B of the compound represented by the above 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 2θ angle error range is ±0.20.
[0036] In some embodiments, the mesylate salt form B of the compound represented by Formula I has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, which 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.
[0037] In some embodiments, the mesylate salt form B of the compound represented by Formula I has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and 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 2θ angle error range is ±0.20.
[0038] In some embodiments, the mesylate salt form B of the compound represented by Formula I has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and 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 2θ angle error range is ±0.20.
[0039] In some embodiments, the X-ray powder diffraction pattern of Form B of the mesylate salt of the compound represented by Formula I, expressed in terms of a diffraction angle of 2θ, is shown in FIG6 .
[0040] In some embodiments, the mesylate salt form B of the compound represented by Formula I has an endothermic peak at 161° C. in the DSC spectrum, and the error range of the endothermic peak is ±2° C.
[0041] The present disclosure also provides a crystalline form C of a mesylate salt of the compound represented by the above 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 2θ angle error range is ±0.20.
[0042] In some embodiments, the mesylate salt form C of the compound represented by Formula I has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, which has characteristic peaks at 4.522, 7.747, 11.163, 12.676, 15.268, 16.824, 18.549 and 19.759, and the 2θ angle error range is ±0.20.
[0043] In some embodiments, the mesylate salt form C of the compound represented by Formula I has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and 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 2θ angle error range is ±0.20.
[0044] In some embodiments, the mesylate salt form C of the compound represented by Formula I has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and 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 2θ angle error range is ±0.20.
[0045] In some embodiments, the mesylate salt form C of the compound represented by Formula I has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in FIG9 .
[0046] In some embodiments, the mesylate salt form C of the compound represented by Formula I has an endothermic peak at 194° C. in the DSC spectrum, and the error range of the endothermic peak is ±2° C.
[0047] The present disclosure also provides a phosphate D crystal form of the compound represented by the above 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 2θ angle error range is ±0.20.
[0048] In some embodiments, a phosphate D crystal form of a compound represented by 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 2θ angle error range is ±0.20.
[0049] In some embodiments, a phosphate D crystal form of a compound represented by 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 2θ angle error range is ±0.20.
[0050] In some embodiments, a phosphate D crystal form of a compound represented by Formula I, wherein the X-ray powder diffraction pattern represented by a 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 2θ angle error range is ±0.20.
[0051] In some embodiments, the phosphate form D of the compound represented by Formula I has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in FIG12 .
[0052] In some embodiments, the phosphate salt of the compound represented by Formula I, in crystal form D, has endothermic peaks at 130° C. and 143° C. in its DSC spectrum, and the error range of the endothermic peaks is ±2° C.
[0053] The present disclosure also provides an L-tartrate E crystalline form of the compound represented by the above 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, and the 2θ angle error range is ±0.20.
[0054] In some embodiments, the L-tartrate E crystalline form of the compound represented by 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, and the 2θ angle error range is ±0.20.
[0055] In some embodiments, the L-tartrate E crystalline form of the compound represented by 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, and the 2θ angle error range is ±0.20.
[0056] In some embodiments, the L-tartrate E crystal form of the compound represented by Formula I has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in FIG15 .
[0057] In some embodiments, the L-tartrate salt form E of the compound represented by Formula I has an endothermic peak at 132° C. in the DSC spectrum, and the error range of the endothermic peak is ±2° C.
[0058] The present disclosure also provides a hydrobromide salt F crystalline form of the compound represented by the above 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.
[0059] In some embodiments, the hydrobromide salt F form of the compound represented by Formula I has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, which has characteristic peaks at 6.152, 7.133, 10.827, 12.485, 14.422, 17.721 and 18.823, and the 2θ angle error range is ±0.20.
[0060] In some embodiments, the hydrobromide salt F form of the compound represented by 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 2θ angle error range is ±0.20.
[0061] In some embodiments, the hydrobromide salt form F of the compound represented by Formula I has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in FIG18 .
[0062] In some embodiments, the hydrobromide salt of the compound of Formula I, crystalline form F, has endothermic peaks at 99°C and 216°C in its DSC spectrum, and the error range of the endothermic peaks is ±2°C.
