Salts and crystalline forms of dipeptidyl peptidase inhibitor compounds

Abstract

Disclosed are crystals of the compound (S)-N-(((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazacycloheptane-2-carboxamide salt or salts thereof, methods for their preparation, and their use in pharmaceutical compositions and medicaments. TIFF2025508792000052.tif48170

Description

[Technical field]

[0001] The present invention relates to the dipeptidyl peptidase inhibitor compound (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide pharma- ceutically acceptable salts or hydrates, solvates, crystalline forms thereof, processes for their preparation or pharmaceutical compositions, as well as their use in the preparation of dipeptidyl peptidase 1 (DPP1) small molecule inhibitor drugs. [Background technology]

[0002] Dipeptidyl peptidase 1 (DPP1), also known as cathepsin C, is a cysteinyl protease of the lysosomal papain family that is involved in the degradation of intracellular proteins. During the maturation process of neutrophils, DPP1 activates neutrophil serine proteases (NSPs), such as neutrophil elastase (NE), proteinase 3 (Pr3), and cathepsin G (CatG), by cleaving the N-terminal dipeptide of target proteins. DPP1 is associated with various inflammatory diseases, including Wegener's granulomatosis, rheumatoid arthritis, pneumonia, and viral infections. Studies have shown that inhibition of DPP1 can provide good therapeutic effects against highly inflammatory lung diseases caused by neutrophils, such as bronchiectasis, chronic obstructive pulmonary disease (COPD), and acute lung injury.

[0003] Therefore, targeting DPP1 and suppressing excessive activation of NSPs is expected to be effective in treating bronchiectasis. Summary of the Invention

[0004] The present invention provides a salt (designated Compound A) of the following structure, as well as hydrates, solvates, and crystalline forms of those salts, and methods for preparing medicaments or compositions thereof: [ka]

[0005] The salts of compound A and their hydrates, solvates and crystalline forms have better solubility and stability than the free base compound, can exist very stably in diluents (solvents), are resistant to high temperature, high humidity and strong light, and are suitable for preparing pharmaceutical dosage forms. At the same time, they have better pharmacokinetics and bioavailability than the free base compound.

[0006] Specifically, the present invention provides salts of compounds of formula (I), as well as hydrates and solvates thereof: [ka]

[0007] The salts are selected from the group consisting of hydrochloride, sulfate, maleate, phosphate, mucate, tartrate, fumarate, citrate, malate, hippurate, adipate, sebacate, 1,5-naphthalenedisulfonate, methanesulfonate, benzenesulfonate, oxalate, benzoate, hydrobromide, 2-naphthalenesulfonate, p-toluenesulfonate, hemi-1,5-naphthalenedisulfonate, and succinate.

[0008] Furthermore, the salts of the compounds of formula (I) are selected from the group consisting of hydrochlorides, sulfates, maleates, phosphates, mucates, tartrates, fumarates, citrates, malates, hippurates, adipates, sebacates, 1,5-naphthalenedisulfonates, methanesulfonates, benzenesulfonates, oxalates, benzoates, hydrobromides, preferably in crystalline form.

[0009] Furthermore, the salt of the compound of formula (I) is selected from the group consisting of hydrochloride, malate and adipate, preferably in crystalline form.

[0010] The present invention also relates to the hydrochloride salt of compound of formula (I) in a crystalline form (crystalline form A of the hydrochloride salt) having an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 9.38°±0.2°, 16.40°±0.2°, 18.69°±0.2°, 22.04°±0.2°, 23.05°±0.2°, 23.90°±0.2°.

[0011] Furthermore, the present invention also provides crystalline form A of the hydrochloride salt of compound of formula (I), which has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 13.99°±0.2°, 14.75°±0.2°, 17.92°±0.2°, 25.70°±0.2°, 30.32°±0.2°.

[0012] Furthermore, the present invention also provides a crystalline form A of the hydrochloride salt of the compound of formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 30.32°±0.2° using Cu-Kα radiation.

[0013] The present invention provides crystalline Form A of the hydrochloride salt of compound of formula (I), whose 2θ values ​​and corresponding intensities in the X-ray powder diffraction pattern are shown in Table 1, with an error range of 2θ of ±0.2°.

[0014] [Table 1]

[0015] Furthermore, the present invention provides a crystalline Form A of the hydrochloride salt of the compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0016] The present invention provides a crystalline form A of the hydrochloride salt of the compound of formula (I), the differential scanning calorimetry (DSC) of which shows a T start = 219.5℃, T peak = 225.5°C and ΔH = 12.50 J / g.

[0017] The present invention provides a crystalline form A of the hydrochloride salt of the compound of formula (I), the differential scanning calorimetry (DSC) of which shows that it has a melting point of 225.5°C.

[0018] The present invention provides crystalline Form A of the hydrochloride salt of the compound of formula (I), the Differential Scanning Calorimetry (DSC) thermogram of which is shown in FIG.

[0019] The present invention provides a crystalline Form A of the hydrochloride salt of compound of formula (I), whose thermogravimetric analysis (TGA) thermogram shows a weight loss of 1.21% below 150°C and has a decomposition temperature of 250°C.

[0020] The present invention provides crystalline Form A of the hydrochloride salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which is shown in FIG.

[0021] The present invention provides crystalline Form A of the hydrochloride salt of compound of formula (I), which is anhydrous.

[0022] The present invention also provides a sulfate salt of the compound of formula (I), which is in a crystalline form (crystalline form A of the sulfate salt) and whose powder X-ray diffraction pattern has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 6.00°±0.2°, 9.72°±0.2°, 14.53°±0.2°, and 15.25°±0.2°.

[0023] Furthermore, the present invention provides a crystalline form A of the sulfate salt of the compound of formula (I), whose X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions: 12.70°±0.2°, 8.36°±0.2°, using Cu-Kα radiation.

[0024] The present invention provides crystalline Form A of the sulfate salt of compound of formula (I), whose X-ray powder diffraction pattern 2θ values ​​and corresponding intensities are shown in Table 2, with an error range of 2θ of ±0.2°.

[0025] [Table 2]

[0026] The present invention further provides a crystalline Form A of the sulfate salt of the compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0027] The present invention provides a crystalline Form A of the sulfate salt of the compound of formula (I), the differential scanning calorimetry (DSC) of which does not detect a heat signal.

[0028] The present invention provides a crystalline Form A of the sulfate salt of the compound of formula (I), the Differential Scanning Calorimetry (DSC) thermogram of which is shown in FIG.

[0029] The present invention provides a crystalline Form A of the sulfate salt of the compound of formula (I), which exhibits a thermogravimetric analysis (TGA) thermogram of 8.90% weight loss below 150°C and a decomposition temperature of 250°C.

[0030] The present invention provides a crystalline Form A of the sulfate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which is shown in FIG.

[0031] The present invention provides crystalline Form A of the sulfate salt of the compound of formula (I), which is a hydrate.

[0032] The present invention also provides a sulfate salt of the compound of formula (I), which is in a crystalline form (crystalline form B of the sulfate salt) having a powder X-ray diffraction pattern having characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 13.43°±0.2°, 17.35°±0.2°, 18.15°±0.2°, 20.93°±0.2°, 21.37°±0.2°, 24.22°±0.2°, 25.15°±0.2°.

[0033] Furthermore, the present invention provides a crystalline form B of the sulfate salt of the compound of formula (I), whose X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 8.55°±0.2°, 22.42°±0.2°, 22.85°±0.2°, 29.20°±0.2°.

[0034] The present invention provides crystalline form B of the sulfate salt of compound of formula (I), whose 2θ values ​​and corresponding intensities in the X-ray powder diffraction pattern are shown in Table 3, with an error range of 2θ of ±0.2°.

[0035] [Table 3]

[0036] Furthermore, the present invention provides a crystalline form B of the sulfate salt of the compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0037] The present invention provides a crystalline form B of the sulfate salt of the compound of formula (I), the differential scanning calorimetry (DSC) of which shows a T start = 180.4℃, T peak = 189.0 ° C.

[0038] The present invention provides a crystalline form B of the sulfate salt of the compound of formula (I), the differential scanning calorimetry (DSC) of which shows that it has a melting point of 189.0°C.

[0039] The present invention provides crystalline Form B of the sulfate salt of the compound of formula (I), the Differential Scanning Calorimetry (DSC) thermogram of which is shown in FIG.

[0040] The present invention provides a crystalline form B of the sulfate salt of the compound of formula (I), which exhibits a thermogravimetric analysis (TGA) thermogram of 6.95% weight loss below 150°C and a decomposition temperature of 250°C.

[0041] The present invention provides a crystalline Form B of the sulfate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which is shown in FIG.

[0042] The present invention provides crystalline Form B of the sulfate salt of the compound of formula (I), which is a hydrate.

[0043] The present invention also provides a maleate salt of the compound of formula (I), which is in the 0 crystalline form (crystalline form A of the maleate salt) and has a powder X-ray diffraction pattern having characteristic diffraction peaks at the following 2θ positions: 7.26°±0.2°, 18.12°±0.2° using Cu-Kα radiation.

[0044] The present invention provides crystalline Form A of the maleate salt of compound of formula (I), whose 2θ values ​​and corresponding intensities in the X-ray powder diffraction pattern are shown in Table 4, with an error range of 2θ of ±0.2°.

[0045] [Table 4]

[0046] Furthermore, the present invention provides a crystalline Form A of the maleate salt of the compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0047] The present invention provides a crystalline form A of the maleate salt of compound of formula (I), whose differential scanning calorimetry (DSC) shows four endothermic peaks at 54.2°C, 79.9°C, 125.4°C and 178.4°C (peak temperatures).

[0048] The present invention provides a crystalline Form A of the maleate salt of the compound of formula (I), the Differential Scanning Calorimetry (DSC) thermogram of which is shown in FIG.

[0049] The present invention provides a crystalline Form A of the maleate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which exhibits a weight loss of 5.31% below 150°C.

[0050] The present invention provides a crystalline Form A of the maleate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which is shown in FIG.

[0051] The present invention provides crystalline Form A of the maleate salt of the compound of formula (I), which is a hydrate.

[0052] The present invention also provides a maleate salt of the compound of formula (I), which is in a crystalline form (crystalline form B of the maleate salt) having an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 5.10°±0.2°, 7.65°±0.2°, 9.52°±0.2°, 11.67°±0.2°, 17.34°±0.2°, and 21.38°±0.2°.

[0053] Furthermore, the present invention provides crystalline form B of the maleate salt of compound of formula (I), whose X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 6.24°±0.2°, 19.01°±0.2°, 19.93°±0.2°, 22.90°±0.2°, 23.48°±0.2°, 24.33°±0.2°.

[0054] The present invention provides crystalline Form B of the maleate salt of compound of formula (I), whose 2θ values ​​and corresponding intensities in the X-ray powder diffraction pattern are shown in Table 1, with an error range of 2θ of ±0.2°.

[0055] [Table 5]

[0056] Furthermore, the present invention provides a crystalline form B of the maleate salt of the compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0057] The present invention provides a crystalline form B of the maleate salt of compound of formula (I), whose differential scanning calorimetry (DSC) shows three endothermic peaks at 77.5° C., 125.4° C. and 179.1° C. (peak temperatures).

[0058] The present invention provides crystalline Form B of the maleate salt of the compound of formula (I), the Differential Scanning Calorimetry (DSC) thermogram of which is shown in FIG.

[0059] The present invention provides a crystalline form B of the maleate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which exhibits a weight loss of 3.79% below 150°C.

[0060] The present invention provides a crystalline form B of the maleate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which is shown in FIG.

[0061] The present invention provides crystalline Form B of the maleate salt of the compound of formula (I), which is a hydrate.

[0062] The present invention also provides a maleate salt of the compound of formula (I), which is in a crystalline form (crystalline form C of the maleate salt) having an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 4.44°±0.2°, 6.39°±0.2°, 11.90°±0.2°, 16.85°±0.2°, 17.96°±0.2°, 18.19°±0.2°, 22.30°±0.2°, 24.22°±0.2°.

[0063] Furthermore, the present invention provides crystalline form C of the maleate salt of compound of formula (I), whose X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 8.88°±0.2°, 14.67°±0.2°, 21.78°±0.2°, 22.30°±0.2°, 25.82°±0.2°, 26.92°±0.2°.

[0064] The present invention provides crystalline Form C of the maleate salt of compound of formula (I), whose 2θ values ​​and corresponding intensities in the X-ray powder diffraction pattern are shown in Table 6, with an error range of 2θ of ±0.2°.

[0065] [Table 6]

[0066] Furthermore, the present invention provides a crystalline form C of the maleate salt of the compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0067] The present invention provides a crystalline form C of the maleate salt of compound of formula (I), whose differential scanning calorimetry (DSC) shows two endothermic peaks at 126.6° C. and 183.9° C. (peak temperatures).

[0068] The present invention provides crystalline Form C of the maleate salt of the compound of formula (I), the differential scanning calorimetry (DSC) thermogram of which is shown in FIG.

[0069] The present invention provides a crystalline Form C of the maleate salt of the compound of formula (I), whose thermogravimetric analysis (TGA) thermogram shows a weight loss of 1.7% when the sample is heated to 100° C. and a weight loss of 3.7% when the sample is continued to be heated to 150° C.

[0070] The present invention provides crystalline Form C of the maleate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which is shown in FIG.

[0071] The present invention provides crystalline Form C of the maleate salt of the compound of formula (I), which is a hydrate.

[0072] The present invention also provides a phosphate salt of the compound of formula (I), which is in a crystalline form (phosphate crystalline form A) and whose powder X-ray diffraction pattern has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 13.61°±0.2°, 16.67°±0.2°, 21.04°±0.2°.

[0073] The present invention provides crystalline Form A of the phosphate salt of the compound of formula (I), whose X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions: 15.45°±0.2°, 18.45°±0.2° using Cu-Kα radiation.

[0074] The present invention provides crystalline Form A of the phosphate salt of compound of formula (I), the 2θ values ​​and corresponding intensities in its X-ray powder diffraction pattern are shown in Table 7, with an error range of 2θ of ±0.2°.

[0075] [Table 7]

[0076] The present invention further provides a crystalline form A of the phosphate salt of the compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0077] The present invention provides a crystalline form A of the phosphate salt of the compound of formula (I), whose differential scanning calorimetry (DSC) shows two endothermic peaks at 61.4° C. and 150.9° C. (peak temperatures).

[0078] The present invention provides a crystalline Form A of the phosphate salt of the compound of formula (I), the differential scanning calorimetry (DSC) thermogram of which is shown in FIG.

