Salt crystal form of plinabulin

Abstract

The present invention provides a salt crystal form of plinabulin. Specifically, the present invention provides a salt crystal form of a compound as represented by formula I. The salt crystal form of the present invention has excellent solubility, hygroscopicity and pharmacokinetic properties.

Description

Plinabulin salt crystal form Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, in particular to a crystalline form of Plinabulin salt, and a preparation method and application thereof. Background Art

[0002] Plinabulin ((3Z,6Z)-3-[(5-tert-butyl-1H-imidazol-4-yl)methylene]-6-(benzylidene)-2,5-piperazinedione) is a synthetic analog of the diketopiperazine phenylahistin (phenyltrimethylammonium chloride) found in marine and terrestrial Aspergillus species. Its structure is shown below:

[0003] Plinabulin is structurally distinct from colchicine and its combretastatin-like analogs (e.g., combretastatin phosphate) and binds at or near the colchicine binding site on tubulin monomers. Previous studies have shown that Plinabulin at low concentrations induces vascular endothelial cell tubulin depolymerization and monolayer permeability compared to colchicine, and have been shown to induce apoptosis in Jurkat leukemia cells. Studies of Plinabulin as a single agent in patients with advanced malignancies (lung, prostate, and colon cancer) have demonstrated favorable pharmacokinetic, pharmacodynamic, and safety profiles.

[0004] However, there is still a need to provide a crystalline form of Plinabulin salt with appropriate physicochemical properties to improve its solubility in solvents. Summary of the Invention

[0005] The object of the present invention is to provide a crystalline form of Plinabulin salt, which has excellent solubility and hygroscopicity and a simple preparation process, thereby facilitating the industrial production of Plinabulin.

[0006] In the first aspect of the present invention, a crystalline salt of a compound of formula I is provided.

[0007] Wherein, the salt crystal form is selected from the following group: oxalate crystal form, maleate crystal form, fumarate crystal form, succinate crystal form, D-tartrate crystal form, L-tartrate crystal form, D-malate crystal form, L-malate crystal form, L-glutamate crystal form, citrate crystal form, benzoate crystal form, salicylate crystal form, methanesulfonate crystal form, ethanesulfonate crystal form, benzenesulfonate crystal form, p-toluenesulfonate crystal form, acetate crystal form, trifluoroacetate crystal form, propionate crystal form, hydrochloride crystal form, hydrobromide crystal form, sulfate crystal form, phosphate crystal form, and nitrate crystal form.

[0008] In another preferred embodiment, the oxalate crystalline form is oxalate crystalline form Form 1, wherein the X-ray powder diffraction pattern of the crystalline form Form 1 includes 3 or more (e.g., 4 or 5) 2θ values ​​selected from the following group: 10.3±0.2, 12.5±0.2, 23.9±0.2, 25.4±0.2, and 29.0±0.2.

[0009] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 1 includes 5 or more (e.g., 6, 7, 8, 9) 2θ values ​​selected from the following group: 5.2±0.2, 10.3±0.2, 12.5±0.2, 16.1±0.2, 18.3±0.2, 19.4±0.2, 22.7±0.2, 23.1±0.2, 23.9±0.2, 25.4±0.2, 25.8±0.2, 29.0±0.2.

[0010] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 1 includes 10 or more (e.g., 12, 14, 15, 16, 18) 2θ values ​​selected from the following group: 5.2±0.2, 8.4±0.2, 10.3±0.2, 12.5±0.2, 14.2±0.2, 14.6±0.2, 15.3±0.2, 16.1±0.2, 17.2±0.2, 18.3±0.2, 19.1±0.2, 19.4±0.2, 22.7±0.2, 23.1±0.2, 23.5±0.2, 23.9±0.2, 25.4±0.2, 25.8±0.2, and 29.0±0.2.

[0011] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 1 includes the following 2θ values: 3.9±0.2, 5.2±0.2, 7.7±0.2, 8.4±0.2, 10.3±0.2, 12.5±0.2, 14.2±0.2, 14.6±0.2, 15.3±0.2, 16.1±0.2, 17.2±0.2, 18.3±0.2, 18.8±0.2, 1 9.1±0.2, 19.4±0.2, 21.5±0.2, 22.7±0.2, 23.1±0.2, 23.5±0.2, 23.9±0.2, 25.0±0.2, 25.4±0.2, 25.8±0.2, 26.5±0.2, 28.0±0.2, 29.0±0.2, 29.9±0.2, 37.0±0.2.

[0012] In another preferred embodiment, the crystal form Form 1 has an X-ray powder diffraction pattern substantially as shown in FIG2 .

[0013] In another preferred embodiment, the crystal form Form 1 has an NMR spectrum substantially as shown in FIG1 .

[0014] In another preferred embodiment, the crystal form Form 1 has a thermogravimetric curve substantially as shown in FIG3 .

[0015] In another preferred embodiment, the crystal form Form 1 gradually loses weight from the beginning of heating, with the end temperature being between 210-240°C (e.g., 230°C); the second stage always starts at a temperature between 260-300°C (e.g., 290°C) until it is completely decomposed.

[0016] In another preferred embodiment, the molar ratio of the compound of formula I to oxalic acid in the crystalline form Form 1 is 0.8-1.5:0.8-1.5, for example, 1:1, 1:1.2, 1:1.4, 1:1.5.

[0017] In another preferred embodiment, the maleate crystalline form is maleate crystalline form Form 2, wherein the X-ray powder diffraction pattern of the crystalline form Form 2 includes 3 or more (e.g., 4) 2θ values ​​selected from the following group: 6.7±0.2, 16.5±0.2, 22.3±0.2, and 25.4±0.2.

[0018] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 2 includes 5 or more (e.g., 6, 7, 8, 9) 2θ values ​​selected from the following group: 6.7±0.2, 16.5±0.2, 18.5±0.2, 19.4±0.2, 19.8±0.2, 20.1±0.2, and 29.4±0.2.

[0019] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 2 includes 10 or more (e.g., 12, 14, 15, 16, 17) 2θ values ​​selected from the following group: 6.7±0.2, 12.5±0.2, 16.0±0.2, 16.5±0.2, 18.5±0.2, 19.4±0.2, 19.8±0.2, 20.1±0.2, 22.3±0.2, 22.7±0.2, 23.5±0.2, 24.8±0.2, 25.4±0.2, 28.5±0.2, 29.4±0.2, and 30.6±0.2.

[0020] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 2 includes the following 2θ values: 6.7±0.2, 12.5±0.2, 13.4±0.2, 14.6±0.2, 15.0±0.2, 15.6±0.2, 16.0±0.2, 16.5±0.2, 17.8±0.2, 18.5±0.2, 19.4±0.2, 19.8±0.2, 20.1±0.2, 21.6±0.2, 22.3±0.2, 22.7±0.2, 23.5±0.2, 24.8±0.2, 25.4±0.2, 26.0±0.2, 26.8±0.2, 28.5±0.2, 29.4±0.2, and 30.6±0.2.

[0021] In another preferred embodiment, the crystal form Form 2 has an X-ray powder diffraction pattern substantially as shown in FIG5 .

[0022] In another preferred embodiment, the crystal form Form 2 has an NMR spectrum substantially as shown in FIG4 .

[0023] In another preferred embodiment, the crystal form Form 2 has a thermogravimetric curve substantially as shown in FIG6 .

[0024] In another preferred embodiment, the thermogravimetric test of the crystal form Form 2 includes two weight loss processes, the starting temperature of the first stage is between 160-220°C (e.g., 200°C), and the ending temperature is between 230-260°C (e.g., 250°C); the starting temperature of the second stage is between 270-300°C (e.g., 280°C), until the final complete decomposition.

[0025] In another preferred embodiment, the molar ratio of the compound of formula I to maleic acid in the crystalline form Form 2 is 0.8-1.2:0.8-1.2, for example 1:1.

[0026] In another preferred embodiment, the fumarate crystalline form is fumarate crystalline form Form 3, wherein the X-ray powder diffraction pattern of the crystalline form Form 3 includes 3 or more (e.g., 4 or 5) 2θ values ​​selected from the following group: 6.6±0.2, 16.4±0.2, 20.0±0.2, 22.2±0.2, and 25.3±0.2.

[0027] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 3 includes 5 or more (e.g., 6, 7, 8, 9, 10) 2θ values ​​selected from the following group: 6.6±0.2, 12.4±0.2, 15.9±0.2, 16.4±0.2, 18.5±0.2, 19.7±0.2, 20.0±0.2, 22.2±0.2, 23.4±0.2, 24.8±0.2, 25.3±0.2, 28.5±0.2, 29.4±0.2.

[0028] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 3 includes 10 or more (e.g., 12, 14, 15, 16) 2θ values ​​selected from the following group: 6.6±0.2, 12.4±0.2, 15.9±0.2, 16.4±0.2, 18.5±0.2, 19.4±0.2, 19.7±0.2, 20.0±0.2, 22.2±0.2, 22.6±0.2, 23.4±0.2, 24.8±0.2, 25.3±0.2, 28.5±0.2, 29.4±0.2, and 30.5±0.2.

[0029] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 3 includes the following 2θ values: 6.6±0.2, 9.8±0.2, 11.2±0.2, 12.4±0.2, 13.3±0.2, 14.6±0.2, 14.9±0.2, 15.6±0.2, 15.9±0.2, 16.4±0.2, 17.8±0.2, 18.5±0.2, 19.4±0.2, 19.7±0.2, 20.0±0.2, 22.2±0.2, 22.6±0.2, 23.4±0.2, 24.8±0.2, 25.3±0.2, 25.9±0.2, 26.8±0.2, 28.5±0.2, 29.4±0.2, 30.5±0.2, 33.3±0.2.

[0030] In another preferred embodiment, the crystal form Form 3 has an X-ray powder diffraction pattern substantially as shown in FIG8 .

[0031] In another preferred embodiment, the crystal form Form 3 has an NMR spectrum substantially as shown in FIG7 .

[0032] In another preferred embodiment, the crystal form Form 3 has a thermogravimetric curve substantially as shown in FIG9 .

[0033] In another preferred embodiment, the thermogravimetric test of the crystal form Form 3 includes two weight loss processes, the starting temperature of the first stage is between 110-150°C (for example, 130°C), and the ending temperature is between 240-270°C (for example, 260°C); the starting temperature of the second stage is between 270-300°C (for example, 280°C), until the final complete decomposition.

[0034] In another preferred embodiment, the molar ratio of the compound of formula I to fumaric acid in the crystalline form Form 3 is 0.8-1.2:0.8-1.2, for example 1:1.

[0035] In another preferred embodiment, the succinate salt crystal form is succinate salt crystal form Form 4, wherein the X-ray powder diffraction pattern of the crystal form Form 4 includes 3 or more (e.g., 4 or 5) 2θ values ​​selected from the following group: 8.2±0.2, 13.1±0.2, 20.1±0.2, 26.2±0.2, and 31.6±0.2.

[0036] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 4 includes 5 or more (e.g., 6, 7, 8, 9, 10) 2θ values ​​selected from the following group: 8.2±0.2, 13.1±0.2, 20.1±0.2, 23.9±0.2, 24.3±0.2, 26.2±0.2, 26.6±0.2, 29.4±0.2, 31.6±0.2.

[0037] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 4 includes 10 or more 2θ values ​​(e.g., 11, 12, 13, 14, 15) selected from the following group: 8.2±0.2, 13.1±0.2, 16.3±0.2, 17.7±0.2, 19.2±0.2, 20.1±0.2, 22.9±0.2, 23.9±0.2, 24.3±0.2, 24.6±0.2, 25.4±0.2, 26.2±0.2, 26.6±0.2, 29.4±0.2, 31.6±0.2.

[0038] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 4 includes the following 2θ values: 8.2±0.2, 13.1±0.2, 14.8±0.2, 16.1±0.2, 16.3±0.2, 17.7±0.2, 19.2±0.2, 20.1±0.2, 22.4±0.2, 22.9±0.2, 23.9±0.2, 24.3±0.2, 24.6±0.2, 25.4±0.2, 26.2±0.2, 26.6±0.2, 29.4±0.2, and 31.6±0.2.

[0039] In another preferred embodiment, the crystal form Form 4 has an X-ray powder diffraction pattern substantially as shown in FIG11 .

[0040] In another preferred embodiment, the crystal form Form 4 has an NMR spectrum substantially as shown in FIG10 .

[0041] In another preferred embodiment, the molar ratio of the compound of formula I to succinic acid in the crystalline form Form 4 is 0.8-1.2:0.8-1.2, for example 1:1.

[0042] In another preferred embodiment, the D-tartrate crystalline form is D-tartrate crystalline form Form 5, wherein the X-ray powder diffraction pattern of the crystalline form Form 5 includes 3 or more (e.g., 4, 5) 2θ values ​​selected from the following group: 7.0±0.2, 18.5±0.2, 22.2±0.2, 25.07±0.2, and 26.0±0.2.

[0043] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 5 includes 5 or more (e.g., 6, 7, 8, 9, 10) 2θ values ​​selected from the following group: 7.0±0.2, 9.1±0.2, 12.9±0.2, 17.6±0.2, 18.1±0.2, 18.5±0.2, 20.1±0.2, 22.2±0.2, 25.07±0.2, 26.0±0.2.

[0044] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 5 includes 10 or more (e.g., 11, 12, 13, 14, 15) 2θ values ​​selected from the following group: 7.0±0.2, 9.1±0.2, 11.8±0.2, 12.3±0.2, 12.9±0.2, 17.3±0.2, 17.6±0.2, 18.1±0.2, 18.5±0.2, 20.1±0.2, 22.2±0.2, 25.07±0.2, 26.0±0.2, 27.9±0.2.

[0045] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 5 includes the following 2θ values: 7.0±0.2, 9.1±0.2, 11.8±0.2, 12.3±0.2, 12.9±0.2, 17.3±0.2, 17.6±0.2, 18.1±0.2, 18.5±0.2, 20.1±0.2, 20.7±0.2, 21.07±0.2, 22.2±0.2, 25.07±0.2, 26.0±0.2, 27.9±0.2, and 28.7±0.2.

[0046] In another preferred embodiment, the crystal form Form 5 has an X-ray powder diffraction pattern substantially as shown in FIG13 .

[0047] In another preferred embodiment, the crystal form Form 5 has an NMR spectrum substantially as shown in FIG12 .

[0048] In another preferred embodiment, the molar ratio of the compound of formula I to D-tartaric acid in the crystalline form Form 5 is 0.8-1.2:0.8-1.2, for example 1:1.

[0049] In another preferred embodiment, the L-tartrate crystalline form is L-tartrate crystalline form Form 6, wherein the X-ray powder diffraction pattern of the crystalline form Form 6 includes 3 or more (e.g., 4 or 5) 2θ values ​​selected from the following group: 8.2±0.2, 13.1±0.2, 23.8±0.2, 24.2±0.2, and 26.6±0.2.

[0050] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 6 includes 5 or more (e.g., 6, 7, 8, 9, 10) 2θ values ​​selected from the following group: 8.2±0.2, 13.1±0.2, 16.1±0.2, 19.2±0.2, 22.9±0.2, 23.8±0.2, 24.2±0.2, 25.4±0.2, 26.6±0.2, 29.3±0.2.