[0063] The "2θ or 2θ angle" mentioned in the present disclosure refers to the diffraction angle, θ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2θ is ±0.20 (including the case where the number exceeding 1 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, 0.20.
[0064] The present disclosure also provides a pharmaceutical composition containing a pharmaceutically acceptable salt of the compound of Formula I, a hydrochloride salt form A of the compound of Formula I, a methanesulfonate salt form B of the compound of Formula I, a methanesulfonate salt form C of the compound of Formula I, a phosphate salt form D of the compound of Formula I, an L-salt salt form E of the compound of Formula I, a hydrobromide salt form F of the compound of Formula I, and a pharmaceutically acceptable excipient.
[0065] The present disclosure also provides a method for preparing a pharmaceutical composition, comprising the steps of mixing Form A of the hydrochloride salt of the compound shown in Formula I, Form B of the methanesulfonate salt of the compound shown in Formula I, Form C of the methanesulfonate salt of the compound shown in Formula I, Form D of the phosphate salt of the compound shown in Formula I, Form E of the L-tartrate salt of the compound shown in Formula I, and Form F of the hydrobromide salt of the compound shown in Formula I with a pharmaceutically acceptable excipient.
[0066] The present disclosure also relates to the use of a pharmaceutically acceptable salt of the compound of Formula I, Form A of the hydrochloride salt of the compound of Formula I, Form B of the methanesulfonate salt of the compound of Formula I, Form C of the methanesulfonate salt of the compound of Formula I, Form D of the phosphate salt of the compound of Formula I, Form E of the L-tartrate salt of the compound of Formula I, Form F of the hydrobromide salt of the compound of Formula I, or the above-mentioned combination in the preparation of a medicament 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, sinusitis, hidradenitis suppurativa, or cancer.
[0067] 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, sinusitis, hidradenitis suppurativa, or cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of the compound of Formula I, Form A of the hydrochloride salt of the compound of Formula I, Form B of the methanesulfonate salt of the compound of Formula I, Form C of the methanesulfonate salt of the compound of Formula I, Form D of the phosphate salt of the compound of Formula I, Form E of the L-tartrate salt of the compound of Formula I, Form F of the hydrobromide salt of the compound of Formula I, or the above-mentioned combination.
[0068] The present disclosure also relates to pharmaceutically acceptable salts of the compound of Formula I, Form A of the hydrochloride salt of the compound of Formula I, Form B of the methanesulfonate salt of the compound of Formula I, Form C of the methanesulfonate salt of the compound of Formula I, Form D of the phosphate salt of the compound of Formula I, Form E of the L-tartrate salt of the compound of Formula I, Form F of the hydrobromide salt of the compound of Formula I, or the above-mentioned compositions, which are used to prevent and / or treat asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, α1-antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease, rheumatoid arthritis, sinusitis, hidradenitis suppurativa, or cancer.
[0069] The "excipients" described in this disclosure include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, 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 by humans or livestock animals.
[0070] The starting material used in the crystal form preparation method of the present invention can be a compound in any form, including but not limited to: amorphous, any crystal form, hydrate, solvate, etc.
[0071] The "differential scanning calorimetry or DSC" mentioned in this disclosure refers to measuring the temperature difference and heat flow difference between a sample and a reference during the process of heating or maintaining the sample at a constant temperature to characterize all physical and chemical changes related to thermal effects and obtain phase change information of the sample.