[0079] The present invention provides a crystalline Form A of the phosphate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which exhibits a weight loss of 6.20% below 150°C.

[0080] The present invention provides a crystalline Form A of the phosphate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which is shown in FIG.

[0081] The present invention provides crystalline Form A of the phosphate salt of the compound of formula (I), which is a hydrate.

[0082] The present invention also provides a phosphate salt of the compound of formula (I), which is in a crystalline form (phosphate crystalline form B) and whose powder X-ray diffraction pattern has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 10.82°±0.2°, 18.08°±0.2°.

[0083] The present invention provides crystalline form B of the phosphate salt of compound of formula (I), the 2θ values ​​and corresponding intensities in its X-ray powder diffraction pattern are shown in Table 8, with an error range of 2θ of ±0.2°.

[0084] [Table 8]

[0085] Furthermore, the present invention provides a crystalline form B of the phosphate salt of the compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0086] The present invention provides a crystalline form B of the phosphate salt of the compound of formula (I), whose differential scanning calorimetry (DSC) shows two endothermic peaks at 74.8° C. and 142.6° C. (peak temperatures).

[0087] The present invention provides crystalline Form B of the phosphate salt of the compound of formula (I), the Differential Scanning Calorimetry (DSC) thermogram of which is shown in FIG.

[0088] The present invention provides a crystalline form B of the phosphate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which exhibits a weight loss of 4.36% below 150°C.

[0089] The present invention provides a crystalline form B of the phosphate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which is shown in FIG.

[0090] The present invention provides crystalline form B of the phosphate salt of the compound of formula (I), which is a hydrate.

[0091] The present invention also provides a phosphate salt of the compound of formula (I), which is in a crystalline form (phosphate crystalline form C) having an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 3.45°±0.2°, 7.85°±0.2°, 13.70°±0.2°, 24.79°±0.2°.

[0092] The present invention provides a crystalline form C of the phosphate salt of the compound of formula (I), whose X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions: 10.50°±0.2°, 26.85°±0.2°, using Cu-Kα radiation.

[0093] The present invention provides crystalline Form C of the phosphate salt of compound of formula (I), the 2θ values ​​and corresponding intensities in its X-ray powder diffraction pattern are shown in Table 9, with an error range of ±0.2° for 2θ.

[0094] [Table 9]

[0095] Furthermore, the present invention provides a crystalline form C of the phosphate salt of the compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0096] The present invention provides a crystalline form C of the phosphate salt of the compound of formula (I), whose differential scanning calorimetry (DSC) shows two endothermic peaks at 81.7° C. and 159.4° C. (peak temperatures).

[0097] The present invention provides crystalline Form C of the phosphate salt of the compound of formula (I), the differential scanning calorimetry (DSC) thermogram of which is shown in FIG.

[0098] The present invention provides a crystalline Form C of the phosphate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which exhibits a weight loss of 4.00% below 150°C.

[0099] The present invention provides a crystalline Form C of the phosphate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which is shown in FIG.

[0100] The present invention provides crystalline form C of the phosphate salt of the compound of formula (I), which is a hydrate.

[0101] The present invention also provides a mucate salt of the compound of formula (I), which is in a crystalline form (mucate salt crystalline form A) having an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 5.10°±0.2°, 16.44°±0.2°, 17.83°±0.2°, 19.36°±0.2°, 19.68°±0.2°.

[0102] The present invention provides crystalline Form A of the mucate salt of compound of formula (I), whose X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 10.15°±0.2°, 13.11°±0.2°, 23.05°±0.2°, 30.83°±0.2°.

[0103] The present invention provides crystalline Form A of the mucate salt of compound of formula (I), the 2θ values ​​and corresponding intensities in its X-ray powder diffraction pattern are shown in Table 10, with an error range of 2θ of ±0.2°.

[0104] [Table 10]

[0105] Furthermore, the present invention provides a crystalline Form A of the mucate salt of the compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0106] The present invention provides a crystalline form A of the mucate salt of the compound of formula (I), the differential scanning calorimetry (DSC) of which shows a T start = 186.2℃, T peak = 191.5 °C, ΔH = 177.7 J / g.

[0107] The present invention provides a crystalline form A of the mucate salt of the compound of formula (I), the differential scanning calorimetry (DSC) of which shows that it has a melting point of 191.5°C.

[0108] The present invention provides crystalline Form A of the mucate salt of the compound of formula (I), the differential scanning calorimetry (DSC) thermogram of which is shown in FIG.

[0109] The present invention provides a crystalline Form A of the mucate salt of the compound of formula (I), whose thermogravimetric analysis (TGA) thermogram exhibits a weight loss of 1.28% below 150°C.

[0110] The present invention provides a crystalline Form A of the mucate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which is shown in FIG.

[0111] The present invention provides crystalline Form A of the mucate salt of the compound of formula (I), which is anhydrous.

[0112] The present invention also provides a tartrate salt of the compound of formula (I), in a crystalline form (crystalline form A of the tartrate salt) having a powder X-ray diffraction pattern having characteristic diffraction peaks at the following 2θ positions: 8.21°±0.2°, 15.16°±0.2° using Cu-Kα radiation.

[0113] The present invention provides crystalline Form A of the tartrate salt of compound of formula (I), whose X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions: 16.46°±0.2°, 21.02°±0.2° using Cu-Kα radiation.

[0114] The present invention provides crystalline Form A of the tartrate salt of compound of formula (I), the 2θ values ​​and corresponding intensities in its X-ray powder diffraction pattern are shown in Table 11, with an error range of 2θ of ±0.2°.

[0115] [Table 11]

[0116] Furthermore, the present invention provides a crystalline Form A of the tartrate salt of the compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0117] The present invention provides a crystalline form A of the tartrate salt of compound of formula (I), whose differential scanning calorimetry (DSC) shows three endothermic peaks at 67.6° C., 178.0° C. and 204.6° C. (peak temperatures).

[0118] The present invention provides crystalline Form A of the tartrate salt of the compound of formula (I), the Differential Scanning Calorimetry (DSC) thermogram of which is shown in FIG.

[0119] The present invention provides a crystalline Form A of the tartrate salt of the compound of formula (I), whose thermogravimetric analysis (TGA) thermogram exhibits a weight loss of 3.63% below 150°C.

[0120] The present invention provides crystalline Form A of the tartrate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which is shown in FIG.

[0121] The present invention provides crystalline Form A of the tartrate salt of the compound of formula (I), which is a hydrate.

[0122] The present invention also provides a tartrate salt of the compound of formula (I), which is in a crystalline form (crystalline form B of the tartrate salt) and whose powder X-ray diffraction pattern has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 19.81°±0.2°.

[0123] The present invention provides crystalline Form B of the tartrate salt of compound of formula (I), the 2θ values ​​and corresponding intensities in its X-ray powder diffraction pattern are shown in Table 12, with an error range of 2θ of ±0.2°.

[0124] [Table 12]

[0125] Furthermore, the present invention provides a crystalline form B of the tartrate salt of the compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0126] The present invention provides crystalline Form B of the tartrate salt of compound of formula (I), whose Differential Scanning Calorimetry (DSC) shows three endothermic peaks at 67.3°C, 128.8°C and 193.3°C (peak temperatures).

[0127] The present invention provides crystalline Form B of the tartrate salt of the compound of formula (I), the Differential Scanning Calorimetry (DSC) thermogram of which is shown in FIG.

[0128] The present invention provides a crystalline form B of the tartrate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which exhibits a weight loss of 4.90% below 150°C.

[0129] The present invention provides crystalline Form B of the tartrate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which is shown in FIG.

[0130] The present invention provides crystalline Form B of the tartrate salt of the compound of formula (I), which is a hydrate.

[0131] The present invention also provides a tartrate salt of the compound of formula (I), in a crystalline form (crystalline form C of the tartrate salt) having an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 4.74°±0.2°, 10.82°±0.2°, 13.70°±0.2°, 14.37°±0.2°, 16.21°±0.2°.

[0132] The present invention provides crystalline Form C of the tartrate salt of compound of formula (I), whose X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 5.85°±0.2°, 17.83°±0.2°, 18.97°±0.2°, 21.76°±0.2°.

[0133] The present invention provides crystalline Form C of the tartrate salt of compound of formula (I), the 2θ values ​​and corresponding intensities of its X-ray powder diffraction pattern are shown in Table 13, with an error range of 2θ of ±0.2°.

[0134] [Table 13]

[0135] Furthermore, the present invention provides a crystalline form C of the tartrate salt of the compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0136] The present invention provides crystalline Form C of the tartrate salt of compound of formula (I), whose Differential Scanning Calorimetry (DSC) shows three endothermic peaks at 79.5°C, 134.2°C and 189.7°C (peak temperatures).

[0137] The present invention provides crystalline Form C of the tartrate salt of the compound of formula (I), the differential scanning calorimetry (DSC) thermogram of which is shown in FIG.

[0138] The present invention provides crystalline Form C of the tartrate salt of the compound of formula (I), whose thermogravimetric analysis (TGA) thermogram exhibits a weight loss of 5.63% below 150°C.

[0139] The present invention provides crystalline Form C of the tartrate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which is shown in FIG.

[0140] The present invention provides crystalline Form C of the tartrate salt of the compound of formula (I), which is a hydrate.

[0141] The present invention also provides a fumarate salt of the compound of formula (I), which is in a crystalline form (crystalline form A of the fumarate salt) having an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 6.45°±0.2°, 12.91°±0.2°, 13.50°±0.2°, 17.11°±0.2°, 19.42°±0.2°, 19.92°±0.2°, 20.76°±0.2°, 25.99°±0.2°.

[0142] The present invention provides crystalline Form A of the fumarate salt of compound of formula (I), whose X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 16.52°±0.2°, 23.99°±0.2°, 24.64°±0.2°, 27.16°±0.2°.

[0143] The present invention provides crystalline Form A of the fumarate salt of compound of formula (I), the 2θ values ​​and corresponding intensities in its X-ray powder diffraction pattern are shown in Table 14, and the error range of 2θ is ±0.2°.

[0144] [Table 14]

[0145] Furthermore, the present invention provides a crystalline Form A of the fumarate salt of the compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0146] The present invention provides a crystalline Form A of the fumarate salt of the compound of formula (I), whose Differential Scanning Calorimetry (DSC) shows three endothermic peaks at 145.9° C., 162.5° C. and 192.1° C. (peak temperatures).

[0147] The present invention provides crystalline Form A of the fumarate salt of the compound of formula (I), the differential scanning calorimetry (DSC) thermogram of which is shown in FIG.

[0148] The present invention provides a crystalline Form A of the fumarate salt of the compound of formula (I), whose thermogravimetric analysis (TGA) thermogram exhibits a weight loss of 2.09% below 150°C.

[0149] The present invention provides crystalline Form A of the fumarate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which is shown in FIG.

[0150] The present invention provides crystalline Form A of the fumarate salt of the compound of formula (I), which is anhydrous.

[0151] The present invention also provides a fumarate salt of the compound of formula (I), which is in a crystalline form (crystalline form B of the fumarate salt) and whose powder X-ray diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 12.23°±0.2°, 20.02°±0.2° using Cu-Kα radiation.

[0152] The present invention provides crystalline form B of the fumarate salt of compound of formula (I), whose X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions: 16.09°±0.2°, 22.38°±0.2° using Cu-Kα radiation.

[0153] The present invention provides crystalline form B of the fumarate salt of compound of formula (I), whose 2θ values ​​and corresponding intensities in the X-ray powder diffraction pattern are shown in Table 15, with an error range of 2θ of ±0.2°.

[0154] [Table 15]

[0155] Furthermore, the present invention provides a crystalline form B of the fumarate salt of the compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0156] The present invention provides a crystalline form B of the fumarate salt of compound of formula (I), whose differential scanning calorimetry (DSC) shows three endothermic peaks at 62.8° C., 154.1° C. and 190.9° C. (peak temperatures).

[0157] The present invention provides crystalline Form B of the fumarate salt of the compound of formula (I), the Differential Scanning Calorimetry (DSC) thermogram of which is shown in FIG.

[0158] The present invention provides a crystalline form B of the fumarate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which exhibits a weight loss of 3.38% below 120°C.

[0159] The present invention provides crystalline Form B of the fumarate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which is shown in FIG.

[0160] The present invention provides crystalline Form B of the fumarate salt of the compound of formula (I), which is a hydrate.

[0161] The present invention also provides a citrate salt of the compound of formula (I), which is in a crystalline form (crystalline form A of the citrate salt) having an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 4.59°±0.2°, 9.19°±0.2°, 11.05°±0.2°, 18.00°±0.2°, 19.06°±0.2°, and 21.31°±0.2°.

[0162] The present invention provides crystalline Form A of the citrate salt of the compound of formula (I), whose X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 12.79°±0.2°, 13.73°±0.2°, 23.06°±0.2°, 24.61°±0.2°, 26.03°±0.2°.

[0163] The present invention provides crystalline Form A of the citrate salt of compound of formula (I), the 2θ values ​​and corresponding intensities of its X-ray powder diffraction pattern are shown in Table 16, with an error range of 2θ of ±0.2°.

[0164] [Table 16]

[0165] Furthermore, the present invention provides a crystalline Form A of the citrate salt of the compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0166] The present invention provides a crystalline Form A of the citrate salt of the compound of formula (I), whose Differential Scanning Calorimetry (DSC) shows two endothermic peaks at 113.6° C. and 174.6° C. (peak temperatures).

[0167] The present invention provides a crystalline Form A of the citrate salt of the compound of formula (I), the Differential Scanning Calorimetry (DSC) thermogram of which is shown in FIG.

[0168] The present invention provides a crystalline Form A of the citrate salt of the compound of formula (I), whose thermogravimetric analysis (TGA) thermogram exhibits a weight loss of 6.60% below 150°C.

[0169] The present invention provides a crystalline Form A of the citrate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which is shown in FIG.

[0170] The present invention provides crystalline Form A of the citrate salt of the compound of formula (I), which is a hydrate.

[0171] The present invention also provides a citrate salt of the compound of formula (I), which is in a crystalline form (crystalline form B of the citrate salt) having an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 7.70°±0.2°, 8.74°±0.2°, 14.70°±0.2°, 16.42°±0.2°, 17.47°±0.2°, 28.70°±0.2°.

[0172] The present invention provides crystalline form B of the citrate salt of the compound of formula (I), whose X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 13.20°±0.2°, 19.87°±0.2°, 22.23°±0.2°, 23.48°±0.2°.