[0051] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 6 includes 10 or more (e.g., 12, 14, 16, 18, 20) 2θ values ​​selected from the following group: 8.2±0.2, 13.1±0.2, 14.8±0.2, 15.5±0.2, 16.1±0.2, 16.3±0.2, 17.6±0.2, 19.2±0.2, 19.4±0.2, 22.4±0.2, 22.9±0.2, 23.8±0.2, 24.2±0.2, 24.5±0.2, 25.4±0.2, 26.6±0.2, 27.5±0.2, 29.3±0.2, 31.8±0.2, and 33.0±0.2.

[0052] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 6 includes the following 2θ values: 8.2±0.2, 8.6±0.2, 9.2±0.2, 11.2±0.2, 13.1±0.2, 13.9±0.2, 14.1±0.2, 14.8±0.2, 15.5±0.2, 16.1±0.2, 16.3±0.2, 17.6±0.2, 18.5±0.2, 19.2±0.2, 19.4±0.2, 19.8±0.2, 20.9±0.2, 21.2±0.2, 22.4±0.2, 23. 0.2, 2.9±0.2, 23.4±0.2, 23.8±0.2, 24.2±0.2, 24.5±0.2, 25.4±0.2, 25.8±0.2, 26.6±0.2, 27.2±0.2, 27.5±0.2, 27.9±0.2, 28.3±0.2, 28.9±0.2, 29.3±0.2, 29.9±0.2, 31.3±0.2, 31.8±0.2, 32.4±0.2, 33.0±0.2, 35.7±0.2, and 38.6±0.2.

[0053] In another preferred embodiment, the crystal form Form 6 has an X-ray powder diffraction pattern substantially as shown in FIG15 .

[0054] In another preferred embodiment, the crystal form Form 6 has an NMR spectrum substantially as shown in FIG14 .

[0055] In another preferred embodiment, the molar ratio of the compound of formula I to L-tartaric acid in the crystalline form Form 6 is 0.8-1.2:0.8-1.2, for example 1:1.

[0056] In another preferred embodiment, the D-malate crystalline form is D-malate crystalline form Form 7, wherein the X-ray powder diffraction pattern of the crystalline form Form 7 includes 3 or more (e.g., 4) 2θ values ​​selected from the following group: 8.1±0.2, 23.8±0.2, 24.2±0.2, and 24.4±0.2.

[0057] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 7 includes 5 or more (e.g., 6, 7, 8, 9) 2θ values ​​selected from the following group: 8.1±0.2, 13.0±0.2, 16.2±0.2, 22.8±0.2, 23.8±0.2, 24.2±0.2, 24.4±0.2, 26.5±0.2, 29.3±0.2.

[0058] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 7 includes 10 or more (e.g., 12, 14, 15, 16, 17) 2θ values ​​selected from the following group: 8.1±0.2, 13.0±0.2, 16.0±0.2, 16.2±0.2, 17.6±0.2, 19.1±0.2, 19.7±0.2, 20.8±0.2, 22.4±0.2, 22.8±0.2, 23.8±0.2, 24.2±0.2, 24.4±0.2, 25.3±0.2, 26.5±0.2, 29.3±0.2.

[0059] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 7 includes the following 2θ values: 8.1±0.2, 9.2±0.2, 11.1±0.2, 13.0±0.2, 13.9±0.2, 14.1±0.2, 14.8±0.2, 15.4±0.2, 16.0±0.2, 16.2±0.2, 17.6±0.2, 18.4±0.2, 19.1±0.2, 197±0.2, 20.8±0.2, 21.2±0.2, 22.4±0.2, 22.8±0.2, 23.4± 0.2, 23.8±0.2, 24.2±0.2, 24.4±0.2, 25.3±0.2, 25.7±0.2, 26.5±0.2, 27.1±0.2, 27.4±0.2, 27.9±0.2, 28.3±0.2, 28.9±0.2, 29.3±0.2, 30.6±0.2, 31.2±0.2, 31.7±0.2, 32.4±0.2, 32.9±0.2, 35.7±0.2, 38.5±0.2, and 38.8±0.2.

[0060] In another preferred embodiment, the crystal form Form 7 has an X-ray powder diffraction pattern substantially as shown in FIG17 .

[0061] In another preferred embodiment, the crystal form Form 7 has an NMR spectrum substantially as shown in FIG16 .

[0062] In another preferred embodiment, the molar ratio of the compound of formula I to D-malic acid in the crystalline form Form 7 is 0.8-1.2:0.8-1.2, for example, 1:1, 1:1.1, or 1:1.2.

[0063] In another preferred embodiment, the L-malate crystalline form is L-malate crystalline form Form 8, wherein the X-ray powder diffraction pattern of the crystalline form Form 8 includes 3 or more (e.g., 4 or 5) 2θ values ​​selected from the following group: 10.2±0.2, 20.0±0.2, 20.6±0.2, 33.7±0.2, and 35.7±0.2.

[0064] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 8 includes 5 or more (e.g., 6, 7, 8, 9, 10) 2θ values ​​selected from the following group: 10.2±0.2, 20.0±0.2, 20.6±0.2, 21.5±0.2, 22.1±0.2, 24.3±0.2, 26.2±0.2, 28.9±0.2, 33.7±0.2, 35.7±0.2.

[0065] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 8 includes 10 or more (e.g., 12, 13, 14, 15, 16) 2θ values ​​selected from the following group: 10.2±0.2, 20.0±0.2, 20.6±0.2, 21.5±0.2, 22.1±0.2, 23.8±0.2, 24.3±0.2, 25.7±0.2, 26.2±0.2, 28.9±0.2, 30.1±0.2, 31.1±0.2, 33.1±0.2, 33.7±0.2, 35.7±0.2, 38.0±0.2.

[0066] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 8 includes the following 2θ values: 10.2±0.2, 13.8±0.2, 20.0±0.2, 20.6±0.2, 21.5±0.2, 22.1±0.2, 23.2±0.2, 23.8±0.2, 24.3±0.2, 25.7±0.2, 26.2±0.2, 27.7±0.2, 28.9±0.2, 30.1±0.2, 31.1±0.2, 33.1±0.2, 33.7±0.2, 35.7±0.2, 38.0±0.2, and 38.7±0.2.

[0067] In another preferred embodiment, the crystal form Form 8 has an X-ray powder diffraction pattern substantially as shown in FIG19 .

[0068] In another preferred embodiment, the crystal form Form 8 has an NMR spectrum substantially as shown in FIG18 .

[0069] In another preferred embodiment, the molar ratio of the compound of formula I to L-malic acid in the crystalline form Form 8 is 0.8-1.2:0.8-1.2, for example, 1:1, 1:1.1.

[0070] In another preferred embodiment, the L-glutamate crystalline form is L-glutamate crystalline form Form 9, wherein the X-ray powder diffraction pattern of the crystalline form Form 9 includes 3 or more (e.g., 4 or 5) 2θ values ​​selected from the following group: 7.3±0.2, 17.2±0.2, 19.8±0.2, 22.5±0.2, and 23.1±0.2.

[0071] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 9 includes 5 or more (e.g., 6, 7, 8, 9, 10, 11) 2θ values ​​selected from the following group: 7.3±0.2, 11.2±0.2, 14.7±0.2, 17.2±0.2, 17.5±0.2, 19.8±0.2, 20.6±0.2, 22.5±0.2, 23.1±0.2, 23.8±0.2, 27.5±0.2.

[0072] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 9 includes 10 or more (e.g., 12, 14, 15, 16, 18) 2θ values ​​selected from the following group: 7.3±0.2, 11.2±0.2, 14.7±0.2, 15.4±0.2, 17.2±0.2, 17.5±0.2, 18.1±0.2, 19.8±0.2, 20.6±0.2, 22.1±0.2, 22.5±0.2, 23.1±0.2, 23.8±0.2, 24.9±0.2, 26.4±0.2, 27.5±0.2, 28.6±0.2, 29.2±0.2.

[0073] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 9 includes the following 2θ values: 7.3±0.2, 11.2±0.2, 14.7±0.2, 15.4±0.2, 17.2±0.2, 17.5±0.2, 18.1±0.2, 19.8±0.2, 20.6±0.2, 22.1±0.2, 22.5±0.2, 23.1±0.2, 23.8±0.2, 24.9±0.2, 26.4±0.2, 27.5±0.2, 28.6±0.2, 29.2±0.2, 30.4±0.2, and 39.2±0.2.

[0074] In another preferred embodiment, the crystal form Form 9 has an X-ray powder diffraction pattern substantially as shown in FIG. 21 .

[0075] In another preferred embodiment, the crystal form Form 9 has an NMR spectrum substantially as shown in FIG. 20 .

[0076] In another preferred embodiment, the molar ratio of the compound of formula I to L-glutamic acid in the crystalline form Form 9 is 0.8-1.2:0.8-1.2, for example, 1:1, 1:1.1.

[0077] In another preferred embodiment, the citrate salt crystalline form is citrate salt crystalline form Form 10, wherein the X-ray powder diffraction pattern of the crystalline form Form 10 includes 3 or more (e.g., 4 or 5) 2θ values ​​selected from the following group: 7.3±0.2, 17.1±0.2, 19.7±0.2, 23.1±0.2, and 23.8±0.2.

[0078] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 10 includes 5 or more (e.g., 6, 7, 8, 9, 10) 2θ values ​​selected from the following group: 7.3±0.2, 8.1±0.2, 17.1±0.2, 17.4±0.2, 19.7±0.2, 22.4±0.2, 23.1±0.2, 23.8±0.2, 27.5±0.2, 29.2±0.2.

[0079] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 10 includes 10 or more (e.g., 12, 14, 16, 18, 20) 2θ values ​​selected from the following group: 7.3±0.2, 8.1±0.2, 11.2±0.2, 13.0±0.2, 14.6±0.2, 15.4±0.2, 17.1±0.2, 17.4±0.2, 18.1±0.2, 19.2±0.2, 19.7±0.2, 20.6±0.2, 22.0±0.2, 22.4±0.2, 23.1±0.2, 23.8±0.2, 24.2±0.2, 24.8±0.2, 26.6±0.2, 27.5±0.2, and 29.2±0.2.

[0080] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 10 includes the following 2θ values: 3.5±0.2, 7.3±0.2, 8.1±0.2, 11.2±0.2, 13.0±0.2, 14.6±0.2, 15.4±0.2, 16.0±0.2, 16.3±0.2, 17.1±0.2, 17.4±0.2, 18.1±0.2, 19.2±0.2, 19.7±0.2, 20.6±0.2, 22.0±0.2, 22.4±0.2, 23.1±0.2, 23.8±0.2, 24.2±0.2, 24.4±0.2, 24.8±0.2, 25.3±0.2, 25.7±0.2, 26.3±0.2, 26.6±0.2, 27.5±0.2, 27.9±0.2, 28.6±0.2, 29.2±0.2, 30.4±0.2, 32.0±0.2, 33.0±0.2, 33.9±0.2, 34.1±0.2, 35.3±0.2, 38.6±0.2, and 39.1±0.2.

[0081] In another preferred embodiment, the crystal form Form 10 has an X-ray powder diffraction pattern substantially as shown in FIG. 23 .

[0082] In another preferred embodiment, the crystal form Form 10 has an NMR spectrum substantially as shown in FIG. 22 .

[0083] In another preferred embodiment, the molar ratio of the compound of formula I to citric acid in the crystalline form Form 10 is 0.8-1.2:0.8-1.2, for example, 1:0.9, 1:1, or 1:1.1.

[0084] In another preferred embodiment, the benzoate salt crystal form is benzoate salt crystal form 11, wherein the X-ray powder diffraction pattern of the crystal form 11 includes 3 or more (e.g., 4) 2θ values ​​selected from the following group: 7.3±0.2, 17.2±0.2, 23.1±0.2, and 23.8±0.2.

[0085] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 11 includes 5 or more (e.g., 6, 7, 8, 9) 2θ values ​​selected from the following group: 7.3±0.2, 17.2±0.2, 17.5±0.2, 19.7±0.2, 20.6±0.2, 22.4±0.2, 23.1±0.2, 23.8±0.2, and 27.5±0.2.

[0086] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 11 includes 10 or more 2θ values ​​(e.g., 12, 14, 16, 18, 19) selected from the group consisting of 7.3±0.2, 11.0±0.2, 11.2±0.2, 14.6±0.2, 15.4±0.2, 17.2±0.2, 17.5±0.2, 18.1±0.2, 19.7±0.2, 20.6±0.2, 21.4±0.2, 22.0±0.2, 22.4±0.2, 23.1±0.2, 23.8±0.2, 24.4±0.2, 24.8±0.2, 27.5±0.2, and 29.2±0.2.

[0087] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 11 includes the following 2θ values: 7.3±0.2, 8.1±0.2, 11.0±0.2, 11.2±0.2, 12.3±0.2, 14.6±0.2, 15.4±0.2, 16.4±0.2, 17.2±0.2, 17.5±0.2, 18.1±0.2, 19.7±0.2, 20.6±0.2, 21.4±0.2, 22.0±0.2, 22.4±0.2, 23.1±0.2, 23.8±0.2, 24.4±0.2, 24.8±0.2, 25.7±0.2, 26.3±0.2, 26.6±0.2, 27.5±0.2, 28.6±0.2, 29.2±0.2, 30.4±0.2, 31.0±0.2, 33.0±0.2, 33.9±0.2, 35.3±0.2, 39.2±0.2.

[0088] In another preferred embodiment, the crystal form Form 11 has an X-ray powder diffraction pattern substantially as shown in FIG. 25 .

[0089] In another preferred embodiment, the crystal form Form 11 has an NMR spectrum substantially as shown in FIG. 24 .

[0090] In another preferred embodiment, the molar ratio of the compound of formula I to benzoic acid in the crystalline form Form 11 is 0.8-1.2:0.8-1.2, for example, 1:1, 1:1.1, 1:1.2.

[0091] In another preferred embodiment, the salicylate crystalline form is salicylate crystalline form Form 12, wherein the X-ray powder diffraction pattern of the crystalline form Form 12 includes 3 or more (e.g., 4 or 5) 2θ values ​​selected from the following group: 7.3±0.2, 17.1±0.2, 19.7±0.2, 23.1±0.2, and 27.5±0.2.

[0092] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 12 includes 5 or more (e.g., 6, 7, 8, 9, 10) 2θ values ​​selected from the following group: 7.3±0.2, 17.1±0.2, 17.4±0.2, 19.7±0.2, 20.6±0.2, 22.4±0.2, 23.1±0.2, 23.8±0.2, 27.5±0.2, 29.2±0.2.

[0093] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 12 includes 10 or more 2θ values ​​(e.g., 12, 14, 15, 16, 18) selected from the following group: 7.3±0.2, 11.2±0.2, 12.3±0.2, 14.6±0.2, 15.4±0.2, 17.1±0.2, 17.4±0.2, 18.1±0.2, 19.7±0.2, 20.6±0.2, 22.0±0.2, 22.4±0.2, 23.1±0.2, 23.8±0.2, 24.8±0.2, 25.7±0.2, 27.5±0.2, and 29.2±0.2.