[0072] Numerical values in this disclosure, such as those related to substance content, are derived from measurements and calculations, and therefore inevitably have a certain degree of error. Generally speaking, ±10% is considered within a reasonable error range. While there may be some degree of error depending on the context in which they are used, this error may not exceed ±10% and may include ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%. BRIEF DESCRIPTION OF THE DRAWINGS
[0073] FIG1 is an XRPD pattern of the hydrochloride salt form A of the compound represented by Formula I;
[0074] FIG2 is a DSC diagram of the hydrochloride salt A crystal form of the compound represented by Formula I;
[0075] FIG3 is a TGA diagram of the hydrochloride crystal form A of the compound represented by Formula I;
[0076] FIG4 is a DVS diagram of the hydrochloride salt form A of the compound represented by Formula I;
[0077] FIG5 is an XRPD pattern of Form A hydrochloride of the compound represented by Formula I before and after DVS (the upper portion is the XRPD pattern before DVS, and the lower portion is the XRPD pattern after DVS);
[0078] FIG6 is an XRPD pattern of Form B of the mesylate salt of the compound represented by Formula I;
[0079] FIG7 is a DSC diagram of the mesylate salt of the compound represented by Formula I, Form B;
[0080] FIG8 is a TGA diagram of the mesylate salt of the compound represented by Formula I, Form B;
[0081] FIG9 is an XRPD pattern of Form C of the methanesulfonate salt of the compound represented by Formula I;
[0082] FIG10 is a DSC diagram of the mesylate salt of the compound represented by Formula I, Form C;
[0083] FIG11 is a TGA diagram of the mesylate salt of the compound represented by Formula I, Form C;
[0084] FIG12 is an XRPD pattern of the phosphate salt of the compound represented by Formula I, Form D;
[0085] FIG13 is a DSC graph of the phosphate crystal form D of the compound represented by Formula I;
[0086] FIG14 is a TGA diagram of the phosphate crystal form D of the compound represented by Formula I;
[0087] Figure 15 is an XRPD pattern of the L-tartrate crystalline form E of the compound represented by Formula I;
[0088] Figure 16 is a DSC graph of the L-tartrate crystalline form E of the compound represented by Formula I;
[0089] Figure 17 is a TGA chart of the L-tartrate crystalline form E of the compound represented by Formula I;
[0090] FIG18 is an XRPD spectrum of the hydrobromide salt Form F of the compound represented by Formula I;
[0091] FIG19 is a DSC spectrum of the hydrobromide salt Form F of the compound represented by Formula I;
[0092] FIG20 is a TGA spectrum of the hydrobromide salt of the compound represented by Formula I, Form F;
[0093] FIG21 is an NMR spectrum of the hydrobromide salt Form F of the compound represented by Formula I;
[0094] FIG22 is an XRPD pattern of the hydrochloride A' crystal form of the compound represented by Formula I;
[0095] FIG23 is a DSC graph of the hydrochloride A' crystal form of the compound represented by Formula I;
[0096] FIG24 is a TGA chart of the hydrochloride A′ crystal form of the compound represented by Formula I. DETAILED DESCRIPTION
[0097] The present disclosure will be explained in more detail below with reference to embodiments or experimental examples. The embodiments or experimental examples in the present disclosure are only used to illustrate the technical solutions in the present disclosure, and are not intended to limit the essence and scope of the present disclosure.
[0098] The abbreviations used in this disclosure are explained as follows: XRPD X-ray powder diffraction DSC Differential Scanning Calorimetry TGA Thermogravimetric Analysis DVS Dynamic Water Sorption 1H-NMR liquid nuclear magnetic hydrogen spectrum DMF N,N-dimethylformamide MEK butanone MTBE methyl tert-butyl ether THF tetrahydrofuran IPA isopropyl alcohol ACN acetonitrile MeOH methanol EOH ethanol ACT acetone PA phosphoric acid TA tartaric acid HBr hydrobromic acid HCl hydrochloric acid DCM dichloromethane
[0099] Test conditions of the instruments used in the experiments in this disclosure:
[0100] 1. X-ray Powder Diffraction (XRPD)
[0101] Instrument model: Malver Panalytical Aeris X-ray powder diffractometer
[0102] Radiation: Monochromatic Cu-Kα radiation (λ=1.54188)
[0103] Scanning mode: θ / 2θ, scanning range (2θ range): 3.5~50°
[0104] Voltage: 40kV, Current: 15mA
[0105] 2. Differential Scanning Calorimeter (DSC)
[0106] Instrument model: TA DSC250
[0107] Purge gas: nitrogen; nitrogen purge rate: 50mL / min
[0108] Heating rate: 10℃ / min
[0109] Temperature range: 25℃-250℃
[0110] 3. Thermogravimetric Analysis (TGA)
[0111] Instrument model: TA TGA550
[0112] Purge gas: nitrogen; nitrogen purge speed: 20ml / min
[0113] Scan rate: 10℃ / min
[0114] Temperature range: 30℃-350℃
[0115] 4. Dynamic moisture sorption (DVS)
[0116] The test was performed using SMS Intrinsic PLUS at 25°C, with humidity ranging from 50% to 0% to 90% in 10% increments. The judgment standard was that the mass change dM / dT for each gradient was less than 0.002%, TMAX was 360 min, and the cycle was repeated twice.
