Crystal form of acid salt of protein inhibitor or degrader, preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a crystal form of an acid salt of a protein inhibitor or degrader, a preparation method therefor and the use thereof. Provided in the present invention is crystal form A of a monomaleate salt of a compound represented by formula I, wherein the crystal form has characteristic peaks in X-ray powder diffraction at diffraction angles 2θ of 6.9°±0.2°, 11.0°±0.2°, 16.0°±0.2° and 23.9°±0.2° using Cu-Kα radiation. The crystal form A of the monomaleate salt of the protein inhibitor or degrader according to the present invention has a low hygroscopicity, good stability and a good bioavailability, and has good druggability prospects.

Description

Crystal forms of acidic salts of protein inhibitors or degraders, their preparation methods and uses.

[0001] This application claims priority to Chinese Patent Application No. 2024117914456, filed on December 6, 2024, and Chinese Patent Application No. 2025118184559, filed on December 4, 2025. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to the field of chemical medicine, and in particular to the crystal forms of acid salts of protein inhibitors or degraders, their preparation methods and uses. Background Technology

[0003] PROTACs (proteolysis-targeting chimeras) are a newly emerging and popular research area in recent years. PROTAC molecules generally consist of three parts: a small molecule fragment (warhead) that binds to a specific target protein at one end, an E3 ligand ligand with ubiquitination function at the other end, and a linker connecting the two. PROTAC molecules utilize the cellular protein ubiquitination degradation pathway to selectively degrade target proteins. Specifically, because the two ends of a PROTAC molecule are the target protein and the E3 ligand fragment, respectively, the PROTAC molecule can simultaneously bind to both the target protein and the E3 ligand, promoting the ubiquitination of the target protein, which is then recognized and degraded by the proteasome.

[0004] Lung cancer is a major disease affecting human health, and its mortality rate ranks first among all malignant tumors. Among non-small cell lung cancer patients, those with activating mutations in EGFR (Epidermal Growth Factor Receptor), ALK (anaplastic lymphoma kinase), and ROS1 (ROS proto-oncogene 1 receptor tyrosine kinase) account for approximately 30%, 8%, and 2%, respectively. Compound E5 (compound of formula I in this patent) in patent WO2022268229 has been disclosed as a fourth-generation EGFR-PROTAC molecule, demonstrating degradation activity and excellent selectivity against various EGFR mutant proteins. To facilitate subsequent drug manufacturing and large-scale preparation, and to adapt to clinical research, screening and developing certain forms of formula I compounds with superior solubility, stability, and bioavailability are issues that need further resolution. Summary of the Invention

[0005] The technical problem to be solved by this invention is to overcome the deficiency of the limited variety of protein inhibitors or degraders in the prior art. To this end, this invention provides a crystalline form of an acid salt of a protein inhibitor or degrader, its preparation method, and its uses. The monomaleate crystalline form A of the protein inhibitor or degrader of this invention has low hygroscopicity, good stability, and good bioavailability, and has promising prospects for drug development.

[0006] The first aspect of the present invention provides a monomaleate crystal form A of the compound shown in Formula I, which, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at diffraction angles 2θ of 6.9°±0.2°, 11.0°±0.2°, 16.0°±0.2°, and 23.9°±0.2°.

[0007] In one embodiment of the present invention, the X-ray powder diffraction of the monomaleate crystal form A of the compound as shown in Formula I also has characteristic peaks at one or more locations with diffraction angles 2θ of 9.2°±0.2°, 13.7°±0.2°, 19.4°±0.2°, 20.4°±0.2° and 21.3°±0.2°.

[0008] In one embodiment of the present invention, the X-ray powder diffraction of the monomaleate crystal form A of the compound as shown in Formula I also has characteristic peaks at one or more of the diffraction angles 2θ of 14.7°±0.2°, 17.4°±0.2°, 18.1°±0.2°, 22.3°±0.2°, 25.5°±0.2° and 29.6°±0.2°.

[0009] In one embodiment of the present invention, the monomaleate crystal form A of the compound shown in Formula I is the monomaleate monohydrate crystal form A of the compound shown in Formula I.

[0010] In one embodiment of the present invention, the X-ray powder diffraction of the monomaleate crystal form A of the compound as shown in Formula I exhibits characteristic peaks at diffraction angles 2θ of 6.9°±0.2°, 9.2°±0.2°, 11.0°±0.2°, 13.7°±0.2°, 14.7°±0.2°, 16.0°±0.2°, 17.4°±0.2°, 18.1°±0.2°, 19.4°±0.2°, 20.4°±0.2°, 21.3°±0.2°, 22.3°±0.2°, 23.9°±0.2°, 25.5°±0.2°, and 29.6°±0.2°.

[0011] In one embodiment of the present invention, the X-ray powder diffraction pattern of monomaleate crystal form A of the compound as shown in Formula I is substantially as shown in Figure 1.

[0012] In one embodiment of the present invention, the liquid-state 1H NMR spectrum of the monomaleate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 2.

[0013] In one embodiment of the invention, the monomaleate crystal form A of the compound shown in Formula I exhibits a weight loss of 0.2%-1.2% (e.g., 0.7%) when heated to 60±5°C and a weight loss of 1.5%-2.5% (e.g., 1.9%) when heated to 100±5°C during thermogravimetric analysis. The percentage of weight loss is the percentage of the sample's weight reduction compared to its weight before this weight loss.

[0014] In one embodiment of the invention, the thermogravimetric analysis (TGA) diagram of monomaleate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 3.

[0015] In one embodiment of the present invention, the monomaleate crystal form A of the compound as shown in Formula I has an endothermic signal when heated to 122±5°C (e.g., 122°C) and / or an endothermic signal when heated to 200±5°C (e.g., 200°C) during differential scanning calorimetry analysis.

[0016] In one embodiment of the invention, the monomaleate crystal form A of the compound as shown in Formula I is substantially as shown in Figure 4 by differential scanning calorimetry (DSC).

[0017] In one embodiment of the present invention, the single crystal of monomaleate form A of the compound shown in Formula I belongs to the monoclinic crystal system, space group P21, and has the following cell parameters: α=90°, β=94.4460(10)°, γ=90°,

[0018] In one embodiment of the present invention, the single crystal of monomaleate form A of the compound as shown in Formula I is a monohydrate.

[0019] In one embodiment of the invention, the X-ray powder diffraction pattern of a single crystal of monomaleate form A of the compound as shown in Formula I is essentially as shown in Figure 79.

[0020] In one embodiment of the present invention, the schematic diagram of the asymmetric unit of the single crystal structure model of the monomaleate crystal form A of the compound as shown in Formula I is basically as shown in Figure 80.

[0021] In one embodiment of the present invention, the molecular packing structure schematic diagram in the single crystal structural model of the monomaleate crystal form A of the compound as shown in Formula I is basically as shown in Figure 81.

[0022] In one embodiment of the present invention, a method for preparing a single crystal of monomaleate form A of the compound shown in Formula I includes the following steps: dissolving the solid monomaleate of the compound shown in Formula I in an amide solvent, and then allowing it to stand in an ester solvent for crystallization to obtain a single crystal of monomaleate form A of the compound shown in Formula I.

[0023] In one embodiment of the present invention, in the method for preparing a single crystal of monomaleic acid form A of the compound shown in Formula I, the amide solvent is N,N-dimethylformamide; and the ester solvent is methyl acetate.

[0024] A second aspect of the present invention provides a method for preparing monomaleate crystal form A of the compound as shown in Formula I as described above, comprising method a or method b:

[0025] Method a, comprising the following steps: at room temperature, crystallizing the free base of the compound shown in Formula I with maleic acid in a solvent to obtain maleate crystal form A of the compound shown in Formula I; wherein the solvent is a ketone solvent, an alcohol solvent, or an ester solvent;

[0026] Method b includes the following steps: at room temperature, dissolving the monomaleate of the compound shown in Formula I in a positive solvent, and then crystallizing after adding an antisolvent to obtain the monomaleate crystal form A of the compound shown in Formula I; the positive solvent is a pyrrolidone solvent or a sulfoxide solvent, and the antisolvent is water, an alcohol solvent or an ester solvent.

[0027] In one embodiment of the present invention, in method a, the ketone solvent is acetone; the alcohol solvent is isopropanol; and the ester solvent is ethyl acetate.

[0028] In one embodiment of the present invention, in method a, the crystallization is carried out by suspension stirring.

[0029] In one embodiment of the present invention, in method a, the molar ratio of the free base of the compound as shown in Formula I to maleic acid is 1:(1-1.2); preferably 1:1.

[0030] In one embodiment of the present invention, in method a, the mass-to-volume ratio of the free base of the compound as shown in Formula I to the solvent is (20-60) mg / mL; preferably 30 mg / mL, 40 mg / mL or 50 mg / mL.

[0031] In one embodiment of the present invention, in method a, the crystallization time is 2.5-3.5 days, preferably 3 days.

[0032] In one embodiment of the present invention, in method a, the room temperature is 20°C-30°C, preferably 25°C.

[0033] In one embodiment of the present invention, in method b, the pyrrolidone solvent is N-methylpyrrolidone; the sulfoxide solvent is dimethyl sulfoxide; the ester solvent is isopropyl acetate or ethyl acetate; and the alcohol solvent is isopropanol.

[0034] In one embodiment of the present invention, in method b, the mass-to-volume ratio of the monomaleate of the compound as shown in Formula I to the positive solvent is (20-60) mg / mL; preferably 30 mg / mL or 50 mg / mL.

[0035] In one embodiment of the present invention, in method b, the mass-to-volume ratio of the monomaleate of the compound as shown in Formula I to the antisolvent is (2-80) mg / mL; preferably 6.7 mg / mL, 3.4 mg / mL, 74.5 mg / mL or 3.3 mg / mL.

[0036] In one embodiment of the present invention, in method b, the volume ratio of the positive solvent to the negative solvent is 1:(0.5-18)mg / mL; preferably 1:4.4, 1:9, 1:0.67 or 1:15.

[0037] The third aspect of the present invention provides a dimaleate crystal form A of the compound shown in Formula I, which, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at diffraction angles 2θ of 5.1°±0.2°, 6.8°±0.2°, 8.8°±0.2°, and 19.2°±0.2°.

[0038] In one embodiment of the present invention, the X-ray powder diffraction of the dimaleate crystal form A of the compound as shown in Formula I also has characteristic peaks at one or more locations with diffraction angles 2θ of 8.4°±0.2°, 10.1°±0.2°, 12.0°±0.2°, 16.7°±0.2° and 21.6°±0.2°.

[0039] In one embodiment of the present invention, the X-ray powder diffraction of the dimaleate crystal form A of the compound as shown in Formula I also has characteristic peaks at one or more locations with diffraction angles 2θ of 11.2°±0.2°, 14.5°±0.2°, 20.0°±0.2°, 23.7°±0.2°, 25.4°±0.2° and 27.0°±0.2°.

[0040] In one embodiment of the present invention, the X-ray powder diffraction pattern of the dimaleate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 5.

[0041] In one embodiment of the present invention, the liquid-state 1H NMR spectrum of the dimaleate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 6.

[0042] In one embodiment of the present invention, the dimaleate crystal form A of the compound shown in Formula I exhibits a weight loss of 3.1%-4.1% (e.g., 3.6%) when heated to 130±5°C during thermogravimetric analysis. The percentage of weight loss is the percentage of the sample's weight reduction relative to its weight before this weight loss.

[0043] In one embodiment of the present invention, the thermogravimetric analysis (TGA) diagram of the dimaleate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 7.

[0044] In one embodiment of the present invention, the dimaleate crystal form A of the compound shown in Formula I exhibits an endothermic signal when heated to 79±5°C (e.g., 79°C) and / or an endothermic signal when heated to 166±5°C (e.g., 166°C) during differential scanning calorimetry analysis.

[0045] In one embodiment of the invention, the DSC of the dimaleate crystal form A of the compound as shown in Formula I is substantially as shown in FIG8.

[0046] The fourth aspect of the present invention provides a method for preparing the dimaleate crystal form A of the compound shown in Formula I as described above, comprising the following steps: crystallizing the free base of the compound shown in Formula I with maleic acid in a solvent to obtain the dimaleate crystal form A of the compound shown in Formula I; wherein the solvent is an alcohol solvent, an ester solvent or a ketone solvent.

[0047] In one embodiment of the present invention, in the method for preparing the dimaleate crystal form A of the compound shown in Formula I, the alcohol solvent is ethanol; the ester solvent is ethyl acetate; and the ketone solvent is acetone.

[0048] In one embodiment of the present invention, in the method for preparing the dimaleate crystal form A of the compound shown in Formula I, the molar ratio of the compound shown in Formula I to maleic acid is 1:(1-2.2); preferably 1:2.

[0049] In one embodiment of the present invention, in the method for preparing the dimaleate crystal form A of the compound as shown in Formula I, the mass-volume ratio of the compound as shown in Formula I to the solvent is (20-40) mg / mL; preferably 30 mg / mL.

[0050] In one embodiment of the present invention, in the method for preparing the dimaleate crystal form A of the compound as shown in Formula I, the reaction crystallization time is 3.5-4.5 days, preferably 4 days.

[0051] In one embodiment of the present invention, in the method for preparing the dimaleate crystal form A of the compound shown in Formula I, the reaction crystallization temperature is 20°C-30°C, preferably 25°C.

[0052] The fifth aspect of the present invention provides a single hydrochloride crystal form A of the compound shown in Formula I, which, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at diffraction angles 2θ of 6.8°±0.2°, 9.2°±0.2°, 15.7°±0.2°, and 23.8°±0.2°.

[0053] In one embodiment of the present invention, the X-ray powder diffraction of the single hydrochloride crystal form A of the compound as shown in Formula I also has characteristic peaks at one or more locations with diffraction angles 2θ of 10.2°±0.2°, 12.1°±0.2°, 17.4°±0.2°, 19.2°±0.2° and 25.3°±0.2°.

[0054] In one embodiment of the present invention, the X-ray powder diffraction of the single hydrochloride crystal form A of the compound as shown in Formula I also has characteristic peaks at one or more of the diffraction angles 2θ of 18.1°±0.2°, 20.4°±0.2°, 21.0°±0.2°, 22.2°±0.2°, 23.3°±0.2° and 28.0°±0.2°.

[0055] In one embodiment of the present invention, the single hydrochloride crystal form A of the compound as shown in Formula I has an X-ray powder diffraction pattern that is essentially as shown in Figure 9.

[0056] In one embodiment of the present invention, the liquid-state hydrogen NMR spectrum of the monohydrochloride crystal form A of the compound as shown in Formula I is essentially as shown in Figure 10.

[0057] In one embodiment of the present invention, the hydrochloride crystal form A of the compound shown in Formula I, when heated to 120±5°C during thermogravimetric analysis, has a weight loss of 5.8%-6.8% (e.g., 6.3%).