[0173] The present invention provides crystalline Form B of the citrate salt of compound of formula (I), the 2θ values ​​and corresponding intensities of its X-ray powder diffraction pattern are shown in Table 17, with an error range of 2θ of ±0.2°.

[0174] [Table 17]

[0175] Furthermore, the present invention provides a crystalline form B of the citrate salt of the compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0176] The present invention provides a crystalline form B of the citrate salt of the compound of formula (I), whose differential scanning calorimetry (DSC) shows three endothermic peaks at 98.9° C., 159.6° C. and 183.1° C. (peak temperatures).

[0177] The present invention provides crystalline Form B of the citrate salt of the compound of formula (I), the Differential Scanning Calorimetry (DSC) thermogram of which is shown in FIG.

[0178] The present invention provides a crystalline Form B of the citrate salt of the compound of formula (I), whose thermogravimetric analysis (TGA) thermogram exhibits a weight loss of 3.85% below 150°C.

[0179] The present invention provides a crystalline form B of the citrate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which is shown in FIG.

[0180] The present invention provides crystalline Form B of the citrate salt of the compound of formula (I) which is anhydrous.

[0181] The present invention also provides a malate salt of the compound of formula (I), which is in a crystalline form (Malate Crystal Form A) having an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 8.75°±0.2°, 9.82°±0.2°, 15.08°±0.2°, 16.65°±0.2°, 20.89°±0.2°, 21.89°±0.2°, 23.75°±0.2°.

[0182] The present invention provides crystalline Form A of the malate salt of compound of formula (I), whose X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 11.80°±0.2°, 14.04°±0.2°, 14.69°±0.2°, 24.81°±0.2°, 25.91°±0.2°.

[0183] The present invention provides crystalline Form A of the malate salt of compound of formula (I), the 2θ values ​​and corresponding intensities in its X-ray powder diffraction pattern are shown in Table 18, with an error range of ±0.2° for 2θ.

[0184] [Table 18]

[0185] The present invention further provides a crystalline Form A of the malate salt of the compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0186] The present invention provides a crystalline form A of the malate salt of the compound of formula (I), the differential scanning calorimetry (DSC) of which shows a T start = 176.2℃, T peak = 183.6 °C, ΔH = 78.06 J / g.

[0187] The present invention provides a crystalline Form A of the malate salt of compound of formula (I), whose Differential Scanning Calorimetry (DSC) shows two endothermic peaks at 183.6° C. and 207.1° C. (peak temperatures).

[0188] The present invention provides crystalline Form A of the malate salt of the compound of formula (I), the differential scanning calorimetry (DSC) thermogram of which is shown in FIG.

[0189] The present invention provides a crystalline Form A of the malate salt of compound of formula (I), which exhibits a thermogravimetric analysis (TGA) thermogram that exhibits a weight loss of 4.24% below 150°C and a decomposition temperature of 200°C.

[0190] The present invention provides crystalline Form A of the malate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which is shown in FIG.

[0191] The present invention provides crystalline Form A of the malate salt of the compound of formula (I), which is a hydrate.

[0192] The present invention also provides a malate salt of the compound of formula (I), which is in a crystalline form (Malate Crystal Form B) having an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 7.60°±0.2°, 15.68°±0.2°, 22.15°±0.2°, 24.86°±0.2°.

[0193] The present invention provides crystalline form B of the malate salt of compound of formula (I), whose X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 13.30°±0.2°, 17.62°±0.2°, 23.76°±0.2°, 28.88°±0.2°.

[0194] The present invention provides crystalline Form B of the malate salt of compound of formula (I), the 2θ values ​​and corresponding intensities of its X-ray powder diffraction pattern are shown in Table 19, with an error range of 2θ of ±0.2°.

[0195] [Table 19]

[0196] Furthermore, the present invention provides a crystalline form B of the malate salt of compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0197] The present invention provides a crystalline form B of the malate salt of the compound of formula (I), the differential scanning calorimetry (DSC) of which shows a T start = 172.3℃, T peak = 180.3 °C, ΔH = 59.25 J / g.

[0198] The present invention provides a crystalline form B of the malate salt of the compound of formula (I), the differential scanning calorimetry (DSC) of which shows that it has a melting point of 180.3°C.

[0199] The present invention provides crystalline Form B of the malate salt of compound of formula (I), the Differential Scanning Calorimetry (DSC) thermogram of which is shown in FIG.

[0200] The present invention provides a crystalline form B of the malate salt of compound of formula (I), whose thermogravimetric analysis (TGA) thermogram exhibits a weight loss of 2.31% below 150°C.

[0201] The present invention provides crystalline Form B of the malate salt of compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which is shown in FIG.

[0202] The present invention provides crystalline Form B of the malate salt of the compound of formula (I), which is anhydrous.

[0203] The present invention also provides hiprinate of the compound of formula (I), in a crystalline form (hiprinate crystalline form A) having an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 7.64°±0.2°, 9.13°±0.2°, 15.33°±0.2°, 21.78°±0.2°, and 25.22°±0.2°.

[0204] Furthermore, the present invention provides crystalline Form A of the hippurate salt of compound of formula (I), whose X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 11.43°±0.2°, 14.10°±0.2°, 16.05°±0.2°, 17.50°±0.2°, 18.31°±0.2°, 18.83°±0.2°, 22.45°±0.2°, 27.71°±0.2°.

[0205] The present invention provides crystalline Form A of hippurate salt of compound of formula (I), the 2θ values ​​and corresponding intensities of its X-ray powder diffraction pattern are shown in Table 20, with an error range of 2θ of ±0.2°.

[0206] [Table 20]

[0207] Further, the present invention provides a crystalline Form A of the hippurate salt of the compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0208] The present invention provides a crystalline form A of the hippurate salt of compound of formula (I), the differential scanning calorimetry (DSC) of which shows two endothermic peaks (peak temperatures) at 88.7°C and 141.8°C.

[0209] The present invention provides crystalline Form A of the hippurate salt of the compound of formula (I), the Differential Scanning Calorimetry (DSC) thermogram of which is shown in FIG.

[0210] The present invention provides a crystalline Form A of the hippurate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which exhibits a weight loss of 7.39% below 150°C.

[0211] The present invention provides crystalline Form A of the hippurate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which is shown in FIG.

[0212] The present invention provides crystalline Form A of the hippurate salt of the compound of formula (I), which is a hydrate.

[0213] The present invention also provides an adipate salt of the compound of formula (I), which is in a crystalline form (crystalline form A of the adipate salt) having a powder X-ray diffraction pattern having characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 6.59°±0.2°, 8.54°±0.2°, 17.46°±0.2°.

[0214] Furthermore, the present invention provides a crystalline form A of the adipate salt of compound of formula (I), whose X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 13.55°±0.2°, 15.13°±0.2°, 16.02°±0.2°.

[0215] The present invention provides crystalline Form A of the adipate salt of compound of formula (I), the 2θ values ​​and corresponding intensities of its X-ray powder diffraction pattern are shown in Table 21, with an error range of 2θ of ±0.2°.

[0216] [Table 21]

[0217] Further, the present invention provides a crystalline form A of adipic acid compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0218] The present invention provides a crystalline form A of adipic acid of compound of formula (I), whose differential scanning calorimetry (DSC) shows two endothermic peaks at 132.5° C. and 153.0° C. (peak temperatures).

[0219] The present invention provides crystalline Form A of adipic acid of compound of formula (I), whose Differential Scanning Calorimetry (DSC) thermogram is shown in FIG.

[0220] The present invention provides a crystalline form A of adipic acid compound of formula (I), whose thermogravimetric analysis (TGA) thermogram exhibits a weight loss of 7.79% below 150°C.

[0221] The present invention provides a crystalline form A of adipic acid of compound of formula (I), whose thermogravimetric analysis (TGA) thermogram is shown in FIG.

[0222] The present invention provides crystalline Form A of the adipate salt of the compound of formula (I), which is a hydrate.

[0223] The present invention also provides an adipate salt of the compound of formula (I), which is in a crystalline form (crystalline form B of adipate salt) having an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 8.10°±0.2°, 12.18°±0.2°, 16.24°±0.2°, 17.68°±0.2°, and 20.33°±0.2°.

[0224] Furthermore, the present invention provides crystalline form B of the adipate salt of compound of formula (I), whose X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 10.68°±0.2°, 14.02°±0.2°, 19.60°±0.2°, 20.95°±0.2°.

[0225] The present invention provides crystalline form B of adipic acid compound of formula (I), whose 2θ values ​​and corresponding intensities in the X-ray powder diffraction pattern are shown in Table 22, with an error range of 2θ of ±0.2°.

[0226] [Table 22]

[0227] Further, the present invention provides a crystalline form B of adipic acid compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0228] The present invention provides a crystalline form B of adipic acid of the compound of formula (I), the differential scanning calorimetry (DSC) of which shows a T start = 152.0℃, T peak = 154.3 °C, ΔH = 87.83 J / g.

[0229] The present invention provides a crystalline form B of adipic acid of compound of formula (I), the differential scanning calorimetry (DSC) of which shows that its melting point is 154.3°C.

[0230] The present invention provides crystalline Form B of adipic acid of compound of formula (I), the Differential Scanning Calorimetry (DSC) thermogram of which is shown in FIG.

[0231] The present invention provides a crystalline form B of adipic acid compound of formula (I), whose thermogravimetric analysis (TGA) thermogram shows a weight loss of 0.51% below 150°C and a decomposition temperature of 160°C.

[0232] The present invention provides crystalline Form B of adipic acid of compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which is shown in FIG.

[0233] The present invention provides crystalline Form B of the adipic acid of compound of formula (I) which is anhydrous.

[0234] The present invention also provides a sebacate salt of the compound of formula (I), which is in a crystalline form (crystalline form A of the sebacate salt) and has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 8.91°±0.2°, 12.12°±0.2°, 20.39°±0.2°, 25.08°±0.2°.

[0235] Furthermore, the present invention provides a crystalline form A of the sebacate salt of compound of formula (I), whose X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 14.14°±0.2°, 16.01°±0.2°, 18.96°±0.2°, 23.90°±0.2°.

[0236] The present invention provides crystalline Form A of the sebacate salt of compound of formula (I), the 2θ values ​​and corresponding intensities of its X-ray powder diffraction pattern are shown in Table 23, with an error range of 2θ of ±0.2°.

[0237] [Table 23]

[0238] Further, the present invention provides a crystalline form A of the sebacate salt of the compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0239] The present invention provides a crystalline Form A of the sebacate salt of compound of formula (I), whose Differential Scanning Calorimetry (DSC) shows three endothermic peaks at 102.6° C., 160.1° C. and 173.7° C. (peak temperatures).

[0240] The present invention provides a crystalline Form A of the sebacate salt of the compound of formula (I), the Differential Scanning Calorimetry (DSC) thermogram of which is shown in FIG.

[0241] The present invention provides a crystalline Form A of the sebacate salt of compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which exhibits a weight loss of 6.19% below 150°C.

[0242] The present invention provides a crystalline Form A of the sebacate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which is shown in FIG.

[0243] The present invention provides crystalline Form A of the sebacate salt of compound of formula (I), which is a hydrate.

[0244] The present invention also provides a sebacate salt of the compound of formula (I), which is in a crystalline form (crystalline form B of the sebacate salt) and has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 5.14°±0.2°, 7.40°±0.2°, 8.48°±0.2°, 10.99°±0.2°, 16.60°±0.2°, 16.86°±0.2°.

[0245] Furthermore, the present invention provides a crystalline form B of the sebacate salt of compound of formula (I), whose X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 13.80°±0.2°, 20.07°±0.2°, 21.19°±0.2°, 22.33°±0.2°.

[0246] The present invention provides crystalline form B of the sebacate salt of compound of formula (I), the 2θ values ​​and corresponding intensities of its X-ray powder diffraction pattern are shown in Table 24, with an error range of 2θ of ±0.2°.

[0247] [Table 24]

[0248] Furthermore, the present invention provides a crystalline form B of the sebacate salt of compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0249] The present invention provides a crystalline form B of the sebacate salt of compound of formula (I), whose differential scanning calorimetry (DSC) shows three endothermic peaks at 53.2°C, 110.8°C and 157.8°C (peak temperatures).

[0250] The present invention provides crystalline Form B of the sebacate salt of compound of formula (I), the Differential Scanning Calorimetry (DSC) thermogram of which is shown in FIG.

[0251] The present invention provides a crystalline form B of the sebacate salt of compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which exhibits a weight loss of 5.4% below 150°C.

[0252] The present invention provides a crystalline form B of the sebacate salt of compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which is shown in FIG.

[0253] The present invention provides crystalline Form B of the sebacate salt of compound of formula (I), which is a hydrate.

[0254] The present invention also provides a sebacate salt of the compound of formula (I), in a crystalline form (crystalline form C of the sebacate salt) having an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 5.02°±0.2°, 7.52°±0.2°, 15.08°±0.2°, 19.91°±0.2°.

[0255] The present invention further provides crystalline form C of the sebacate salt of compound of formula (I), whose X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 12.37°±0.2°, 18.68°±0.2°, 21.52°±0.2°, 22.85°±0.2°, 24.07°±0.2°.

[0256] The present invention provides crystalline Form C of the sebacate salt of compound of formula (I), the 2θ values ​​and corresponding intensities of its X-ray powder diffraction pattern are shown in Table 25, with an error range of 2θ of ±0.2°.

[0257] [Table 25]

[0258] Furthermore, the present invention provides a crystalline form C of the sebacate salt of compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0259] The present invention provides crystalline Form C of the sebacate salt of compound of formula (I), whose Differential Scanning Calorimetry (DSC) shows three endothermic peaks at 111.4°C, 125.1°C and 156.4°C (peak temperatures).

[0260] The present invention provides crystalline Form C of the sebacate salt of compound of formula (I), the Differential Scanning Calorimetry (DSC) thermogram of which is shown in FIG.

[0261] The present invention provides a crystalline Form C of the sebacate salt of compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which exhibits a weight loss of 3.1% below 150°C.

[0262] The present invention provides a crystalline form C of the sebacate salt of compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which is shown in FIG.

[0263] The present invention provides crystalline Form C of the sebacate salt of compound of formula (I), which is anhydrous.

[0264] The present invention also provides 1,5-naphthalenedisulfonate of the compound of formula (I), which is in a crystalline form (crystalline form A of 1,5-naphthalenedisulfonate) and whose powder X-ray diffraction pattern has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 8.36°±0.2°, 12.55°±0.2°, 13.03°±0.2° and 16.69°±0.2°.