[0117] 5. The high performance liquid chromatography (HPLC) chart described in the stability test of Form A of the present disclosure was collected on an Agilent 1260 Infinity II.
[0118] The HPLC conditions in the content detection method of the high performance liquid chromatography described in the present disclosure are as follows: chromatographic column: Agilent Eclipse Plus C18 4.6mm*150mm, 3.5μm; mobile phase: A: 10mmol / L sodium dihydrogen phosphate solution (pH8.0), B-ACN; flow rate: 1.0ml / min; wavelength: 210nm.
[0119] The HPLC conditions for the high performance liquid chromatography method for detecting related substances disclosed herein are as follows: chromatographic column: Agilent Eclipse Plus C18 4.6 mm*150 mm, 3.5 μm; mobile phase: A: 10 mmol / L ammonium acetate solution, B-ACN; flow rate: 1.0 ml / min; wavelength: 210 nm.
[0120] Example 1: Preparation of (S)-N-((S)-1-cyano-2-(8-cyano-2-fluoro-6H-benzo[c]chroman-3-yl)ethyl)-1,4-oxazepane-2-carboxamide (compound shown in Formula I)
[0121] Synthesis of compound I-2
[0122] 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. The reaction mixture was heated to 40°C and stirred for 12 hours. Water (300 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain Compound I-2. 1 H NMR (400MHz, CDCl3) δ7.87(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).
[0123] Synthesis of compound I-3
[0124] Under nitrogen at room temperature, compound I-2 (2.90 g, 6.37 mmol), palladium 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). The reaction mixture was heated to 120°C and stirred for 1.5 hours. After completion of the reaction, the mixture was cooled to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL x 2). The organic phases were combined, washed with saturated brine (200 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1) to afford compound I-3. 1 H NMR (400MHz, CDCl3) δ7.80-7.72(m,2H),7.60(d,1H),7.52-7.49(m,2H),5.18(s,2H),3.98(s,3H).
[0125] Synthesis of compound I-4
[0126] 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. 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, water (200 mL) was added, and extraction was performed with ethyl acetate (200 mL x 2). The organic phases were combined, washed with saturated brine (200 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound I-4. 1 H NMR (400MHz, CDCl3) δ7.67(s,2H),7.47(s,1H),7.38(d,1H),7.12(d,1H),5.11(s,2H),4.77(s,2H).
[0127] Synthesis of compound I-5
[0128] At room temperature, compound I-3 (450 mg, 1.59 mmol) was dissolved in dichloromethane (15 mL), followed by the dropwise addition of phosphorus tribromide (520 mg, 1.92 mmol). The reaction mixture was stirred at room temperature for 20 minutes. After completion of the reaction, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to afford compound I-5. 1 H NMR (300MHz, CDCl3) δ7.73(s,2H),7.52(s,1H),7.45(d,1H),7.10(d,1H),5.17(s,2H),4.53(s,2H).
[0129] Synthesis of compound I-6
[0130] At room temperature, diphenylmethyleneaminoacetonitrile (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). The reaction mixture was heated to 35°C and stirred for 24 hours. Water (30 mL) was added, and the mixture was extracted with dichloromethane (30 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1) to obtain compound I-6. MS-ESI: m / z 458.4 [M+1] + .
[0131] Synthesis of compound I-7
[0132] At room temperature, compound I-6 (520 mg, 0.90 mmol) was dissolved in tetrahydrofuran (10 mL), followed by the dropwise addition of 1 M aqueous hydrochloric acid solution (4 mL). 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 mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1) to obtain compound I-7. MS-ESI: m / z 293.9 [M+1] + .
[0133] Synthesis of compound I-8
[0134] At room temperature, 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). The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, compound I-8 was isolated by preparative liquid chromatography (C18, acetonitrile / water system). MS-ESI: m / z 465.1 [M-56+1] + .