[0058] In one embodiment of the invention, the thermogravimetric analysis (TGA) diagram of the monohydrochloride crystal form A of the compound as shown in Formula I is essentially as shown in Figure 11.

[0059] In one embodiment of the present invention, the monohydrochloride crystal form A of the compound shown in Formula I, when subjected to differential scanning calorimetry, exhibits an endothermic signal when heated to 99±5°C (e.g., 99°C) and / or an endothermic signal when heated to 186±5°C (e.g., 186°C).

[0060] In one embodiment of the present invention, the DSC of the monohydrochloride crystal form A of the compound as shown in Formula I is substantially as shown in FIG12.

[0061] The sixth aspect of the present invention provides a method for preparing a monohydrochloride crystal form A of the compound shown in Formula I as described above, comprising the following steps: crystallizing the free base of the compound shown in Formula I with hydrochloric acid in a solvent to obtain a monohydrochloride crystal form A of the compound shown in Formula I; wherein the solvent is an alcohol solvent, an ester solvent or a ketone solvent.

[0062] In one embodiment of the present invention, the hydrochloric acid is 12 mol / L hydrochloric acid.

[0063] In one embodiment of the present invention, in the method for preparing the monohydrochloride crystal form A of the compound shown in Formula I, the alcohol solvent is isopropanol; the ester solvent is ethyl acetate; and the ketone solvent is acetone.

[0064] In one embodiment of the present invention, in the method for preparing the monohydrochloride crystal form A of the compound as shown in Formula I, the molar ratio of the compound as shown in Formula I to hydrochloric acid is 1:(1-1.2); preferably 1:1.

[0065] In one embodiment of the present invention, in the method for preparing the monohydrochloride crystal form A of the compound as shown in Formula I, the mass-to-volume ratio of the compound as shown in Formula I to the solvent is (30-50) mg / mL; preferably 40 mg / mL or 41 mg / mL.

[0066] In one embodiment of the present invention, in the method for preparing the monohydrochloride crystal form A of the compound as shown in Formula I, the reaction time for the crystallization reaction is 2.5-3.5 days, preferably 3 days.

[0067] In one embodiment of the present invention, in the method for preparing the monohydrochloride crystal form A of the compound as shown in Formula I, the reaction temperature of the crystallization reaction is 20°C-30°C, preferably 25°C.

[0068] The seventh aspect of the present invention provides a trihydrochloride crystal form B of the compound shown in Formula I, which, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at diffraction angles 2θ of 14.8°±0.2°, 15.6°±0.2°, 16.7°±0.2° and 26.9°±0.2°.

[0069] In one embodiment of the present invention, the X-ray powder diffraction of the trihydrochloride crystal form B of the compound as shown in Formula I also has characteristic peaks at one or more locations with diffraction angles 2θ of 9.1°±0.2°, 10.4°±0.2°, 22.3°±0.2°, 23.7°±0.2° and 25.3°±0.2°.

[0070] In one embodiment of the present invention, the X-ray powder diffraction pattern of the trihydrochloride crystal form B of the compound as shown in Formula I is essentially as shown in Figure 13.

[0071] In one embodiment of the present invention, the liquid-state 1H NMR spectrum of the trihydrochloride crystal form B of the compound as shown in Formula I is essentially as shown in Figure 14.

[0072] In one embodiment of the present invention, the trihydrochloride crystal form B of the compound shown in Formula I, when heated to 150±5°C during thermogravimetric analysis, exhibits a weight loss of 8.3%-9.3% (e.g., 8.8%). The percentage of weight loss is the percentage of the sample's weight reduction relative to its weight before this weight loss.

[0073] In one embodiment of the invention, the thermogravimetric analysis (TGA) diagram of the trihydrochloride crystal form B of the compound as shown in Formula I is essentially as shown in Figure 15.

[0074] In one embodiment of the present invention, the trihydrochloride crystal form B of the compound as shown in Formula I exhibits an endothermic signal when heated to 113±5°C (e.g., 113°C), 169±5°C (e.g., 169°C), 203±5°C (e.g., 203°C), and / or 218±5°C (e.g., 218°C) during differential scanning calorimetry analysis.

[0075] In one embodiment of the invention, the DSC of the trihydrochloride crystal form B of the compound as shown in Formula I is substantially as shown in FIG16.

[0076] The eighth aspect of the present invention provides a method for preparing the trihydrochloride crystal form B of the compound shown in Formula I as described above, comprising the following steps: crystallizing the free base of the compound shown in Formula I with hydrochloric acid in a ketone solvent to obtain the hydrochloride crystal form B of the compound shown in Formula I.

[0077] In one embodiment of the present invention, in the method for preparing the trihydrochloride crystal form B of the compound as shown in Formula I, the ketone solvent is acetone.

[0078] In one embodiment of the present invention, in the method for preparing the monohydrochloride crystal form B of the compound as shown in Formula I, the molar ratio of the compound as shown in Formula I to hydrochloric acid is 1:3.

[0079] In one embodiment of the present invention, in the method for preparing the trihydrochloride crystal form B of the compound as shown in Formula I, the mass-to-volume ratio of the compound as shown in Formula I to the solvent is (30-50) mg / mL; preferably 41 mg / mL.

[0080] In one embodiment of the present invention, in the method for preparing the trihydrochloride crystal form B of the compound as shown in Formula I, the crystallization time is 2.5-3.5 days, preferably 3 days.

[0081] In one embodiment of the present invention, in the method for preparing the trihydrochloride crystal form B of the compound as shown in Formula I, the crystallization temperature is 20°C-30°C, preferably 25°C.

[0082] The ninth aspect of the present invention provides a monosulfate crystal form A of the compound shown in Formula I, which, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at diffraction angles 2θ of 6.8°±0.2°, 9.2°±0.2°, 15.9°±0.2°, and 20.4°±0.2°.

[0083] In one embodiment of the present invention, the X-ray powder diffraction of the monosulfate crystal form A of the compound as shown in Formula I also has characteristic peaks at one or more locations with diffraction angles 2θ of 10.9°±0.2°, 19.3°±0.2°, 22.8°±0.2°, 23.9°±0.2° and 25.4°±0.2°.

[0084] In one embodiment of the present invention, the X-ray powder diffraction of the monosulfate crystal form A of the compound as shown in Formula I also has characteristic peaks at one or more locations with diffraction angles 2θ of 10.2°±0.2°, 14.6°±0.2°, 17.4°±0.2°, 18.0°±0.2°, 21.2°±0.2° and 22.2°±0.2°.

[0085] In one embodiment of the present invention, the X-ray powder diffraction pattern of the monosulfate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 17.

[0086] In one embodiment of the present invention, the liquid state 1H NMR spectrum of the monosulfate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 18.

[0087] In one embodiment of the present invention, the monosulfate crystal form A of the compound shown in Formula I, when heated to 150±5°C during thermogravimetric analysis, exhibits a weight loss of 8.8%-9.8% (e.g., 9.3%). The percentage of weight loss is the percentage of the sample's weight reduction relative to its weight before this weight loss.

[0088] In one embodiment of the present invention, the thermogravimetric analysis (TGA) diagram of the sulfate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 19.

[0089] In one embodiment of the present invention, the monosulfate crystal form A of the compound as shown in Formula I has an endothermic signal when heated to 86±5°C (e.g., 86°C), 120±5°C (e.g., 120°C), and / or heated to 191.0±5°C (e.g., 191.0°C) during differential scanning calorimetry analysis.

[0090] In one embodiment of the invention, the DSC of the monosulfate crystal form A of the compound as shown in Formula I is substantially as shown in FIG20.

[0091] The tenth aspect of the present invention provides a method for preparing monosulfate crystal form A of the compound shown in Formula I as described above, comprising the following steps: crystallizing the free base of the compound shown in Formula I as described above with sulfuric acid in an ester solvent to obtain monosulfate crystal form A of the compound shown in Formula I.

[0092] In one embodiment of the present invention, the sulfuric acid is 4 mol / L sulfuric acid.

[0093] In one embodiment of the present invention, in the method for preparing the monosulfate crystal form A of the compound as shown in Formula I, the ester solvent is ethyl acetate.

[0094] In one embodiment of the present invention, in the method for preparing the monosulfate crystal form A of the compound as shown in Formula I, the molar ratio of the compound as shown in Formula I to sulfuric acid is 1:(1-1.2); preferably 1:1.

[0095] In one embodiment of the present invention, in the method for preparing the monosulfate crystal form A of the compound as shown in Formula I, the mass-to-volume ratio of the compound as shown in Formula I to the solvent is (30-50) mg / mL; preferably 40 mg / mL.

[0096] In one embodiment of the present invention, in the method for preparing the monosulfate crystal form A of the compound as shown in Formula I, the crystallization time is 2.5-3.5 days, preferably 3 days.

[0097] In one embodiment of the present invention, in the method for preparing the monosulfate crystal form A of the compound as shown in Formula I, the crystallization temperature is 20°C-30°C, preferably 25°C.

[0098] The eleventh aspect of the present invention provides a monofumarate crystal form A of the compound shown in Formula I, which, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at diffraction angles 2θ of 3.8°±0.2°, 5.6°±0.2°, 9.5°±0.2°, and 17.2°±0.2°.

[0099] In one embodiment of the present invention, the X-ray powder diffraction of the monofumarate crystal form A of the compound as shown in Formula I also has characteristic peaks at one or more locations with diffraction angles 2θ of 11.0°±0.2°, 12.0°±0.2°, 20.0°±0.2°, 21.0°±0.2° and 21.6°±0.2°.

[0100] In one embodiment of the present invention, the X-ray powder diffraction of the monofumarate crystal form A of the compound as shown in Formula I also has characteristic peaks at one or more of the diffraction angles 2θ of 14.6°±0.2°, 14.9°±0.2°, 18.4°±0.2°, 19.5°±0.2°, 24.1°±0.2° and 24.7°±0.2°.

[0101] In one embodiment of the present invention, the X-ray powder diffraction pattern of the monofumarate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 21.

[0102] In one embodiment of the present invention, the liquid-state hydrogen NMR spectrum of the monofumarate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 22.

[0103] In one embodiment of the invention, the monofumarate crystal form A of the compound shown in Formula I, when heated to 150±5°C during thermogravimetric analysis, exhibits a weight loss of 2.6%-3.6% (e.g., 3.1%). The percentage of weight loss is the percentage of the sample's weight reduction relative to its weight before this weight loss.

[0104] In one embodiment of the invention, the thermogravimetric analysis (TGA) diagram of the fumarate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 23.

[0105] In one embodiment of the present invention, the monofumarate crystal form A of the compound as shown in Formula I has an endothermic signal when heated to 56±5°C (e.g., 56°C) and / or an endothermic signal when heated to 179±5°C (e.g., 179°C) during differential scanning calorimetry analysis.

[0106] In one embodiment of the invention, the DSC of the monofumarate crystal form A of the compound as shown in Formula I is essentially as shown in FIG24.

[0107] The twelfth aspect of the present invention provides a method for preparing monofumarate crystal form A of the compound shown in Formula I as described above, comprising the following steps: crystallizing the free base of the compound shown in Formula I with fumaric acid in a ketone solvent to obtain monofumarate crystal form A of the compound shown in Formula I; wherein the mass-volume ratio of the compound shown in Formula I to the ketone solvent is 40 mg / mL.

[0108] In one embodiment of the present invention, in the method for preparing the monofumarate crystal form A of the compound as shown in Formula I, the ketone solvent is acetone.

[0109] In one embodiment of the present invention, in the method for preparing the monofumarate crystal form A of the compound as shown in Formula I, the molar ratio of the compound as shown in Formula I to fumaric acid is 1:(1-1.2); preferably 1:1.

[0110] In one embodiment of the present invention, in the method for preparing the monofumarate crystal form A of the compound as shown in Formula I, the crystallization time is 2.5-3.5 days, preferably 3 days.

[0111] In one embodiment of the present invention, in the method for preparing monofumarate crystal form A of the compound as shown in Formula I, the crystallization temperature is 20°C-30°C, preferably 25°C.

[0112] The thirteenth aspect of the present invention provides a monofumarate crystal form B of the compound shown in Formula I, which, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at diffraction angles 2θ of 5.1°±0.2°, 6.8°±0.2°, 9.7°±0.2°, and 19.7°±0.2°.

[0113] In one embodiment of the present invention, the X-ray powder diffraction of the monofumarate crystal form B of the compound as shown in Formula I also has characteristic peaks at one or more locations with diffraction angles 2θ of 8.4°±0.2°, 13.8°±0.2°, 15.5°±0.2°, 17.5°±0.2° and 24.5°±0.2°.

[0114] In one embodiment of the present invention, the X-ray powder diffraction of the monofumarate crystal form B of the compound as shown in Formula I also has characteristic peaks at one or more of the diffraction angles 2θ of 10.1°±0.2°, 11.0°±0.2°, 16.8°±0.2°, 18.9°±0.2°, 22.4°±0.2° and 28.2°±0.2°.

[0115] In one embodiment of the invention, the X-ray powder diffraction pattern of monofumarate crystal form B of the compound as shown in Formula I is essentially as shown in Figure 25.

[0116] In one embodiment of the present invention, the liquid-state 1H NMR spectrum of the monofumarate crystal form B of the compound as shown in Formula I is essentially as shown in Figure 26.

[0117] In one embodiment of the invention, the monofumarate crystal form B of the compound shown in Formula I exhibits a weight loss of 5.9%-6.9% (e.g., 6.4%) when heated to 150±5°C during thermogravimetric analysis. The percentage of weight loss is the percentage of the sample's weight reduction relative to its weight before this weight loss.

[0118] In one embodiment of the invention, the thermogravimetric analysis (TGA) diagram of monofumarate form B of the compound as shown in Formula I is essentially as shown in Figure 27.

[0119] In one embodiment of the present invention, the monofumarate crystal form B of the compound as shown in Formula I has an endothermic signal when heated to 65±5°C (e.g., 65°C) and / or an endothermic signal when heated to 171±5°C (e.g., 171°C) during differential scanning calorimetry analysis.

[0120] In one embodiment of the invention, the DSC of the monofumarate crystal form B of the compound as shown in Formula I is substantially as shown in FIG28.

[0121] The fourteenth aspect of the present invention provides a method for preparing monofumarate crystal form B of the compound shown in Formula I as described above, comprising the following steps: crystallizing the free base of the compound shown in Formula I with fumaric acid in a ketone solvent to obtain monofumarate crystal form B of the compound shown in Formula I; wherein the mass-to-volume ratio of the compound shown in Formula I to the ketone solvent is 36 mg / mL.