[0265] Furthermore, the present invention provides a crystalline form A of 1,5-naphthalenedisulfonic acid salt of compound of formula (I), whose X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 7.40°±0.2°, 21.64°±0.2°, 23.16°±0.2°, 26.45°±0.2°.

[0266] The present invention provides crystalline Form A of 1,5-naphthalenedisulfonic acid salt of compound of formula (I), the 2θ values ​​and corresponding intensities of its X-ray powder diffraction pattern are shown in Table 26, with an error range of 2θ of ±0.2°.

[0267] [Table 26]

[0268] Furthermore, the present invention provides a crystalline form A of the 1,5-naphthalenedisulfonic acid salt of the compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0269] The present invention provides a crystalline form A of 1,5-naphthalenedisulfonic acid salt of the compound of formula (I), whose differential scanning calorimetry (DSC) shows two endothermic peaks at 65.4° C. and 231.1° C. (peak temperatures).

[0270] The present invention provides a crystalline Form A of the 1,5-naphthalenedisulfonic acid salt of the compound of formula (I), whose differential scanning calorimetry (DSC) thermogram is shown in FIG.

[0271] The present invention provides a crystalline Form A of 1,5-naphthalenedisulfonic acid salt of the compound of formula (I), whose thermogravimetric analysis (TGA) thermogram exhibits a weight loss of 3.2% below 150°C.

[0272] The present invention provides a crystalline Form A of the 1,5-naphthalenedisulfonic acid salt of the compound of formula (I), whose thermogravimetric analysis (TGA) thermogram is shown in FIG.

[0273] The present invention provides crystalline Form A of the 1,5-naphthalenedisulfonic acid salt of the compound of formula (I), which is a hydrate.

[0274] The present invention also provides a methanesulfonate salt of the compound of formula (I), which is in a crystalline form (crystalline form A of the methanesulfonate salt) having an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 8.41°±0.2°, 13.22±0.2°, 16.95°±0.2°, 20.50°±0.2°, 20.86°±0.2°, 21.89°±0.2°, 22.48°±0.2°, and 24.38°±0.2°.

[0275] The present invention further provides crystalline form A of the methanesulfonate salt of compound of formula (I), whose X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 10.39°±0.2°, 12.32°±0.2°, 18.06°±0.2°, 25.31°±0.2°, 26.15°±0.2°, 32.19°±0.2°.

[0276] The present invention provides crystalline Form A of the methanesulfonate salt of compound of formula (I), whose X-ray powder diffraction pattern 2θ values ​​and corresponding intensities are shown in Table 27, with an error range of 2θ of ±0.2°.

[0277] [Table 27]

[0278] Furthermore, the present invention provides a crystalline form A of the methanesulfonate salt of the compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0279] The present invention provides a crystalline form A of the methanesulfonate salt of the compound of formula (I), the differential scanning calorimetry (DSC) of which shows a T start = 238.9℃ and T peak = 242.5 ° C.

[0280] The present invention provides a crystalline form A of the methanesulfonate salt of the compound of formula (I), the differential scanning calorimetry (DSC) of which shows a melting point of 242.5.

[0281] The present invention provides crystalline Form A of the methanesulfonate salt of the compound of formula (I), the differential scanning calorimetry (DSC) thermogram of which is shown in FIG.

[0282] The present invention provides a crystalline Form A of the methanesulfonate salt of the compound of formula (I), which exhibits a thermogravimetric analysis (TGA) thermogram that exhibits a weight loss of 1.3% below 150°C and a decomposition temperature of 250°C.

[0283] The present invention provides a crystalline Form A of the methanesulfonate salt of the compound of formula (I), whose thermogravimetric analysis (TGA) thermogram is shown in FIG.

[0284] The present invention provides crystalline Form A of the methanesulfonate salt of the compound of formula (I), which is anhydrous.

[0285] The present invention also provides a benzenesulfonate salt of the compound of formula (I), which is in a crystalline form (crystalline form A of the benzenesulfonate salt) and has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 7.12°±0.2°, 14.01°±0.2°, 16.11°±0.2°, 21.40°±0.2°, and 22.87°±0.2°.

[0286] The present invention further provides crystalline Form A of the benzenesulfonate salt of compound of formula (I), whose X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 13.37°±0.2°, 14.78°±0.2°, 17.60°±0.2°, 20.23°±0.2°, 20.63°±0.2°, 25.38°±0.2°, 26.11°±0.2°, 27.57°±0.2° (using Cu-Kα radiation).

[0287] The present invention provides crystalline Form A of the benzenesulfonate salt of compound of formula (I), whose 2θ values ​​and corresponding intensities in the X-ray powder diffraction pattern are shown in Table 28, with an error range of 2θ of ±0.2°.

[0288] [Table 28]

[0289] Furthermore, the present invention provides a crystalline form A of the benzenesulfonate salt of the compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0290] The present invention provides a crystalline form A of the benzenesulfonate salt of the compound of formula (I), whose differential scanning calorimetry (DSC) shows two endothermic peaks at 66.9° C. and 151.0° C. (peak temperatures).

[0291] The present invention provides a crystalline form A of the benzenesulfonate salt of the compound of formula (I), whose differential scanning calorimetry (DSC) thermogram is shown in FIG.

[0292] The present invention provides a crystalline Form A of the benzenesulfonate salt of the compound of formula (I), whose thermogravimetric analysis (TGA) thermogram exhibits a weight loss of 2.1% below 150°C.

[0293] The present invention provides a crystalline Form A of the benzenesulfonate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which is shown in FIG.

[0294] The present invention provides crystalline Form A of the benzenesulfonate salt of the compound of formula (I), which is anhydrous.

[0295] The present invention also provides a benzenesulfonate salt of the compound of formula (I), which is in a crystalline form (crystalline form B of the benzenesulfonate salt) and whose powder X-ray diffraction pattern has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 13.87°±0.2°, 16.56°±0.2°, 17.78°±0.2°, and 26.39°±0.2°.

[0296] Furthermore, the present invention provides crystalline form B of the benzenesulfonate salt of compound of formula (I), whose X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 7.37°±0.2°, 22.47°±0.2°, 24.85°±0.2°.

[0297] The present invention provides crystalline form B of the benzenesulfonate salt of compound of formula (I), the 2θ values ​​and corresponding intensities in its X-ray powder diffraction pattern are shown in Table 29, with an error range of 2θ of ±0.2°.

[0298] [Table 29]

[0299] Furthermore, the present invention provides a crystalline form B of the benzenesulfonate salt of the compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0300] The present invention provides a crystalline form B of the benzenesulfonate salt of the compound of formula (I), the differential scanning calorimetry (DSC) of which shows a T start = 134.3℃, T peak = 147.7 ° C, ΔH = 43.82 J / g.

[0301] The present invention provides a crystalline form B of the benzenesulfonate salt of the compound of formula (I), the differential scanning calorimetry (DSC) of which shows that it has a melting point of 147.7°C.

[0302] The present invention provides crystalline Form B of the benzenesulfonate salt of the compound of formula (I), whose Differential Scanning Calorimetry (DSC) thermogram is shown in FIG.

[0303] The present invention provides a crystalline form B of the benzenesulfonate salt of the compound of formula (I), whose thermogravimetric analysis (TGA) thermogram exhibits a weight loss of 3.0% below 150°C.

[0304] The present invention provides a crystalline form B of the benzenesulfonate salt of the compound of formula (I), whose thermogravimetric analysis (TGA) thermogram is shown in FIG.

[0305] The present invention provides crystalline Form B of the benzenesulfonate salt of the compound of formula (I), which is a hydrate.

[0306] The present invention also provides an oxalate salt of the compound of formula (I), which is in a crystalline form (crystalline form A of the oxalate salt) and whose powder X-ray diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 17.14°±0.2° using Cu-Kα radiation.

[0307] The present invention provides crystalline Form A of the oxalate salt of compound of formula (I), the 2θ values ​​and corresponding intensities of its X-ray powder diffraction pattern are shown in Table 30, with an error range of 2θ of ±0.2°.

[0308] [Table 30]

[0309] Furthermore, the present invention provides a crystalline Form A of the oxalate salt of the compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0310] The present invention provides a crystalline Form A of the oxalate salt of compound of formula (I), whose Differential Scanning Calorimetry (DSC) shows two endothermic peaks at 199.6° C. and 211.6° C. (peak temperatures).

[0311] The present invention provides a crystalline Form A of the oxalate salt of the compound of formula (I), the Differential Scanning Calorimetry (DSC) thermogram of which is shown in FIG.

[0312] The present invention provides a crystalline Form A of the oxalate salt of the compound of formula (I), whose thermogravimetric analysis (TGA) thermogram exhibits a weight loss of 4.9% below 150°C.

[0313] The present invention provides a crystalline Form A of the oxalate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which is shown in FIG.

[0314] The present invention provides crystalline Form A of the oxalate salt of the compound of formula (I), which is a hydrate.

[0315] The present invention also provides a benzoate salt of the compound of formula (I), which is in a crystalline form (benzoate crystalline form A) having an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 8.23°±0.2°, 13.48°±0.2°, 14.86°±0.2°, 15.13°±0.2°.

[0316] Furthermore, the present invention provides a crystalline form A of the benzoate salt of the compound of formula (I), whose X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 6.62°±0.2°, 7.30°±0.2°, 12.11°±0.2°, 20.37°±0.2°, 22.37°±0.2°.

[0317] The present invention provides crystalline Form A of the benzoate salt of compound of formula (I), the 2θ values ​​and corresponding intensities of its X-ray powder diffraction pattern are shown in Table 31, with an error range of 2θ of ±0.2°.

[0318] [Table 31]

[0319] Furthermore, the present invention provides a crystalline Form A of the benzoate salt of the compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0320] The present invention provides a crystalline Form A of the benzoate salt of compound of formula (I), whose differential scanning calorimetry (DSC) shows four endothermic peaks at 67.5°C, 100.4°C, 118.6°C and 157.9°C (peak temperatures).

[0321] The present invention provides crystalline Form A of the benzoate salt of the compound of formula (I), the Differential Scanning Calorimetry (DSC) thermogram of which is shown in FIG.

[0322] The present invention provides a crystalline Form A of the benzoate salt of the compound of formula (I), whose thermogravimetric analysis (TGA) thermogram exhibits a weight loss of 5.9% below 120°C.

[0323] The present invention provides a crystalline Form A of the benzoate salt of the compound of formula (I), whose thermogravimetric analysis (TGA) thermogram is shown in FIG.

[0324] The present invention provides crystalline Form A of the benzoate salt of compound of formula (I), which is a hydrate.

[0325] The present invention also provides a benzoate salt of the compound of formula (I), which is in a crystalline form (crystalline form B of the benzoate salt) having an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 7.95°±0.2°, 13.51°±0.2°, 15.87°±0.2°, and 20.88°±0.2°.

[0326] Furthermore, the present invention provides a crystalline form B of the benzoate salt of the compound of formula (I), whose X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 14.82°±0.2°, 17.73°±0.2°, 18.95°±0.2°, 25.58°±0.2°.

[0327] The present invention provides crystalline Form B of the benzoate salt of compound of formula (I), the 2θ values ​​and corresponding intensities of its X-ray powder diffraction pattern are shown in Table 32, with an error range of 2θ of ±0.2°.

[0328] [Table 32]

[0329] Furthermore, the present invention provides a crystalline form B of the benzoate salt of the compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0330] The present invention provides a crystalline form B of the benzoate salt of compound of formula (I), whose differential scanning calorimetry (DSC) shows four endothermic peaks at 111.6°C, 124.1°C, 129.1°C and 156.6°C (peak temperatures).

[0331] The present invention provides crystalline Form B of the benzoate salt of the compound of formula (I), the Differential Scanning Calorimetry (DSC) thermogram of which is shown in FIG.

[0332] The present invention provides a crystalline form B of the benzoate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which exhibits a weight loss of 7.1% below 150°C.

[0333] The present invention provides crystalline Form B of the benzoate salt of the compound of formula (I), whose thermogravimetric analysis (TGA) thermogram is shown in FIG.

[0334] The present invention provides crystalline form B of the benzoate salt of compound of formula (I), which is a hydrate.

[0335] The present invention also provides a benzoate salt of the compound of formula (I), which is in a crystalline form (crystalline form C of the benzoate salt) having an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 5.01°±0.2°, 7.24°±0.2°, 12.07°±0.2°, 14.51°±0.2°, 17.12°±0.2°, 18.62°±0.2°.

[0336] Furthermore, the present invention provides crystalline form C of the benzoate salt of compound of formula (I), whose X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 15.84°±0.2°, 23.46°±0.2°, 24.42°±0.2°, 25.43°±0.2°.

[0337] The present invention provides crystalline Form C of the benzoate salt of compound of formula (I), the 2θ values ​​and corresponding intensities of its X-ray powder diffraction pattern are provided in Table 33, with an error range of 2θ of ±0.2°.

[0338] [Table 33]

[0339] Furthermore, the present invention provides a crystalline form C of the benzoate salt of the compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0340] The present invention provides crystalline Form C of the benzoate salt of compound of formula (I), whose differential scanning calorimetry (DSC) shows four endothermic peaks at 106.6° C., 120.7° C., 126.4° C. and 143.9° C. (peak temperatures).

[0341] The present invention provides crystalline Form C of the benzoate salt of the compound of formula (I), the Differential Scanning Calorimetry (DSC) thermogram of which is shown in FIG.

[0342] The present invention provides a crystalline form C of the benzoate salt of the compound of formula (I), the thermogravimetric analysis (TGA) thermogram of which exhibits a weight loss of 1.9% below 100°C.

[0343] The present invention provides crystalline Form C of the benzoate salt of compound of formula (I), whose thermogravimetric analysis (TGA) thermogram is shown in FIG.

[0344] The present invention provides crystalline Form C of the benzoate salt of compound of formula (I), which is anhydrous.

[0345] The present invention also provides the hydrobromide salt of the compound of formula (I), which is in a crystalline form (crystalline form A of the hydrobromide salt) having an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 7.53°±0.2°, 18.52°±0.2°, 21.69°±0.2°, 22.88°±0.2°.

[0346] Furthermore, the present invention provides crystalline form A of the hydrobromide salt of compound of formula (I), whose X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 9.21°±0.2°, 12.94°±0.2°, 13.85°±0.2°, 22.35°±0.2°, 25.34°±0.2°, 30.09°±0.2°.

[0347] The present invention provides crystalline Form A of the hydrobromide salt of compound of formula (I), whose X-ray powder diffraction pattern 2θ values ​​and corresponding intensities are shown in Table 34, with an error range of 2θ of ±0.2°.