[0094] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 12 includes the following 2θ values: 6.2±0.2, 7.3±0.2, 11.2±0.2, 12.3±0.2, 14.6±0.2, 15.4±0.2, 16.4±0.2, 17.1±0.2, 17.4±0.2, 18.1±0.2, 19.2±0.2, 19.7±0.2, 20.6±0.2, 22.0±0.2, 22.4±0.2, 23.1±0.2, 23.8±0.2, 24.4±0.2, 24.8±0.2, 25.4±0.2, 25.7±0.2, 26.3±0.2, 26.6±0.2, 27.5±0.2, 28.5±0.2, 29.2±0.2, 30.4±0.2, 31.0±0.2, 31.5±0.2, 32.0±0.2, 33.0±0.2, 34.0±0.2, 35.3±0.2, and 39.1±0.2.

[0095] In another preferred embodiment, the crystal form Form 12 has an X-ray powder diffraction pattern substantially as shown in FIG. 27 .

[0096] In another preferred embodiment, the crystal form Form 12 has an NMR spectrum substantially as shown in FIG. 26 .

[0097] In another preferred embodiment, the molar ratio of the compound of formula I to salicylic acid in the crystalline form Form 12 is 0.8-1.2:0.8-1.2, for example, 1:0.9, 1:1, 1:1.1, 1:1.2.

[0098] In another preferred embodiment, the mesylate salt crystalline form is mesylate salt crystalline form 13, wherein the X-ray powder diffraction pattern of the crystalline form 13 includes 3 or more (e.g., 4 or 5) 2θ values ​​selected from the following group: 12.1±0.2, 15.6±0.2, 19.8±0.2, 23.0±0.2, and 26.3±0.2.

[0099] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 13 includes 6 or more (e.g., 7, 8, 10, 12) 2θ values ​​selected from the following group: 9.9±0.2, 12.1±0.2, 15.6±0.2, 16.5±0.2, 18.0±0.2, 18.9±0.2, 19.8±0.2, 20.5±0.2, 21.0±0.2, 23.0±0.2, 23.9±0.2, 24.9±0.2, and 26.3±0.2.

[0100] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 13 includes 10 or more 2θ values ​​(e.g., 12, 14, 15, 16, 18) selected from the group consisting of 9.9±0.2, 12.1±0.2, 15.6±0.2, 16.5±0.2, 18.0±0.2, 18.9±0.2, 19.8±0.2, 20.5±0.2, 21.0±0.2, 21.9±0.2, 23.0±0.2, 23.5±0.2, 23.9±0.2, 24.9±0.2, 26.3±0.2, 26.7±0.2, 27.9±0.2, 28.3±0.2, 28.8±0.2, and 31.6±0.2.

[0101] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 13 includes the following 2θ values: 9.9±0.2, 12.1±0.2, 14.2±0.2, 14.6±0.2, 15.6±0.2, 16.5±0.2, 18.0±0.2, 18.9±0.2, 19.8±0.2, 20.5±0.2, 21.0±0.2, 21.9±0.2, 23.0±0.2, 23.5±0.2, 23.9±0.2, 24.4 ±0.2, 24.9±0.2, 26.3±0.2, 26.7±0.2, 27.4±0.2, 27.9±0.2, 28.3±0.2, 28.8±0.2, 29.4±0.2, 29.9±0.2, 30.4±0.2, 31.2±0.2, 31.6±0.2, 33.5±0.2, 34.2±0.2, 35.1±0.2, 37.9±0.2, and 39.2±0.2.

[0102] In another preferred embodiment, the crystal form Form 13 has an X-ray powder diffraction pattern substantially as shown in FIG. 29 .

[0103] In another preferred embodiment, the crystal form Form 13 has an NMR spectrum substantially as shown in FIG. 28 .

[0104] In another preferred embodiment, the crystal form Form 13 has a thermogravimetric curve substantially as shown in FIG. 30 .

[0105] In another preferred embodiment, the thermogravimetric test of the crystal form Form 13 includes two weight loss processes. The first stage gradually loses weight from the beginning of heating, and the end temperature is between 150-180°C (for example, 170°C); the second stage starts at a temperature between 250-280°C (for example, 270°C) until it is completely decomposed.

[0106] In another preferred embodiment, the molar ratio of the compound of formula I to methanesulfonic acid in the crystalline form Form 13 is 1:0.8-20, for example, 1:1, 1:1.5, 1:2, 1:5, 1:10, or 1:15.

[0107] In another preferred embodiment, the ethanesulfonate crystalline form is ethanesulfonate crystalline form Form 14, wherein the X-ray powder diffraction pattern of the crystalline form Form 14 includes 3 or more (e.g., 4 or 5) 2θ values ​​selected from the following group: 5.5±0.2, 9.89±0.2, 20.9±0.2, 23.4±0.2, and 25.4±0.2.

[0108] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 14 includes 6 or more (e.g., 8, 10, 12, 13) 2θ values ​​selected from the following group: 5.5±0.2, 8.7±0.2, 9.89±0.2, 11.7±0.2, 15.1±0.2, 16.6±0.2, 17.3±0.2, 18.4±0.2, 20.9±0.2, 21.9±0.2, 23.4±0.2, 25.4±0.2, and 27.6±0.2.

[0109] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 14 includes 10 or more 2θ values ​​(e.g., 12, 14, 15, 16, 18) selected from the following group: 5.5±0.2, 8.7±0.2, 9.89±0.2, 11.7±0.2, 13.6±0.2, 14.2±0.2, 15.1±0.2, 16.0±0.2, 16.6±0.2, 17.3±0.2, 17.9±0.2, 18.4±0.2, 19.8±0.2, 20.9±0.2, 21.9±0.2, 23.4±0.2, 24.4±0.2, 25.4±0.2, and 27.6±0.2.

[0110] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 14 includes the following 2θ values: 4.2±0.2, 5.5±0.2, 7.6±0.2, 8.7±0.2, 9.89±0.2, 11.7±0.2, 13.6±0.2, 14.2±0.2, 15.1±0.2, 16.0±0.2, 16.6±0.2, 17.3±0.2, 17.9±0.2, 18.4±0.2, 19.8±0.2, 20.9±0.2, 21.9±0.2, 23.4±0.2, 24.4±0.2, 25.4±0.2, 27.6±0.2, 28.7±0.2, 30.7±0.2, and 37.2±0.2.

[0111] In another preferred embodiment, the crystal form Form 14 has an X-ray powder diffraction pattern substantially as shown in FIG32 .

[0112] In another preferred embodiment, the crystal form Form 14 has an NMR spectrum substantially as shown in FIG31 .

[0113] In another preferred embodiment, the crystal form Form 14 has a thermogravimetric curve substantially as shown in FIG. 33 .

[0114] In another preferred embodiment, the thermogravimetric test of the crystal form Form 14 includes two weight loss processes. The first stage gradually loses weight from the beginning of heating, and the end temperature is between 100-140°C (for example, 120°C); the second stage starts at a temperature between 230-270°C (for example, 250°C) until it is completely decomposed.

[0115] In another preferred embodiment, the molar ratio of the compound of formula I to ethanesulfonic acid in the crystalline form Form 14 is 1:0.8-20, for example, 1:1, 1:1.5, 1:2, 1:5, 1:10, or 1:15.

[0116] In another preferred embodiment, the benzenesulfonate crystalline form is benzenesulfonate crystalline form Form 15, wherein the X-ray powder diffraction pattern of the crystalline form Form 15 includes 3 or more (e.g., 4 or 5) 2θ values ​​selected from the following group: 5.7±0.2, 16.2±0.2, 17.4±0.2, 18.4±0.2, and 22.8±0.2.

[0117] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 15 includes 6 or more (e.g., 8, 9, 10, 12) 2θ values ​​selected from the following group: 5.7±0.2, 13.7±0.2, 14.9±0.2, 16.2±0.2, 16.6±0.2, 17.4±0.2, 18.4±0.2, 22.4±0.2, 22.8±0.2, 23.9±0.2, 24.6±0.2, 25.2±0.2.

[0118] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 15 includes 10 or more (e.g., 12, 14, 15, 16, 18) 2θ values ​​selected from the following group: 5.7±0.2, 6.8±0.2, 8.6±0.2, 10.9±0.2, 12.5±0.2, 13.7±0.2, 14.9±0.2, 16.2±0.2, 16.6±0.2, 17.4±0.2, 18.4±0.2, 19.5±0.2, 19.9±0.2, 22.4±0.2, 22.8±0.2, 23.9±0.2, 24.6±0.2, and 25.2±0.2.

[0119] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 15 includes the following 2θ values: 5.7±0.2, 6.8±0.2, 8.6±0.2, 9.0±0.2, 9.3±0.2, 10.0±0.2, 10.9±0.2, 11.5±0.2, 12.5±0.2, 13.7±0.2, 14.9±0.2, 16.2±0.2, 16.6±0.2, 17.4±0.2, 1 8.4±0.2, 19.5±0.2, 19.9±0.2, 20.6±0.2, 22.4±0.2, 22.8±0.2, 23.9±0.2, 24.6±0.2, 25.2±0.2, 26.3±0.2, 27.6±0.2, 28.8±0.2, 29.7±0.2, 30.4±0.2, 36.3±0.2, 36.7±0.2.

[0120] In another preferred embodiment, the crystal form Form 15 has an X-ray powder diffraction pattern substantially as shown in FIG. 35 .

[0121] In another preferred embodiment, the crystal form Form 15 has an NMR spectrum substantially as shown in FIG34 .

[0122] In another preferred embodiment, the crystal form Form 15 has a thermogravimetric curve substantially as shown in FIG. 36 .

[0123] In another preferred embodiment, the thermogravimetric test of the crystal form Form 15 includes two weight loss processes. The first stage gradually loses weight from the beginning of heating, and the end temperature is between 260-300°C (for example, 280°C); the second stage starts at a temperature between 260-300°C (for example, 280°C) until it is completely decomposed.

[0124] In another preferred embodiment, the molar ratio of the compound of formula I to benzenesulfonic acid in the crystalline form Form 15 is 1:0.8-5, for example, 1:0.9, 1:1, 1:1.2, 1:1.5, or 1:2.

[0125] In another preferred embodiment, the p-toluenesulfonate crystalline form is p-toluenesulfonate crystalline form Form 16, wherein the X-ray powder diffraction pattern of the crystalline form Form 16 includes 3 or more (e.g., 4 or 5) 2θ values ​​selected from the following group: 6.6±0.2, 15.1±0.2, 16.2±0.2, 21.5±0.2, and 24.5±0.2.

[0126] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 16 includes 6 or more (e.g., 7, 8, 9, 10) 2θ values ​​selected from the following group: 6.6±0.2, 8.5±0.2, 8.8±0.2, 14.3±0.2, 15.1±0.2, 16.2±0.2, 21.5±0.2, 23.6±0.2, 24.5±0.2, and 27.4±0.2.

[0127] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 16 includes 10 or more (e.g., 12, 14, 15, 16, 17) 2θ values ​​selected from the following group: 6.6±0.2, 8.5±0.2, 8.8±0.2, 14.3±0.2, 15.1±0.2, 16.2±0.2, 17.0±0.2, 17.7±0.2, 18.5±0.2, 18.8±0.2, 20.0±0.2, 21.5±0.2, 23.6±0.2, 24.5±0.2, 27.4±0.2, 28.4±0.2, and 29.2±0.2.

[0128] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 16 includes the following 2θ values: 6.3±0.2, 6.6±0.2, 8.5±0.2, 8.8±0.2, 12.7±0.2, 14.3±0.2, 15.1±0.2, 16.2±0.2, 17.0±0.2, 17.7±0.2, 18.5±0.2, 18.8±0.2, 20.0±0.2, 20.4±0.2, 21.5±0.2, 22.4±0.2, 23.6±0.2, 24.0±0.2, 24.5±0.2, 26.2±0.2, 27.4±0.2, 28.4±0.2, 29.2±0.2, and 31.5±0.2.

[0129] In another preferred embodiment, the crystal form Form 16 has an X-ray powder diffraction pattern substantially as shown in FIG. 38 .

[0130] In another preferred embodiment, the crystal form Form 16 has an NMR spectrum substantially as shown in FIG. 37 .

[0131] In another preferred embodiment, the crystal form Form 16 has a thermogravimetric curve substantially as shown in FIG. 39 .

[0132] In another preferred embodiment, in the thermogravimetric test of the crystal form Form 16, the crystal form gradually loses weight from the beginning of heating until it is completely decomposed.

[0133] In another preferred embodiment, the molar ratio of the compound of formula I to p-toluenesulfonic acid in the crystalline form Form 16 is 1:0.8-2, for example, 1:0.9, 1:1, 1:15, 1:1.2, or 1:1.5.

[0134] In another preferred embodiment, the acetate salt crystalline form is acetate salt crystalline form 17, wherein the X-ray powder diffraction pattern of the crystalline form 17 includes 3 or more (e.g., 4 or 5) 2θ values ​​selected from the following group: 8.2±0.2, 13.1±0.2, 23.8±0.2, 24.2±0.2, and 26.5±0.2.

[0135] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 17 includes 6 or more (e.g., 7, 8, 9, 10) 2θ values ​​selected from the following group: 8.2±0.2, 13.1±0.2, 16.0±0.2, 22.8±0.2, 23.8±0.2, 24.2±0.2, 24.5±0.2, 25.3±0.2, 26.5±0.2, 29.3±0.2.

[0136] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 17 includes 10 or more (e.g., 12, 13, 14, 15, 16) 2θ values ​​selected from the following group: 8.2±0.2, 13.1±0.2, 14.8±0.2, 16.0±0.2, 17.6±0.2, 19.1±0.2, 19.8±0.2, 20.8±0.2, 22.4±0.2, 22.8±0.2, 23.8±0.2, 24.2±0.2, 24.5±0.2, 25.3±0.2, 26.5±0.2, 29.3±0.2.

[0137] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 17 includes the following 2θ values: 8.2±0.2, 9.2±0.2, 11.2±0.2, 13.1±0.2, 13.9±0.2, 14.1±0.2, 14.8±0.2, 15.5±0.2, 16.0±0.2, 16.3±0.2, 17.6±0.2, 18.4±0.2, 19.1±0.2, 19.8±0.2, 20.8±0.2, 21.2±0.2, 22.4±0.2, 22.8±0.2, 23.8 ±0.2, 24.2±0.2, 24.5±0.2, 25.3±0.2, 25.7±0.2, 26.5±0.2, 27.1±0.2, 27.4±0.2, 27.9±0.2, 28.3±0.2; 28.9±0.2, 29.3±0.2, 30.6±0.2, 31.2±0.2, 31.7±0.2, 32.4±0.2, 33.0±0.2, 34.6±0.2, 35.7±0.2, 37.2±0.2, 38.5±0.2.

[0138] In another preferred embodiment, the crystal form Form 17 has an X-ray powder diffraction pattern substantially as shown in FIG41 .

[0139] In another preferred embodiment, the crystal form Form 17 has an NMR spectrum substantially as shown in FIG40 .