[0122] In one embodiment of the present invention, in the method for preparing the monofumarate crystal form B of the compound as shown in Formula I, the ketone solvent is acetone.

[0123] In one embodiment of the present invention, in the method for preparing the monofumarate crystal form B of the compound shown in Formula I, the molar ratio of the compound shown in Formula I to fumaric acid is 1:(1-1.2); preferably 1:1.

[0124] In one embodiment of the present invention, in the method for preparing the monofumarate crystal form B of the compound as shown in Formula I, the crystallization time is 2.5-3.5 days, preferably 3 days.

[0125] In one embodiment of the present invention, in the method for preparing monofumarate crystal form B of the compound as shown in Formula I, the crystallization temperature is 20°C-30°C, preferably 25°C.

[0126] The fifteenth aspect of the present invention provides a single citrate crystal form A of the compound shown in Formula I, which, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at diffraction angles 2θ of 5.4°±0.2°, 11.5°±0.2°, 13.4°±0.2°, and 16.6°±0.2°.

[0127] In one embodiment of the present invention, the X-ray powder diffraction of the monocitrate crystal form A of the compound as shown in Formula I also has characteristic peaks at one or more locations with diffraction angles 2θ of 7.6°±0.2°, 10.8°±0.2°, 14.1±0.2°, 19.6°±0.2° and 23.4°±0.2°.

[0128] In one embodiment of the present invention, the X-ray powder diffraction of the monocitrate crystal form A of the compound as shown in Formula I also has characteristic peaks at one or more locations with diffraction angles 2θ of 7.0°±0.2°, 9.1°±0.2°, 15.3°±0.2°, 17.5°±0.2°, 21.7°±0.2° and 24.7°±0.2°.

[0129] In one embodiment of the invention, the X-ray powder diffraction pattern of the monocitrate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 29.

[0130] In one embodiment of the present invention, the liquid-state 1H NMR spectrum of the monocitrate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 30.

[0131] In one embodiment of the invention, the monocitrate crystal form A of the compound shown in Formula I, when heated to 150±5°C during thermogravimetric analysis, exhibits a weight loss of 5.3%-6.3% (e.g., 5.8%). The percentage of weight loss is the percentage of the sample's weight reduction relative to its weight before this weight loss.

[0132] In one embodiment of the invention, the thermogravimetric analysis (TGA) diagram of the citrate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 31.

[0133] In one embodiment of the present invention, the citrate crystal form A of the compound as shown in Formula I has an endothermic signal when heated to 174±5°C (e.g., 174°C) during differential scanning calorimetry analysis, and / or has an endothermic signal when heated to 189±5°C (e.g., 189°C).

[0134] In one embodiment of the invention, the DSC of the monocitrate crystal form A of the compound as shown in Formula I is substantially as shown in FIG32.

[0135] The sixteenth aspect of the present invention provides a method for preparing monocitrate crystal form A of the compound shown in Formula I as described above, comprising the following steps: crystallizing the free base of the compound shown in Formula I as described above with citric acid in a ketone solvent to obtain monocitrate crystal form A of the compound shown in Formula I.

[0136] In one embodiment of the present invention, in the method for preparing the monocitrate crystal form A of the compound as shown in Formula I, the ketone solvent is acetone.

[0137] In one embodiment of the present invention, in the method for preparing the monocitrate crystal form A of the compound as shown in Formula I, the molar ratio of the compound as shown in Formula I to citric acid is 1:(1-1.2); preferably 1:1.

[0138] In one embodiment of the present invention, in the method for preparing the monocitrate crystal form A of the compound as shown in Formula I, the mass-to-volume ratio of the compound as shown in Formula I to the ketone solvent is (30-50) mg / mL; preferably 40 mg / mL.

[0139] In one embodiment of the present invention, in the method for preparing the monocitrate crystal form A of the compound as shown in Formula I, the crystallization time is 2.5-3.5 days, preferably 3 days.

[0140] In one embodiment of the present invention, in the method for preparing the monocitrate crystal form A of the compound as shown in Formula I, the crystallization temperature is 20°C-30°C, preferably 25°C.

[0141] The seventeenth aspect of the present invention provides a single L-malate crystal form A of the compound shown in Formula I, which, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at diffraction angles 2θ of 6.8°±0.2°, 15.9°±0.2°, 20.4°±0.2°, and 23.9°±0.2°.

[0142] In one embodiment of the present invention, the X-ray powder diffraction of the single L-malate crystal form A of the compound as shown in Formula I also has characteristic peaks at one or more locations with diffraction angles 2θ of 9.2°±0.2°, 10.9°±0.2°, 19.3°±0.2°, 21.3°±0.2° and 25.5°±0.2°.

[0143] In one embodiment of the present invention, the X-ray powder diffraction of the single L-malate crystal form A of the compound as shown in Formula I also has characteristic peaks at one or more of the diffraction angles 2θ of 9.7°±0.2°, 10.2°±0.2°, 14.0°±0.2°, 17.7°±0.2°, 18.1°±0.2° and 22.8°±0.2°.

[0144] In one embodiment of the invention, the X-ray powder diffraction pattern of the single L-malate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 33.

[0145] In one embodiment of the present invention, the liquid-state 1H NMR spectrum of the single L-malate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 34.

[0146] In one embodiment of the invention, the mono-L-malate crystal form A of the compound shown in Formula I exhibits a weight loss of 3.38%-4.38% (e.g., 3.8%) when heated to 150±5°C during thermogravimetric analysis. The percentage of weight loss is the percentage of the sample's weight reduction relative to its weight before this weight loss.

[0147] In one embodiment of the invention, the thermogravimetric analysis (TGA) diagram of the mono-L-malate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 35.

[0148] In one embodiment of the present invention, the mono-L-malate crystal form A of the compound as shown in Formula I has an endothermic signal when heated to 104±5°C (e.g., 104°C) and / or an endothermic signal when heated to 196±5°C (e.g., 196°C) during differential scanning calorimetry analysis.

[0149] In one embodiment of the invention, the DSC of the mono-L-malate crystal form A of the compound as shown in Formula I is substantially as shown in FIG36.

[0150] The eighteenth aspect of the present invention provides a method for preparing mono-L-malate crystal form A of the compound shown in Formula I as described above, comprising the following steps: crystallizing the free base of the compound shown in Formula I as described above with L-malic acid in a solvent to obtain mono-L-malate crystal form A of the compound shown in Formula I; wherein the solvent is an ester solvent or a ketone solvent.

[0151] In one embodiment of the present invention, in the method for preparing the mono-L-malate crystal form A of the compound as shown in Formula I, the ester solvent is ethyl acetate; and the ketone solvent is acetone.

[0152] In one embodiment of the present invention, in the method for preparing the L-malate crystal form A of the compound as shown in Formula I, the molar ratio of the compound as shown in Formula I to L-malic acid is 1:(1-1.2); preferably 1:1.

[0153] In one embodiment of the present invention, in the method for preparing the mono-L-malate crystal form A of the compound as shown in Formula I, the mass-volume ratio of the compound as shown in Formula I to the solvent is (30-50) mg / mL; preferably 40 mg / mL.

[0154] In one embodiment of the present invention, in the method for preparing the mono-L-malate crystal form A of the compound as shown in Formula I, the crystallization time is 2.5-3.5 days, preferably 3 days.

[0155] In one embodiment of the present invention, in the method for preparing the mono-L-malate crystal form A of the compound as shown in Formula I, the crystallization temperature satisfies any of the following conditions:

[0156] ① The crystallization temperature is 20℃-30℃, preferably 25℃;

[0157] ② The crystallization temperature is 50-5℃, which is raised and lowered (for example, raised from room temperature to 50℃ within 20 minutes and held at that temperature for 2 hours; then lowered to 5℃ within 450 minutes and held at that temperature for 2 hours).

[0158] The nineteenth aspect of the present invention provides a monosuccinate crystal form A of the compound shown in Formula I, which, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at diffraction angles 2θ of 5.8°±0.2°, 10.9°±0.2°, 20.6°±0.2°, and 23.1°±0.2°.

[0159] In one embodiment of the present invention, the X-ray powder diffraction of the monosuccinate crystal form A of the compound as shown in Formula I also has characteristic peaks at one or more locations with diffraction angles 2θ of 9.0°±0.2°, 10.3°±0.2°, 12.7°±0.2°, 16.2°±0.2° and 20.1°±0.2°.

[0160] In one embodiment of the present invention, the X-ray powder diffraction of the monosuccinate crystal form A of the compound as shown in Formula I also has characteristic peaks at one or more locations with diffraction angles 2θ of 13.5°±0.2°, 14.2°±0.2°, 18.6°±0.2°, 22.4°±0.2°, 23.7°±0.2° and 27.4°±0.2°.

[0161] In one embodiment of the invention, the X-ray powder diffraction pattern of the succinate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 37.

[0162] In one embodiment of the present invention, the liquid-state 1H NMR spectrum of the monosuccinate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 38.

[0163] In one embodiment of the invention, the monosuccinate form A of the compound shown in Formula I, when heated to 160±5°C during thermogravimetric analysis, exhibits a weight loss of 6.8%-7.7% (e.g., 7.2%). The percentage of weight loss is the percentage of the sample's weight reduction relative to its weight before this weight loss.

[0164] In one embodiment of the invention, the thermogravimetric analysis (TGA) diagram of monosuccinate form A of the compound as shown in Formula I is essentially as shown in Figure 39.

[0165] In one embodiment of the present invention, the monosuccinate crystal form A of the compound as shown in Formula I exhibits an endothermic signal when heated to 79±5°C (e.g., 79°C), 126±5°C (e.g., 126°C), and / or 185±5°C (e.g., 185°C) during differential scanning calorimetry analysis.

[0166] In one embodiment of the invention, the DSC of the monosuccinate crystal form A of the compound as shown in Formula I is essentially as shown in FIG40.

[0167] The twentieth aspect of the present invention provides a method for preparing monosuccinate crystal form A of the compound shown in Formula I, comprising the following steps: crystallizing the free base of the compound shown in Formula I as described above with succinic acid in a solvent to obtain monosuccinate crystal form A of the compound shown in Formula I; wherein the solvent is an alcohol solvent, an ester solvent or a ketone solvent.

[0168] In one embodiment of the present invention, in the method for preparing the monosuccinate crystal form A of the compound shown in Formula I, the alcohol solvent is isopropanol; the ester solvent is ethyl acetate; and the ketone solvent is acetone.

[0169] In one embodiment of the present invention, in the method for preparing the monosuccinate crystal form A of the compound shown in Formula I, the molar ratio of the compound shown in Formula I to succinic acid is 1:(1-1.2); preferably 1:1.

[0170] In one embodiment of the present invention, in the method for preparing monosuccinate crystal form A of the compound as shown in Formula I, the mass-to-volume ratio of the compound as shown in Formula I to the solvent is (30-50) mg / mL; preferably 40 mg / mL.

[0171] In one embodiment of the present invention, in the method for preparing the monosuccinate crystal form A of the compound as shown in Formula I, the crystallization time is 2.5-3.5 days, preferably 3 days.

[0172] In one embodiment of the present invention, in the method for preparing monosuccinate crystal form A of the compound as shown in Formula I, the crystallization temperature is 20°C-30°C, preferably 25°C.

[0173] The twenty-first aspect of the present invention provides a monomethanesulfonate crystal form A of the compound shown in Formula I, wherein the X-ray powder diffraction of the monomethanesulfonate crystal form A of the compound shown in Formula I has characteristic peaks at diffraction angles 2θ of 5.4°±0.2°, 6.8°±0.2°, 15.6°±0.2° and 17.4°±0.2° using Cu-Kα radiation;

[0174] In one embodiment of the present invention, the X-ray powder diffraction of the monomethanesulfonate crystal form A of the compound as shown in Formula I also has characteristic peaks at one or more locations with diffraction angles 2θ of 4.5°±0.2°, 10.7°±0.2°, 11.5°±0.2°, 19.1°±0.2° and 22.4°±0.2°.

[0175] In one embodiment of the present invention, the X-ray powder diffraction of the monomethanesulfonate crystal form A of the compound as shown in Formula I also has characteristic peaks at one or more of the diffraction angles 2θ of 7.8°±0.2°, 9.0°±0.2°, 12.1°±0.2°, 12.8°±0.2°, 20.9°±0.2° and 21.8°±0.2°.

[0176] In one embodiment of the invention, the X-ray powder diffraction pattern of monomethanesulfonate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 41.

[0177] In one embodiment of the present invention, the liquid-state 1H NMR spectrum of the monomethanesulfonate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 42.

[0178] In one embodiment of the invention, the monomethanesulfonate crystal form A of the compound shown in Formula I, when heated to 150±5°C during thermogravimetric analysis, exhibits a weight loss of 6.2%-7.2% (e.g., 6.7%). The percentage of weight loss is the percentage of the sample's weight reduction relative to its weight before this weight loss.

[0179] In one embodiment of the invention, the thermogravimetric analysis (TGA) diagram of monomethanesulfonate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 43.

[0180] In one embodiment of the present invention, the monomethanesulfonate crystal form A of the compound shown in Formula I exhibits an endothermic signal when heated to 70±5°C (e.g., 70°C), 184±5°C (e.g., 184°C), and / or 202±5°C (e.g., 202°C) during differential scanning calorimetry analysis.

[0181] In one embodiment of the invention, the DSC of monomethanesulfonate crystal form A of the compound as shown in Formula I is substantially as shown in FIG44.

[0182] The twenty-second aspect of the present invention provides a method for preparing monomethanesulfonate crystal form A of the compound shown in Formula I as described above, comprising the following steps: crystallizing the free base of the compound shown in Formula I as described above with methanesulfonic acid in a ketone solvent to obtain monomethanesulfonate crystal form A of the compound shown in Formula I.

[0183] In one embodiment of the present invention, in the method for preparing monomethanesulfonate crystal form A of the compound as shown in Formula I, the ketone solvent is acetone.

[0184] In one embodiment of the present invention, in the method for preparing the monomethanesulfonate crystal form A of the compound as shown in Formula I, the molar ratio of the compound as shown in Formula I to methanesulfonic acid is 1:(1-1.2); preferably 1:1.

[0185] In one embodiment of the present invention, in the method for preparing monomethanesulfonate crystal form A of the compound as shown in Formula I, the mass-to-volume ratio of the compound as shown in Formula I to the ketone solvent is (30-50) mg / mL; preferably 40 mg / mL.

[0186] In one embodiment of the present invention, in the method for preparing monomethanesulfonate crystal form A of the compound as shown in Formula I, the crystallization time is 2.5-3.5 days, preferably 3 days.

[0187] In one embodiment of the present invention, in the method for preparing monomethanesulfonate crystal form A of the compound shown in Formula I, the crystallization temperature is 50-5°C with temperature fluctuation (e.g., from room temperature to 50°C within 20 minutes, held at that temperature for 2 hours; then cooled to 5°C within 450 minutes and held at that temperature for 2 hours).