[0135] Synthesis of compound I-9
[0136] Compound I-8 (280 mg, 0.51 mmol) was subjected to chiral separation (chromatographic column: chiralpak IE, 250*25 mm, 5 μm; mobile phase: n-hexane, ethanol; gradient ratio: 30% n-hexane phase; flow rate: 15 mL / min; column temperature: 30°C) to obtain compound I-9 (two diastereoisomer peaks in total, compound I-9 is the first eluting peak). 1H NMR(300MHz,DMSO-d6)δ8.89(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),5.09-5.0 7(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).
[0137] Synthesis of Compound I
[0138] 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, preparative liquid chromatography (C18, ammonium bicarbonate / acetonitrile / water system) afforded Compound I. XRPD analysis revealed the compound to be amorphous. MS-ESI: m / z 421.2 [M+1]+. 1 H NMR(400MHz,DMSO-d6)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),4.00-3.9 7(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).
[0139] Example 2: Biological evaluation of the compound represented by Formula I - in vitro CatC cell activity detection experiment
[0140] 1. Experimental Materials
[0141] 2. Experimental steps
[0142] Prepare complete culture medium (RPMI1640 + 10% FBS) and mix thoroughly. Resuscitate the U937 cell line, passage it for approximately two generations, and select a cell line with good growth. Aspirate the cell suspension and transfer it to a centrifuge tube. Centrifuge at 800-1000 rpm for 3-5 minutes. Discard the supernatant. Add an appropriate volume of culture medium to the centrifuge tube and gently pipette to resuspend the cells evenly. Count the cells using a Vi-Cell XR cell counter. Adjust the cell suspension to the appropriate concentration. Add the cell suspension to a 384-well plate at 25,000 μl / well. Prepare a 10 mM solution of the compound in DMSO. Dilute the compound to a 1 mM solution in DMSO and perform 10 half-log dilutions in DMSO using an HPD300. Prepare a 35 mM solution of Gly-Phe-AFC in DMSO, aliquot, and dilute Gly-Phe-AFC to 1.75 mM using serum-free culture medium. After adding the drug, incubate in the incubator for 1 hour. Then, add the substrate, AFC, and aspirate 12.5 μl to the plate. After incubation for 30 minutes, measure the plate. Place the plate in an EnSpire reader and record fluorescence at Ex = 400 nm and Em = 505 nm. Calculate the inhibition rate using the following formula: Inhibition rate (%) = (1 - (RFU compound - RFU blank) / (RFU DMSO - RFU blank)) × 100%. Use XLFit to plot the inhibition rate curve and calculate the IC. 50 The 4-parameter model [fit = (A + ((BA) / (1 + ((C / x)^D))))] was used.
[0143] The inhibition of the activity of the compound of formula I disclosed in the present invention on CatC cells in vitro was determined by the above test, and the measured IC 50 The value is 6.1nM, which has a significant inhibitory effect on CatC cell activity.
[0144] Example 3: Preparation of Hydrochloride Form A of the Compound of Formula I
[0145] Method 1:
[0146] The compound of Formula I (1.01 g) was added to 76 mL of acetone and stirred at 60°C. Once dissolved, 586.0 μL of diluted hydrochloric acid solution (500 μL of hydrochloric acid and 500 μL of purified water were added and mixed thoroughly for later use) was added. A precipitate formed after the hydrochloric acid was added. The heat was turned off and the mixture was stirred overnight. The next day, the sample was poured onto filter paper, air-dried in a fume hood, and collected to obtain the hydrochloride salt of the compound of Formula I, which was sealed and stored as an off-white solid (960 mg, yield: 95%).
[0147] X-ray powder diffraction analysis identified the product as Form A of the hydrochloride salt of the compound represented by Formula I. The XRPD pattern is shown in Figure 1, and the positions of its characteristic peaks are shown in Table 1. The DSC spectrum is shown in Figure 2, with an endothermic peak at approximately 268°C. The TGA spectrum, shown in Figure 3, shows a rapid weight loss above 200°C.
[0148] The chloride ion content of the Form A sample was tested (ion chromatography) and the result was 7.64%, which is basically consistent with the theoretical value of 7.7% for 1 mol of hydrochloride salt, confirming that hydrochloric acid and the free base of the compound represented by Formula I form a salt in a molar ratio of 1:1.