[0140] In another preferred embodiment, the molar ratio of the compound of formula I to acetic acid in the crystalline form Form 17 is 1:0.8-2, for example, 1:0.9, 1:1, 1:15, 1:1.2, 1:1.5, 1:1.8.

[0141] In another preferred embodiment, the trifluoroacetate crystalline form is trifluoroacetate crystalline form Form 18, wherein the X-ray powder diffraction pattern of the crystalline form Form 18 includes 3 or more (e.g., 4) 2θ values ​​selected from the following group: 9.3±0.2, 17.0±0.2, 18.6±0.2, and 25.4±0.2.

[0142] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 18 includes 6 or more (e.g., 7, 8, 9) 2θ values ​​selected from the following group: 9.3±0.2, 10.5±0.2, 17.0±0.2, 18.6±0.2, 20.5±0.2, 21.1±0.2, 23.9±0.2, 25.4±0.2, and 29.2±0.2.

[0143] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 18 includes 10 or more (e.g., 12, 14, 15, 16, 18) 2θ values ​​selected from the following group: 6.7±0.2, 9.3±0.2, 10.5±0.2, 13.6±0.2, 15.5±0.2, 17.0±0.2, 18.6±0.2, 20.0±0.2, 20.5±0.2, 21.1±0.2, 22.3±0.2, 23.5±0.2, 23.9±0.2, 24.7±0.2, 25.4±0.2, 26.1±0.2, 26.9±0.2, and 29.2±0.2.

[0144] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 18 includes the following 2θ values: 6.7±0.2, 9.3±0.2, 10.5±0.2, 13.6±0.2, 14.8±0.2, 15.5±0.2, 17.0±0.2, 17.6±0.2, 18.1±0.2, 18.6±0.2, 19.6±0.2, 20.0±0.2, 20.5±0.2, 21.1±0.2, 22.3±0.2, 22.9±0.2, 23.5 ±0.2, 23.9±0.2, 24.4±0.2, 24.7±0.2, 25.4±0.2, 26.1±0.2, 26.9±0.2, 27.4±0.2, 28.0±0.2, 28.7±0.2, 29.2±0.2, 29.9±0.2, 31.1±0.2, 31.7±0.2, 32.8±0.2, 34.5±0.2, 35.9±0.2, 37.0±0.2, and 37.8±0.2.

[0145] In another preferred embodiment, the crystal form Form 18 has an X-ray powder diffraction pattern substantially as shown in FIG43 .

[0146] In another preferred embodiment, the crystal form Form 18 has an NMR spectrum substantially as shown in FIG42 .

[0147] In another preferred embodiment, the crystal form Form 18 has a thermogravimetric curve substantially as shown in FIG. 44 .

[0148] In another preferred embodiment, the thermogravimetric test of the crystal form Form 18 includes two weight loss processes. The first stage gradually loses weight from the beginning of heating, and the end temperature is between 230-280°C (for example, 250°C); the second stage starts at a temperature between 230-280°C (for example, 250°C) until it is completely decomposed.

[0149] In another preferred embodiment, the molar ratio of the compound of formula I to trifluoroacetic acid in the crystalline form Form 18 is 1:0.8-20, for example, 1:1, 1:1.5, 1:2, 1:5, 1:10, or 1:15.

[0150] In another preferred embodiment, the propionate salt crystalline form is propionate salt crystalline form Form 19, wherein the X-ray powder diffraction pattern of the crystalline form Form 19 includes 3 or more (e.g., 4 or 5) 2θ values ​​selected from the following group: 7.3±0.2, 17.2±0.2, 17.4±0.2, 22.5±0.2, and 23.1±0.2.

[0151] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 19 includes 6 or more (e.g., 7, 8, 9, 10) 2θ values ​​selected from the following group: 7.3±0.2, 11.2±0.2, 14.6±0.2, 17.2±0.2, 17.4±0.2, 19.7±0.2, 22.5±0.2, 23.1±0.2, 23.8±0.2, and 27.5±0.2.

[0152] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 19 includes 10 or more (e.g., 12, 13, 14, 15, 16) 2θ values ​​selected from the following group: 7.3±0.2, 11.2±0.2, 14.6±0.2, 15.4±0.2, 17.2±0.2, 17.4±0.2, 18.0±0.2, 19.7±0.2, 20.6±0.2, 22.5±0.2, 23.1±0.2, 23.8±0.2, 24.8±0.2, 26.6±0.2, 27.5±0.2, 28.5±0.2, 29.2±0.2.

[0153] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 19 includes the following 2θ values: 7.3±0.2, 11.2±0.2, 14.6±0.2, 15.4±0.2, 16.4±0.2, 17.2±0.2, 17.4±0.2, 18.0±0.2, 19.2±0.2, 19.7±0.2, 20.6±0.2, 22.5±0.2, 23.1±0.2, 23.8±0.2 , 24.4±0.2, 24.8±0.2, 25.7±0.2, 26.3±0.2, 26.6±0.2, 27.5±0.2, 28.5±0.2, 29.2±0.2, 30.4±0.2, 31.6±0.2, 32.0±0.2, 33.0±0.2, 34.1±0.2, 35.3±0.2, 36.9±0.2, and 39.1±0.2.

[0154] In another preferred embodiment, the crystal form Form 19 has an X-ray powder diffraction pattern substantially as shown in FIG. 46 .

[0155] In another preferred embodiment, the crystal form Form 19 has an NMR spectrum substantially as shown in FIG. 45 .

[0156] In another preferred embodiment, the molar ratio of the compound of formula I to propionic acid in the crystalline form Form 19 is 1:0.8-30, for example, 1:1, 1:1.5, 1:2, 1:5, 1:10, 1:15, 1:20, 1:25, or 1:28.

[0157] In another preferred embodiment, the hydrochloride salt crystalline form is hydrochloride salt crystalline form 20, wherein the X-ray powder diffraction pattern of the crystalline form 20 includes 3 or more (e.g., 4 or 5) 2θ values ​​selected from the following group: 12.2±0.2, 13.7±0.2, 21.0±0.2, 21.6±0.2, and 22.8±0.2.

[0158] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 20 includes 6 or more (e.g., 7, 8, 9, 10) 2θ values ​​selected from the following group: 4.6±0.2, 9.1±0.2, 12.2±0.2, 13.7±0.2, 21.0±0.2, 21.6±0.2, 22.8±0.2, 23.3±0.2, 24.1±0.2, 28.8±0.2.

[0159] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 20 includes 10 or more (e.g., 12, 14, 15, 16, 18) 2θ values ​​selected from the following group: 4.6±0.2, 9.1±0.2, 12.2±0.2, 13.7±0.2, 14.5±0.2, 17.7±0.2, 19.0±0.2, 19.7±0.2, 21.0±0.2, 21.6±0.2, 22.8±0.2, 23.3±0.2, 24.1±0.2, 24.6±0.2, 26.2±0.2, 27.5±0.2, 28.8±0.2, and 32.2±0.2.

[0160] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 20 includes the following 2θ values: 4.6±0.2, 9.1±0.2, 12.2±0.2, 13.7±0.2, 14.5±0.2, 15.1±0.2, 17.7±0.2, 18.2±0.2, 19.0±0.2, 19.7±0.2, 21.0±0.2, 21.6±0.2, 22.8±0.2, 23.3±0.2, 24.1±0.2, 24.6±0.2, 24.9±0.2, 26.2±0.2, 26.6±0.2, 27.2±0.2, 27.5±0.2, 28.5±0.2, 28.8±0.2, 29.7±0.2, 30.2±0.2, 30.6±0.2, 31.7±0.2, 32.2±0.2, 33.0±0.2, 35.3±0.2, 36.0±0.2, 38.8±0.2.

[0161] In another preferred embodiment, the crystal form Form 20 has an X-ray powder diffraction pattern substantially as shown in FIG. 48 .

[0162] In another preferred embodiment, the crystal form Form 20 has an NMR spectrum substantially as shown in FIG. 47 .

[0163] In another preferred embodiment, the crystal form Form 20 has a thermogravimetric curve substantially as shown in FIG. 49 .

[0164] In another preferred embodiment, the thermogravimetric test of the crystal form Form 20 includes two weight loss processes. The first stage gradually loses weight from the beginning of heating, and the end temperature is between 130-180°C (e.g., 150°C); the second stage starts at a temperature between 250-300°C (e.g., 280°C) until it is completely decomposed.

[0165] In another preferred embodiment, the molar ratio of the compound of formula I to hydrochloric acid in the crystalline form Form 20 is 1:0.8-40, for example, 1:1, 1:2, 1:5, 1:10, 1:15, 1:20, 1:25, 1:30, or 1:35.

[0166] In another preferred embodiment, the hydrobromide salt crystalline form is hydrobromide salt crystalline form Form 21, wherein the X-ray powder diffraction pattern of the crystalline form Form 21 includes 3 or more (e.g., 4, 5, 6) 2θ values ​​selected from the following group: 11.2±0.2, 17.7±0.2, 19.7±0.2, 21.6±0.2, 22.9±0.2, 23.8±0.2, and 24.7±0.2.

[0167] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 21 includes 6 or more (e.g., 8, 10, 12, 13) 2θ values ​​selected from the following group: 11.2±0.2, 11.4±0.2, 14.8±0.2, 17.7±0.2, 19.7±0.2, 21.6±0.2, 22.9±0.2, 23.8±0.2, 24.7±0.2, 26.1±0.2, 27.6±0.2, 28.3±0.2, and 29.9±0.2.

[0168] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 21 includes 10 or more (e.g., 12, 15, 18, 20, 24) 2θ values ​​selected from the following group: 9.0±0.2, 11.2±0.2, 11.4±0.2, 12.1±0.2, 14.8±0.2, 15.9±0.2, 16.1±0.2, 17.7±0.2, 19.4±0 .2, 19.7±0.2, 20.2±0.2, 20.9±0.2, 21.6±0.2, 22.9±0.2, 23.8±0.2, 24.7±0.2, 26.1±0.2, 26.3±0.2, 27.6±0.2, 28.3±0.2, 29.9±0.2, 31.5±0.2, 33.4±0.2.

[0169] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 21 includes the following 2θ values: 9.0±0.2, 11.2±0.2, 11.4±0.2, 12.1±0.2, 12.8±0.2, 13.5±0.2, 14.8±0.2, 15.9±0.2, 16.1±0.2, 17.2±0.2, 17.7±0.2, 18.9±0.2, 19.4±0.2, 19.7±0.2, 20.2±0.2, 20.9±0.2, 21.6±0.2, 22.9±0.2, 23.8±0.2, 24.7 ±0.2, 25.1±0.2, 25.5±0.2, 26.1±0.2, 26.3±0.2, 26.8±0.2, 27.3±0.2, 27.6±0.2, 28.3±0.2, 28.8±0.2, 29.7±0.2, 29.9±0.2, 30.5±0.2, 31.5±0.2, 32.3±0.2, 32.6±0.2, 32.9±0.2, 33.4±0.2, 34.6±0.2, 36.6±0.2, 37.0±0.2, and 38.6±0.2.

[0170] In another preferred embodiment, the crystal form Form 21 has an X-ray powder diffraction pattern substantially as shown in FIG51 .

[0171] In another preferred embodiment, the crystal form Form 21 has an NMR spectrum substantially as shown in FIG50 .

[0172] In another preferred embodiment, the crystal form Form 21 has a thermogravimetric curve substantially as shown in FIG. 52 .

[0173] In another preferred embodiment, the thermogravimetric test of the crystal form Form 21 includes two weight loss processes. The first stage gradually loses weight from the beginning of heating, and the end temperature is between 280-320°C (for example, 300°C); the second stage starts at a temperature between 300-350°C (for example, 310°C) until it is completely decomposed.

[0174] In another preferred embodiment, the molar ratio of the compound of formula I to hydrobromic acid in the crystalline form Form 21 is 1:0.8-5, for example, 1:0.9, 1:1, 1:1.5, 1:2, 1:3, or 1:5.

[0175] In another preferred embodiment, the sulfate salt crystal form is sulfate salt crystal form Form 22, wherein the X-ray powder diffraction pattern of the crystal form Form 22 includes 3 or more (e.g., 4) 2θ values ​​selected from the following group: 4.3±0.2, 12.4±0.2, 20.5±0.2, and 23.5±0.2.

[0176] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 22 includes 6 or more (e.g., 7, 8, 9, 10) 2θ values ​​selected from the following group: 4.3±0.2, 8.4±0.2, 12.4±0.2, 14.4±0.2, 16.8±0.2, 20.5±0.2, 23.5±0.2, 23.8±0.2, 25.8±0.2, and 33.8±0.2.

[0177] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 22 includes 10 or more (e.g., 12, 13, 15, 18, 20) 2θ values ​​selected from the following group: 4.3±0.2, 8.4±0.2, 12.4±0.2, 14.4±0.2, 16.8±0.2, 17.2±0.2, 18.3±0.2, 19.3±0.2, 20.5±0.2, 23.0±0.2, 23.5±0.2, 23.8±0.2, 24.1±0.2, 24.7±0.2, 24.9±0.2, 25.8±0.2, 26.4±0.2, 33.8±0.2, 34.6±0.2, and 35.9±0.2.

[0178] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 22 includes the following 2θ values: 4.3±0.2, 8.4±0.2, 10.5±0.2, 12.4±0.2, 14.4±0.2, 14.7±0.2, 15.3±0.2, 16.4±0.2, 16.8±0.2, 17.2±0.2, 18.3±0.2, 19.1±0.2, 19.3±0.2, 20.5±0.2, 21.0±0.2, 21.8±0.2, 22.2±0.2, 23.0±0. 2, 23.5±0.2, 23.8±0.2, 24.1±0.2, 24.7±0.2, 24.9±0.2, 25.8±0.2, 26.4±0.2, 27.6±0.2, 28.1±0.2, 29±0.2, 29.9±0.2, 30.8±0.2, 31.5±0.2, 31.8±0.2, 32.1±0.2, 33.8±0.2, 34.6±0.2, 35.9±0.2, 36.5±0.2, and 38±0.2.

[0179] In another preferred embodiment, the crystal form Form 22 has an X-ray powder diffraction pattern substantially as shown in FIG. 54 .

[0180] In another preferred embodiment, the crystal form Form 22 has an NMR spectrum substantially as shown in FIG53 .

[0181] In another preferred embodiment, the crystal form Form 22 has a thermogravimetric curve substantially as shown in FIG. 55 .

[0182] In another preferred embodiment, the thermogravimetric test of the crystal form Form 22 includes two weight loss processes. The first stage is gradual weight loss from the beginning of heating, with the end temperature between 200-250°C (e.g., 220°C); the second stage is until the final complete decomposition.

[0183] In another preferred embodiment, the molar ratio of the compound of formula I to sulfuric acid in the crystalline form Form 22 is 1:0.8-20, for example, 1:1, 1:2, 1:3, 1:5, 1:8, 1:10, 1:15, or 1:18.

[0184] In another preferred embodiment, the phosphate crystal form is phosphate crystal form Form 23, wherein the X-ray powder diffraction pattern of the crystal form Form 23 includes 3 or more (e.g., 4) 2θ values ​​selected from the following group: 8.0±0.2, 18.5±0.2, 25.8±0.2, and 30.4±0.2.