[0188] The twenty-third aspect of the present invention provides a monobenzene sulfonate crystal form A of the compound shown in Formula I, which, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at diffraction angles 2θ of 5.4°±0.2°, 12.7°±0.2°, 13.3°±0.2°, and 17.8°±0.2°.

[0189] In one embodiment of the present invention, the X-ray powder diffraction of the monobenzenesulfonate crystal form A of the compound as shown in Formula I also has characteristic peaks at one or more locations with diffraction angles 2θ of 14.5°±0.2°, 16.4°±0.2°, 16.8°±0.2°, 23.5°±0.2° and 25.3°±0.2°.

[0190] In one embodiment of the present invention, the X-ray powder diffraction of the monobenzenesulfonate crystal form A of the compound as shown in Formula I also has characteristic peaks at one or more of the diffraction angles 2θ of 11.3°±0.2°, 14.1°±0.2°, 14.8°±0.2°, 17.3°±0.2°, 20.9°±0.2° and 22.6°±0.2°.

[0191] In one embodiment of the present invention, the X-ray powder diffraction pattern of the monobenzene sulfonate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 45.

[0192] In one embodiment of the present invention, the liquid state 1H NMR spectrum of the monobenzene sulfonate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 46.

[0193] In one embodiment of the present invention, the monobenzenesulfonate crystal form A of the compound shown in Formula I, when heated to 150±5°C during thermogravimetric analysis, exhibits a weight loss of 5.7%-6.7% (e.g., 6.2%). The percentage of weight loss is the percentage of the sample's weight reduction relative to its weight before this weight loss.

[0194] In one embodiment of the invention, the thermogravimetric analysis (TGA) diagram of monobenzenesulfonate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 47.

[0195] In one embodiment of the present invention, the monobenzene sulfonate crystal form A of the compound as shown in Formula I has an endothermic signal when heated to 74±5°C (e.g., 74°C) and / or to 186±5°C (e.g., 186°C) during differential scanning calorimetry analysis.

[0196] In one embodiment of the invention, the DSC of monobenzenesulfonate crystal form A of the compound as shown in Formula I is essentially as shown in FIG48.

[0197] The twenty-fourth aspect of the present invention provides a method for preparing monobenzene sulfonate crystal form A of the compound shown in Formula I as described above, comprising the following steps: crystallizing the free base of the compound shown in Formula I with benzenesulfonic acid in a ketone solvent to obtain monobenzene sulfonate crystal form A of the compound shown in Formula I; wherein the mass-volume ratio of the compound shown in Formula I to the ketone solvent is 40 mg / mL.

[0198] In one embodiment of the present invention, in the method for preparing the monobenzene sulfonate crystal form A of the compound shown in Formula I, the ketone solvent is acetone.

[0199] In one embodiment of the present invention, in the method for preparing the monobenzenesulfonate crystal form A of the compound as shown in Formula I, the molar ratio of the compound as shown in Formula I to benzenesulfonic acid is 1:(1-1.2); preferably 1:1.

[0200] In one embodiment of the present invention, in the method for preparing the monobenzenesulfonate crystal form A of the compound as shown in Formula I, the crystallization time is 2.5-3.5 days, preferably 3 days.

[0201] In one embodiment of the present invention, in the method for preparing monobenzenesulfonate crystal form A of the compound as shown in Formula I, the crystallization temperature is 50-5°C with temperature fluctuation (for example, heating from room temperature to 50°C within 20 minutes, holding at that temperature for 2 hours; then cooling to 5°C within 450 minutes and holding at that temperature for 2 hours).

[0202] The twenty-fifth aspect of the present invention provides a monobenzene sulfonate crystal form B of the compound shown in Formula I, which, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at diffraction angles 2θ of 5.5°±0.2°, 12.8°±0.2°, 14.5°±0.2°, and 18.1°±0.2°.

[0203] In one embodiment of the present invention, the X-ray powder diffraction of the monobenzenesulfonate crystal form B of the compound as shown in Formula I also has characteristic peaks at one or more locations with diffraction angles 2θ of 13.8°±0.2°, 16.8°±0.2°, 17.4°±0.2°, 20.3°±0.2° and 26.0°±0.2°.

[0204] In one embodiment of the present invention, the X-ray powder diffraction of the monobenzenesulfonate crystal form B of the compound as shown in Formula I also has characteristic peaks at one or more of the diffraction angles 2θ of 8.6°±0.2°, 9.1°±0.2°, 12.2°±0.2°, 15.1°±0.2°, 22.3°±0.2° and 27.7°±0.2°.

[0205] In one embodiment of the invention, the X-ray powder diffraction pattern of monobenzenesulfonate crystal form B of the compound as shown in Formula I is essentially as shown in Figure 49.

[0206] In one embodiment of the present invention, the liquid state 1H NMR spectrum of the monobenzene sulfonate crystal form B of the compound as shown in Formula I is essentially as shown in Figure 50.

[0207] In one embodiment of the present invention, the monobenzenesulfonate crystal form B of the compound shown in Formula I, when heated to 150±5°C during thermogravimetric analysis, exhibits a weight loss of 1.7%-2.7% (e.g., 2.2%). The percentage of weight loss is the percentage of the sample's weight reduction relative to its weight before this weight loss.

[0208] In one embodiment of the invention, the thermogravimetric analysis (TGA) diagram of monobenzenesulfonate crystal form B of the compound as shown in Formula I is essentially as shown in Figure 51.

[0209] In one embodiment of the present invention, the monobenzenesulfonate crystal form B of the compound as shown in Formula I exhibits an absorption signal when heated to 62±5°C (e.g., 62°C) and / or to 186±5°C (e.g., 186°C) during differential scanning calorimetry analysis.

[0210] In one embodiment of the invention, the DSC of the monobenzene sulfonate crystal form B of the compound as shown in Formula I is substantially as shown in FIG52.

[0211] The twenty-sixth aspect of the present invention provides a method for preparing monobenzene sulfonate crystal form B of the compound shown in Formula I as described above, comprising the following steps: crystallizing the free base of the compound shown in Formula I with benzenesulfonic acid in a ketone solvent to obtain monobenzene sulfonate crystal form B of the compound shown in Formula I; wherein the mass-volume ratio of the compound shown in Formula I to the ketone solvent is 66.7 mg / mL.

[0212] In one embodiment of the present invention, in the method for preparing the monobenzene sulfonate crystal form B of the compound shown in Formula I, the ketone solvent is acetone.

[0213] In one embodiment of the present invention, in the method for preparing the monobenzenesulfonate crystal form B of the compound as shown in Formula I, the molar ratio of the compound as shown in Formula I to benzenesulfonic acid is 1:(1-1.2); preferably 1:1.

[0214] In one embodiment of the present invention, in the method for preparing the monobenzene sulfonate crystal form B of the compound as shown in Formula I, the mass-to-volume ratio of the compound as shown in Formula I to the solvent is (60-70) mg / mL; preferably 66.7 mg / mL.

[0215] In one embodiment of the present invention, in the method for preparing the monobenzenesulfonate crystal form B of the compound as shown in Formula I, the crystallization time is 2.5-3.5 days, preferably 3 days.

[0216] In one embodiment of the present invention, in the method for preparing monobenzenesulfonate crystal form B of the compound as shown in Formula I, the crystallization temperature is 50-5°C with temperature fluctuation (for example, heating from room temperature to 50°C within 20 minutes, holding at that temperature for 2 hours; then cooling to 5°C within 450 minutes and holding at that temperature for 2 hours).

[0217] The twenty-seventh aspect of the present invention provides a mono-2-hydroxyethanesulfonate crystal form A of the compound shown in Formula I, which, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at diffraction angles 2θ of 6.8°±0.2°, 15.7°±0.2°, and 25.4°±0.2°.

[0218] In one embodiment of the present invention, the X-ray powder diffraction of the mono-2-hydroxyethanesulfonate crystal form A of the compound as shown in Formula I also has characteristic peaks at one or more locations with diffraction angles 2θ of 9.2°±0.2°, 19.2°±0.2°, 19.9°±0.2°, 20.4°±0.2° and 21.0°±0.2°.

[0219] In one embodiment of the present invention, the X-ray powder diffraction of the mono-2-hydroxyethanesulfonate crystal form A of the compound as shown in Formula I also has characteristic peaks at one or more of the diffraction angles 2θ of 9.7°±0.2°, 10.8°±0.2°, 14.7°±0.2°, 18.2°±0.2°, 21.6°±0.2° and 22.2°±0.2°.

[0220] In one embodiment of the present invention, the X-ray powder diffraction pattern of mono-2-hydroxyethanesulfonate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 53.

[0221] In one embodiment of the present invention, the liquid-state 1H NMR spectrum of the mono-2-hydroxyethanesulfonate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 54.

[0222] In one embodiment of the invention, the mono-2-hydroxyethanesulfonate crystal form A of the compound shown in Formula I, when heated to 150±5°C during thermogravimetric analysis, exhibits a weight loss of 7.6%-8.6% (e.g., 8.1%). The percentage of weight loss is the percentage of the sample's weight reduction relative to its weight before this weight loss.

[0223] In one embodiment of the invention, the thermogravimetric analysis (TGA) diagram of mono-2-hydroxyethanesulfonate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 55.

[0224] In one embodiment of the present invention, the mono-2-hydroxyethanesulfonate crystal form A of the compound shown in Formula I exhibits an endothermic signal when heated to 83±5°C (e.g., 83°C), 149±5°C (e.g., 149°C), and / or 178±5°C (e.g., 178°C) during differential scanning calorimetry analysis.

[0225] In one embodiment of the invention, the DSC of mono-2-hydroxyethanesulfonate crystal form A of the compound as shown in Formula I is substantially as shown in FIG56.

[0226] The twenty-eighth aspect of the present invention provides a method for preparing mono-2-hydroxyethanesulfonate crystal form A of the compound shown in Formula I as described above, comprising the following steps: crystallizing the free base of the compound shown in Formula I as described above with 2-hydroxyethanesulfonic acid in a solvent to obtain 2-hydroxyethanesulfonate crystal form A of the compound shown in Formula I; wherein the solvent is a ketone solvent or an ester solvent.

[0227] In one embodiment of the present invention, in the method for preparing mono-2-hydroxyethanesulfonate crystal form A of the compound shown in Formula I, the ketone solvent is acetone; and the ester solvent is ethyl acetate.

[0228] In one embodiment of the present invention, in the method for preparing the mono-2-hydroxyethanesulfonate crystal form A of the compound as shown in Formula I, the molar ratio of the compound as shown in Formula I to 2-hydroxyethanesulfonic acid is 1:(1-1.2); preferably 1:1.

[0229] In one embodiment of the present invention, in the method for preparing mono-2-hydroxyethanesulfonate crystal form A of the compound as shown in Formula I, the mass-volume ratio of the compound as shown in Formula I to the solvent is (30-50) mg / mL; preferably 40 mg / mL.

[0230] In one embodiment of the present invention, in the method for preparing mono-2-hydroxyethanesulfonate crystal form A of the compound as shown in Formula I, the crystallization time is 2.5-3.5 days, preferably 3 days.

[0231] In one embodiment of the present invention, in the method for preparing mono-2-hydroxyethanesulfonate crystal form A of the compound as shown in Formula I, the crystallization temperature is 20°C-30°C, preferably 25°C.

[0232] The twenty-ninth aspect of the present invention provides a monoethanesulfonate crystal form A of the compound shown in Formula I, which, when subjected to Cu-Kα radiation, exhibits characteristic peaks in X-ray powder diffraction at diffraction angles 2θ of 6.8°±0.2°, 9.2°±0.2°, 15.7°±0.2°, and 23.9°±0.2°.

[0233] In one embodiment of the present invention, the X-ray powder diffraction of the monoethanesulfonate crystal form A of the compound as shown in Formula I also has characteristic peaks at one or more locations with diffraction angles 2θ of 19.2°±0.2°, 20.5°±0.2°, 21.0°±0.2°, 22.1°±0.2° and 25.4°±0.2°.

[0234] In one embodiment of the present invention, the X-ray powder diffraction of the monoethanesulfonate crystal form A of the compound as shown in Formula I also has characteristic peaks at one or more of the diffraction angles 2θ of 9.8°±0.2°, 10.2°±0.2°, 10.8°±0.2°, 14.0°±0.2°, 14.7°±0.2° and 18.6°±0.2°.

[0235] In one embodiment of the invention, the X-ray powder diffraction pattern of the monoethanesulfonate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 57.

[0236] In one embodiment of the present invention, the liquid-state 1H NMR spectrum of the monoethanesulfonate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 58.

[0237] In one embodiment of the invention, the monoethanesulfonate crystal form A of the compound shown in Formula I, when heated to 150±5°C during thermogravimetric analysis, exhibits a weight loss of 5.5-6.5% (e.g., 6.0%). The percentage of weight loss is the percentage of the sample's weight reduction relative to its weight before this weight loss.

[0238] In one embodiment of the invention, the thermogravimetric analysis (TGA) diagram of the ethanesulfonate crystal form A of the compound as shown in Formula I is essentially as shown in Figure 59.

[0239] In one embodiment of the present invention, the monoethanesulfonate crystal form A of the compound as shown in Formula I, when heated to 90±5°C (e.g., 90°C) by differential scanning calorimetry, exhibits an endothermic signal, and / or when heated to 169±5°C (e.g., 169°C).

[0240] In one embodiment of the invention, the DSC of monoethanesulfonate crystal form A of the compound as shown in Formula I is essentially as shown in FIG60.

[0241] The thirtieth aspect of the present invention provides a method for preparing monoethanesulfonate crystal form A of the compound shown in Formula I as described above, comprising the following steps: crystallizing the free base of the compound shown in Formula I as described above with ethanesulfonic acid in a solvent to obtain monoethanesulfonate crystal form A of the compound shown in Formula I; wherein the solvent is an ester solvent or a ketone solvent.

[0242] In one embodiment of the present invention, in the method for preparing the monoethanesulfonate crystal form A of the compound shown in Formula I, the ester solvent is ethyl acetate and the ketone solvent is acetone.

[0243] In one embodiment of the present invention, in the method for preparing the monoethanesulfonate crystal form A of the compound as shown in Formula I, the molar ratio of the compound as shown in Formula I to ethanesulfonic acid is 1:(1-1.2); preferably 1:1.

[0244] In one embodiment of the present invention, in the method for preparing the monoethanesulfonate crystal form A of the compound as shown in Formula I, the mass-to-volume ratio of the compound as shown in Formula I to the solvent is (30-50) mg / mL; preferably 40 mg / mL.