[0149] DVS analysis, as shown in Figure 4, shows a moisture absorption weight gain of approximately 1.1% under accelerated experimental conditions (i.e., 80% RH). Desorption and adsorption of the sample were consistent across humidity ranges from 0% to 90% RH. The crystal form was re-measured after DVS analysis, and the XRPD spectrum, shown in Figure 5, demonstrates no change in crystal form before and after DVS analysis.
[0150] Table 1 XRPD characteristic diffraction peak data of hydrochloride A crystal form
[0151] Method 2:
[0152] 30 mg of the free base of the compound represented by Formula I was added to 0.3 mL of the solvent in Table 2, and a suspension was obtained under stirring. A 4 mol / L aqueous hydrochloric acid solution was added to the suspension at a molar ratio of 1.2:1 to the free base, and the liquid volume was adjusted to 1.2 mL. The mixture was stirred at 50° C. for 3 hours, then cooled to 25° C. and stirred overnight. The precipitated solid was centrifuged and dried under reduced pressure at 60° C. for 6 hours to obtain a solid. The obtained solid was determined to be Form A by XRPD.
[0153] Table 2 Preparation of Hydrochloride A Crystalline Form by Beating
[0154] Method 3:
[0155] 10 mg of the hydrochloride of the compound represented by Formula I was added to 0.2 mL of the solvent described in Table 3. Formula I was kept in the solvent to form a slurry and stirred for one week. The solvent was quickly removed using filter paper. The resulting solid was determined to be in Form A by XRPD.
[0156] Table 3 Preparation of Hydrochloride A Crystalline Form by Beating
[0157] Example 4: Preparation of Form B of the Methanesulfonate Salt of the Compound of Formula I
[0158] 15 mg of the compound represented by Formula I was dissolved in 1 ml of DMF, and methanesulfonic acid (4.1 mg) was added. The solution was heated to 50°C and stirred at this temperature for 4 hours. The solution was then cooled to 0°C and stirred at this temperature for more than two days to react. The solid obtained by vacuum drying is the mesylate form B of the compound represented by Formula I. Its XRPD spectrum is shown in FIG6 , and the positions of its characteristic peaks are shown in Table 4 . Its DSC spectrum is shown in FIG7 , and an endothermic peak appears at 161°C, indicating a low degree of crystallinity. Its TGA spectrum is shown in FIG8 .
[0159] Table 4 XRPD characteristic diffraction peak data of the mesylate salt form B of the compound represented by formula I
[0160] Example 5: Preparation of Form C of the Methanesulfonate Salt of the Compound of Formula I
[0161] 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 this temperature for 4 hours. The temperature was then lowered to 0°C and the reaction was continued with controlled stirring for more than two days. The resulting solid was vacuum dried and XRPD analysis revealed that it was Form C of the mesylate salt of the compound of Formula I. The XRPD data for Form C of the mesylate salt of the compound of Formula I are shown in Table 5, its XRPD spectrum is shown in Figure 9, its DSC spectrum is shown in Figure 10, and the endothermic peak is approximately 194°C. Its TGA spectrum is shown in Figure 11.
[0162] Table 5 XRPD characteristic diffraction peak data of mesylate C crystal form
[0163] Example 6: Preparation of Phosphate D Crystalline Form of the Compound of Formula I
[0164] 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 this temperature for 4 hours. The temperature was then lowered to 0°C and the reaction was continued with controlled stirring for more than two days. The resulting solid was vacuum dried and XRPD analysis revealed that it was the phosphate salt Form D of the compound of Formula I. The XRPD data for the phosphate salt Form D of the compound of Formula I are shown in Table 6, its XRPD spectrum is shown in Figure 12, and its DSC spectrum is shown in Figure 13. Endothermic peaks appeared at 130°C and 143°C. Its TGA spectrum is shown in Figure 14. Ion chromatography analysis revealed a phosphate content of 24.18%, indicating a 1:1 salt formation between phosphoric acid and the free base.