[0185] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 23 includes 6 or more (e.g., 7, 8, 9, 10) 2θ values ​​selected from the following group: 8.0±0.2, 16.0±0.2, 17.8±0.2, 18.5±0.2, 19.8±0.2, 24.1±0.2, 24.4±0.2, 24.8±0.2, 25.8±0.2, and 30.4±0.2.

[0186] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 23 includes 10 or more 2θ values ​​(e.g., 11, 12, 13, 14, 15) selected from the following group: 8.0±0.2, 9.1±0.2, 12.0±0.2, 16.0±0.2, 17.8±0.2, 18.2±0.2, 18.5±0.2, 19.8±0.2, 21.5±0.2, 24.1±0.2, 24.4±0.2, 24.8±0.2, 25.8±0.2, 27.8±0.2, and 30.4±0.2.

[0187] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 23 includes the following 2θ values: 8.0±0.2, 9.1±0.2, 12.0±0.2, 16.0±0.2, 16.6±0.2, 17.8±0.2, 18.2±0.2, 18.5±0.2, 19.8±0.2, 21.5±0.2, 24.1±0.2, 24.4±0.2, 24.8±0.2, 25.8±0.2, 27.8±0.2, 28.6±0.2, and 30.4±0.2.

[0188] In another preferred embodiment, the crystal form Form 23 has an X-ray powder diffraction pattern substantially as shown in Figure 57.

[0189] In another preferred embodiment, the crystal form Form 23 has an NMR spectrum substantially as shown in FIG56 .

[0190] In another preferred embodiment, the crystal form Form 23 has a thermogravimetric curve substantially as shown in FIG. 58 .

[0191] In another preferred embodiment, the thermogravimetric test of the crystal form Form 23 includes two weight loss processes. The first stage is gradual weight loss from the beginning of heating, with the end temperature between 280-320°C (e.g., 300°C); the second stage is until the final complete decomposition.

[0192] In another preferred embodiment, the molar ratio of the compound of formula I to phosphoric acid in the crystalline form Form 23 is 1:0.8-20, for example, 1:1, 1:2, 1:3, 1:5, 1:8, 1:10, 1:15, or 1:18.

[0193] In another preferred embodiment, the nitrate crystal form is nitrate crystal form Form 24, wherein the X-ray powder diffraction pattern of the crystal form Form 24 includes 3 or more (e.g., 4 or 5) 2θ values ​​selected from the following group: 12.4±0.2, 19.3±0.2, 20.8±0.2, 23.8±0.2, and 27.9±0.2.

[0194] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 24 includes 6 or more (e.g., 7, 8, 10, 12) 2θ values ​​selected from the following group: 12.4±0.2, 14.4±0.2, 19.0±0.2, 19.3±0.2, 19.6±0.2, 20.8±0.2, 22.5±0.2, 23.4±0.2, 23.8±0.2, 24.6±0.2, 24.9±0.2, 27.9±0.2.

[0195] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 24 includes 10 or more 2θ values ​​(e.g., 12, 14, 15, 18, 20) selected from the group consisting of 4.3±0.2, 8.6±0.2, 12.4±0.2, 13.9±0.2, 14.4±0.2, 16.2±0.2, 16.8±0.2, 18.0±0.2, 19.0±0.2, 19.3±0.2, 196±0.2, 20.4±0.2, 20.8±0.2, 22.5±0.2, 23.4±0.2, 23.8±0.2, 24.6±0.2, 24.9±0.2, 25.3±0.2, and 27.9±0.2.

[0196] In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form Form 24 includes the following 2θ values: 4.3±0.2, 8.6±0.2, 12.4±0.2, 12.9±0.2, 13.9±0.2, 14.4±0.2, 16.2±0.2, 16.8±0.2, 17.4±0.2, 18.0±0.2, 19.0±0.2, 19.3±0.2, 196±0.2, 20.4±0.2, 20.8 ±0.2, 22.1±0.2, 22.5±0.2, 23.4±0.2, 23.8±0.2, 24.6±0.2, 24.9±0.2, 25.3±0.2, 26.9±0.2, 27.9±0.2, 28.3±0.2, 30.2±0.2, 31.4±0.2, 32.7±0.2, 33.8±0.2, 34.7±0.2, and 36.2±0.2.

[0197] In another preferred embodiment, the crystal form Form 24 has an X-ray powder diffraction pattern substantially as shown in FIG60 .

[0198] In another preferred embodiment, the crystal form Form 24 has an NMR spectrum substantially as shown in FIG. 59 .

[0199] In another preferred embodiment, the molar ratio of the compound of formula I to nitric acid in the crystalline form Form 24 is 1:0.8-20, for example, 1:1, 1:2, 1:3, 1:5, 1:8, 1:10, 1:15, or 1:18.

[0200] In a second aspect of the present invention, there is provided a method for preparing a crystalline salt of the compound of formula I according to the first aspect of the present invention, the method comprising the following steps:

[0201] The compound of formula I is mixed with a solvent, and then a corresponding acid is added, followed by continued mixing to crystallize or evaporate to obtain the salt crystal form.

[0202] In another preferred embodiment, the compound of formula I is a free base of the compound of formula I, preferably a free base amorphous form or a free base crystalline form.

[0203] In another preferred embodiment, the solvent is selected from the group consisting of methanol, dichloromethane, acetonitrile, ethyl acetate, acetone, or a combination thereof.

[0204] In another preferred embodiment, the acid is selected from the group consisting of oxalic acid, maleic acid, fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, D-malic acid, L-malic acid, L-glutamic acid, citric acid, benzoic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid.

[0205] In another preferred embodiment, the acid is in the form of an acid, an aqueous solution of an acid, or a hydrate of an acid.

[0206] In another preferred embodiment, the molar ratio of the compound of formula I to the corresponding acid is 1:0.8-2 or 1:5-40, for example, 1:0.9, 1:1, 1:1.2, 1:1.5, 1:5, 1:8, 1:10, 1:15, 1:20, 1:25, 1:30, 1:35, or 1:37.

[0207] In another preferred embodiment, the mass volume fraction of the compound of formula I and the solvent is 1-5 g / L, for example, 2.5 g / L.

[0208] In another preferred embodiment, the method comprises the steps of adding the compound of formula I to a solvent, mixing to dissolve the solution, then adding the corresponding acid, continuing to mix, and crystallizing or volatilizing to obtain the corresponding salt crystal form.

[0209] In the third aspect of the present invention, a pharmaceutical composition is provided, comprising a crystalline salt of the compound of formula I as described in the first aspect of the present invention, and a pharmaceutically acceptable carrier.

[0210] In a fourth aspect of the present invention, there is provided a use of a crystalline salt of the compound of formula I as described in the first aspect of the present invention for preparing a composition for preventing and / or treating cancer.

[0211] In another preferred embodiment, the cancer is selected from the group consisting of lung cancer, prostate cancer, colon cancer, and leukemia.

[0212] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0213] Figure 1 shows the NMR spectrum of oxalate salt Form 1.

[0214] FIG2 shows the powder XRD spectrum of the oxalate salt form 1.

[0215] FIG3 shows the TG curve of the oxalate salt crystal form 1.

[0216] Figure 4 shows the NMR spectrum of maleate crystalline form 2.

[0217] FIG5 shows the powder XRD spectrum of Form 2 of the maleate salt.

[0218] FIG6 shows the TG curve of the maleate crystalline form Form 2.

[0219] Figure 7 shows the NMR spectrum of the fumarate salt crystalline form 3.

[0220] FIG8 shows the powder XRD pattern of the fumarate crystalline form 3.

[0221] FIG9 shows the TG curve of the fumarate crystalline form Form 3.

[0222] Figure 10 shows the NMR spectrum of Form 4 of the succinate salt.

[0223] FIG11 shows the powder XRD pattern of Form 4 of the succinate salt.

[0224] Figure 12 shows the NMR spectrum of D-tartrate crystalline form Form 5.

[0225] FIG13 shows the powder XRD pattern of Form 5 of the D-tartrate salt.

[0226] Figure 14 shows the NMR spectrum of L-tartrate salt Form 6.

[0227] FIG15 shows the powder XRD pattern of Form 6 of the L-tartrate salt.

[0228] Figure 16 shows the NMR spectrum of D-malate crystalline form Form 7.

[0229] FIG17 shows the powder XRD pattern of Form 7 of the D-malate salt.

[0230] Figure 18 shows the NMR spectrum of L-malate crystalline Form 8.

[0231] FIG19 shows the powder XRD pattern of Form 8 of the L-malate salt.

[0232] FIG20 shows the NMR spectrum of L-glutamate crystalline form Form 9.

[0233] FIG21 shows the powder XRD pattern of L-glutamate crystalline form Form 9.

[0234] Figure 22 shows the NMR spectrum of Form 10 of the citrate salt.

[0235] FIG23 shows the powder XRD pattern of Form 10 of the citrate salt.

[0236] Figure 24 shows the NMR spectrum of Form 11 of the benzoate salt.

[0237] FIG25 shows the powder XRD pattern of Form 11 of the benzoate salt.

[0238] Figure 26 shows the NMR spectrum of salicylate crystalline form Form 12.

[0239] FIG27 shows the powder XRD pattern of salicylate crystalline form Form 12.

[0240] Figure 28 shows the NMR spectrum of the mesylate salt crystalline form Form 13.

[0241] FIG29 shows the powder XRD pattern of Form 13 of the mesylate salt.

[0242] FIG30 shows the TG curve of the mesylate salt crystalline form Form 13.

[0243] Figure 31 shows the NMR spectrum of Form 14 of the ethanesulfonate salt.

[0244] FIG32 shows the powder XRD pattern of Form 14 of the ethanesulfonate salt.

[0245] FIG33 shows the TG curve of the ethanesulfonate crystal form Form 14.

[0246] Figure 34 shows the NMR spectrum of Form 15 of the benzenesulfonate salt.

[0247] FIG35 shows the powder XRD pattern of Form 15 of the benzenesulfonate salt.

[0248] Figure 36 shows the TG curve of benzenesulfonate crystalline form Form 15.

[0249] Figure 37 shows the NMR spectrum of the p-toluenesulfonate crystalline form Form 16.

[0250] FIG38 shows the powder XRD pattern of the p-toluenesulfonate crystalline form 16.

[0251] FIG39 shows the TG curve of the p-toluenesulfonic acid salt crystalline form Form 16.

[0252] Figure 40 shows the NMR spectrum of acetate salt Form 17.

[0253] FIG41 shows the powder XRD pattern of the acetate salt Form 17.

[0254] Figure 42 shows the NMR spectrum of trifluoroacetate crystalline Form 18.

[0255] FIG43 shows the powder XRD pattern of the trifluoroacetate crystalline Form 18.

[0256] Figure 44 shows the TG curve of trifluoroacetate crystalline form Form 18.

[0257] Figure 45 shows the NMR spectrum of propionate salt crystalline form Form 19.

[0258] FIG46 shows the powder XRD pattern of the propionate salt crystalline form 19.

[0259] Figure 47 shows the NMR spectrum of the hydrochloride salt Form 20.

[0260] FIG48 shows the powder XRD pattern of the hydrochloride salt Form 20.

[0261] Figure 49 shows the TG curve of hydrochloride salt Form 20.

[0262] Figure 50 shows the NMR spectrum of the hydrobromide salt crystalline form Form 21.

[0263] FIG51 shows the powder XRD pattern of the hydrobromide salt crystalline form 21.

[0264] Figure 52 shows the TG curve of the hydrobromide salt crystalline form Form 21.

[0265] Figure 53 shows the NMR spectrum of the sulfate salt crystal form Form 22.

[0266] FIG54 shows the powder XRD pattern of the sulfate salt crystalline form Form 22.

[0267] Figure 55 shows the TG curve of sulfate salt crystal form Form 22.

[0268] Figure 56 shows the NMR spectrum of the phosphate crystal form Form 23.

[0269] FIG57 shows the powder XRD pattern of the phosphate crystal form Form 23.

[0270] Figure 58 shows the TG curve of phosphate crystal form Form 23.

[0271] Figure 59 shows the NMR spectrum of the nitrate salt crystal form Form 24.

[0272] FIG60 shows the powder XRD pattern of the nitrate salt Form 24. DETAILED DESCRIPTION

[0273] After extensive and in-depth research, the inventors discovered for the first time a crystalline form of the acid salt of Plinabulin. This crystalline form of the acid salt has excellent solubility, hygroscopicity, and pharmacokinetic properties. Based on this, the present invention was completed.

[0274] the term

[0275] Unless defined otherwise, 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 belongs.

[0276] As used herein, the terms "comprise," "include," and "contain" are used interchangeably to include not only closed definitions but also semi-closed and open definitions. In other words, the terms include "consisting of," "consisting essentially of."

[0277] As used herein, when used in reference to a specific recited value, the term "about" means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0278] Crystal form

[0279] The present invention provides an acid salt crystalline form of a compound of formula I, wherein the crystalline form is selected from the following group: oxalate crystalline form Form 1, maleate crystalline form Form 2, fumarate crystalline form Form 3, succinate crystalline form Form 4, D-tartrate crystalline form Form 5, L-tartrate crystalline form Form 6, D-malate crystalline form Form 7, L-malate crystalline form Form 8, L-glutamate crystalline form Form 9, citrate crystalline form Form 1, benzoate crystalline form Form 11, salicylate crystalline form Form 12, methanesulfonate crystalline form Form 13, ethanesulfonate crystalline form Form 14, benzenesulfonate crystalline form Form 15, p-toluenesulfonate crystalline form Form 16, acetate crystalline form Form 17, trifluoroacetate crystalline form Form 18, propionate crystalline form Form 19, hydrochloride crystalline form Form 20, hydrobromide crystalline form Form 21, sulfate crystalline form Form 22, phosphate crystalline form Form 23. 23. Nitrate crystal form Form 24.

[0280] Pharmaceutical compositions and methods of administration

[0281] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one or more salt crystal forms described in the first aspect of the present invention and a pharmaceutically acceptable carrier.

[0282] Since the acid salt crystal form of the present invention has excellent activity in preventing and / or treating cancer, the crystal form of the present invention can be used to treat, prevent and alleviate cancer.

[0283] The pharmaceutical composition of the present invention comprises a safe and effective amount of a crystalline salt form of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the crystalline form of the present invention sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the crystalline form of the present invention per dose, more preferably 10-1000 mg of the crystalline form of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0284] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the crystal form of the present invention and with each other without significantly reducing their efficacy. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0285] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0286] There is no particular limitation on the administration of the crystalline form or pharmaceutical composition of the present invention. Representative administrations include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0287] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0288] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0289] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0290] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0291] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0292] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0293] The dosage forms of the crystalline form of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.

[0294] The crystalline form of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0295] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0296] When using a pharmaceutical composition, a safe and effective amount of the crystalline form of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0297] The main advantages of the present invention include:

[0298] The salt crystal form of the present invention has excellent stability and solubility.