[0348] [Table 34]

[0349] The present invention further provides a crystalline form A of the hydrobromide salt of the compound of formula (I), the X-ray powder diffraction pattern of which is substantially as shown in FIG.

[0350] The present invention provides a crystalline form A of the hydrobromide salt of the compound of formula (I), the differential scanning calorimetry (DSC) of which shows a T start = 220.2℃, T peak = 225.7 °C, ΔH = 11.29 J / g.

[0351] The present invention provides a crystalline form A of the hydrobromide salt of the compound of formula (I), the differential scanning calorimetry (DSC) of which shows that it has a melting point of 225.7°C.

[0352] The present invention provides crystalline Form A of the hydrobromide salt of the compound of formula (I), whose Differential Scanning Calorimetry (DSC) thermogram is shown in FIG.

[0353] The present invention provides a crystalline Form A of the hydrobromide salt of the compound of formula (I), which exhibits a thermogravimetric analysis (TGA) thermogram that exhibits a weight loss of 1.3% below 150°C and a decomposition temperature of 250°C.

[0354] The present invention provides a crystalline Form A of the hydrobromide salt of the compound of formula (I), whose thermogravimetric analysis (TGA) thermogram is shown in FIG.

[0355] The present invention provides crystalline Form A of the hydrobromide salt of compound of formula (I) which is anhydrous.

[0356] The salts or crystalline forms of the present invention are present in an amount from about 5% to about 100% by weight of the drug substance.

[0357] In some embodiments, the salt or crystalline form of the invention is present at about 10% to about 100% by weight of the pharmaceutical agent.

[0358] In some embodiments, the salt or crystalline form of the invention is present at about 15% to about 100% by weight of the pharmaceutical agent.

[0359] In some embodiments, the salt or crystalline form of the invention is present at about 20% to about 100% by weight of the pharmaceutical agent.

[0360] In some embodiments, the salt or crystalline form of the invention is present at about 25% to about 100% by weight of the pharmaceutical agent.

[0361] In some embodiments, the salt or crystalline form of the invention is present at about 30% to about 100% by weight of the pharmaceutical agent.

[0362] In some embodiments, the salt or crystalline form of the invention is present at about 35% to about 100% by weight of the pharmaceutical agent.

[0363] In some embodiments, the salt or crystalline form of the invention is present at about 40% to about 100% by weight of the pharmaceutical agent.

[0364] In some embodiments, the salt or crystalline form of the invention is present at about 45% to about 100% by weight of the pharmaceutical agent.

[0365] In some embodiments, the salt or crystalline form of the invention is present at about 50% to about 100% by weight of the pharmaceutical agent.

[0366] In some embodiments, the salt or crystalline form of the invention is present at about 55% to about 100% by weight of the pharmaceutical agent.

[0367] In some embodiments, the salt or crystalline form of the invention is present at about 60% to about 100% by weight of the pharmaceutical agent.

[0368] In some embodiments, the salt or crystalline form of the invention is present at about 65% to about 100% by weight of the pharmaceutical agent.

[0369] In some embodiments, the salt or crystalline form of the invention is present at about 70% to about 100% by weight of the pharmaceutical agent.

[0370] In some embodiments, the salt or crystalline form of the invention is present at about 75% to about 100% by weight of the pharmaceutical agent.

[0371] In some embodiments, the salt or crystalline form of the invention is present at about 80% to about 100% by weight of the pharmaceutical agent.

[0372] In some embodiments, the salt or crystalline form of the invention is present at about 85% to about 100% by weight of the pharmaceutical agent.

[0373] In some embodiments, the salt or crystalline form of the invention is present at about 90% to about 100% by weight of the pharmaceutical agent.

[0374] In some embodiments, the salt or crystalline form of the invention is present at about 95% to about 100% by weight of the pharmaceutical agent.

[0375] In some embodiments, the salt or crystalline form of the invention is present at about 98% to about 100% by weight of the pharmaceutical agent.

[0376] In some embodiments, the salt or crystalline form of the invention is present at about 99% to about 100% by weight of the pharmaceutical agent.

[0377] In certain embodiments, substantially all of the pharmaceutical agent is a salt or crystalline form of the invention, ie, the pharmaceutical agent is a substantially phase pure salt or phase pure crystal.

[0378] The structure of the crystalline forms of the present invention can be analyzed using a variety of analytical techniques known to those skilled in the art, including, but not limited to, X-ray powder diffraction (XRD), differential scanning calorimetry (DSC) and / or thermogravimetry (TG).

[0379] Thermogravimetric analysis (TGA) is also known as thermogravimetry (TG).

[0380] As is well known in the field of differential scanning calorimetry (DSC), it can be appreciated that the height of the melting peak in a DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline compounds of the present invention are characterized by a DSC thermogram having a characteristic peak position having substantially the same properties as the DSC thermograms provided in the figures of the present invention with an error tolerance of ±3°C.

[0381] Materials having substantially the same X-ray powder diffraction patterns, DSC thermograms or TGA thermograms as those disclosed herein are also within the scope of the present invention.

[0382] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of the salts of the compounds of formula (I) according to the present invention, as well as their hydrates, solvates and crystalline forms thereof, and a pharma- ceutically acceptable carrier or excipient.

[0383] The present invention also relates to the salts of compounds of formula (I) according to the invention and their hydrates, solvates and their crystalline forms and pharmaceutical compositions in the manufacture of medicaments for the treatment of diseases mediated by DPP1.

[0384] Further, for use according to the present invention, the disease mediated by DPP1 is selected from the group consisting of non-cystic fibrosis bronchiectasis, cystic fibrosis bronchiectasis, acute lung injury, airway obstructive disease, bronchiectasis, cystic fibrosis, asthma, emphysema and chronic obstructive pulmonary disease.

[0385] Compared with the prior art, the present invention has the following beneficial effects: Advantages of the salt or crystalline form of the salt according to the present invention include, but are not limited to, higher solubility, better pharmacokinetic properties and good stability, they are suitable for the preparation of pharmaceutical formulations, the preparation method of the crystalline form is simple and effective, and they are easy to scale up for production.

[0386] The salt or salt crystal according to the present invention has excellent physical properties, including but not limited to solubility, dissolution rate, light resistance, low hygroscopicity, high temperature resistance, high humidity resistance, flowability and significantly improved viscosity. For example, the crystalline form according to the present invention can greatly shorten the filtration time, shorten the manufacturing cycle and save costs during the preparation process. The crystalline form according to the present invention also has good light stability, heat stability and humidity stability, which can ensure the reliability of the crystalline form during storage and transportation, which can ensure the safety of the formulation, and the crystalline form does not require special packaging to protect against the effects of light, temperature and humidity, and therefore can reduce costs. The crystalline form does not deteriorate due to the effects of light, high temperature and humidity, so the safety of the formulation and the efficacy after long-term storage are improved. Patients taking the crystalline form do not need to worry about photosensitivity reactions of the formulation due to exposure to sunlight.

[0387] The salt or salt crystal according to the present invention hardly deteriorates when stored or transported at room temperature, has good thermal stability, can be stably maintained for a long period of time, and is suitable for standard preparation and manufacturing processes.

[0388] The salt or crystal thereof according to the present invention has good chemical and physical stability, is easy to prepare, and is more suitable for preparation of pharmaceutical preparations. In particular, the crystalline form according to the present invention has better crushing stability.

[0389] The salt or salt crystals according to the present invention have good flowability, good compressibility, high bulk density, low hygroscopicity and uniform particle size distribution.

[0390] The salt or its crystal of the present invention is suitable for large-scale preparation and convenient.The preparation prepared using the above crystal form can reduce irritation and improve absorbability, so that it can solve the problem of metabolic rate, greatly reduce toxicity, improve safety, and effectively ensure the quality and efficacy of the preparation.

[0391] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. In the event of a conflict, the definitions set forth in this application shall prevail. When an amount, concentration, or other value or parameter is expressed in the form of a range, a preferred range, or an upper and lower preferred numerical limit, it should be understood that any range is specifically disclosed by combining any upper or preferred range value with any lower or preferred range limit, regardless of whether the range is specifically disclosed. Unless otherwise specified, numerical ranges described herein are intended to include the endpoints of the range and all integers and fractions (decimals) within the range.

[0392] The terms "about" or "approximately" used with a numerical variable generally mean that the value of the variable and all values ​​of the variable are within experimental error (e.g., within a 95% confidence interval of the mean) or within ±10% of the specified value or a wider range.

[0393] "Effective dosage" means an amount of a compound that elicits a physiological or medical response in a tissue, system, or subject in which such amount is desired, and includes an amount of a compound sufficient to prevent the occurrence of, or to alleviate to some extent, one or more symptoms of the disease or condition being treated, when administered to a subject.

[0394] "IC50" refers to the half-inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.

[0395] Unless otherwise specified, percentages, parts, etc. herein are by weight.

[0396] "Amorphous" refers to a solid that has no three-dimensional order.

[0397] In some cases, amorphous solids can be characterized by known techniques, including XRPD crystal diffraction analysis, differential scanning calorimetry (DSC), solid-state nuclear magnetic resonance (ssNMR), or a combination thereof. As described below, amorphous solids produce XRPD patterns that lack obvious diffraction characteristic peaks.

[0398] As used herein, the term "crystalline form" or "crystal" refers to any solid material that exhibits three-dimensional order and, in contrast to amorphous solid materials, produces a characteristic XRPD pattern with well-defined peaks.

[0399] As used herein, the term "crystal seed" refers to the formation of crystal nuclei by the addition of an insoluble additive in a crystallization process that accelerates or promotes the growth of enantiomeric crystals of the same crystal form or configuration.

[0400] As used herein, the term "X-ray powder diffraction pattern (XRPD pattern)" refers to an experimentally observed diffraction pattern or parameters, data, or values ​​derived therefrom. XRPD patterns are typically characterized by peak positions (abscissa) or peak intensities (ordinate).

[0401] As used herein, the term "2θ" refers to the peak position in degrees (°) based on the X-ray diffraction experimental setup, typically in units of the horizontal axis of the diffraction pattern. If the reflection diffracts when the incident beam makes an angle θ with the lattice plane, the experimental setup requires that the reflected beam be recorded at an angle 2θ. It should be understood that references herein to specific 2θ values ​​for a particular crystal form are intended to mean the 2θ values ​​(expressed in degrees) measured using the X-ray diffraction experimental conditions described herein.

[0402] In this specification, the term "substantially the same" of X-ray diffraction peaks is meant to take into account typical peak position and intensity variations. For example, one skilled in the art would understand that peak positions (2θ) typically vary by about 0.1 to 0.2 degrees, and that variations also occur depending on the instrument used for the diffraction measurement. Furthermore, one skilled in the art would understand that relative peak intensities vary depending on instrumental variations, as well as crystallinity, preferred orientation, preferred prepared sample surface, and other factors known to those skilled in the art, and should be considered merely for qualitative measurements.

[0403] A "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or physiologically / pharmaceutical acceptable salts thereof, with other components, including physiologically / pharmaceutical acceptable carriers and excipients.

[0404] The term "carrier" refers to a carrier or diluent that is not significantly irritating to the living body and does not eliminate the biological activity and properties of the compound being administered.

[0405] "Excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like.

[0406] It should be understood that the numerical values ​​described and claimed herein are approximations, and variations in the numerical values ​​can result from instrument calibration, instrument error, crystal purity, crystal size, sample size, and other factors. [Brief description of the drawings]

[0407] FIG. 1 is an X-ray powder diffraction pattern of crystalline Form A of the hydrochloride salt of compound of formula (I).

[0408] FIG. 2 is a thermogravimetric analysis thermogram of crystalline Form A of the hydrochloride salt of compound of formula (I).

[0409] FIG. 3 is a differential scanning calorimetry curve of crystalline form A of the hydrochloride salt of compound of formula (I).

[0410] FIG. 4 is an X-ray powder diffraction pattern of crystalline Form A of the malate salt of compound of formula (I).

[0411] FIG. 5 is a thermogravimetric analysis thermogram of crystalline Form A of the malate salt of compound of formula (I).

[0412] FIG. 6 is a differential scanning calorimetry curve of crystalline form A of the malate salt of compound of formula (I).

[0413] FIG. 7 is a powder X-ray diffraction pattern of crystalline form B of the adipate salt of compound of formula (I).

[0414] FIG. 8 is a thermogravimetric analysis thermogram of crystalline Form B of the adipate salt of compound of formula (I).

[0415] FIG. 9 is a differential scanning calorimetry curve of the adipic acid crystalline form B of the compound represented by formula (I).

[0416] FIG. 10 is an X-ray powder diffraction pattern of crystalline Form A of the sulfate salt of compound of formula (I).

[0417] FIG. 11 is a thermogravimetric analysis thermogram of crystalline Form A of the sulfate salt of compound of Formula (I).

[0418] FIG. 12 is a differential scanning calorimetry curve for crystalline form A of the sulfate salt of compound of formula (I).

[0419] FIG. 13 is an X-ray powder diffraction pattern of crystalline form B of the sulfate salt of compound of formula (I).

[0420] FIG. 14 is a thermogravimetric analysis thermogram of crystalline Form B of the sulfate salt of compound of Formula (I).

[0421] FIG. 15 is a differential scanning calorimetry curve of crystalline form B of the sulfate salt of compound of formula (I).

[0422] FIG. 16 is an X-ray powder diffraction pattern for crystalline Form A of the maleate salt of compound of formula (I).

[0423] FIG. 17 is a thermogravimetric analysis thermogram of crystalline Form A of the maleate salt of compound of formula (I).

[0424] FIG. 18 is a differential scanning calorimetry curve of crystalline form A of the maleate salt of compound represented by formula (I).

[0425] FIG. 19 is an X-ray powder diffraction pattern of crystalline Form B of the maleate salt of compound of formula (I).

[0426] FIG. 20 is a thermogravimetric analysis thermogram of crystalline Form B of the maleate salt of compound of formula (I).

[0427] FIG. 21 is a differential scanning calorimetry curve of crystalline form B of the maleate salt of compound of formula (I).

[0428] FIG. 22 is an X-ray powder diffraction pattern of crystalline Form C of the maleate salt of compound of formula (I).

[0429] FIG. 23 is a thermogravimetric analysis thermogram of crystalline Form C of the maleate salt of compound of formula (I).

[0430] FIG. 24 is a differential scanning calorimetry curve of crystalline form C of the maleate salt of compound of formula (I).

[0431] FIG. 25 is an X-ray powder diffraction pattern of crystalline Form A of the phosphate salt of the compound of formula (I).

[0432] FIG. 26 is a thermogravimetric analysis thermogram of crystalline Form A of the phosphate salt of compound of formula (I).