[0165] Table 6 XRPD characteristic diffraction peak data of the phosphate D crystal form of the compound represented by formula I
[0166] Example 7: Preparation of L-tartrate E crystal form of the compound represented by formula I
[0167] 15 mg of the compound represented by 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 this temperature for 4 hours. The temperature was then lowered to 0°C and the reaction was continued with controlled stirring for more than two days. The resulting solid was vacuum dried and XRPD analysis revealed that it was the L-tartrate Form E of the compound represented by Formula I. The XRPD data for the L-tartrate Form E of the compound represented by Formula I are shown in Table 7, its XRPD spectrum is shown in Figure 15, its DSC spectrum is shown in Figure 16, an endothermic peak appears at 132°C, and its TGA spectrum is shown in Figure 17.
[0168] Table 7 XRPD characteristic diffraction peak data of the L-tartrate E crystal form of the compound represented by formula I
[0169] Example 8: Preparation of the Hydrobromide Salt Form F of the Compound of Formula I
[0170] 80 mg of the compound of Formula I was dissolved in 1 ml of dioxane. Hydrobromic acid was added at a molar ratio of acid to API of 1.2:1. Solid precipitated and the mixture was stirred at room temperature for 12 hours. The resulting solid was dried under vacuum. XRPD analysis confirmed that the hydrobromide salt Form F of the compound of Formula I was obtained. The XRPD data are shown in Table 8, the XRPD spectrum is shown in Figure 18, and the DSC spectrum is shown in Figure 19, with endothermic peaks at 99°C and 216°C. The TGA spectrum is shown in Figure 20. NMR results (Figure 21) showed that the salt of Compound I and hydrobromic acid was approximately 1:1.
[0171] Table 8 XRPD characteristic diffraction peak data of the hydrobromide salt F crystal form of the compound represented by formula I
[0172] Example 9: Stability Test of Crystal Form A of the Hydrochloride Salt of the Compound of Formula I
[0173] To determine whether light, temperature, and humidity affect the stability of Form A, the hydrochloride salt of the compound represented by Formula I, the following factors were tested: Form A was placed in a light-proof stabilization chamber and subjected to a series of temperature and humidity combinations. Samples were removed after aging under various light and temperature and humidity conditions for different days. The resulting solids were compared with the initial Form A hydrochloride salt. High-performance liquid chromatography (HPLC) analysis revealed no significant increase in the isomers of the compound represented by Formula I (as shown in Table 9). XRPD analysis of a sample removed on the final day of aging under various light and temperature and humidity conditions revealed no change in Form A, indicating good stability.
[0174] Table 9 Hydrochloride A crystal form influencing factors experimental isomer determination results
[0175] Example 10: Preparation of the Hydrochloride A' Crystalline Form of the Compound of Formula I
[0176] 0.42 g (0.1 mmol) of the compound represented by Formula I was weighed, 25 ml of ethanol was added, and the mixture was stirred at 70°C. After dissolution, the mixture was filtered, and a white solid precipitated from the filtrate. The filtrate was transferred to a 70°C oil bath, and after dissolution, 2 ml of a 1:1 hydrochloric acid-ethanol solution was added, resulting in a large amount of solid precipitation. The mixture was cooled to room temperature for crystallization for 4 hours, filtered, and the filter cake was dried at 50°C for 12 hours to obtain 0.39 g of Form A', with a yield of 85.5%. Its XRPD spectrum is shown in Figure 22, and its characteristic peak positions are shown in Table 10. Its DSC spectrum is shown in Figure 23, showing an endothermic peak at 161°C, indicating low crystallinity. Its TGA spectrum is shown in Figure 24.
[0177] Table 10 XRPD characteristic diffraction peak data of the hydrochloride A' crystal form of the compound represented by formula I
Claims
1. A pharmaceutically acceptable salt of a compound of formula I, wherein the pharmaceutically acceptable salt is an acid addition salt selected from hydrochloride, methanesulfonate, phosphate, L-tartrate, maleate, p-toluenesulfonate, sulfate, fumarate, succinate, citrate, malate and hydrobromide, preferably, the pharmaceutically acceptable salt is in crystalline form.