[0299] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which no specific conditions are specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0300] Example 1: Preparation and Characterization of Plinabulin Oxalate Compound (Form 1)

[0301] 1. Experimental methods

[0302] Add 50 mg (0.14 mmol) of Plinabulin to 20 ml of methanol (or a solvent system such as dichloromethane, acetonitrile, or ethyl acetate), stir until the solution becomes clear, then add 18.3 mg (0.2 mmol) of oxalic acid, continue stirring, and gradually precipitate crystals. Filter, let stand, and evaporate to obtain a sample.

[0303] 2. Nuclear Magnetic Resonance Data

[0304] The NMR spectrum of Form 1 is shown in Figure 1.

[0305] 1 H-NMR (300MHz, DMSO-d6, ppm): δ1.387 (s, 9H), 6.750 (m, 2H), 7.294 (t, J = 7.2, 1H),7.393(t,J=7.8,2H),7.513(d,J=7.5,2H),7.845(s,1H),12.228(s,2H).

[0306] 3. XRD data

[0307] The powder XRD spectrum of Form 1 is shown in Figure 2.

[0308] In the X-ray powder diffraction pattern at room temperature (25°C) and Cu-kα radiation, the crystalline form 1 of the compound Plinabulin oxalate will show at least 15 of the following diffraction peaks, 28 2θ values ​​are provided, and the peak positions are as follows:

[0309] 3.9±0.2, 5.2±0.2, 7.7±0.2, 8.4±0.2, 10.3±0.2, 12.5±0.2, 14.2±0.2, 14.6±0.2, 15.3±0.2, 16.1±0.2, 17.2±0.2, 18.3±0.2, 18.8±0.2, 19.1±0.2, 19 .4±0.2, 21.5±0.2, 22.7±0.2, 23.1±0.2, 23.5±0.2, 23.9±0.2, 25.0±0.2, 25.4±0.2, 25.8±0.2, 26.5±0.2, 28.0±0.2, 29.0±0.2, 29.9±0.2, 37.0±0.2.

[0310] 4. TG data analysis

[0311] The TG curve of Form 1 is shown in Figure 3. In the first stage, there is a gradual weight loss from the beginning of heating, ending at around 230°C. In the second stage, the starting temperature is always 290°C until the final complete decomposition.

[0312] Example 2: Preparation and Characterization of Plinabulin Maleate Compound (Form 2)

[0313] 1. Experimental methods

[0314] 50 mg (0.14 mmol) of Plinabulin was added to 20 ml of methanol (or a solvent system such as dichloromethane, acetonitrile, or ethyl acetate), and the solution was dissolved under stirring. Then, 17.3 mg (0.14 mmol) of maleic acid was added, and the stirring was continued. The sample was filtered and allowed to stand for evaporation to obtain a sample.

[0315] 2. Nuclear Magnetic Resonance Data

[0316] The NMR spectrum of Form 2 is shown in Figure 4.

[0317] 1 H NMR(400MHz,DMSO-d6)δ12.34(s,1H),12.16(s,1H),10.00(s,1H),7.88-7.83(m,1H),7.53-7.45(m,2H ),7.38(dd,J=8.4,6.9Hz,2H),7.33-7.24(m,1H),6.81(s,1H),6.71(s,1H),6.22(s,2H),1.35(s,9H).

[0318] 3. XRD data

[0319] The powder XRD spectrum of Form 2 is shown in Figure 5.

[0320] In the X-ray powder diffraction pattern at room temperature (25°C) and Cu-kα radiation, Plinabulin maleate crystalline form 2 will show at least 13 of the following diffraction peaks, 24 2θ values ​​are provided, and the peak positions are as follows:

[0321] ± 0.2, 6.7±0.2, 12.5±0.2, 13.4±0.2, 14.6±0.2, 15.0±0.2, 15.6±0.2, 16.0±0.2, 16.5±0.2, 17.8±0.2, 18.5±0.2, 19.4±0.2, 19.8±0.2, 20.1±0.2, 21.6±0.2, 22.3±0.2, 22.7±0.2, 23.5±0.2, 24.8±0.2, 25.4±0.2, 26.0±0.2, 26.8±0.2, 28.5±0.2, 29.4±0.2, and 30.6±0.2.

[0322] 4. TG data analysis

[0323] The TG curve of Form 2 is shown in Figure 6. The first stage starts at a temperature of about 200°C and ends at a temperature of about 250°C. The second stage starts at a temperature of about 280°C and ends at a temperature of about 250°C.

[0324] Example 3: Preparation and Characterization of Plinabulin Fumarate Compound (Form 3)

[0325] 1. Experimental methods

[0326] Add 50 mg (0.14 mmol) of Plinabulin to 20 ml of methanol (or a solvent system such as dichloromethane, acetonitrile, ethyl acetate, or acetone), stir until the solution becomes clear, then add 17.3 mg (0.14 mmol) of fumaric acid, continue stirring, filter, let stand, and evaporate to obtain a sample.

[0327] 2. Nuclear Magnetic Resonance Data

[0328] The NMR spectrum of Form 3 is shown in Figure 7.

[0329] 1 H NMR (400MHz, DMSO-d6) δ12.33(s,1H),12.17(s,1H),9.99(s,1H),7.85(s,1H),7.49(dd,J=7.9,1.4Hz,2 H),7.38(dd,J=8.4,6.9Hz,2H),7.33-7.24(m,1H),6.81(s,1H),6.71(s,1H),6.22(s,2H),1.35(s,9H).

[0330] 3. XRD data

[0331] The powder XRD spectrum of Form 3 is shown in Figure 8.

[0332] In the X-ray powder diffraction pattern at room temperature (25°C) and Cu-kα radiation, the crystalline form 3 of the compound Plinabulin fumarate will show at least 14 of the following diffraction peaks, and 26 2θ values ​​are provided. The peak positions are as follows: 6.6±0.2, 9.8±0.2, 11.2±0.2, 12.4±0.2, 13.3±0.2, 14.6±0.2, 14.9±0.2, 15.6±0.2, 15.9±0.2, 16.4±0.2, 17.8±0.2, 18 .5±0.2, 19.4±0.2, 19.7±0.2, 20.0±0.2, 22.2±0.2, 22.6±0.2, 23.4±0.2, 24.8±0.2, 25.3±0.2, 25.9±0.2, 26.8±0.2, 28.5±0.2, 29.4±0.2, 30.5±0.2, 33.3±0.2.

[0333] 4. TG data analysis

[0334] The TG curve of Form 3 is shown in Figure 9. There are two weight loss processes: the first stage: starting at a temperature of about 130°C and ending at a temperature of about 260°C; the second stage: starting at a temperature of about 280°C until complete decomposition.

[0335] Example 4: Preparation and Characterization of Plinabulin Succinate Compound (Form 4)

[0336] 1. Experimental methods

[0337] 50 mg (0.14 mmol) of Plinabulin was added to 20 ml of methanol (or a solvent system such as dichloromethane, acetonitrile, or ethyl acetate), and the solution was dissolved under stirring. Then, 17 mg (0.14 mmol) of succinic acid (butanedioic acid) was added, and the stirring was continued. The solution was filtered, allowed to stand, and evaporated to obtain a sample.

[0338] 2. Nuclear Magnetic Resonance Data

[0339] The NMR spectrum of Form 4 is shown in Figure 10.

[0340] 1H NMR (400MHz, DMSO-d6) δ12.29(s,1H),12.21(s,1H),12.10(s,2H),9.98(s,1H),7.81(d,J=1.0Hz,1H),7.52-7.46(m ,2H),7.38(dd,J=8.4,6.9Hz,2H),7.33-7.24(m,1H),6.82(d,J=0.6Hz,1H),6.71(s,1H),2.38(s,6H),1.35(s,9H).

[0341] 3. XRD data

[0342] The powder XRD spectrum of Form 4 is shown in Figure 11.

[0343] In the X-ray powder diffraction pattern at room temperature (25°C) and Cu-kα radiation, Form 4 of the compound Plinabulin succinate will show at least 10 of the following diffraction peaks. 18 2θ values ​​are provided, and the peak positions are as follows: 8.2±0.2, 13.1±0.2, 14.8±0.2, 16.1±0.2, 16.3±0.2, 17.7±0.2, 19.2±0.2, 20.1±0.2, 22.4±0.2, 22.9±0.2, 23.9±0.2, 24.3±0.2, 24.6±0.2, 25.4±0.2, 26.2±0.2, 26.6±0.2, 29.4±0.2, and 31.6±0.2.

[0344] Example 5: Preparation and Characterization of D-Tartrate Salt of Plinabulin (Form 5)

[0345] 1. Experimental methods

[0346] 50 mg (0.148 mmol) of Plinabulin was added to 20 ml of methanol (or a solvent system such as dichloromethane or acetonitrile) and stirred until the solution became clear. Then, 22 mg of D-tartaric acid was added and stirred continuously until a yellow transparent solution was obtained. The solution was filtered, allowed to stand, and evaporated to obtain a sample.

[0347] 2. Nuclear Magnetic Resonance Data

[0348] The NMR spectrum of Form 5 is shown in Figure 12.

[0349] 1H NMR(400MHz,DMSO-d6)δ12.30(s,1H),12.22(s,1H),10.00(s,1H),7.82(s,1H),7.52-7.46(m,2H),7. 42-7.34(m,2H),7.33-7.24(m,1H),6.82(s,1H),6.71(s,1H),4.99(s,2H),4.26(s,2H),1.35(s,9H).

[0350] 3. XRD data

[0351] The powder XRD spectrum of Form 5 is shown in Figure 13.

[0352] In the X-ray powder diffraction pattern at room temperature (25°C) and Cu-kα radiation, the crystalline form 5 of the compound Plinabulin D-tartrate will show at least 10 of the following diffraction peaks. 17 2θ values ​​are provided, and the peak positions are as follows: 7.0±0.2, 9.1±0.2, 11.8±0.2, 12.3±0.2, 12.9±0.2, 17.3±0.2, 17.6±0.2, 18.1±0.2, 18.5±0.2, 20.1±0.2, 20.7±0.2, 21.07±0.2, 22.2±0.2, 25.07±0.2, 26.0±0.2, 27.9±0.2, and 28.7±0.2.

[0353] Example 6: Preparation and Characterization of L-Tartrate Salt of Plinabulin (Form 6)

[0354] 1. Experimental methods

[0355] 50 mg (0.148 mmol) of Plinabulin was added to 30 ml of methanol (or dichloromethane or other solvent systems) and stirred until the solution became clear. 22 mg of L-tartaric acid was added and stirred continuously until a yellow transparent solution was obtained. The solution was filtered, allowed to stand, and evaporated to obtain a sample.

[0356] 2. Nuclear Magnetic Resonance Data

[0357] The NMR spectrum of Form 6 is shown in Figure 14.

[0358] 1H NMR (400MHz, DMSO-d6) δ12.29(s,0.5H),12.23(d,J=13.1Hz,1H),12.02(s,0.5H),10.70(s,0.5H),9.98(s,0.5H),7.80(d,J=10.4Hz,1H),7.50(d t,J=9.2,3.2Hz,2H),7.38(dd,J=8.4,6.9Hz,1H),7.33-7.15(m,2H),6.8 2(s,0.5H),6.73(d,J=14.9Hz,1H),6.48(s,0.5H),1.34(d,J=3.5Hz,9H).

[0359] 3. XRD data

[0360] The powder XRD spectrum of Form 6 is shown in Figure 15.

[0361] In the X-ray powder diffraction pattern at room temperature (25°C) and Cu-kα radiation, the crystalline form 6 of the compound Plinabulin L-tartrate will show at least 21 of the following diffraction peaks, 40 2θ values ​​are provided, and the peak positions are as follows: 8.2±0.2, 8.6±0.2, 9.2±0.2, 11.2±0.2, 13.1±0.2, 13.9±0.2, 14.1±0.2, 14.8±0.2, 15.5±0.2, 16.1±0.2, 16.3±0.2, 17.6±0.2, 18.5±0.2, 19.2±0.2, 19.4±0.2, 19.8±0.2, 20.9±0.2, 21.2±0.2, 22. .4±0.2, 22.9±0.2, 23.4±0.2, 23.8±0.2, 24.2±0.2, 24.5±0.2, 25.4±0.2, 25.8±0.2, 26.6±0.2, 27.2±0.2, 27.5±0.2, 27.9±0.2, 28.3±0.2, 28.9±0.2, 29.3±0.2, 29.9±0.2, 31.3±0.2, 31.8±0.2, 32.4±0.2, 33.0±0.2, 35.7±0.2, and 38.6±0.2.

[0362] Example 7: Preparation and Characterization of D-malate Compound of Plinabulin (Form 7)

[0363] 1. Experimental methods

[0364] 50 mg (0.148 mmol) of Plinabulin was added to 20 ml of methanol (or a solvent system such as dichloromethane, acetonitrile, or acetone) and stirred until the solution became clear. 22.3 mg of D-malic acid was added and continued stirring. If there was no significant change, the solution became yellow and transparent. The solution was filtered and allowed to stand for evaporation to obtain a sample.

[0365] 2. Nuclear Magnetic Resonance Data

[0366] The NMR spectrum of Form 7 is shown in Figure 16.

[0367] 1 H NMR(400MHz,DMSO-d6)δ12.31-12.19(m,1H),12.02(s,1H),10.70(s,1H),7.84-7.76(m,1H),7.59-7.49(m,1H),7.49-7 .46(m,1H),7.38(t,J=7.7Hz,1H),7.32-7.15(m,3H),6.73(d,J=14.9Hz,1H),6.48(s,1H),1.34(dd,J=3.6,0.7Hz,9H).

[0368] 3. XRD data

[0369] The powder XRD spectrum of Form 7 is shown in Figure 17.

[0370] In the X-ray powder diffraction pattern at room temperature (25°C) and Cu-kα radiation, the crystalline form 7 of the compound Plinabulin D-malate will show at least 20 of the following diffraction peaks, 39 2θ values ​​are provided, and the peak positions are as follows: 8.1±0.2, 9.2±0.2, 11.1±0.2, 13.0±0.2, 13.9±0.2, 14.1±0.2, 14.8±0.2, 15.4±0.2, 16.0±0.2, 16.2±0.2, 17.6±0.2, 18.4±0.2, 19.1±0.2, 19.7±0.2, 20.8±0.2, 21.2±0.2, 22.4±0.2, 22.8±0.2 .2, 23.4±0.2, 23.8±0.2, 24.2±0.2, 24.4±0.2, 25.3±0.2, 25.7±0.2, 26.5±0.2, 27.1±0.2, 27.4±0.2, 27.9±0.2, 28.3±0.2, 28.9±0.2, 29.3±0.2, 30.6±0.2, 31.2±0.2, 31.7±0.2, 32.4±0.2, 32.9±0.2, 35.7±0.2, 38.5±0.2, and 38.8±0.2.

[0371] Example 8: Preparation and Characterization of L-Malate Salt of Plinabulin (Form 8)

[0372] 1. Experimental methods

[0373] Add 50 mg (0.148 mmol) of Plinabulin to 20 ml of methanol (or a solvent system such as dichloromethane, acetonitrile, or acetone), stir until the solution becomes clear, then add 20.8 mg (0.15 mmol) of L-malic acid, continue stirring, filter, let stand, and evaporate to obtain a sample.