[0433] FIG. 27 is a differential scanning calorimetry curve of crystalline form A of the phosphate salt of compound of formula (I).

[0434] FIG. 28 is an X-ray powder diffraction pattern of crystalline form B of the phosphate salt of compound of formula (I).

[0435] FIG. 29 is a thermogravimetric analysis thermogram of crystalline Form B of the phosphate salt of compound of Formula (I).

[0436] FIG. 30 is a differential scanning calorimetry curve of crystalline form B of the phosphate salt of compound of formula (I).

[0437] FIG. 31 is an X-ray powder diffraction pattern of crystalline Form C of the phosphate salt of the compound of formula (I).

[0438] FIG. 32 is a thermogravimetric analysis thermogram of crystalline Form C of the phosphate salt of compound of Formula (I).

[0439] FIG. 33 is a differential scanning calorimetry curve of crystalline form C of the phosphate salt of the compound of formula (I).

[0440] FIG. 34 is an X-ray powder diffraction pattern for crystalline Form A of the mucate salt of the compound of formula (I).

[0441] FIG. 35 is a thermogravimetric analysis thermogram of crystalline Form A of the mucate salt of compound of formula (I).

[0442] FIG. 36 is a differential scanning calorimetry curve of crystalline form A of the mucate salt of the compound of formula (I).

[0443] FIG. 37 is an X-ray powder diffraction pattern for crystalline Form A of the tartrate salt of compound of formula (I).

[0444] FIG. 38 is a thermogravimetric analysis thermogram of crystalline Form A of the tartrate salt of compound of formula (I).

[0445] FIG. 39 is a differential scanning calorimetry curve for crystalline Form A of the tartrate salt of compound of formula (I).

[0446] FIG. 40 is an X-ray powder diffraction pattern for crystalline Form B of the tartrate salt of compound of formula (I).

[0447] FIG. 41 is a thermogravimetric analysis thermogram of crystalline Form B of the tartrate salt of compound of formula (I).

[0448] FIG. 42 is a differential scanning calorimetry curve of crystalline form B of the tartrate salt of compound of formula (I).

[0449] FIG. 43 is an X-ray powder diffraction pattern for crystalline Form C of the tartrate salt of compound of formula (I).

[0450] FIG. 44 is a thermogravimetric analysis thermogram of crystalline Form C of the tartrate salt of compound of formula (I).

[0451] FIG. 45 is a differential scanning calorimetry curve for crystalline Form C of the tartrate salt of compound of formula (I).

[0452] FIG. 46 is an X-ray powder diffraction pattern for crystalline Form A of the fumarate salt of compound of formula (I).

[0453] FIG. 47 is a thermogravimetric analysis thermogram of crystalline Form A of the fumarate salt of compound of Formula (I).

[0454] FIG. 48 is a differential scanning calorimetry curve for crystalline form A of the fumarate salt of compound of formula (I).

[0455] FIG. 49 is an X-ray powder diffraction pattern for crystalline Form B of the fumarate salt of compound of formula (I).

[0456] FIG. 50 is a thermogravimetric analysis thermogram of crystalline Form B of the fumarate salt of compound of formula (I).

[0457] FIG. 51 is a differential scanning calorimetry curve for crystalline form B of the fumarate salt of compound of formula (I).

[0458] FIG. 52 is an X-ray powder diffraction pattern for crystalline Form A of the citrate salt of the compound of Formula (I).

[0459] FIG. 53 is a thermogravimetric analysis thermogram of crystalline Form A of the citrate salt of compound of Formula (I).

[0460] FIG. 54 is a differential scanning calorimetry curve for crystalline form A of the citrate salt of the compound of formula (I).

[0461] FIG. 55 is an X-ray powder diffraction pattern for crystalline form B of the citrate salt of the compound of Formula (I).

[0462] FIG. 56 is a thermogravimetric analysis thermogram of crystalline Form B of the citrate salt of compound of Formula (I).

[0463] FIG. 57 is a differential scanning calorimetry curve for crystalline form B of the citrate salt of compound of Formula (I).

[0464] FIG. 58 is an X-ray powder diffraction pattern for crystalline Form B of the malate salt of compound of formula (I).

[0465] FIG. 59 is a thermogravimetric analysis thermogram of crystalline Form B of the malate salt of compound of Formula (I).

[0466] FIG. 60 is a differential scanning calorimetry curve for crystalline form B of the malate salt of compound of formula (I).

[0467] FIG. 61 is an X-ray powder diffraction pattern for crystalline Form A of the hippurate salt of the compound of formula (I).

[0468] FIG. 62 is a thermogravimetric analysis thermogram of crystalline Form A of the hippurate salt of compound of Formula (I).

[0469] FIG. 63 is a differential scanning calorimetry curve for crystalline form A of the hippurate salt of compound of formula (I).

[0470] FIG. 64 is an X-ray powder diffraction pattern for crystalline Form A of the adipate salt of the compound of formula (I).

[0471] FIG. 65 is a thermogravimetric analysis thermogram of crystalline Form A of the adipate salt of compound of formula (I).

[0472] FIG. 66 is a differential scanning calorimetry curve for crystalline form A of the adipate salt of compound of formula (I).

[0473] FIG. 67 is an X-ray powder diffraction pattern for crystalline Form A of the sebacate salt of compound of formula (I).

[0474] FIG. 68 is a thermogravimetric analysis thermogram of crystalline Form A of the sebacate salt of compound of Formula (I).

[0475] FIG. 69 is a differential scanning calorimetry curve for crystalline form A of the sebacate salt of compound of formula (I).

[0476] FIG. 70 is an X-ray powder diffraction pattern for crystalline form B of the sebacate salt of compound of formula (I).

[0477] FIG. 71 is a thermogravimetric analysis thermogram of crystalline Form B of the sebacate salt of compound of Formula (I).

[0478] FIG. 72 is a differential scanning calorimetry curve of crystalline form B of the sebacate salt of compound of formula (I).

[0479] FIG. 73 is an X-ray powder diffraction pattern for crystalline Form C of the sebacate salt of compound of formula (I).

[0480] FIG. 74 is a thermogravimetric analysis thermogram of crystalline Form C of the sebacate salt of compound of Formula (I).

[0481] FIG. 75 is a differential scanning calorimetry curve for crystalline Form C of the sebacate salt of compound of Formula (I).

[0482] FIG. 76 is an X-ray powder diffraction pattern for crystalline Form A of the 1,5-naphthalenedisulfonic acid salt of the compound of formula (I).

[0483] FIG. 77 is a thermogravimetric analysis thermogram of crystalline form A of the 1,5-naphthalenedisulfonic acid salt of compound of formula (I).

[0484] FIG. 78 is a differential scanning calorimetry curve for crystalline form A of 1,5-naphthalenedisulfonic acid salt of compound represented by formula (I).

[0485] FIG. 79 is an X-ray powder diffraction pattern for crystalline Form A of the methanesulfonate salt of compound of formula (I).

[0486] FIG. 80 is a thermogravimetric analysis thermogram of crystalline Form A of the methanesulfonate salt of compound of formula (I).

[0487] FIG. 81 is a differential scanning calorimetry curve for crystalline form A of the methanesulfonate salt of compound of formula (I).

[0488] FIG. 82 is an X-ray powder diffraction pattern for crystalline form A of the benzenesulfonate salt of compound of formula (I).

[0489] FIG. 83 is a thermogravimetric analysis thermogram of crystalline form A of the benzenesulfonate salt of compound of formula (I).

[0490] FIG. 84 is a differential scanning calorimetry curve for crystalline form A of the benzenesulfonate salt of compound of formula (I).

[0491] FIG. 85 is an X-ray powder diffraction pattern for crystalline form B of the benzenesulfonate salt of compound of formula (I).

[0492] FIG. 86 is a thermogravimetric analysis thermogram of crystalline form B of the benzenesulfonate salt of compound of formula (I).

[0493] FIG. 87 is a differential scanning calorimetry curve for crystalline form B of the benzenesulfonate salt of compound of formula (I).

[0494] FIG. 88 is an X-ray powder diffraction pattern for crystalline Form A of the oxalate salt of compound of formula (I).

[0495] FIG. 89 is a thermogravimetric analysis thermogram of crystalline Form A of the oxalate salt of compound of Formula (I).

[0496] FIG. 90 is a differential scanning calorimetry curve for crystalline Form A of the oxalate salt of compound of Formula (I).

[0497] FIG. 91 is an X-ray powder diffraction pattern for crystalline Form A of the benzoate salt of compound of formula (I).

[0498] FIG. 92 is a thermogravimetric analysis thermogram of crystalline Form A of the benzoate salt of compound of Formula (I).

[0499] FIG. 93 is a differential scanning calorimetry curve for crystalline form A of the benzoate salt of compound of formula (I).

[0500] FIG. 94 is an X-ray powder diffraction pattern for crystalline Form B of the benzoate salt of compound of formula (I).

[0501] FIG. 95 is a thermogravimetric analysis thermogram of crystalline Form B of the benzoate salt of compound of Formula (I).

[0502] FIG. 96 is a differential scanning calorimetry curve for crystalline form B of the benzoate salt of compound of formula (I).

[0503] FIG. 97 is an X-ray powder diffraction pattern for crystalline Form C of the benzoate salt of compound of formula (I).

[0504] FIG. 98 is a thermogravimetric analysis thermogram of crystalline Form C of the benzoate salt of compound of Formula (I).

[0505] FIG. 99 is a differential scanning calorimetry curve for crystalline form C of the benzoate salt of compound of formula (I).

[0506] FIG. 100 is an X-ray powder diffraction pattern for crystalline Form A of the hydrobromide salt of compound of formula (I).

[0507] FIG. 101 is a thermogravimetric analysis thermogram of crystalline Form A of the hydrobromide salt of compound of formula (I).

[0508] FIG. 102 is a differential scanning calorimetry curve for crystalline form A of the hydrobromide salt of compound of formula (I).

[0509] FIG. 103 is a dynamic vapor sorption spectrum of crystalline Form A of the hydrochloride salt of compound of formula (I).

[0510] FIG. 104 is a dynamic vapor sorption spectrum for crystalline Form A of the malate salt of compound of formula (I).

[0511] FIG. 105 is a dynamic vapor sorption spectrum of crystalline form B of the adipate salt of compound of formula (I).

[0512] FIG. 106 is a PLM characteristic spectrum of crystalline form A of the hydrochloride salt of compound of formula (I).

[0513] FIG. 107 is a PLM characteristic spectrum of crystalline form A of the malate salt of compound of formula (I).

[0514] FIG. 108 is a PLM characteristic spectrum of crystalline form B of the adipate salt of the compound represented by formula (I).

[0515] Specific embodiments for carrying out the present invention: The implementation process and beneficial effects of the present invention will be described in detail below through specific examples. These examples are intended to enable readers to better understand the essence and characteristics of the present invention, but are not intended to limit the scope of the present invention.

[0516] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS).

[0517] The NMR shift (δ) is 10 -6 The unit is ppm. NMR was measured using a Bruker Avance III 400 and a Bruker Avance 300 nuclear magnetic device. The measurement solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) and the internal standard was tetramethylsilane (TMS).

[0518] MS measurements were performed using an Agilent 6120B (ESI) and an Agilent 6120B (APCI).

[0519] HPLC measurements were performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorba x SB-C18 100 x 4.6 mm).

[0520] Column chromatography typically uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.

[0521] XRD measurements were performed using a Panalytical EMPYREAN powder X-ray diffractometer. Scan parameters are shown in Table 35:

[0522] [Table 35]

[0523] TGA and DSC measurements were performed on a TA Q5000 / 5500 thermogravimetric analyzer and a TA 2500 differential scanning calorimeter, respectively. The test parameters are shown in Table 36:

[0524] [Table 36]

[0525] Known starting materials of the present invention can be synthesized by methods known in the art or can be purchased commercially from sources such as Titan Scientific, Energy Chemical, Shang Hai Demo, Chengdu Kelon Chemical, Accela ChemBio, and J&K Scientific.

[0526] The solution refers to an aqueous solution unless otherwise specified in the examples.

[0527] The reaction temperature is room temperature unless otherwise specified in the examples.

[0528] In the examples, 1M represents a concentration of 1 mol / L.

[0529] The room temperature is between 10℃ and 30℃.

[0530] Example 1: Preparation of compounds of formula (I) Step 1: Preparation of compound a tert-Butyl (S)-(1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamate (compound a) [ka]

[0531] In a 50L reactor, 10.005 kg of 1,4-dioxane, 1.600 kg of compound a-1, and 2.000 kg of compound a-2 were added under stirring, followed by 6.605 kg of potassium carbonate aqueous solution (1.600 kg of potassium carbonate dissolved in 5.005 kg of purified water). After the addition was completed, nitrogen replacement was performed three times. 100.0 g of 1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex was added, and nitrogen replacement was performed once. Under nitrogen protection, the reaction solution was heated to 80±5°C and reacted for about 2 hours, after which a sample was taken for HPLC monitoring. The reaction was stopped when the target value of compound a-2 content became ≦1.0%. 5.000 kg of purified water was added to the reaction liquid, cooled to 10 ± 5 ° C, then 10.005 kg of purified water was added, stirred and crystallized at 10 ± 5 ° C for about 1 hour, then filtered, the filter cake was washed with purified water (2.500 kg × 2), and the filter cake was collected. 12.605 kg of absolute ethanol and the filter cake were added to a 50L reactor, stirred at 20 ± 5 ° C for about 0.5 hours, then filtered, the filter cake was washed with absolute ethanol (1.000 kg × 2), and the filter cake was collected. The filter cake was dried at 55 ± 5 ° C and vacuum ≦ -0.07 MPa for about 16 hours to obtain 2.143 kg of compound a, with a molar yield of 89.4%.

[0532] 1 H NMR (400MHz, DMSO) δ7.90 (s, 1H), 7.72-7.30 (m, 6H), 4.72 (s, 1H), 3.41 (d, 3H), 3.09-3.21 (m, 2H), 1.37 (s, 9H).

[0533] LCMS m / z=356.1[M-56+H] + .