[0245] In one embodiment of the present invention, in the method for preparing the monoethanesulfonate crystal form A of the compound shown in Formula I, the crystallization time is 2.5-3.5 days, preferably 3 days.

[0246] In one embodiment of the present invention, in the method for preparing the monoethanesulfonate crystal form A of the compound as shown in Formula I, the crystallization temperature is 20°C-30°C, preferably 25°C.

[0247] The thirty-first aspect of the present invention provides a pharmaceutical composition comprising:

[0248] (1) Monomaleate crystal form A, dimaleate crystal form A, monohydrochloride crystal form A, trihydrochloride crystal form B, monosulfate crystal form A, monofumarate crystal form A, monofumarate crystal form B, monocitrate crystal form A, monofumarate crystal form B, monofumarate crystal form B, monofumarate crystal form A, monofumarate crystal form B, monocitrate crystal form A, mono-L-malate crystal form A, monosuccinate crystal form A, monomethanesulfonate crystal form A, monobenzenesulfonate crystal form A, monobenzenesulfonate crystal form B, mono-2-hydroxyethanesulfonate crystal form A, monoethanesulfonate crystal form A, or monomaleate monohydrate crystal form A of the compound shown in Formula I as described above; and

[0249] (2) Pharmaceutically acceptable excipients.

[0250] The thirty-second aspect of the present invention also provides a pharmaceutical composition as described above, a monomaleate crystal form A of a compound as described above, a dimaleate crystal form A of a compound as described above, a monohydrochloride crystal form A of a compound as described above, a trihydrochloride crystal form B of a compound as described above, a monosulfate crystal form A of a compound as described above, a monofumarate crystal form A of a compound as described above, a monofumarate crystal form B of a compound as described above, and a monofumarate crystal form B of a compound as described above. Use of a single crystal of citrate form A, mono-L-malate form A of the compound shown in Formula I, mono-succinate form A of the compound shown in Formula I, mono-methanesulfonate form A of the compound shown in Formula I, mono-benzenesulfonate form A of the compound shown in Formula I, mono-benzenesulfonate form B of the compound shown in Formula I, mono-2-hydroxyethanesulfonate form A of the compound shown in Formula I, mono-ethanesulfonate form A of the compound shown in Formula I, or mono-maleate form A of the compound shown in Formula I; said use is selected from:

[0251] (1) Prepare a protein inhibitor or degrader, wherein the protein in the protein inhibitor or degrader is selected from at least one of EGFR (epidermal growth factor receptor), ROSI (c-ros sarcoma oncogenic factor-receptor tyrosine kinase) or ALK (anaplastic lymphoma kinase).

[0252] (2) To prepare drugs for the treatment or prevention of cancer.

[0253] In one embodiment of the present invention, the cancer is selected from lung cancer; lymphoma; inflammatory myofibroblastic tumor; colorectal cancer; glioma; astroblastoma; ovarian cancer; bone marrow cancer; transplant-related cancer; neutropenia; leukemia; Unwerricht syndrome; bronchial cancer; prostate cancer; breast cancer; thyroid cancer; pancreatic cancer; neuroblastoma; extramedullary plasmacytoma; plasmacytoma; gastric cancer; gastrointestinal stromal tumor; esophageal cancer; colorectal adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; melanoma; brain cancer; oral cancer; sarcoma; tumors resistant to targeted drugs; or tumors or diseases dependent on ALK, ROS1, or EGFR or any mutant protein thereof; preferably lung cancer; for example, non-small cell lung cancer.

[0254] definition

[0255] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Furthermore, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe this invention.

[0256] The term "pharmaceuticalally acceptable excipient" refers to any formulation or carrier medium capable of delivering an effective amount of the active substance of the present invention without interfering with the biological activity of the active substance and without toxic side effects on the host or patient. Representative excipients include water, oil, vegetables and minerals, ointment bases, lotion bases, and ointment bases. These bases include suspending agents, thickeners, transdermal penetration enhancers, etc. Their formulations are well known to those skilled in the art of cosmetics or topical pharmaceuticals.

[0257] The term "pharmaceutical composition" refers to a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient and a pharmaceutically acceptable excipient, intended for administration to mammals, such as humans, in need of such treatment.

[0258] The term “treatment” refers to reversing, alleviating, inhibiting, or preventing the progression of an obstacle or condition to which the term applies, or one or more symptoms of such an obstacle or condition. As used herein, the term “treatment” refers to the action of the verb “to treat,” as previously defined.

[0259] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0260] The reagents and raw materials used in this invention are all commercially available.

[0261] The positive and progressive effects of this invention are as follows: the monomaleate crystal form A of the protein inhibitor or degrader of this invention has low hygroscopicity (weight gain of 2-2.5% at 80% relative humidity), good stability (no change in crystal form after grinding and tableting), and good bioavailability (canine pharmacokinetic parameters: T). 1 / 2 134-135; T max 20-21; C max 4039-4040; AUC 0-t For 149548-149549; MRT 0-t It has a value of 24-25; a tumor inhibition rate of 78-82% and good drug development prospects (excellent compressibility and flowability: Karl coefficient of 18%-19%; angle of repose of 22-23°; good water wettability: contact angle of 46-50°). Attached Figure Description

[0262] Figure 1: XRPD diagram of monomaleate crystal form A of compound I.

[0263] Figure 2: Monomaleate crystal form A of compound I 1 H NMR image

[0264] Figure 3: TGA image of monomaleate crystal form A of compound I.

[0265] Figure 4: DSC diagram of monomaleate crystal form A of compound I.

[0266] Figure 5: XRPD diagram of dimaleate crystal form A of compound I.

[0267] Figure 6: Dimaleate crystal form A of compound I 1 H NMR image

[0268] Figure 7: TGA image of dimaleate crystal form A of compound I.

[0269] Figure 8: DSC diagram of dimaleate crystal form A of compound I.

[0270] Figure 9: XRPD diagram of the hydrochloride crystal form A of compound I.

[0271] Figure 10: Crystal form A of the hydrochloride salt of compound I 1 H NMR image

[0272] Figure 11: TGA image of the hydrochloride crystal form A of compound I.

[0273] Figure 12: DSC diagram of crystal form A of the hydrochloride salt of compound I.

[0274] Figure 13: XRPD diagram of the hydrochloride crystal form B of compound I.

[0275] Figure 14: Crystal form B of the hydrochloride salt of compound I. 1 H NMR image

[0276] Figure 15: TGA image of the hydrochloride crystal form B of compound I.

[0277] Figure 16: DSC diagram of crystal form B of the hydrochloride salt of compound I.

[0278] Figure 17: XRPD diagram of sulfate crystal form A of compound I.

[0279] Figure 18: Sulfate crystal form A of compound I 1 H NMR image

[0280] Figure 19: TGA image of sulfate crystal form A of compound I.

[0281] Figure 20: DSC diagram of sulfate crystal form A of compound I.

[0282] Figure 21: XRPD diagram of fumarate crystal form A of compound I.

[0283] Figure 22: Fumarate crystal form A of compound I 1 H NMR image

[0284] Figure 23: TGA diagram of fumarate form A of compound I.

[0285] Figure 24: DSC diagram of fumarate crystal form A of compound I.

[0286] Figure 25: XRPD diagram of fumarate crystal form B of compound I.

[0287] Figure 26: Fumarate crystal form B of compound I 1 H NMR image

[0288] Figure 27: TGA image of fumarate form B of compound I.

[0289] Figure 28: DSC diagram of fumarate crystal form B of compound I.

[0290] Figure 29: XRPD diagram of citrate crystal form A of compound I.

[0291] Figure 30: Citrate crystal form A of compound I 1 H NMR image

[0292] Figure 31: TGA diagram of citrate crystal form A of compound I.

[0293] Figure 32: DSC diagram of citrate crystal form A of compound I.

[0294] Figure 33: XRPD diagram of L-malate crystal form A of compound I.

[0295] Figure 34: Crystal form A of L-malate of compound I 1 H NMR image

[0296] Figure 35: TGA image of L-malate crystal form A of compound I.

[0297] Figure 36: DSC diagram of L-malate crystal form A of compound I.

[0298] Figure 37: XRPD diagram of succinate crystal form A of compound I.

[0299] Figure 38: Succinate crystal form A of compound I 1 H NMR image

[0300] Figure 39: TGA diagram of succinate crystal form A of compound I.

[0301] Figure 40: DSC diagram of succinate crystal form A of compound I.

[0302] Figure 41: XRPD diagram of methanesulfonate crystal form A of compound I.

[0303] Figure 42: Crystal form A of the methanesulfonate of compound I. 1 H NMR image

[0304] Figure 43: TGA diagram of methanesulfonate form A of compound I.

[0305] Figure 44: DSC diagram of methanesulfonate crystal form A of compound I.

[0306] Figure 45: XRPD diagram of benzenesulfonate crystal form A of compound I.

[0307] Figure 46: Crystal form A of benzenesulfonate of compound I 1 H NMR image

[0308] Figure 47: TGA diagram of benzenesulfonate crystal form A of compound I.

[0309] Figure 48: DSC diagram of benzenesulfonate crystal form A of compound I.

[0310] Figure 49: XRPD diagram of benzenesulfonate crystal form B of compound I.

[0311] Figure 50: Crystal form B of benzenesulfonate of compound I 1 H NMR image

[0312] Figure 51: TGA diagram of benzenesulfonate crystal form B of compound I.

[0313] Figure 52: DSC diagram of benzenesulfonate crystal form B of compound I.

[0314] Figure 53: XRPD diagram of 2-hydroxyethanesulfonate crystal form A of compound I.

[0315] Figure 54: Crystal form A of 2-hydroxyethanesulfonate of compound I 1 H NMR image

[0316] Figure 55: TGA image of crystal form A of 2-hydroxyethanesulfonate of compound I.

[0317] Figure 56: DSC diagram of crystal form A of 2-hydroxyethanesulfonate of compound I.

[0318] Figure 57: XRPD diagram of ethanesulfonate form A of compound I.

[0319] Figure 58: Crystal form A of the ethanesulfonate of compound I 1 H NMR image

[0320] Figure 59: TGA diagram of ethanesulfonate form A of compound I.

[0321] Figure 60: DSC diagram of ethanesulfonate form A of compound I

[0322] Figure 61: Solubility curves of different crystal forms of Formula I in pure water

[0323] Figure 62: Solubility curves of different crystal forms of compound I in SGF

[0324] Figure 63: Solubility curves of different crystal forms of compound I in FaSSIF

[0325] Figure 64: Solubility curves of different crystal forms of compound I in FeSSIF

[0326] Figure 65: XRPD overlay of the stability of the fumarate crystal form B of compound I.

[0327] Figure 66: XRPD overlay of the stability of benzenesulfonate crystal form B of compound I.

[0328] Figure 67: XRPD overlay of the stability of monomaleate crystal form A of compound I.

[0329] Figure 68: XRPD overlay of the stability of compound I

[0330] Figure 69: DVS diagram of compound I

[0331] Figure 70: XRPD overlay images of compound I before and after DVS test.

[0332] Figure 71: DVS diagram of fumarate crystal form B of compound I.

[0333] Figure 72: XRPD overlay images of the fumarate crystal form of compound I before and after DVS test.

[0334] Figure 73: DVS diagram of benzenesulfonate crystal form B of compound I.

[0335] Figure 74: XRPD overlay images of the benzenesulfonate crystal form of compound I before and after DVS test.

[0336] Figure 75: DVS diagram of monomaleate monohydrate crystal form A of compound I.

[0337] Figure 76: XRPD overlay images of the monomaleate monohydrate crystal form of compound I before and after ADVS test.

[0338] Figure 77: XRPD overlay before and after the study of the mechanical stability of the hydrochloride salt of compound I.

[0339] Figure 78: XRPD overlay images of monomaleate crystal form A of compound I before and after mechanical stability study.

[0340] Figure 79: XRPD diagram of single crystal A of the monomaleate monohydrate of compound I.

[0341] Figure 80: Schematic diagram of the asymmetric unit cell of the single crystal structure model of the monomaleate monohydrate of compound I.

[0342] Figure 81: Schematic diagram of the molecular packing structure in the single crystal model of monomaleate monohydrate of compound I.

[0343] Figure 82: Comparison of monomaleate crystal form A of compound I, single crystal of monomaleate crystal form A of compound I, and simulated XPRD plot.

[0344] Figure 83: Tumor growth curves of the hydrochloride salt and monomaleate crystal form of the compound shown in Formula I in a mouse model of LD1-0025-200717 human non-small cell lung cancer xenografts (NU / NU) (n=5).

[0345] Figure 84: Hydrochloride and monomaleate crystal forms of compound I; tumor weight at the end of Group A experiment.

[0346] Figure 85: Curves showing the change in average body weight of tumor-bearing mice during treatment with the hydrochloride and monomaleate crystal forms of compound I (Group A). Detailed Implementation

[0347] According to the present invention, the compound of formula I as a raw material The term refers to its solid (crystalline or amorphous), semi-solid, wax, or oil form. Preferably, the compound of formula I used as a raw material is in solid powder form. The "stirring" is performed using conventional methods in the art, such as magnetic stirring or mechanical stirring, at a stirring speed of 50–1800 rpm, wherein magnetic stirring is performed at 200–1500 rpm, preferably 300–1000 rpm, and mechanical stirring is preferably 100–300 rpm.

[0348] In this invention, "crystal" or "polymorph" refers to that confirmed by the X-ray diffraction pattern shown. Those skilled in the art will understand that the physicochemical properties discussed herein can be characterized, and the experimental errors depend on instrument conditions, sample preparation, and sample purity. In particular, it is known to those skilled in the art that X-ray diffraction patterns typically change with instrument conditions. It is particularly important to note that the relative intensities of X-ray diffraction patterns can also vary with experimental conditions, so the order of peak intensities cannot be considered the sole or decisive factor. In fact, the relative intensities of diffraction peaks in an X-ray diffraction pattern are related to the preferred orientation of the crystal, and the peak intensities shown herein are illustrative rather than for absolute comparison. Furthermore, experimental errors in peak angles are typically 5% or less, and these angular errors should also be taken into account, generally allowing for ±0.2° errors. Additionally, due to the influence of experimental factors such as sample thickness, an overall shift in peak angles may occur, and a certain degree of shift is generally permissible. Therefore, those skilled in the art will understand that the X-ray diffraction pattern of a crystal form in this invention need not be completely identical to the X-ray diffraction pattern in the examples referred to herein. The phrase "same X-ray diffraction pattern" does not mean absolutely identical; the positions of the same peaks may differ by ±0.2°, and the peak intensities are allowed to have some variability. Any crystal form with a pattern having the same or similar characteristic peaks as those in these spectra falls within the scope of this invention. Those skilled in the art can compare the spectra listed in this invention with a spectra of an unknown crystal form to verify whether the two sets of spectra reflect the same or different crystal forms.