[0374] 2. Nuclear Magnetic Resonance Data

[0375] The NMR spectrum of Form 8 is shown in Figure 18.

[0376] 1 H NMR (400MHz, DMSO-d6) δ7.81 (s, 1H), 7.49 (d, J = 7.6Hz, 4H), 7.38 (t, J = 7.4Hz, 3 H),6.82(s,1H),6.71(s,1H),1.80(t,J=7.3Hz,9H),1.35(s,28H),1.20(s,6H).

[0377] 3. XRD data

[0378] The powder XRD spectrum of Form 8 is shown in Figure 19.

[0379] In the X-ray powder diffraction pattern at room temperature (25°C) and Cu-kα radiation, the crystalline form 8 of the compound Plinabulin L-malate will show at least 11 of the following diffraction peaks. 20 2θ values ​​are provided, and the peak positions are as follows: 10.2±0.2, 13.8±0.2, 20.0±0.2, 20.6±0.2, 21.5±0.2, 22.1±0.2, 23.2±0.2, 23.8±0.2, 24.3±0.2, 25.7±0.2, 26.2±0.2, 27.7±0.2, 28.9±0.2, 30.1±0.2, 31.1±0.2, 33.1±0.2, 33.7±0.2, 35.7±0.2, 38.0±0.2, and 38.7±0.2.

[0380] Example 9: Preparation and Characterization of L-Glutamate Salt of Plinabulin (Form 9)

[0381] 1. Experimental methods

[0382] 51 mg (0.151 mmol) of Plinabulin was added to 30 ml of methanol (or a solvent system such as dichloromethane, acetonitrile, or acetone), and the solution was dissolved under stirring. Then, 23 mg (0.15 mmol) of L-glutamic acid was added, and the stirring was continued. The sample was filtered and allowed to stand for evaporation to obtain a sample.

[0383] 2. Nuclear Magnetic Resonance Data

[0384] The NMR spectrum of Form 9 is shown in Figure 20.

[0385] 1 H NMR(400MHz,DMSO-d6)δ12.23(d,J=12.8Hz,1H),12.02(s,1H),10.70(s,1H),7.79(s,1H),7. 50(dt,J=8.1,1.2Hz,2H),7.28-7.15(m,3H),6.75(d,J=0.7Hz,1H),6.48(s,1H),1.34(s,9H).

[0386] 3. XRD data

[0387] The powder XRD spectrum of Form 9 is shown in Figure 21.

[0388] In the X-ray powder diffraction pattern at room temperature (25°C) and Cu-kα radiation, the crystalline form 9 of the compound Plinabulin L-glutamate will show at least 11 of the following diffraction peaks. 20 2θ values ​​are provided, and the peak positions are as follows: 7.3±0.2, 11.2±0.2, 14.7±0.2, 15.4±0.2, 17.2±0.2, 17.5±0.2, 18.1±0.2, 19.8±0.2, 20.6±0.2, 22.1±0.2, 22.5±0.2, 23.1±0.2, 23.8±0.2, 24.9±0.2, 26.4±0.2, 27.5±0.2, 28.6±0.2, 29.2±0.2, 30.4±0.2, and 39.2±0.2.

[0389] Example 10: Preparation and Characterization of Plinabulin Citrate Compound (Form 10)

[0390] 1. Experimental methods

[0391] 51 mg (0.151 mmol) of Plinabulin was added to 30 ml of methanol (or a solvent system such as dichloromethane, acetonitrile, or acetone) and stirred until the solution became clear. 30 mg (0.14 mmol) of citric acid monohydrate was then added. If no significant change was observed, the solution was filtered, allowed to stand, and evaporated to obtain a sample.

[0392] 2. Nuclear Magnetic Resonance Data

[0393] The NMR spectrum of Form 10 is shown in Figure 22.

[0394] 1 H NMR(400MHz, DMSO-d6)δ12.25(t,J=14.6Hz,1H),12.02(s,1H),10.70(s,1H),7.84-7.76(m,1H),7.50(ddd, J=5.6,4.4,2.7Hz,3H),7.38(dd,J=8.4,6.9Hz,1H),7.32-7.15(m,3H),6.48(s,1H),1.34(d,J=3.5Hz,12H).

[0395] 3. XRD data

[0396] The powder XRD spectrum of Form 10 is shown in Figure 23.

[0397] In the X-ray powder diffraction pattern at room temperature (25°C) and Cu-kα radiation, the crystalline form 10 of the compound Plinabulin citrate will show at least 20 of the following diffraction peaks, 38 2θ values ​​are provided, and the peak positions are as follows:

[0398] 3.5±0.2, 7.3±0.2, 8.1±0.2, 11.2±0.2, 13.0±0.2, 14.6±0.2, 15.4±0.2, 16.0±0.2, 16.3±0.2, 17.1±0.2, 17.4±0.2, 18.1±0.2, 19.2±0.2, 19.7±0.2, 20.6±0.2, 22.0±0.2, 22.4±0.2, 23.1±0.2, 23.8±0.2, 4.2±0.2, 24.4±0.2, 24.8±0.2, 25.3±0.2, 25.7±0.2, 26.3±0.2, 26.6±0.2, 27.5±0.2, 27.9±0.2, 28.6±0.2, 29.2±0.2, 30.4±0.2, 32.0±0.2, 33.0±0.2, 33.9±0.2, 34.1±0.2, 35.3±0.2, 38.6±0.2, 39.1±0.2.

[0399] Example 11: Preparation and Characterization of Plinabulin Benzoate Compound (Form 11)

[0400] 1. Experimental methods

[0401] 51 mg (0.151 mmol) of Plinabulin was added to 30 ml of methanol (or a solvent system such as dichloromethane or ethyl acetate) and stirred until the solution became clear. Then, 19 mg (0.156 mmol) of benzoic acid was added and stirring was continued. If there was no obvious change, the solution was filtered and allowed to stand for evaporation to obtain a sample.

[0402] 2. Nuclear Magnetic Resonance Data

[0403] The NMR spectrum of Form 11 is shown in Figure 24.

[0404] 1 H NMR (400MHz, DMSO-d6) δ10.23(s,1H),7.59-7.46(m,4H),7.39(dd,J=8.4,6.9Hz,2H),7.34-7.21(m,4H),6.75(s,1H),6.67(s,1H),1.32(s,9H).

[0405] 3. XRD data

[0406] The powder XRD spectrum of Form 11 is shown in Figure 25.

[0407] In the X-ray powder diffraction pattern at room temperature (25°C) and Cu-kα radiation, the crystalline form 11 of the compound Plinabulin benzoate will show at least 17 of the following diffraction peaks, 32 2θ values ​​are provided, and the peak positions are as follows:

[0408] 7.3±0.2, 8.1±0.2, 11.0±0.2, 11.2±0.2, 12.3±0.2, 14.6±0.2, 15.4±0.2, 16.4±0.2, 17.2±0.2, 17.5±0.2, 18.1±0.2, 19.7±0.2, 20.6±0.2, 21.4±0.2, 22.0±0.2, 22.4±0.2 3.1±0.2, 23.8±0.2, 24.4±0.2, 24.8±0.2, 25.7±0.2, 26.3±0.2, 26.6±0.2, 27.5±0.2, 28.6±0.2, 29.2±0.2, 30.4±0.2, 31.0±0.2, 33.0±0.2, 33.9±0.2, 35.3±0.2, 39.2±0.2.

[0409] Example 12: Preparation and Characterization of Plinabulin Salicylate Compound (Form 12)

[0410] 1. Experimental methods

[0411] 51 mg (0.151 mmol) of Plinabulin was added to 30 ml of methanol (or a solvent system such as dichloromethane, acetonitrile, or acetone), and the solution was dissolved under stirring. Then 21 mg (0.15 mmol) of salicylic acid was added, and the stirring was continued. The solution was filtered and allowed to stand for evaporation to obtain a sample.

[0412] 2. Nuclear Magnetic Resonance Data

[0413] The NMR spectrum of Form 12 is shown in Figure 26.

[0414] 1 H NMR(400MHz,DMSO-d6)δ12.25(s,1H),12.02(s,1H),10.70(s,1H),7.79(s,1H),7.57-7.46(m,3H),7.29-7.20 (m,3H),7.20-7.14(m,1H),6.75(d,J=1.3Hz,1H),6.48(s,1H),1.34(d,J=1.3Hz,11H),0.94(d,J=1.3Hz,1H).

[0415] 3. XRD data

[0416] The powder XRD spectrum of Form 12 is shown in Figure 27.

[0417] In the X-ray powder diffraction pattern at room temperature (25°C) and Cu-kα radiation, the crystalline form 12 of the compound Plinabulin salicylate will show at least 18 of the following diffraction peaks, 34 2θ values ​​are provided, and the peak positions are as follows:

[0418] 6.2±0.2, 7.3±0.2, 11.2±0.2, 12.3±0.2, 14.6±0.2, 15.4±0.2, 16.4±0.2, 17.1±0.2, 17.4±0.2, 18.1±0.2, 19.2±0.2, 19.7±0.2, 20.6±0.2, 22.0±0.2, 22.4±0.2, 23.1±0.2, 23.8±0.2, 4.4±0.2, 24.8±0.2, 25.4±0.2, 25.7±0.2, 26.3±0.2, 26.6±0.2, 27.5±0.2, 28.5±0.2, 29.2±0.2, 30.4±0.2, 31.0±0.2, 31.5±0.2, 32.0±0.2, 33.0±0.2, 34.0±0.2, 35.3±0.2, 39.1±0.2.

[0419] Example 13: Preparation and Characterization of Plinabulin Methanesulfonate Compound (Form 13)

[0420] 1. Experimental methods

[0421] 50 mg (0.148 mmol) of Plinabulin was added to 30 ml of methanol (or a solvent system such as dichloromethane, acetonitrile, or acetone), and the solution was dissolved under stirring. Then, 5 drops of methanesulfonic acid were added, and stirring was continued. The solution was filtered and allowed to stand for evaporation to obtain a sample.

[0422] 2. Nuclear Magnetic Resonance Data

[0423] The NMR spectrum of Form 13 is shown in Figure 28.

[0424] 1 H NMR(400MHz,DMSO-d6)δ10.22(s,1H),7.53-7.46(m,2H),7.39(dd,J=8.4,6.8H z,2H),7.34-7.26(m,1H),6.75(s,1H),6.67(s,1H),2.30(s,3H),1.32(s,9H).

[0425] 3. XRD data

[0426] The powder XRD spectrum of Form 13 is shown in Figure 29.

[0427] In the X-ray powder diffraction pattern at room temperature (25°C) and Cu-kα radiation, the crystalline form 13 of the compound Plinabulin mesylate will show at least 17 of the following diffraction peaks, 33 2θ values ​​are provided, and the peak positions are as follows:

[0428] 9.9±0.2, 12.1±0.2, 14.2±0.2, 14.6±0.2, 15.6±0.2, 16.5±0.2, 18.0±0.2, 18.9±0.2, 19.8±0.2, 20.5±0.2, 21.0±0.2, 21.9±0.2, 23.0±0.2, 23.5±0.2, 23.9±0.2, 24.4±0.2, 24.9± 0.2, 26.3±0.2, 26.7±0.2, 27.4±0.2, 27.9±0.2, 28.3±0.2, 28.8±0.2, 29.4±0.2, 29.9±0.2, 30.4±0.2, 31.2±0.2, 31.6±0.2, 33.5±0.2, 34.2±0.2, 35.1±0.2, 37.9±0.2, and 39.2±0.2.

[0429] 4. TG data analysis

[0430] The TG curve of Form 13 is shown in Figure 30. The first stage: Gradual weight loss from the start of heating, ending at around 170°C; the second stage always starts at 270°C until complete decomposition.

[0431] Example 14: Preparation and Characterization of Plinabulin Ethylate Compound (Form 14)

[0432] 1. Experimental methods

[0433] 50 mg (0.148 mmol) of Plinabulin was added to 30 ml of methanol (or dichloromethane, acetonitrile and other solvent systems), and the solution was dissolved under stirring. Then 4 drops of ethanesulfonic acid were added, and the stirring was continued. The sample was filtered and allowed to stand for evaporation to obtain a sample.

[0434] 2. Nuclear Magnetic Resonance Data

[0435] The NMR spectrum of Form 14 is shown in Figure 31.

[0436] 1 H NMR (400MHz, DMSO-d6) δ10.20 (s, 1H), 7.53-7.46 (m, 2H), 7.39 (dd, J = 8.4, 6.8Hz, 2H), 7.34-7. 25(m,1H),6.75(s,1H),6.68(s,1H),2.38(q,J=7.4Hz,2H),1.32(s,9H),1.03(t,J=7.4Hz,3H).

[0437] 3. XRD data

[0438] The powder XRD spectrum of Form 14 is shown in Figure 32.

[0439] In the X-ray powder diffraction pattern at room temperature (25°C) and Cu-kα radiation, the crystalline form 14 of the compound Plinabulin ethanesulfonate will show at least 13 of the following diffraction peaks, 24 2θ values ​​are provided, and the peak positions are as follows:

[0440] 4.2±0.2, 5.5±0.2, 7.6±0.2, 8.7±0.2, 9.89±0.2, 11.7±0.2, 13.6±0.2, 14.2±0.2, 15.1±0.2, 16.0±0.2, 16.6±0.2, 17.3±0.2, 17.9±0.2, 18.4±0.2, 19.8±0.2, 20.9±0.2, 21.9±0.2, 23.4±0.2, 24.4±0.2, 25.4±0.2, 27.6±0.2, 28.7±0.2, 30.7±0.2, 37.2±0.2.

[0441] 4. TG data analysis

[0442] The TG curve of Form 14 is shown in Figure 33. The first stage: Gradual weight loss from the start of heating, ending at around 120°C; the second stage always starts at 250°C until complete decomposition.

[0443] Example 15: Preparation and Characterization of Plinabulin Besylate Compound (Form 15)

[0444] 1. Experimental methods

[0445] 50 mg (0.148 mmol) of Plinabulin was added to 20 ml of methanol (or a solvent system such as dichloromethane, acetonitrile, or ethyl acetate), and the solution was dissolved under stirring. Then, 25 mg (0.4 mmol) of benzenesulfonic acid hydrate was added, and the stirring was continued. The sample was filtered and allowed to stand for evaporation to obtain a sample.

[0446] 2. Nuclear Magnetic Resonance Data

[0447] The NMR spectrum of Form 15 is shown in Figure 34.

[0448] 1 H NMR (300MHz, MEOD) δ8.80(s,1H),7.84-7.81(q,2H),7.52-7.37(m,7H),6.99(s,1H),6.72(s,1H),1.42(s,9H).

[0449] 3. XRD data

[0450] The powder XRD spectrum of Form 15 is shown in Figure 35.