2. The pharmaceutically acceptable salt of the compound of formula I according to claim 1, wherein the chemical ratio of the compound of formula I to the acid molecule or acid radical is 1:0.5 to 1:3, preferably 1:0.5, 1:1, 1:1.2, 1:2 or 1:3; In particular, The pharmaceutically acceptable salt of the compound represented by formula I is hydrochloride, and the chemical ratio of the compound represented by formula I to hydrochloride is 1:
1.
3. A method for preparing a pharmaceutically acceptable salt of the compound of formula I according to claim 1 or 2, comprising the step of forming a salt of the compound of formula I with an acid; In particular, The step of forming a salt with an acid is carried out in a solvent, and the solvent is 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 acetone, methanol, ethanol, ethanol / water, isopropanol / water, ethyl acetate, acetonitrile, tetrahydrofuran, dimethyl sulfoxide / water, 1,4-dioxane, methanol / water, N,N-dimethylformamide and dichloromethane.
4. A hydrochloride crystal form A of the compound of formula I, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angle 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, and the 2θ angle error range is ±0.20, 5. The hydrochloride crystal form A of the compound of formula I according to claim 4, wherein the DSC spectrum has an endothermic peak at 268°C, and the error range of the endothermic peak is ±2°C.
6. A hydrochloride A' crystal form of the compound of formula I, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 8.452, 12.476, 15.884, 17.037, 17.227, 22.328 and 23.566, preferably 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, 14.332, 15.884, 17.037, 17.227, 20.784, 22.328, 23.566 and 27.567, and most preferably have 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 2θ angle error range is ± 0.20, 7 . The hydrochloride crystal form A′ of the compound of formula I according to claim 6 , wherein the DSC spectrum has an endothermic peak at 263° C., and the error range of the endothermic peak is ±2° C.
8. A mesylate salt of a compound of formula I in form B, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angle 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, more preferably at 6.717, 8.105, 8.783, 13.969, 15.902, 16.647, and 17.
515. 2, 16.647, 17.515, 20.446, 21.069, 21.645 and 24.665, and most preferably have 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 2θ angle error range is ± 0.20, 9. The mesylate salt form B of the compound of formula I according to claim 8, wherein the DSC spectrum has an endothermic peak at 161°C, and the error range of the endothermic peak is ±2°C.
10. A crystalline form C of a mesylate salt of a compound of formula I, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 7.747, 11.163, 12.676, 15.268, 16.824, 18.549 and 19.759, preferably 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, 12.676, 15.268, 16.824, 18.549, 19.759, 21.460, 24.637 and 25.497, and most preferably 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, wherein the 2θ angle error range is ± 0.20, 11. The mesylate crystal form C of the compound of formula I according to claim 10, wherein the DSC spectrum has an endothermic peak at 194°C, and the error range of the endothermic peak is ±2°C.
12. A phosphate crystal form D of the compound of formula I, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angle 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, more 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 and 19.245, and most preferably have 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 2θ angle error range is ± 0.20, 13. The phosphate crystal form D of the compound of formula I according to claim 12, wherein the DSC spectrum has endothermic peaks at 130°C and 143°C, and the error range of the endothermic peaks is ±2°C.
14. A crystalline form E of an L-tartrate salt of a compound of formula I, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angle 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 2θ angle error range is ±0.
20.
15. The L-tartrate crystalline form E of the compound of formula I according to claim 14, wherein the DSC spectrum has an endothermic peak at 132°C, and the error range of the endothermic peak is ±2°C.
16. A crystalline form F of the hydrobromide salt of the compound of formula I, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angle 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 2θ angle error range is ±0.
20.
17. The hydrobromide salt crystalline form F of the compound of formula I according to claim 16, wherein the DSC spectrum has endothermic peaks at 99°C and 216°C, and the error range of the endothermic peaks is ±2°C.
18. A pharmaceutical composition comprising a pharmaceutically acceptable salt of the compound of formula I according to claim 1 or 2 or the crystalline form according to any one of claims 4 to 17, and a pharmaceutically acceptable excipient.
19. Use of a pharmaceutically acceptable salt of the compound of formula I according to claim 1 or 2, the crystalline form according to any one of claims 4 to 17, or the pharmaceutical composition according to claim 18 in the preparation of a medicament 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, sinusitis, hidradenitis suppurativa, or cancer.