[0349] In some embodiments, the crystal form of the present invention is pure and singular, substantially free of any other crystal form. In this invention, "substantially free" when referring to a new crystal form means that the crystal form contains less than 20% (by weight) of other crystal forms, particularly less than 10% (by weight), more specifically less than 5% (by weight), and even more specifically less than 1% (by weight). It should be noted that the numerical values ​​and ranges mentioned in this invention should not be narrowly interpreted as numerical values ​​or ranges themselves. Those skilled in the art should understand that they may fluctuate around specific numerical values ​​depending on the specific technical environment, without departing from the spirit and principles of the present invention. In this invention, such fluctuation ranges, foreseeable by those skilled in the art, are often expressed using the term "about".

[0350] The upper and lower limits of the numerical range described in this invention specification can be combined arbitrarily.

[0351] The present invention will be further illustrated by specific embodiments below. Experimental methods not specifically described in the following embodiments are performed according to conventional methods and conditions, or as selected according to the product instructions. Those skilled in the art can make improvements to the preparation methods and instruments used within the scope of the claims, and these improvements should also be considered within the scope of protection of the present invention.

[0352] The abbreviations used in this invention are explained as follows:

[0353] XRPD: X-ray powder diffraction

[0354] 1 1H NMR: Liquid NMR spectrum

[0355] DSC: Differential Scanning Calorimetry

[0356] TGA: Thermogravimetric Analysis

[0357] DVS: Dynamic Moisture Adsorption

[0358] HPLC: High Performance Liquid Chromatography

[0359] SCXRD: Single-crystal X-ray diffraction

[0360] The X-ray powder diffraction pattern described in this invention is in PANalytical Empyrean or X'Pert. 3 Collected using an X-ray powder diffractometer.

[0361] The parameters of the X-ray powder diffraction method described in this invention are as follows:

[0362] X-ray source: Cu, Kα

[0363] Kα1 1.54060; Kα2 1.54439

[0364] Kα2 / Kα1 intensity ratio: 0.50

[0365] Voltage: 45 kV

[0366] Current: 40 milliamperes (mA)

[0367] Diverging slit: 1 / 8 degree

[0368] Scanning mode: Continuous scan

[0369] Scan range: from 3.0 to 40.0 degrees

[0370] Scan step size: 0.0263 degrees

[0371] Scanning time per step: 46.67 degrees

[0372] Scan time: Approximately 5 minutes

[0373] The liquid nuclear magnetic hydrogen spectrum described in this invention ( 1 1H NMR was acquired using a Bruker 400M NMR spectrometer with deuterated dimethyl sulfoxide as the solvent. The liquid-state 1H NMR spectrum described in this invention...1 The method parameters for H NMR are as follows:

[0374] Number of scans: 16

[0375] Spectrometer frequency: 400M

[0376] Temperature: 295.6K

[0377] The differential scanning calorimetry (DSC) images described in this invention were acquired on a TA Discovery 2500. The parameters of the differential scanning calorimetry (DSC) method described in this invention are as follows:

[0378] Method: Linear heating

[0379] Sample tray: Aluminum tray, capped / uncapped

[0380] Temperature range: room temperature to 250℃

[0381] Scan rate: 10℃ / minute

[0382] Protective gas: N2

[0383] The thermogravimetric analysis (TGA) charts described in this invention were acquired using a TA Discovery 5500. The method parameters for the thermogravimetric analysis (TGA) described in this invention are as follows:

[0384] Method: Linear heating

[0385] Sample tray: Aluminum tray, open

[0386] Temperature range: room temperature to 200℃

[0387] Scan rate: 10℃ / minute

[0388] Protective gas: N2

[0389] The dynamic moisture adsorption map described in this invention is acquired using the DVS Intrinsic module of an SMS system. The parameters of the dynamic moisture adsorption method described in this invention are as follows:

[0390] Temperature: 25℃

[0391] Sample size: 20 to 40 mg

[0392] Protective gas and flow rate: N2, 200 ml / min

[0393] Maximum mass change at equilibrium, dm / dt: 0.002% / minute

[0394] Minimum dm / dt equilibration time: 10 minutes

[0395] Maximum balancing time: 180 minutes

[0396] Humidity range: 0%RH to 95%RH to 0%RH

[0397] Humidity variation gradient: 10%RH (between 0%RH and 90%RH), 5%RH (between 90%RH and 95%RH)

[0398] In this invention, the high-performance liquid chromatography (HPLC) purity data were obtained from an Agilent 1260, and the detector used was a diode array detector (DAD). The HPLC method parameters for testing purity described in this invention are as follows:

[0399] 1. Chromatographic column: Acquity UPLC BEH C18, 50 mm × 2.1 mm, 1.7 μm

[0400] 2. Mobile phase: A: 0.1% trifluoroacetic acid aqueous solution

[0401] B: 0.1% trifluoroacetic acid acetonitrile solution

[0402] The elution gradient is as follows:

[0403] 3. Flow rate: 0.5 mL / min

[0404] 4. Injection volume: 2 μL

[0405] 5. Detection wavelength: 254nm

[0406] 6. Column temperature: 30℃

[0407] 7. Injector temperature: room temperature

[0408] 8. Diluent: Acetonitrile / water 1:1 volume ratio

[0409] The single-crystal X-ray diffraction (SCXRD) data described in this invention were collected using a Rigaku XtaLAB Synergy R-type single-crystal diffractometer. The parameters of the single-crystal testing method described in this invention are as follows:

[0410] X-ray source: PhotonJet R(Cu)X-ray Source (Cu / Kα: )

[0411] Detector: Hypix 6000C detector

[0412] Angle measuring system: Four-circle KAPPA geometric angle measuring system

[0413] Cryogenic System: Cryostream-800 Plus (80K~500K)

[0414] Software Suite: CrysAlisPro

[0415] Unless otherwise specified, all the following examples are performed at room temperature.

[0416] Example 1: Preparation of free base of compound I

[0417] The hydrochloride salt of Formula I (2 g, 2 mmol) (compound E5 prepared using the methods of Examples 5 and 6 of patent WO2022268229) was dissolved in CH3CN (10 mL) and water (10 mL). Under ice-water bath conditions, saturated sodium bicarbonate solution was added to adjust the pH to 9. DCM (50 mL x 3) was added and the mixture was extracted three times. The organic layer was washed with brine (50 mL), dried with anhydrous sodium sulfate, filtered, and concentrated. The solid was dissolved in a small amount of DCM, and then acetonitrile was added. The solid was precipitated under sonication. The solid was filtered and dried to obtain the free base of Formula I (white solid, 1.25 g, yield: 70%, 97.5% ee, purity: 99%). 1 H NMR (500MHz, DMSO-d6) δ11.15(s,1H),11.04(s,1H),8.43(s,1H),8.11(d,J=10.7Hz,2H),7.72(dd,J=7.5,1.1Hz,1H),7.63(dd,J =7.6,1.1Hz,1H),7.59–7.50(m,2H),7.43(s,1H),7.32(t,J=7.6Hz,1H),7.11(t,J=7.3Hz,1H),6.78(s,1H),5.17(dd,J=13.4,5.1 Hz,1H),4.46(d,J=17.7Hz,1H),4.31(d,J=17.7Hz,1H),3.75(s,3H),3.05–2.90(m,3H),2.74–2.51(m,14H),2.49–2.37(m,4H),2 .26(s,1H),2.07–2.01(m,1H),1.86(d,J=11.8Hz,2H),1.78(s,3H),1.75(s,3H),1.55(q,J=11.1Hz,2H),1.06(t,J=7.5Hz,3H).MS m / z(ESI):892.4[M+H] + .

[0418] Examples 2-4: Preparation of monomaleate crystal form A of compound I

[0419] Method a: Weigh the free base of the compound of formula I obtained in Example 1 and an equimolar amount of maleic acid into a glass vial, add different solvents to form a suspension, and the solvent conditions are shown in Table 1. Then, place at room temperature (25°C) and stir magnetically for about 3 days. Separate the solid and dry it under vacuum at room temperature (20-30°C). Collect the solid to obtain monomaleate crystal form A of compound of formula I. Detailed conditions of the experiments involved in this example are shown in Table 1. XRPD of monomaleate crystal form A of compound of formula I obtained on a large scale in Example 4. 1 The ¹H NMR, TGA, and DSC results are shown in Figures 1-4, and their X-ray powder diffraction data are shown in Table 2. The XRPD, X-ray diffraction, and X-ray diffraction data of the monomaleate crystal form A prepared in Examples 2-3 are also shown. 1 The 1H NMR, TGA, and DSC characterizations were basically the same as the spectra obtained in Example 4.

[0420] Table 1

[0421] Table 2

[0422] Examples 5-8: Preparation of monomaleate crystal form A of compound I

[0423] Approximately 15 mg of monomaleate crystal form A solid prepared in Example 4 was weighed into a 3 mL vial and dissolved in different solvents. The supernatant was filtered through a 0.45 μm polytetrafluoroethylene filter membrane into another 20 mL vial. While maintaining magnetic stirring, the antisolvent was added dropwise to the filtrate until the solid precipitated. All samples were stirred at room temperature until monomaleate crystal form A was obtained. The detailed conditions of the experiments involved in this example are shown in Table 3. The XRPD characterization of monomaleate crystal form A prepared in Examples 5-8 was basically the same as the spectrum obtained in Example 4.

[0424] Table 3

[0425] Examples 9-11: Preparation of dimaleate crystal form A of compound I

[0426] Approximately 15 mg of the free base of Formula I obtained in Example 1 and two molar amounts of maleic acid were weighed into a glass vial. 0.5 mL of a different solvent was added to form a suspension, which was then magnetically stirred at room temperature for approximately 4 days. The solid was separated and dried under vacuum at room temperature. The solid was collected to obtain the dimaleate crystal form A of Formula I. Detailed conditions of the experiments involved in this example are shown in Table 4. XRPD in Example 11, 1The ¹H NMR, TGA, and DSC data are shown in Figures 5-8, and their X-ray powder diffraction data are shown in Table 5. The XRPD characterization of the dimaleate crystal form A of the compound of formula I prepared in Examples 9-10 is basically the same as the spectrum obtained in Example 11.

[0427] Table 4

[0428] Table 5

[0429] Examples 12-14: Preparation of monohydrochloride crystal form A of compound I

[0430] Approximately 20 mg of the free base of Formula I obtained in Example 1 was weighed into 0.25 mL of a different solvent. An equimolar amount of 12 mol / L hydrochloric acid was transferred into 0.25 mL of the corresponding solvent. The free base solution and acid solution were then mixed and magnetically stirred at room temperature for approximately 3 days. The solid was separated and dried under vacuum at room temperature. The solid was collected to obtain the monohydrochloride crystal form A of Formula I. Detailed conditions of the experiments involved in this example are shown in Table 6. XRPD of Example 14, 1 The ¹H NMR, TGA, and DSC data are shown in Figures 9-12, and their X-ray powder diffraction data are shown in Table 7. The XRPD characterization of the single hydrochloride crystal form A prepared in Examples 12-13 is basically the same as the spectrum obtained in Example 14.

[0431] Table 6

[0432] Table 7

[0433] Example 15: Preparation of the trihydrochloride crystal form B of compound I

[0434] Weigh 20.5 mg of the free base of Formula I obtained in Example 1 into 0.25 mL of acetone solvent. Transfer three molar amounts (5.6 μL) of 12 mol / L hydrochloric acid into 0.25 mL of acetone solvent. Then mix the free base solution and acid solution, and stir magnetically at room temperature for approximately 3 days. Separate the solid and dry it under vacuum at room temperature. Collect the solid to obtain the trihydrochloride crystal form B of Formula I. The XRPD of this example... 1 The H NMR, TGA, and DSC data are shown in Figures 13-16, and their X-ray powder diffraction data are shown in Table 8.

[0435] Table 8

[0436] Example 16: Preparation of monosulfate crystal form A of compound I

[0437] Weigh 19.9 mg of the free base of Formula I obtained in Example 1 into 0.25 mL of ethyl acetate solvent. Transfer an equimolar amount (5.6 μL) of 4 mol / L sulfuric acid into 0.25 mL of ethyl acetate solvent. Then mix the free base solution and acid solution of Formula I and place the mixture at room temperature with magnetic stirring for approximately 3 days. Separate the solid and dry it under vacuum at room temperature. Collect the solid to obtain the monosulfate crystal form A of Formula I. XRPD in this example... 1 The H NMR, TGA, and DSC data are shown in Figures 17-20, and their X-ray powder diffraction data are shown in Table 9.

[0438] Table 9

[0439] Example 17: Preparation of monofumarate crystal form A of compound I

[0440] Weigh 20.1 mg of the free base of Formula I obtained in Example 1 and an equimolar amount (2.6 mg) of fumaric acid into 0.5 mL of acetone solvent, and stir magnetically at room temperature for about 3 days. Separate the solid, dry it under vacuum at room temperature, and collect the solid to obtain the monofumarate crystal form A of Formula I. The XRPD in this example... 1 The H NMR, TGA, and DSC data are shown in Figures 21-24, and their X-ray powder diffraction data are shown in Table 10.

[0441] Table 10

[0442] Example 18: Preparation of monofumarate crystal form B of compound I

[0443] Weigh 400.1 mg of the free base of Formula I obtained in Example 1 and an equimolar amount (52.2 mg) of fumaric acid into 11 mL of acetone solvent, and stir magnetically at room temperature for about 3 days. Separate the solid, dry it under vacuum at room temperature, and collect the solid to obtain the monofumarate crystal form B of Formula I. The XRPD in this example... 1 The H NMR, TGA, and DSC data are shown in Figures 25-28, and their X-ray powder diffraction data are shown in Table 11.

[0444] Table 11

[0445] Example 19: Preparation of monocitrate crystal form A of compound I

[0446] 20.3 mg of the compound of formula I obtained in Example 1 and an equimolar amount (4.5 mg) of citric acid were weighed into 0.5 mL of acetone solvent and magnetically stirred at room temperature for about 3 days. The solid was separated and dried under vacuum at room temperature. The solid was collected to obtain monocitrate crystal form A of the compound of formula I. The XRPD of this example... 1 The H NMR, TGA, and DSC data are shown in Figures 29-32, and their X-ray powder diffraction data are shown in Table 12.