[0534] Step 2: Preparation of compound b (S)-2-Amino-3-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propanonitrile 4-methylbenzenesulfonic acid (compound b) [ka]

[0535] In a 50L glass reactor, 16.785 kg of acetonitrile, 2.1381 kg of compound a, and 2.950 kg of p-toluenesulfonic acid monohydrate were added under stirring. After the addition was completed, the temperature was controlled at 25±5°C, and the reaction was allowed to proceed for about 2 hours, after which a sample was taken for HPLC monitoring. The reaction was stopped when the target value of the content of compound a became ≦1.0%. The reaction solution was filtered, the filter cake was washed with 1.670 kg of acetonitrile, and the filter cake was collected. 2.1381 kg of acetonitrile and the filter cake were added to the reactor, heated to 80±5°C, and stirred for 3 hours. Then, the mixture was cooled to 20±5°C and stirred for 1 hour. After filtering, the filter cake was washed with 1.670 kg of acetonitrile, and the filter cake was collected. The filter cake was dried at 55±5° C. under vacuum≦−0.07 MPa for about 16 hours to give 2.141 kg of compound b, with a molar yield of 85.5%.

[0536] 1 H NMR (400MHz, DMSO) δ9.04(s,3H),7.70-7.37(m,8H),7.13(d,2H),4.90(dd,1H),3.41(s,3H),3.29(t,2H),2.29(s,3H).

[0537] LCMS m / z=312.2[M-172+H] + .

[0538] Step 3: Preparation of compound c tert-Butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (compound c) [ka]

[0539] In a 100L reactor, 19.060 kg of ethyl acetate, 2.1413 kg of compound b, and 1.1300 kg of compound b-1 were added under stirring, and then 1.725 kg of N,N-diisopropylethylamine was added. After the addition was completed, the reaction solution was cooled to 5±5°C under nitrogen protection, and 4.240 kg of anhydrous propyl phosphate was added dropwise while controlling it at 10±5°C. After the addition was completed, the temperature was kept at 25±5°C and the reaction was carried out for about 3 to 8 hours. The reaction solution was washed successively with an aqueous sodium hydrogen carbonate solution (1.070 kg of sodium hydrogen carbonate was dissolved in 20.350 kg of water), an aqueous citric acid solution (2.150 kg of citric acid monohydrate was dissolved in 19.275 kg of water), and an aqueous sodium chloride solution (4.300 kg of sodium chloride was dissolved in 17.135 kg of water). 0.210 kg of medicinal charcoal was added to the organic phase and stirred for about 0.5 hours. Filtered through 0.540 kg of diatomaceous earth pad, the filter cake was washed with 1.905 kg of ethyl acetate. 1.070 kg of anhydrous sodium sulfate was added to the organic phase and dried for about 0.5 hours. Filtered, the filter cake was washed with 1.905 kg of ethyl acetate, the filtrates were combined and concentrated under reduced pressure at 50±5°C until no clear fractions flowed out. 2.385 kg of compound c was obtained, which was used directly in the next reaction step.

[0540] 1 H NMR(400MHz,CDCl3)δ7.54-7.01(m,7H),5.18(s,1H),4.25-3.94(m,3H),3. 54(dd,2H),3.46(s,3H),3.39-3.04(m,4H),1.99(d,2H),1.54-1.39(m,9H).

[0541] LCMS m / z=483.2[M-56+1] + .

[0542] Step 4: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Formula I) [ka]

[0543] In a 50L double-walled glass reactor containing concentrated compound c, 9.305 kg of acetonitrile and 2.530 kg of p-toluenesulfonic acid monohydrate were added under stirring. After the addition was completed, the temperature was kept at 25±5°C, and the reaction was allowed to proceed for about 2 hours, after which a sample was taken for HPLC monitoring. The reaction was stopped when the target value of the content of compound c became ≦1.0%. The reaction was stopped when the content of compound c became ≦1.0%. The reaction solution was cooled to 10±5°C, and dilute aqueous ammonia solution (a mixture of 1.075 kg of aqueous ammonia and 36.000 kg of purified water) was added dropwise, and the temperature of the raw materials was controlled to 25°C or less during the dropwise addition. After the addition was completed, the mixture was cooled to 10±5°C and crystallized for 2 hours. It was filtered, and the filter cake was washed with 11.930 kg of purified water. The filter cake and 14.890 kg of ethanol were added to a 50 L double-walled glass reactor, stirred at 20±5° C. for 0.5 hours, and filtered. The filter cake was washed with 1.860 kg of ethanol, and the filter cake was recovered. The filter cake was dried at 55±5° C. and under vacuum≦−0.07 MPa for about 13 hours to obtain 1.6627 kg of crude compound (Formula I), with a molar yield of 85.6%.

[0544] In a 100L reactor, 9.100kg of acetonitrile, 9.220kg of absolute ethanol and 1.6627kg of crude compound (formula I) were added under stirring. The mixture was heated to an internal temperature of 75±5°C, stirred to dissolve and clarify, and filtered while hot. The filtrate was transferred to a 100L reactor (if the filtrate contains product precipitate, it was heated to dissolve and clarify). The mixture was cooled to 35±5°C under stirring, kept warm until obvious solids were precipitated, and then kept warm and stirred for about 0.5 hours. The mixture was then cooled to 5±5°C and kept warm to crystallize for 2 hours. The mixture was filtered, the filter cake was washed with 1.300kg of ethanol, the filter cake was collected, and the filter cake was dried at 55±5°C and vacuum level ≦-0.07MPa for about 25 hours. 1.4060kg of compound formula I was obtained, with a molar yield of 84.6%.

[0545] 1H NMR(400MHz,DMSO)δ8.69(d,1H),7.64(d,1H),7.61-7.51(m,2H),7.46(t,2H),7.39(d,1H),5.06(q,1H),4.01(dd,1H),3.87(ddd,1H),3.7 3(ddd,1H),3.40(s,3H),3.34-3.28(m,1H),3.20(dd,1H),3.06(dd,1H),2.78(ddd,1H),2.69-2.54(m,2H),2.21(s,1H),1.84-1.63(m,2H).

[0546] LCMS m / z=439.2[M+1] + .

[0547] Example 2: Preparation of Crystalline Form A of the Hydrochloride Salt of Compound of Formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of acetone and 1 eq of 1M hydrochloric acid were added. The mixture was stirred at room temperature for 3 days, filtered, and dried to obtain the crystalline form A of the hydrochloride salt. The crystalline form A of the hydrochloride salt of the compound represented by formula (I) was characterized by XRD, DSC, and TGA, as shown in Figures 1 to 3, respectively.

[0548] Example 3: Preparation of Crystalline Form A of the Sulfate Salt of Compound of Formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of methanol and 1 eq of 1M sulfuric acid were added. The mixture was stirred at room temperature for 3 days, filtered, and dried to obtain crystalline form A of the sulfate salt. The crystalline form A of the sulfate salt of the compound represented by formula (I) was characterized by XRD, DSC, and TGA, as shown in Figures 10 to 12, respectively.

[0549] Example 4: Preparation of Crystalline Form B of the Sulfate Salt of Compound of Formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of acetone and 1 eq of 1M sulfuric acid were added. The mixture was stirred at room temperature for 3 days, filtered, and dried to obtain the crystalline form B of the sulfate salt. The crystalline form B of the sulfate salt of the compound represented by formula (I) was characterized by XRD, DSC, and TGA, and is shown in Figures 13 to 15, respectively.

[0550] Example 5: Preparation of Crystalline Form A of the Maleate Salt of Compound of Formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of methanol and 1 eq of maleic acid were added. The mixture was stirred at room temperature for 3 days, filtered and dried to obtain crystalline form A of the maleate salt. The crystalline form A of the maleate salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA as shown in Figures 16 to 18, respectively.

[0551] Example 6: Preparation of Crystalline Form B of the Maleate Salt of Compound of Formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of acetone and 1 eq of maleic acid were added. The mixture was stirred at room temperature for 3 days, filtered, and dried to obtain crystalline form B of the maleate salt. The crystalline form B of the maleate salt of the compound represented by formula (I) was characterized by XRD, DSC, and TGA, as shown in Figures 19 to 21, respectively.

[0552] Example 7: Preparation of Crystalline Form C of the Maleate Salt of Compound of Formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of 2-methyltetrahydrofuran and 1 eq of maleic acid were added. The mixture was stirred at room temperature for 3 days, filtered, and dried to obtain crystalline form C of the maleate salt. The crystalline form C of the maleate salt of the compound represented by formula (I) was characterized by XRD, DSC, and TGA, as shown in Figures 22 to 24, respectively.

[0553] Example 8: Preparation of Crystalline Form A of the Phosphate Salt of Compound of Formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of methanol and 1 eq of phosphoric acid were added. The mixture was stirred at room temperature for 3 days, filtered and dried to obtain crystalline form A of the phosphate salt. The crystalline form A of the compound represented by formula (I) of the phosphate salt was characterized by XRD, DSC and TGA as shown in Figures 25 to 27, respectively.

[0554] Example 9: Preparation of Crystalline Form B of the Phosphate Salt of Compound of Formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of acetone and 1 eq of phosphoric acid were added. The mixture was stirred at room temperature for 3 days, filtered and dried to obtain crystalline form B of the phosphate salt. The crystalline form B of the phosphate salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA as shown in Figures 28 to 30, respectively.

[0555] Example 10: Preparation of crystalline form C of the phosphate salt of compound of formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of 2-methyltetrahydrofuran and 1 eq of phosphoric acid were added. The suspension was stirred at room temperature for 3 days, filtered, and dried to obtain crystalline form C of the phosphate salt. The crystalline form C of the phosphate salt of the compound represented by formula (I) was characterized by XRD, DSC, and TGA, as shown in Figures 31 to 33, respectively.

[0556] Example 11: Preparation of crystalline form A of the mucate salt of the compound of formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of methanol and 1 eq of mucic acid were added. The mixture was stirred at room temperature for 3 days, filtered and dried to obtain crystalline form A of the mucate salt. The crystalline form A of the mucate salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA as shown in Figures 34 to 36, respectively.

[0557] Example 12: Preparation of Crystalline Form A of the Tartrate Salt of Compound of Formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of methanol and 1 eq of tartaric acid were added. The mixture was stirred at room temperature for 3 days, filtered, and dried to obtain crystalline form A of the tartrate salt. The crystalline form A of the tartrate salt of the compound represented by formula (I) was characterized by XRD, DSC, and TGA, as shown in Figures 37 to 39, respectively.

[0558] Example 13: Preparation of Crystalline Form B of the Tartrate Salt of Compound of Formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of acetone and 1 eq of tartaric acid were added. The mixture was stirred at room temperature for 3 days, filtered and dried to obtain the crystalline form B of the tartrate salt. The crystalline form B of the tartrate salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA as shown in Figures 40 to 42, respectively.

[0559] Example 14: Preparation of Crystalline Form C of the Tartrate Salt of Compound of Formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 ml of 2-methyltetrahydrofuran and 1 eq of tartaric acid were added. The mixture was stirred at room temperature for 3 days, filtered and dried to obtain the crystalline form C of the tartrate salt. The crystalline form C of the tartrate salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA as shown in Figures 43 to 45, respectively.

[0560] Example 15: Preparation of Crystalline Form A of the Fumarate Salt of Compound of Formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of acetone and 1 eq of fumaric acid were added. The mixture was stirred at room temperature for 3 days, filtered and dried to obtain crystalline form A of the fumarate salt. The crystalline form A of the fumarate salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 46 to 48, respectively.

[0561] Example 16: Preparation of Crystalline Form B of the Fumarate Salt of Compound of Formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of 2-methyltetrahydrofuran and 1 eq of fumaric acid were added. The mixture was stirred at room temperature for 3 days, filtered, and dried to obtain crystalline form B of the fumarate salt. The crystalline form B of the fumarate salt of the compound represented by formula (I) was characterized by XRD, DSC, and TGA, as shown in Figures 49 to 51, respectively.

[0562] Example 17: Preparation of Crystalline Form A of the Citrate Salt of Compound of Formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of methanol and 1 eq of citric acid were added. This was stirred at room temperature for 3 days, filtered and dried to obtain crystalline form A of the citrate salt. The crystalline form A of the citrate salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA, and is shown in Figures 52 to 54, respectively.

[0563] Example 18: Preparation of Crystalline Form B of the Citrate Salt of Compound of Formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of acetone and 1 eq of citric acid were added. This was stirred at room temperature for 3 days, filtered and dried to obtain crystalline form B of the citrate salt. The crystalline form B of the citrate salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA, and is shown in Figures 55 to 57, respectively.

[0564] Example 19: Preparation of Crystalline Form A of the Malate Salt of Compound of Formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of methanol and 1 eq of malic acid were added. This was stirred at room temperature for 3 days, filtered and dried to obtain crystalline form A of the malate salt. The crystalline form A of the malate salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA as shown in Figures 4 to 6, respectively.

[0565] Example 20: Preparation of Crystalline Form B of the Malate Salt of Compound of Formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of acetone and 1 eq of malic acid were added. The mixture was stirred at room temperature for 3 days, filtered and dried to obtain crystalline form B of the malate salt. The crystalline form B of the malate salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA, and is shown in Figures 58 to 60, respectively.

[0566] Example 21: Preparation of crystalline form A of the hippurate salt of compound of formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of acetone and 1 eq of hippuric acid were added. The mixture was stirred at room temperature for 3 days, filtered and dried to obtain crystalline form A of hippuric acid salt. The crystalline form A of the hippuric acid salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA as shown in Figures 61 to 63, respectively.

[0567] Example 22: Preparation of Crystalline Form A of the Adipic Acid Salt of Compound of Formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of acetone and 1 eq of adipic acid were added. The mixture was stirred at room temperature for 3 days, filtered and dried to obtain the crystalline form A of the adipate salt. The crystalline form A of the adipate salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA as shown in Figures 64 to 66, respectively.

[0568] Example 23: Preparation of Crystalline Form B of the Adipic Acid Salt of Compound of Formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of ethyl acetate and 1 eq of adipic acid were added. This was stirred at room temperature for 3 days, filtered and dried to obtain the crystalline form B of the adipate salt. The crystalline form B of the adipate salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA as shown in Figures 7-9, respectively.

[0569] Example 24: Preparation of Crystalline Form A of Sebacic Acid Salt of Compound of Formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of methanol and 1 eq of sebacic acid were added. The mixture was stirred at room temperature for 3 days, filtered and dried to obtain crystalline form A of the sebacate salt. The crystalline form A of the sebacate salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 67 to 69, respectively.

[0570] Example 25: Preparation of crystalline form B of the sebacate salt of compound of formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of acetone and 1 eq of sebacic acid were added. The mixture was stirred at room temperature for 3 days, filtered and dried to obtain the crystalline form B of the sebacate salt. The crystalline form B of the sebacate salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA as shown in Figures 70 to 72, respectively.