[0447] Table 12

[0448] Examples 20-21: Preparation of mono-L-malate crystal form A of compound I

[0449] Approximately 20 mg of the free base of Formula I obtained in Example 1 and an equimolar amount of L-malic acid were weighed into 0.5 mL of different solvents and placed at room temperature with magnetic stirring for approximately 3 days, or transferred to 50-5°C with alternating temperature and stirring for 3 days (the procedure was: raising the temperature from room temperature to 50°C within 20 minutes and holding for 2 hours; then lowering it to 5°C within 450 minutes and holding for 2 hours). The solid was separated and dried under vacuum at room temperature. The solid was collected to obtain the mono-L-malate crystal form A of Formula I. Detailed conditions of the experiments involved in this example are shown in Table 13. XRPD of Example 21, 1 The ¹H NMR, TGA, and DSC results are shown in Figures 33-36, and their X-ray powder diffraction data are shown in Table 14. The XRPD characterization of the single hydrochloride crystal form A prepared in Example 20 is basically the same as the spectrum obtained in Example 14.

[0450] Table 13

[0451] Table 14

[0452] Examples 22-24: Preparation of monosuccinate crystal form A of compound I

[0453] Approximately 20 mg of the free base of compound I obtained in Example 1 and an equimolar amount of succinic acid were weighed into 0.5 mL of different solvents and magnetically stirred at room temperature for approximately 3 days. The solid was separated and vacuum dried at room temperature. The solid was collected to obtain monosuccinate crystal form A. Detailed conditions of the experiments involved in this example are shown in Table 15. XRPD of Example 24, 1 The ¹H NMR, TGA, and DSC data are shown in Figures 37-40, and their X-ray powder diffraction data are shown in Table 16. The XRPD characterization of the monosuccinate crystal form A of the compound of formula I prepared in Examples 22-23 is basically the same as the spectrum obtained in Example 24.

[0454] Table 15

[0455] Table 16

[0456] Example 25: Preparation of monomethanesulfonate crystal form A of compound I

[0457] Weigh 19.9 mg of the free base of Formula I obtained in Example 1 into 0.25 mL of acetone solvent. Transfer an equimolar amount (2.2 mg) of methanesulfonic acid into 0.25 mL of acetone solvent. Then mix the free base solution and acid solution of Formula I, and transfer to a 50-5°C temperature range with stirring for 3 days (the procedure is: raise the temperature from room temperature to 50°C within 20 minutes, hold for 2 hours; then lower the temperature to 5°C within 450 minutes and hold for 2 hours). Separate the solid and dry it under vacuum at room temperature. Collect the solid to obtain the monomethanesulfonate crystal form A of Formula I. XRPD in this example... 1 The H NMR, TGA, and DSC data are shown in Figures 41-44, and their X-ray powder diffraction data are shown in Table 17.

[0458] Table 17

[0459] Example 26: Preparation of monobenzenesulfonate crystal form A of compound I

[0460] Weigh 19.8 mg of the free base of compound I obtained in Example 1 and an equimolar amount (4.2 mg) of benzenesulfonic acid into 0.5 mL of acetone solvent. Transfer the solution to a 50-5°C temperature range and stir for 3 days (the procedure is: raise the temperature from room temperature to 50°C within 20 minutes, hold for 2 hours; then lower the temperature to 5°C within 450 minutes and hold for 2 hours). Separate the solid and dry it under vacuum at room temperature. Collect the solid to obtain the monobenzenesulfonate crystal form A of compound I. The XRPD in this example... 1 The H NMR, TGA, and DSC data are shown in Figures 45-48, and their X-ray powder diffraction data are shown in Table 18.

[0461] Table 18

[0462] Example 27: Preparation of monobenzenesulfonate crystal form B of compound I

[0463] Weigh 400.2 mg of the free base of Formula I obtained in Example 1 and an equimolar amount (70.5 mg) of benzenesulfonic acid into 6 mL of acetone solvent. Transfer to a 50-5°C temperature range and stir for 3 days (programmed as follows: increase temperature from room temperature to 50°C within 20 minutes, hold for 2 hours; then decrease to 5°C within 450 minutes and hold for 2 hours). Separate the solid and dry it under vacuum at room temperature. Collect the solid to obtain the monobenzenesulfonate crystal form B of Formula I. The XRPD of this example... 1 The H NMR, TGA, and DSC data are shown in Figures 49-52, and their X-ray powder diffraction data are shown in Table 19.

[0464] Table 19

[0465] Examples 28-29: Preparation of mono-2-hydroxyethanesulfonate crystal form A of compound I

[0466] Approximately 20 mg of the free base of Formula I obtained in Example 1 and an equimolar amount of 2-hydroxyethanesulfonic acid were weighed into 0.5 mL of different solvents and magnetically stirred at room temperature for approximately 3 days. The solid was separated and dried under vacuum at room temperature. The solid was collected to obtain mono-2-hydroxyethanesulfonate crystal form A of Formula I. Detailed conditions of the experiments involved in this example are shown in Table 20. XRPD of Example 29, 1 The ¹H NMR, TGA, and DSC results are shown in Figures 53-56, and their X-ray powder diffraction data are shown in Table 21. The XRPD of the monomaleate crystal form A prepared in Example 28... 1 The ¹H NMR, TGA, and DSC characterizations were basically the same as the spectra obtained in Example 29.

[0467] Table 20

[0468] Table 21

[0469] Examples 30-31: Preparation of monoethanesulfonate crystal form A of compound I

[0470] Approximately 20 mg of the free base of Formula I obtained in Example 1 was weighed into 0.25 mL of a different solvent. An equimolar amount of ethanesulfonic acid was transferred into 0.25 mL of the corresponding solvent. The free base solution and acid solution of Formula I were then mixed and magnetically stirred at room temperature for approximately 3 days. The solid was separated and vacuum dried at room temperature. The solid was collected to obtain the monoethanesulfonate crystal form A of Formula I. Detailed experimental conditions in this example are shown in Table 22. XRPD of Example 31, 1The 1H NMR, TGA, and DSC results are shown in Figures 57-60, and their X-ray powder diffraction data are shown in Table 23. The XRPD of the monomaleate crystal form A prepared in Example 30... 1 The 1H NMR, TGA, and DSC characterizations were basically the same as the spectra obtained in Example 31.

[0471] Table 22

[0472] Table 23

[0473] Example 34: Solubility Study of Crystal Forms

[0474] The free base of compound I, monofumarate crystal form B of compound I, monobenzenesulfonate crystal form B of compound I, and monomaleate crystal form A of compound I prepared in Example 1 of this invention were respectively prepared into suspensions using SGF (artificial gastric juice), FaSSIF (artificial intestinal juice under fasting conditions), FeSSIF (artificial intestinal juice under feeding conditions), and pure water. After equilibration for 1 hour, 2 hours, 4 hours, and 24 hours, the suspensions were filtered to obtain saturated solutions. The content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC). The experimental results are shown in Table 24, and the solubility curves are shown in Figures 61-64. The experimental results show that the solubility of monofumarate crystal form B and monomaleate crystal form A of compound I in pure water is better than that of the free base of compound I. In the SGF system, monomaleate crystal form A has better solubility. In addition, except for monomaleate crystal form A, crystal form changes were observed in the test solvents for all salt forms.

[0475] Table 24

[0476] Example 35: Stability Study

[0477] Approximately 15 mg each of the following compounds prepared according to this invention were weighed: monofumarate crystal form B (initial purity 97.90%), monobenzenesulfonate crystal form B (initial purity 98.47%), monomaleate crystal form A (initial purity 97.76%), and free base (initial purity 97.49%). These were placed in open containers in stability chambers at 25°C / 60% RH and 40°C / 75% RH (RH represents relative humidity). Samples were taken after one week for XRPD and HPLC analysis. The stability of monofumarate crystal form B of compound I is shown in Figure 65, the stability of monobenzenesulfonate crystal form B of compound I is shown in Figure 66, the stability of monomaleate crystal form A of compound I is shown in Figure 67, and the stability of the entire compound I is shown in Figure 68. The experimental results are summarized in Table 25. The results show that under the conditions of 25℃ / 60%RH, no obvious purity changes were observed in any of the samples. Under the conditions of 40℃ / 75%RH, new impurities appeared in the monofumarate crystal form B of Formula I and the free base sample. The monofumarate crystal form B and the monobenzenesulfonate crystal form B showed crystal form changes.

[0478] Table 25

[0479] Relative purity = (Purity after storage / Initial purity) × 100%

[0480] Example 36: Hygroscopicity Study

[0481] Approximately 10 mg each of the free base of compound I prepared in this invention, monofumarate crystal form B of compound I, monobenzenesulfonate crystal form B of compound I, and monomaleate crystal form A of compound I were weighed for dynamic moisture adsorption (DVS) testing, and then samples were taken to measure XRPD. The experimental results are shown in Table 26. The DVS of compound I is shown in Figure 69, and the XRPD results of the samples before and after the DVS test are shown in Figure 70; the DVS of monofumarate crystal form B of compound I is shown in Figure 71, and the XRPD results of the samples before and after the DVS test are shown in Figure 72; the DVS of monobenzenesulfonate crystal form B of compound I is shown in Figure 73, and the XRPD results of the samples before and after the DVS test are shown in Figure 74; the DVS of monomaleate crystal form A of compound I is shown in Figure 75, and the XRPD results of the samples before and after the DVS test are shown in Figure 76. The experimental results show that the moisture absorption weight gain of each crystal form of compound I at 25℃ / 80%RH is shown in Table 26. The monofumarate crystal form B and monobenzenesulfonate crystal form B of Formula I showed crystal form changes after DVS testing, while the monomaleate crystal form A did not show crystal form changes.

[0482] Table 26

[0483] Description of hygroscopic characteristics and definition of hygroscopic weight gain (Guidelines for Hygroscopicity Testing of Drugs in the General Chapters of the Chinese Pharmacopoeia 2020 Edition):

[0484] Deliquescence: Absorbs sufficient water to form a liquid.

[0485] Extremely hygroscopic: Moisture absorption increases weight by at least 15%.

[0486] It has hygroscopic properties: the weight gain due to moisture absorption is less than 15% but not less than 2%.

[0487] Slightly hygroscopic: Moisture absorption increases weight by less than 2% but not less than 0.2%.

[0488] None or almost none hygroscopicity: moisture-induced weight gain less than 0.2%.

[0489] Example 37: Mechanical Stability

[0490] Take 20-30 mg of monomaleate crystal form A of compound I of the present invention and hydrochloride of compound I (prepared using the methods of preparation examples 5 and 6 of patent WO2022268229), place them in an agate mortar, grind them manually for about 10 minutes, and then test the crystal form.

[0491] Take appropriate amounts of monomaleate crystal form A and hydrochloride sample of compound I, add them to a tablet press, compress them under a pressure of 350 MPa, and then test the crystal form.

[0492] The experimental results showed that monomaleate A of Formula I did not undergo a crystal form transformation after grinding, but its crystallinity decreased. The hydrochloride sample, however, showed a decrease in crystallinity to amorphous after grinding. These results indicate that monomaleate A of Formula I has better grinding stability than the hydrochloride sample. Monomaleate A of Formula I did not undergo a crystal form transformation after tableting, but its crystallinity decreased. The hydrochloride sample, on the other hand, underwent a crystal form transformation, and the decrease in crystallinity was more pronounced, indicating that monomaleate A has better pressure stability than the hydrochloride sample. Specific results are shown in Figures 77 and 78.

[0493] Example 38: Compressibility and Flowability

[0494] Weigh appropriate amounts of monomaleate crystal form A and hydrochloride (prepared using methods 5 and 6 of patent WO2022268229) of the present invention, and add them to a 5 mL graduated cylinder, recording the volume. Tap the graduated cylinder lightly on the table 300 times, recording the volume. Separately, take appropriate amounts of monomaleate crystal form A and hydrochloride samples of the present invention. Fix a funnel on an iron stand, perpendicular to the table. Add the monomaleate crystal form A and hydrochloride samples to the funnel, allowing them to fall freely and form a cone. Measure the height and diameter of the cone to calculate the angle of repose. Perform three parallel tests. The experimental results are shown in Table 27. The results show that monomaleate crystal form A has a smaller Cartesian coefficient and angle of repose than the hydrochloride sample, exhibiting better compressibility and flowability.

[0495] Table 27

[0496] Carr index = (tap density - loose density) / tap density.

[0497] Example 39: Contact angle of crystal sample

[0498] 20 mg each of the monomaleate crystal form A and hydrochloride sample of compound I of this invention were weighed, and their contact angles with water were tested. The results showed that the contact angle of monomaleate crystal form A was 46.7–49.9°, and the contact angle of the hydrochloride sample was 39.2–42.1°, indicating that both monomaleate crystal form A and the hydrochloride sample have good water wettability.

[0499] Example 40: Preparation of monomaleate crystal form A of compound of formula I

[0500] 15.4 mg of the monomaleate crystal form A of compound I prepared in Example 4 was weighed into a 3 mL glass vial, and 0.5 mL of N,N-dimethylformamide was added to dissolve the solid sample and form a sample solution. The solution was then filtered into a single crystal growth bottle. The single crystal bottle was sealed with a PE single crystal stopper, and a small hole was punched in the stopper. The single crystal bottle was then placed into a 20 mL vial pre-filled with 4 mL of methyl acetate, sealed, and left to stand at room temperature until solid precipitated, yielding a single crystal of monomaleate crystal form A. The X-ray powder diffraction pattern of this example is shown in Figure 79, and the schematic diagram of the asymmetric unit of the structural model is shown in Figure 80, showing that the single crystal is a monohydrate with an acid-base molar ratio of 1:1. The schematic diagram of the molecular packing structure in the structural model is shown in Figure 81. The XPRD comparison of the single crystals of monomaleate crystal form A prepared in Example 4 and the single crystals of monomaleate crystal form A prepared in this example is shown in Figure 82, showing that they are consistent. The stereochemical structure of compound I was confirmed by experiments, and the absolute configuration of the chiral carbon atom in its molecule was S-configuration. The crystallographic data and structural refinement parameters of the single crystal are shown in Table 28.

[0501] Table 28

[0502] Example 41: Canine Pharmacokinetic Test

[0503] Experimental animals: three male shuffled beagles.

[0504] Experimental Design: All animals were not fasted before administration; Dosage: 25 mg / kg; Concentration: 5 mg / mL; Volume: 5 mL / kg; Administration: Weighed before administration, and the dosage was calculated based on body weight. Administration was via gavage or oral administration, a single dose; Sample Collection: Plasma. The administration solvent for Compound I hydrochloride (compound E5 prepared using the methods of Examples 5 and 6 of patent WO2022268229) was: 5% DMSO + 10% polyethylene glycol stearate (Solutol) + 85% physiological saline (Saline); the administration solvent for Compound I monomaleate crystal form A was: 20% sulfobutyl ether-β-cyclodextrin (SBE-β-CD) + 0.5% hydroxypropyl methylcellulose E5 (HPMC E5) + 5.0% (15-hydroxystearic acid polyethylene glycol ester) HS15, with the pH adjusted to 2.0.

[0505] Blood collection time points: 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 24h, 48h; blood is collected via the jugular vein or other suitable vein, with approximately 1mL collected per sample. K2-EDTA is used for anticoagulation, and the samples are placed on ice after collection.

[0506] Plasma sample processing: After blood sample collection, place on ice and centrifuge to separate plasma within 0.5 hours (centrifugation conditions: 2200g, 10 minutes, 2-8℃). Plasma samples should be stored at -80℃ before analysis. Intra-day accuracy evaluation of quality control samples should be performed simultaneously with sample analysis, requiring that over 66.7% of the quality control samples maintain an accuracy between 80-120%.

[0507] Results Analysis: Pharmacokinetic parameters were calculated using Phoenix WinNonlin 7.0 based on blood drug concentration data at different time points, providing AUC. 0-t MRT 0-t C max T max and T 1 / 2 Parameters such as these.

[0508] The pharmacokinetic parameters of the canines are shown in Tables 29 and 30. The comparison shows that the monomaleate crystal form A of compound I has a longer elimination half-life and a higher in vivo exposure.

[0509] Table 29

[0510] Table 30

[0511] Example 42: In vivo efficacy study

[0512] 1.1 Experimental Methods and Procedures

[0513] Human non-small cell lung cancer (LD1-0025-200717) xenografts (the tumor tissue was obtained from a biopsy of a male lung cancer patient and subsequently used to establish an animal model in mice; the passage number used in this experiment was P10; the mutation information was: EGFR 19del EGFR T790 MEGFR C797S) were cut into tumor tissues approximately 3mm × 3mm × 3mm in size (approximately 45–60 mg) and subcutaneously inoculated into the right back of NU / NU mice. The mice were observed after inoculation, and tumor growth was monitored. On day 20 after inoculation, the average tumor volume of the tumor-bearing mice was 111.41 mm². 3 Dosing was administered in groups, with the day of group dosing defined as day 0 (due to the presence of other compounds, the hydrochloride of compound I was numbered group 8, and the monomaleate crystal form A of compound I was numbered group 9), as detailed in Table 31 below:

[0514] Table 31. Dosage and Grouping Note: N: Number of animals; PO: Gavage administration. Q2D: Administer once every two days; BIW: Administer twice a week; Administration volume: Adjust administration volume according to tumor-bearing rat weight (0.2ml / 20g).

[0515] 1.2 Solvents and preparation of the test drug

[0516] Table 32. Preparation of test drugs

[0517] *All compound dosages are based on free base.

[0518] 1.3 Experimental Observation

[0519] Throughout the experiment, the use and observation of laboratory animals were conducted in accordance with the relevant regulations for the use and management of animals by AAALAC. After inoculation with tumor tissue, the laboratory animals were observed daily, and their morbidity and mortality were recorded. In accordance with standard experimental procedures, all laboratory animals were monitored and recorded for behavior, food and water intake, weight changes, coat luster, and other abnormalities.

[0520] 1.4 Evaluation Indicators

[0521] The main purpose is to test the growth-inhibiting effect or complete cure capability of the drug on the human non-small cell lung cancer xenograft model LD1-0025-200717.

[0522] Tumor volume and weight of tumor-bearing mice were measured twice a week using vernier calipers. The tumor volume was calculated using the formula V = 0.5a × b. 2 a and b represent the long and wide diameters of the tumor, respectively;

[0523] The relative tumor volume (RTV) is calculated based on the tumor measurement results. The formula is: RTV = V t / V o Where V0 is the dose distribution in groups (i.e., d) o The average tumor volume obtained by measurement, V t T represents the average tumor volume at a given measurement. RTV With C RTV Take data from the same day.

[0524] Tumor growth inhibition rate TGI (%) = [1-(T i -T o ) / (V i -V o )]×100, T i T represents the average tumor volume after the start of drug administration for the compound group. o V represents the average tumor volume at the first administration of the compound group. o V represents the average tumor volume at the first administration in the solvent control group. i The mean tumor volume after the start of drug administration in the solvent control group.

[0525] All data are expressed as mean ± SEM, where SEM = SD / SQRT(n), and n = number of animals in the experimental group. One-way ANOVA was used to compare tumor volume differences between the treatment and control groups. All data were analyzed using Graphpad, and p < 0.05 was considered statistically significant.

[0526] 1.5 Experimental Results

[0527] The purpose of this experiment was to establish a xenograft animal model of human non-small cell lung cancer (NSCLC) by subcutaneously inoculating NU / NU mice with LD1-0025-200717, and to evaluate the antitumor efficacy of the test drug, compound I hydrochloride and compound I monomaleate crystal form A, in this tumor model. Changes in tumor volume, tumor weight, and animal body weight in the control and treatment groups are shown in Figures 83, 84, 85, and Table 33.

[0528] Table 33 Summary of the antitumor efficacy evaluation of the test drug in a human non-small cell lung cancer subcutaneous xenograft model (LD1-0025-200717).

[0529] The experiment lasted for 28 days, and no abnormalities were observed in the animals. Their weight fluctuated within the normal range and maintained a trend of weight gain, indicating that the hydrochloride of compound I and maleate crystal form A exhibited good safety at this dose.

[0530] After 28 days of drug administration, the average tumor volume in the control group of tumor-bearing mice was 1212.11 ± 229.31 mm. 3 The mean tumor volume of the tumor-bearing mice in the BIW group (80 mg / kg of compound I hydrochloride) and the BIW group (80 mg / kg of monomaleate A) were 486.53 ± 114.56 mm, respectively. 3 320.73±49.78mm 3 The relative tumor volume T / C (%) were 34.07% and 19.01%, respectively; the tumor volume growth inhibition rate (TGI) (%) were 65.93% and 80.99%, respectively. The experimental results showed that both groups of compounds exhibited statistically significant inhibitory effects on tumor growth compared with the control group (p<0.05).

[0531] On the last day of the experiment, all tumor-bearing mice were euthanized, and the subcutaneous tumor grafts were removed and weighed. The average tumor weights in the control group, the 80 mg / kg BIW group of compound I hydrochloride, and the 80 mg / kg BIW group of compound I monomaleate crystal form A were 1.281±0.224 g, 0.449±0.123 g, and 0.305±0.093 g, respectively. The tumor weights in all treatment groups showed statistically significant inhibitory effects on tumor growth (p<0.05). Comparing tumor volume and weight, at the same dose and frequency, the tumor-inhibiting effect of compound I monomaleate crystal form A was superior to that of its hydrochloride form.

Claims

1. A monomaleate crystal form A of a compound as shown in Formula I, characterized in that, Using Cu-Kα radiation, its X-ray powder diffraction has characteristic peaks at diffraction angles 2θ of 6.9°±0.2°, 11.0°±0.2°, 16.0°±0.2° and 23.9°±0.2°; 2. The monomaleate salt Form A of the compound of Formula I according to claim 1, characterized in that, It satisfies one or two of the following conditions: (1) The X-ray powder diffraction of the monomaleate crystal form A of the compound shown in Formula I also shows characteristic peaks at one or more locations with diffraction angles 2θ of 9.2°±0.2°, 13.7°±0.2°, 19.4°±0.2°, 20.4°±0.2° and 21.3°±0.2°; and (2) The monomaleate crystal form A of the compound shown in Formula I is the monomaleate monohydrate crystal form A of the compound shown in Formula I.

3. The monomaleate salt Form A of the compound of Formula I according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) The X-ray powder diffraction of the monomaleate crystal form A of the compound shown in Formula I also shows characteristic peaks at one or more locations with diffraction angles 2θ of 14.7°±0.2°, 17.4°±0.2°, 18.1°±0.2°, 22.3°±0.2°, 25.5°±0.2° and 29.6°±0.2°; preferably, The X-ray powder diffraction of the monomaleate crystal form A of the compound shown in Formula I exhibits characteristic peaks at diffraction angles 2θ of 6.9°±0.2°, 9.2°±0.2°, 11.0°±0.2°, 13.7°±0.2°, 14.7°±0.2°, 16.0°±0.2°, 17.4°±0.2°, 18.1°±0.2°, 19.4°±0.2°, 20.4°±0.2°, 21.3°±0.2°, 22.3°±0.2°, 23.9°±0.2°, 25.5°±0.2°, and 29.6°±0.2°. (2) The monomaleate crystal form A of the compound shown in Formula I, when heated to 60±5℃, exhibits a weight loss of 0.2%-1.2%, for example 0.7%, during thermogravimetric analysis; and a weight loss of 1.5%-2.5%, for example 1.9%, when heated to 100±5℃; and (3) The monomaleate crystal form A of the compound shown in Formula I has an endothermic signal when heated to 122±5°C, for example, 122°C, during differential scanning calorimetry analysis; and / or an endothermic signal when heated to 200±5°C, for example, 200°C.

4. The monomaleate crystal form A of the compound as shown in Formula I according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) The X-ray powder diffraction pattern of monomaleate crystal form A of the compound shown in Formula I is basically as shown in Figure 1. (2) The liquid-state 1H NMR spectrum of the monomaleate crystal form A of the compound shown in Formula I is basically as shown in Figure 2. (3) The thermogravimetric analysis (TGA) diagram of monomaleate crystal form A of the compound shown in Formula I is essentially as shown in Figure 3; and (4) The monomaleate crystal form A of the compound shown in Formula I is basically as shown in Figure 4 by differential scanning calorimetry (DSC).

5. The monomaleate crystal form A of the compound of formula I according to any one of claims 1-4, characterized in that, The monomaleate crystal form A of the compound shown in Formula I belongs to the monoclinic crystal system, space group P21, and its unit cell parameters are: α=90°,β=94.4460°,γ=90°, Preferably, the single crystal of monomaleate form A of the compound shown in Formula I satisfies one or more of the following conditions: (1) The single crystal of monomaleate crystal form A of the compound shown in Formula I is a monohydrate. (2) The X-ray powder diffraction pattern of a single crystal of monomaleate form A of the compound shown in Formula I is basically as shown in Figure 79. (3) The schematic diagram of the asymmetric unit of the single crystal structure model of the monomaleate crystal form A of the compound shown in Formula I is basically as shown in Figure 80. and (4) The schematic diagram of the molecular packing structure in the single crystal structure model of the monomaleate crystal form A of the compound shown in Formula I is basically as shown in Figure 81.

6. The monomaleate crystal form A of the compound as shown in Formula I according to claim 5, characterized in that, The method for preparing its single crystal includes the following steps: dissolving the solid monomaleate of the compound shown in Formula I in an amide solvent, and then allowing it to stand in an ester solvent for crystallization to obtain a single crystal of the monomaleate of the compound shown in Formula I, crystal form A; the amide solvent may be N,N-dimethylformamide; the ester solvent may be methyl acetate.

7. A method for preparing monomaleate crystal form A of the compound of formula I as described in any one of claims 1-4, characterized in that, It includes method a or method b: Method a, comprising the following steps: at room temperature, crystallizing the free base of the compound shown in Formula I with maleic acid in a solvent to obtain maleate crystal form A of the compound shown in Formula I; wherein the solvent is a ketone solvent, an alcohol solvent, or an ester solvent; Method b includes the following steps: at room temperature, dissolving the monomaleate of the compound shown in Formula I in a positive solvent, and then crystallizing after adding an antisolvent to obtain the monomaleate crystal form A of the compound shown in Formula I; the positive solvent is a pyrrolidone solvent or a sulfoxide solvent, and the antisolvent is water, an alcohol solvent or an ester solvent.

8. The method for preparing monomaleate crystal form A of the compound as shown in Formula I according to claim 7, characterized in that, It satisfies one or more of the following conditions: (1) In method a, the ketone solvent is acetone; the alcohol solvent is isopropanol; and the ester solvent is ethyl acetate; (2) In method a, the crystallization is carried out by suspension stirring; (3) In method a, the molar ratio of the free base of the compound shown in formula I to maleic acid is 1:(1-1.2); preferably 1:1; (4) In method a, the mass-to-volume ratio of the free base to the solvent of the compound shown in Formula I is (20-60) mg / mL; preferably 30 mg / mL, 40 mg / mL or 50 mg / mL. (5) In method a, the crystallization time is 2.5-3.5 days, preferably 3 days; (6) In method a, the room temperature is 20℃-30℃, preferably 25℃; (7) In method b, the pyrrolidone solvent is N-methylpyrrolidone; (8) In method b, the sulfoxide solvent is dimethyl sulfoxide; (9) In method b, the ester solvent is isopropyl acetate or ethyl acetate; the alcohol solvent is isopropanol; and (10) In method b, the mass-to-volume ratio of the monomaleate of the compound shown in Formula I to the positive solvent is (20-60) mg / mL; preferably 30 mg / mL or 50 mg / mL; (11) In method b, the mass-to-volume ratio of the monomaleate of the compound shown in Formula I to the antisolvent is (2-80) mg / mL; preferably 6.7 mg / mL, 3.4 mg / mL, 74.5 mg / mL, or 3.3 mg / mL; (12) In method b, the volume ratio of the positive solvent to the negative solvent is 1:(0.5-18)mg / mL; preferably 1:4.4, 1:9, 1:0.67 or 1:

15.

9. A pharmaceutical composition, characterized by, The pharmaceutical composition comprises: (1) A single crystal of monomaleate form A of the compound of formula I as described in any one of claims 1-4, or a single crystal of monomaleate form A of the compound of formula I as described in claim 5; and (2) Pharmaceutically acceptable excipients.

10. Use of a pharmaceutical composition as claimed in claim 9, a monomaleate crystal form A of a compound of formula I as claimed in any one of claims 1-4, or a single crystal of a monomaleate crystal form A of a compound of formula I as claimed in claim 5; characterized in that, The uses are selected from: (1) Prepare a protein inhibitor or degrader, wherein the protein in the protein inhibitor or degrader is selected from at least one of EGFR (epidermal growth factor receptor), ROSI (c-ros sarcoma oncogenic factor-receptor tyrosine kinase) or ALK (anaplastic lymphoma kinase). (2) To prepare drugs for the treatment or prevention of cancer; Preferably, the cancer is selected from lung cancer; lymphoma; inflammatory myofibroblastic tumor; colorectal cancer; glioma; astroblastoma; ovarian cancer; bone marrow cancer; transplant-related cancer; neutropenia; leukemia; Unwerricht syndrome; bronchial cancer; prostate cancer; breast cancer; thyroid cancer; pancreatic cancer; neuroblastoma; extramedullary plasmacytoma; plasmacytoma; gastric cancer; gastrointestinal stromal tumor; esophageal cancer; colorectal adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; melanoma; brain cancer; oral cancer; sarcoma; tumors resistant to targeted drugs; or tumors or diseases dependent on ALK, ROS1, or EGFR or any mutant protein thereof; preferably lung cancer; for example, non-small cell lung cancer.

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