[0571] Example 26: Preparation of crystalline form C of the sebacate salt of compound of formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of ethyl acetate and 1 eq of sebacic acid were added. The mixture was stirred at room temperature for 3 days, filtered and dried to obtain the crystalline form C of the sebacate salt. The crystalline form C of the sebacate salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA as shown in Figures 73-75, respectively.

[0572] Example 27: Preparation of Crystalline Form A of 1,5-Naphthalenedisulfonic Acid Salt of Compound of Formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of methanol and 1 eq of 1,5-naphthalenedisulfonic acid were added. The mixture was stirred at room temperature for 3 days, filtered, and dried to obtain crystalline form A of 1,5-naphthalenedisulfonic acid salt. The crystalline form A of 1,5-naphthalenedisulfonic acid salt of the compound represented by formula (I) was characterized by XRD, DSC, and TGA, and is shown in Figures 76 to 78, respectively.

[0573] Example 28: Preparation of Crystalline Form A of the Methanesulfonate Salt of Compound of Formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of methanol and 1 eq of methanesulfonic acid were added. The mixture was stirred at room temperature for 3 days, filtered and dried to obtain crystalline form A of the methanesulfonate salt. The crystalline form A of the methanesulfonate salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA as shown in Figures 79-81, respectively.

[0574] Example 29: Preparation of crystalline form A of the benzenesulfonate salt of compound of formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of acetone and 1 eq of benzenesulfonic acid were added. The mixture was stirred at room temperature for 3 days, filtered and dried to obtain crystalline form A of the benzenesulfonate salt. The crystalline form A of the benzenesulfonate salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA as shown in Figures 82 to 84, respectively.

[0575] Example 30: Preparation of crystalline form B of the benzenesulfonate salt of compound of formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of ethyl acetate and 1 eq of benzenesulfonic acid were added. This was stirred at room temperature for 3 days, filtered and dried to obtain crystalline form B of the benzenesulfonate salt. The crystalline form B of the benzenesulfonate salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA as shown in Figures 85 to 87, respectively.

[0576] Example 31: Preparation of Crystalline Form A of the Oxalate Salt of Compound of Formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of ethyl acetate and 1 eq of oxalic acid were added. The mixture was stirred at room temperature for 3 days, filtered and dried to obtain crystalline form A of the oxalate salt. The crystalline form A of the oxalate salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA as shown in Figures 88-90, respectively.

[0577] Example 32: Preparation of Crystalline Form A of the Benzoate Salt of Compound of Formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of methanol and 1 eq of benzoic acid were added. This was stirred at room temperature for 3 days, filtered and dried to obtain crystalline form A of the benzoate salt. The crystalline form A of the benzoate salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA, and is shown in Figures 91 to 93, respectively.

[0578] Example 33: Preparation of Crystalline Form B of the Benzoate Salt of Compound of Formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of acetone and 1 eq of benzoic acid were added. The mixture was stirred at room temperature for 3 days, filtered and dried to obtain crystalline form B of the benzoate salt. The crystalline form B of the benzoate salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA, and is shown in Figures 94 to 96, respectively.

[0579] Example 34: Preparation of Crystalline Form C of the Benzoate Salt of Compound of Formula (I) 200 mg of the compound represented by formula (I) was taken, and 5 mL of ethyl acetate and 1 eq of benzoic acid were added. The mixture was stirred at room temperature for 3 days, filtered and dried to obtain crystalline form C of the benzoate salt. The crystalline form C of the benzoate salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA as shown in Figures 97-99, respectively.

[0580] Example 35: Preparation of Crystalline Form A of the Hydrobromide Salt of Compound of Formula (I) 200 mg of the compound represented by formula (I) was taken, 5 mL of ethyl acetate and 1 eq of hydrobromic acid were added, and seeds were added. This was stirred at room temperature for 3 days, filtered and dried to obtain crystalline form A of the hydrobromide salt. The crystalline form A of the hydrobromide salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA as shown in Figures 100 to 102, respectively.

[0581] Crystal morphology evaluation test 1. After placing the hydrochloride salt crystal A, the malate salt crystal A, and the adipate salt crystal B at 25°C / 60%RH and 40°C / 75%RH, the physical and chemical stability was tested by XRPD and HPLC, respectively. The results are shown in Table 37.

[0582] [Table 37]

[0583] As a result, the crystal form of each sample did not change even after being left to stand for one week to one month under conditions of 25°C / 60% RH and 40°C / 75% RH, and the purity did not decrease significantly, indicating good stability.

[0584] 2. HPLC Impurities of Solid Stability Samples After storing the hydrochloride A, malate A, and adipate B at 25°C / 60%RH and 40°C / 75%RH for 1 week and 3 weeks, respectively, the solid stability samples were tested for impurities by HPLC. The HPLC test conditions are shown in Table 38, and the test results are shown in Table 39.

[0585] [Table 38]

[0586] [Table 39]

[0587] As a result, even when left to stand for one week to one month under conditions of 25°C / 60% RH and 40°C / 75% RH, the purity of each sample did not decrease significantly and the stability was good.

[0588] 3.Dynamic solubility Approximately 20 mg of material (calculated as the free base) was weighed into a 5 mL vial and 4 mL of solvent was added and rotated and mixed (25 rpm) at 37° C. for 1, 2, 4, and 24 hours. Approximately 0.9 mL samples were taken, centrifuged, filtered, and tested by XRPD for the solid and by HPLC for concentration and pH. The test results are shown in Table 40.

[0589] [Table 40]

[0590] Solubility: mg / mL. N / A: The sample dissolved and became clear; no XRPD data was collected. L: The sample was nearly clear and had too little solids content, so XRPD data was not collected. G: The sample has gelled. A: Amorphous. C: Disproportionated to the free state.

[0591] Results: The water solubility of both salts was significantly improved compared to the free base.

[0592] 4.Hygroscopicity The hygroscopicity of the hydrochloride crystal A, malate crystal A and adipate crystal B was evaluated by a Dynamic Vapor Sorption (DVS) apparatus. The crystal form C started from ambient humidity (~60%RH), and the crystal form B started from 0% relative humidity (0%RH). The test was conducted under a constant temperature condition of 25°C, and the mass change rate of the samples with humidity change (60%RH-95%RH-0%RH-95%RH or 0%RH-95%RH-0%RH) was collected. The test results are shown in Figures 103, 104 and 105, respectively. As a result, the water sorption of the hydrochloride crystal A, malate crystal A and adipate crystal B at 25°C / 80%RH was 0.47%, 1.27% and 0.24%, respectively. The crystal forms of all the samples did not change after the DVS test. This indicates that the crystalline form of the present invention has low hygroscopicity and low requirements for pharmaceutical packaging and storage conditions.

[0593] 5. PLM The PLM characteristics were evaluated for the hydrochloride crystal A, the malate crystal A, and the adipate crystal B. The results (Figures 106 to 108) showed that the particle size of each sample was 20 μm or less.

[0594] Biological testing 1. In vitro DPP1 enzyme activity detection test Recombinant human DPP1 enzyme (R&D System, Cat. No. 1071-CY) at a final concentration of 100 μg / mL and recombinant human cathepsin L (R&D System, Cat. No. 952-CY) at a final concentration of 20 μg / mL were mixed and incubated at room temperature for 1 hour to activate the DPP1 enzyme. The activated DPP1 enzyme was diluted 100-fold, and 5 μL of different concentrations of compounds and 5 μL of diluted DPP1 enzyme were added to a 384-well plate and incubated at room temperature for 30 minutes. After adding 10 μL of 20 μM concentration of substrate Gly-Arg-AMC (bachem, Cat. No. I-1215), the incubation was continued at room temperature for 60 minutes. The fluorescence intensity was detected by a microplate reader with an excitation wavelength of 380 nm and an emission wavelength of 460 nm. The IC50 values ​​were calculated using the DosResp function of Origin2019 software.

[0595] [Table 41]

[0596] Conclusion: Compound 1 exhibited high inhibitory activity against the DPP1 receptor.

[0597] 2. Pharmacokinetics Test in Rats 1.1 Test animals: male SD rats, approximately 220 g, 6-8 weeks old, 6 rats / compound. Purchased from Chengdu Senwell Experimental Animals Co., Ltd.

[0598] 1.2 Test plan: On the day of the test, 6 SD rats were randomly divided into groups according to weight. On the day before administration, they were given only water and no food for 12 to 14 hours, and then given food 4 hours after administration.

[0599] [Table 42]

[0600] Vehicle for intravenous administration: 5% DMA + 5% Solutol + 90% saline; Vehicle for oral administration: 0.5% MC; Reference compound INS1007, compound 2 of patent WO2015110826A1, was prepared according to the method of the patent.

[0601] Before and after administration, 0.1 mL of blood was collected from the orbit under isoflurane anesthesia. This was placed in an EDTAK2 centrifuge tube and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected at the following times for the intravenous administration group: 0, 5, 15, 30 minutes, 1, 2, 4, 6, 8, and 24 hours. Blood was collected at the following times for the oral administration group: 0, 5, 15, 30 minutes, 1, 2, 4, 6, 8, and 24 hours. All samples were stored at -80°C before analysis and detection.

[0602] [Table 43]

[0603] Conclusion: The compounds of the present invention have good bioavailability and pharmacokinetic properties.

[0604] 3. 14-day repeated oral dose toxicity test using rats SD rats were randomly divided into vehicle control group (0.5% MC), INS1007 groups (30, 100, 300 mg / kg), and compound I groups (30, 100, 300 mg / kg) according to body weight. Each drug treatment group contained 16 animals, and the vehicle control group contained 10 animals, half of which were male and half of which were female. Corresponding concentrations of drugs or vehicle were orally administered daily for 14 days, followed by a recovery period of 7 days. During the treatment period, general symptoms were observed in each group, and body weight and food intake were measured. At the end of the treatment and recovery periods, hematological, serum biochemical, and gross anatomical examinations were performed in each group.

[0605] Conclusion: At the same dose, the compounds of the present invention are less toxic and safer than INS1007.

Claims

1. Formula (I) 【Chemistry 1】 Salts of compounds represented by the formula: wherein the salt is selected from the group consisting of hydrochloride, sulfate, maleate, phosphate, mucate, tartrate, fumarate, citrate, malate, hippurate, adipate, sebacate, 1,5-naphthalenedisulfonate, methanesulfonate, benzenesulfonate, oxalate, benzoate, hydrobromide, 2-naphthalenesulfonate, p-toluenesulfonate, hemi-1,5-naphthalenedisulfonate, or succinate.

2. 2. The salts and hydrates and solvates thereof according to claim 1, wherein the salts are selected from the group consisting of hydrochlorides, sulfates, maleates, phosphates, mucates, tartrates, fumarates, citrates, malates, hippurates, adipates, sebacates, 1,5-naphthalenedisulfonates, methanesulfonates, benzenesulfonates, oxalates, benzoates or hydrobromides, preferably in crystalline form.

3. 2. The salts according to claim 1, and their hydrates and solvates, wherein the salts are selected from the group consisting of hydrochlorides, malates or adipates, preferably in crystalline form.

4. The salt, and the hydrate and solvate thereof according to any one of claims 1 to 3, wherein the salt is selected from the group consisting of hydrochlorides, and the hydrochloride is in a crystalline form (crystalline form A of the hydrochloride), and its X-ray powder diffraction pattern using Cu-Kα radiation has characteristic diffraction peaks at the following 2θ positions: 9.38°±0.2°, 16.40°±0.2°, 18.69°±0.2°, 22.04°±0.2°, 23.05°±0.2°, and 23.90°±0.2°.

5. The salt and its hydrate and solvate according to claim 4, wherein the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 13.99°±0.2°, 14.75°±0.2°, 17.92°±0.2°, 25.70°±0.2°, and 30.32°±0.2°.

6. The salt and its hydrates and solvates according to claim 5, wherein the X-ray powder diffraction pattern is shown in FIG.

7. The salt and its hydrates and solvates according to claim 5, whose thermogravimetric analysis (TGA) thermogram is shown in FIG. 2 and whose differential scanning calorimetry (DSC) thermogram is shown in FIG.

8. The salt, and the hydrate and solvate thereof according to any one of claims 1 to 3, wherein the salt is selected from the group consisting of malates, and the malate is in a crystalline form (crystalline form A of malate), and its X-ray powder diffraction pattern using Cu-Kα radiation has characteristic diffraction peaks at the following 2θ positions: 8.75°±0.2°, 9.82°±0.2°, 15.08°±0.2°, 16.65°±0.2°, 20.89°±0.2°, 21.89°±0.2°, and 23.75°±0.2°.

9. The salt and its hydrate and solvate according to claim 8, wherein the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 11.80°±0.2°, 14.04°±0.2°, 14.69°±0.2°, 24.81°±0.2°, and 25.91°±0.2°.

10. The salt and hydrates and solvates thereof according to claim 9, wherein the X-ray powder diffraction pattern is shown in FIG.

11. The salt and hydrates and solvates thereof according to claim 9, whose thermogravimetric analysis (TGA) thermogram is shown in FIG. 5 and whose differential scanning calorimetry (DSC) thermogram is shown in FIG.

12. The salt and the hydrate and solvate thereof according to any one of claims 1 to 3, wherein the salt is selected from the group consisting of adipate salts, and the adipate salt is in a crystalline form (crystalline form B of adipate salt), and the X-ray powder diffraction pattern thereof has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 8.10°±0.2°, 12.18°±0.2°, 16.24°±0.2°, 17.68°±0.2°, and 20.33°±0.2°.

13. The salt and its hydrate and solvate according to claim 12, wherein the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 10.68°±0.2°, 14.02°±0.2°, 19.60°±0.2°, and 20.95°±0.2°.

14. The salt and hydrates and solvates thereof according to claim 13, wherein the X-ray powder diffraction pattern is shown in FIG.

15. The salt and hydrates and solvates thereof according to claim 13, whose thermogravimetric analysis (TGA) thermogram is shown in FIG. 8 and whose differential scanning calorimetry (DSC) thermogram is shown in FIG.

16. 10. A pharmaceutical composition comprising a therapeutically effective amount of the salt of claim 1 and hydrates and solvates thereof, and a pharmaceutically acceptable carrier or excipient.

17. 17. Use of the salts and hydrates and solvates thereof according to claim 1 or the pharmaceutical composition according to claim 16 in the manufacture of a medicament for treating a disease mediated by DPP1.

18. 18. The use of claim 17, wherein the disease mediated by DPP1 is selected from the group consisting of non-cystic fibrosis bronchiectasis, cystic fibrosis bronchiectasis, acute lung injury, airway obstructive disease, bronchiectasis, cystic fibrosis, asthma, emphysema, and chronic obstructive pulmonary disease.

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