[0451] In the X-ray powder diffraction pattern at room temperature (25°C) and Cu-kα radiation, the crystalline form 15 of the compound Plinabulin besylate will show at least 16 of the following diffraction peaks, 30 2θ values ​​are provided, and the peak positions are as follows:

[0452] 5.7±0.2, 6.8±0.2, 8.6±0.2, 9.0±0.2, 9.3±0.2, 10.0±0.2, 10.9±0.2, 11.5±0.2, 12.5±0.2, 13.7±0.2, 14.9±0.2, 16.2±0.2, 16.6±0.2, 17.4±0.2, 18.4±0.2, 19 .5±0.2, 19.9±0.2, 20.6±0.2, 22.4±0.2, 22.8±0.2, 23.9±0.2, 24.6±0.2, 25.2±0.2, 26.3±0.2, 27.6±0.2, 28.8±0.2, 29.7±0.2, 30.4±0.2, 36.3±0.2, 36.7±0.2.

[0453] 4. TG data analysis

[0454] The TG curve of Form 15 is shown in Figure 36. In the first stage, there is a gradual weight loss from the beginning of heating, ending at around 280°C. In the second stage, the starting temperature is always 280°C until the final complete decomposition.

[0455] Example 16: Preparation and Characterization of Plinabulin p-Toluenesulfonate Compound (Form 16)

[0456] 1. Experimental methods

[0457] 50.5 mg (0.150 mmol) of Plinabulin was added to 20 ml of methanol (or a solvent system such as dichloromethane or acetonitrile), and the solution was dissolved under stirring. Then 36 mg (0.209 mmol) of p-toluenesulfonic acid was added, and the stirring was continued. The sample was filtered and allowed to stand for evaporation to obtain a sample.

[0458] 2. Nuclear Magnetic Resonance Data

[0459] The NMR spectrum of Form 16 is shown in Figure 37.

[0460] 1 H NMR (500MHz, DMSO-d6) δ8.97(s,1H),8.28(s,1H),7.75-7.73(d,J=8Hz 2H),7.47-7.44(q,4H),7.37-7.34(m,1H),7.18-7.17(d,J=8Hz 2H),6.93(s,1H),6.81(s,1H),2.36(s,6H),1.42(s,9H).

[0461] 3. XRD data

[0462] The powder XRD spectrum of Form 16 is shown in Figure 38.

[0463] In the X-ray powder diffraction pattern at room temperature (25°C) and Cu-kα radiation, the crystalline form 16 of the compound Plinabulin p-toluenesulfonate will show at least 13 of the following diffraction peaks, 24 2θ values ​​are provided, and the peak positions are as follows:

[0464] 0.2, 6.3±0.2, 6.6±0.2, 8.5±0.2, 8.8±0.2, 12.7±0.2, 14.3±0.2, 15.1±0.2, 16.2±0.2, 17.0±0.2, 17.7±0.2, 18.5±0.2, 18.8±0.2, 20.0±0.2, 20.4±0.2, 21.5±0.2, 22.4±0.2, 23.6±0.2, 24.0±0.2, 24.5±0.2, 26.2±0.2, 27.4±0.2, 28.4±0.2, 29.2±0.2, 31.5±0.2.

[0465] 4. TG data analysis

[0466] The TG curve of Form 16 is shown in Figure 39. Stage 1: Gradual weight loss from the beginning of heating until complete decomposition.

[0467] Example 17: Preparation and Characterization of Plinabulin Acetate Compound (Form 17)

[0468] 1. Experimental methods

[0469] 50 mg (0.148 mmol) of Plinabulin was added to 35 ml of methanol (or a solvent system such as acetonitrile, acetone, or dichloromethane), and the solution was dissolved under stirring. Then 15 mg (0.25 mmol) of acetic acid was added, and the stirring was continued. The solution was filtered, allowed to stand, and evaporated to obtain a sample.

[0470] 2. Nuclear Magnetic Resonance Data

[0471] The NMR spectrum of Form 17 is shown in Figure 40.

[0472] 1 H NMR (400MHz, DMSO-d6) δ12.27(d,J=15.1Hz,1H),12.21(s,1H),7.80(dd,J=10.5,0.7Hz,1H),7.50(ddd,J=7.4,4.7,1.4 Hz,2H),7.38(dd,J=8.4,6.9Hz,1H),7.33-7.14(m,2H),6.82(d,J=0.7Hz,1H),6.77-6.69(m,1H),1.34(d,J=3.5Hz,9H).

[0473] 3. XRD data

[0474] The powder XRD spectrum of Form 17 is shown in Figure 41.

[0475] In the X-ray powder diffraction pattern at room temperature (25°C) and Cu-kα radiation, the crystalline form 17 of the compound Plinabulin acetate will show at least 21 of the following diffraction peaks, 39 2θ values ​​are provided, and the peak positions are as follows:

[0476] 8.2±0.2, 9.2±0.2, 11.2±0.2, 13.1±0.2, 13.9±0.2, 14.1±0.2, 14.8±0.2, 15.5±0.2, 16.0±0.2, 16.3±0.2, 17.6±0.2, 18.4±0.2, 19.1±0.2, 19.8±0.2, 20.8±0.2, 21.2±0.2, 22.4±0.2, 22.8±0.2, 23.8±0.2, 24.2± 0.2, 24.5±0.2, 25.3±0.2, 25.7±0.2, 26.5±0.2, 27.1±0.2, 27.4±0.2, 27.9±0.2, 28.3±0.2; 28.9±0.2, 29.3±0.2, 30.6±0.2, 31.2±0.2, 31.7±0.2, 32.4±0.2, 33.0±0.2, 34.6±0.2, 35.7±0.2, 37.2±0.2, 38.5±0.2.

[0477] Example 18: Preparation and Characterization of Trifluoroacetate Salt of Plinabulin (Form 18)

[0478] 1. Experimental methods

[0479] Dissolve 50 mg (0.148 mmol) of Plinabulin in 40 ml of methanol (or other solvents such as dichloromethane or acetonitrile). Stir until the solution becomes clear. Add three drops of trifluoroacetic acid and continue stirring. Milky white floccules will form and the solution will become almost colorless. Evaporate to obtain the sample.

[0480] 2. Nuclear Magnetic Resonance Data

[0481] The NMR spectrum of Form 18 is shown in Figure 42.

[0482] 1H NMR(400MHz,DMSO-d6)δ12.57(s,1H),11.96(s,1H),10.06(s,1H),8.02(s,1H),7.4 9(d,J=7.4Hz,2H),7.38(s,1H),7.29(s,1H),6.77(s,1H),6.73(s,1H),1.34(s,9H).

[0483] 3. XRD data

[0484] The powder XRD spectrum of Form 18 is shown in Figure 43.

[0485] In the X-ray powder diffraction pattern at room temperature (25°C) and Cu-kα radiation, the crystalline form 18 of the compound Plinabulin trifluoroacetate will show at least 18 of the following diffraction peaks, 35 2θ values ​​are provided, and the peak positions are as follows:

[0486] 6.7±0.2, 9.3±0.2, 10.5±0.2, 13.6±0.2, 14.8±0.2, 15.5±0.2, 17.0±0.2, 17.6±0.2, 18.1±0.2, 18.6±0.2, 19.6±0.2, 20.0±0.2, 20.5±0.2, 21.1±0.2, 22.3±0.2, 22.9±0.2, 23.5±0.2, 23.9± 0.2, 24.4±0.2, 24.7±0.2, 25.4±0.2, 26.1±0.2, 26.9±0.2, 27.4±0.2, 28.0±0.2, 28.7±0.2, 29.2±0.2, 29.9±0.2, 31.1±0.2, 31.7±0.2, 32.8±0.2, 34.5±0.2, 35.9±0.2, 37.0±0.2, 37.8±0.2.

[0487] 4. TG data analysis

[0488] The TG curve of Form 18 is shown in Figure 44. The first stage: Gradual weight loss from the start of heating, ending at around 250°C; the second stage always starts at 250°C until complete decomposition.

[0489] Example 19: Preparation and Characterization of Plinabulin Propionate Compound (Form 19)

[0490] 1. Experimental methods

[0491] Dissolve 50 mg (0.148 mmol) of Plinabulin in 20 ml of methanol (or other solvents such as dichloromethane, acetonitrile, or acetone). Stirring results in a clear, yellow, transparent solution. Add 6 drops of propionic acid and continue stirring. No significant change occurs. Evaporate to obtain a sample.

[0492] 2. Nuclear Magnetic Resonance Data

[0493] The NMR spectrum of Form 19 is shown in Figure 45.

[0494] 1 H NMR(400MHz,DMSO-d6)δ12.02(s,1H),10.70(s,1H),7.78(s,1H),7.66-7.39 (m,2H),7.37-7.04(m,3H),6.75(d,J=0.6Hz,1H),6.48(s,1H),1.34(s,9H).

[0495] 3. XRD data

[0496] The powder XRD spectrum of Form 19 is shown in Figure 46.

[0497] In the X-ray powder diffraction pattern at room temperature (25°C) and Cu-kα radiation, the crystalline form 19 of the compound Plinabulin propionate will show at least 16 of the following diffraction peaks, 30 2θ values ​​are provided, and the peak positions are as follows:

[0498] 7.3±0.2, 11.2±0.2, 14.6±0.2, 15.4±0.2, 16.4±0.2, 17.2±0.2, 17.4±0.2, 18.0±0.2, 19.2±0.2, 19.7±0.2, 20.6±0.2, 22.5±0.2, 23.1±0.2, 23.8±0.2, 24.4±0.2, 24.8±0.2, 25.7±0.2, 26.3±0.2, 26.6±0.2, 27.5±0.2, 28.5±0.2, 29.2±0.2, 30.4±0.2, 31.6±0.2, 32.0±0.2, 33.0±0.2, 34.1±0.2, 35.3±0.2, 36.9±0.2, 39.1±0.2.

[0499] Example 20: Preparation and Characterization of Plinabulin Hydrochloride Compound (Form 20)

[0500] 1. Experimental methods

[0501] 50 mg (0.148 mmol) of Plinabulin was added to 25 ml of methanol (or a solvent system such as acetonitrile or dichloromethane), and the solution was dissolved under stirring. Then, 4 drops of 35% aqueous hydrochloric acid solution were added, and the stirring was continued. The solution was filtered and allowed to stand for evaporation to obtain a sample.

[0502] 2. Nuclear Magnetic Resonance Data

[0503] The NMR spectrum of Form 20 is shown in Figure 47.

[0504] 1 H NMR(400MHz,DMSO-d6)δ11.52(s,1H),10.21(s,1H),8.41(s,1H),7.53-7.46(m,2H ),7.39(t,J=7.6Hz,3H),7.34-7.25(m,1H),6.75(s,1H),6.68(s,1H),1.32(s,9H).

[0505] 3. XRD data

[0506] The powder XRD spectrum of Form 20 is shown in Figure 48.

[0507] In the X-ray powder diffraction pattern at room temperature (25°C) and Cu-kα radiation, the crystalline form 20 of the compound Plinabulin hydrochloride will show at least 17 of the following diffraction peaks, 32 2θ values ​​are provided, and the peak positions are as follows:

[0508] 4.6±0.2, 9.1±0.2, 12.2±0.2, 13.7±0.2, 14.5±0.2, 15.1±0.2, 17.7±0.2, 18.2±0.2, 19.0±0.2, 19.7±0.2, 21.0±0.2, 21.6±0.2, 22.8±0.2, 23.3±0.2, 24.1±0.2, 24.6±0.2, 4.9±0.2, 26.2±0.2, 26.6±0.2, 27.2±0.2, 27.5±0.2, 28.5±0.2, 28.8±0.2, 29.7±0.2, 30.2±0.2, 30.6±0.2, 31.7±0.2, 32.2±0.2, 33.0±0.2, 35.3±0.2, 36.0±0.2, 38.8±0.2.

[0509] 4. TG data analysis

[0510] The TG curve of Form 20 is shown in Figure 49. The first stage: Gradual weight loss from the start of heating, ending at around 150°C; the second stage ends at around 260°C; and the third stage always starts at 280°C until complete decomposition.

[0511] Example 21: Preparation and Characterization of Plinabulin Hydrobromide Compound (Form 21)

[0512] 1. Experimental methods

[0513] 50 mg (0.148 mmol) of Plinabulin was added to 20 ml of methanol (or a solvent system such as acetonitrile or dichloromethane), and the solution was dissolved under stirring. Then, 1 drop of 48% hydrobromic acid solution was added, and the stirring was continued. The solution was filtered and allowed to stand for evaporation to obtain a sample.

[0514] 2. Nuclear Magnetic Resonance Data

[0515] The NMR spectrum of Form 21 is shown in Figure 50.

[0516] 1 H NMR (400MHz, DMSO-d6) δ10.22(s,1H),7.53-7.46(m,2H),7.39(dd,J=8.4,6.9Hz,2H),7.34-7.25(m,1H),6.75(s,1H),6.67(s,1H),1.32(s,9H).

[0517] 3. XRD data

[0518] The powder XRD spectrum of Form 21 is shown in Figure 51.

[0519] In the X-ray powder diffraction pattern at room temperature (25°C) and Cu-kα radiation, the crystalline form 21 of the compound Plinabulin hydrobromide will show at least 21 of the following diffraction peaks, 41 2θ values ​​are provided, and the peak positions are as follows:

[0520] 9.0±0.2, 11.2±0.2, 11.4±0.2, 12.1±0.2, 12.8±0.2, 13.5±0.2, 14.8±0.2, 15.9±0.2, 16.1±0.2, 17.2±0.2, 17.7±0.2, 18.9±0.2, 19.4±0.2, 197±0.2, 20.2±0.2, 20.9±0.2, 21.6±0.2, 22.9±0.2, 23.8±0.2, 24.7±0.2, 25.1± 0.2, 25.5±0.2, 26.1±0.2, 26.3±0.2, 26.8±0.2, 27.3±0.2, 27.6±0.2, 28.3±0.2, 28.8±0.2, 29.7±0.2, 29.9±0.2, 30.5±0.2, 31.5±0.2, 32.3±0.2, 32.6±0.2, 32.9±0.2, 33.4±0.2, 34.6±0.2, 36.6±0.2, 37.0±0.2, 38.6±0.2.

[0521] 4. TG data analysis

[0522] The TG curve of Form 21 is shown in Figure 52. The first stage: Gradual weight loss from the beginning of heating, ending at around 300°C; the second stage ends at around 310°C, until it is completely decomposed.

[0523] Example 22: Preparation and Characterization of Plinabulin Sulfate Compound (Form 22)

[0524] 1. Experimental methods

[0525] 50.7 mg of Plinabulin was dissolved in 16 ml of methanol (or other solvent systems such as acetonitrile and dichloromethane). The solution became clear and yellow and transparent under stirring. After adding 3 drops of sulfuric acid and continuing to stir, the color of the system became lighter and light yellow and transparent.

[0526] 2. Nuclear Magnetic Resonance Data

[0527] The NMR spectrum of Form 22 is shown in Figure 53.

[0528] 1 H NMR (400MHz, DMSO-d6) δ10.25(s,1H),7.53-7.46(m,2H),7.39(dd,J=8.4,6.8Hz,2H),7.34-7.26(m,1H),6.76(s,1H),6.65(s,1H),1.32(s,9H).

[0529] 3. XRD data

[0530] The powder XRD spectrum of Form 22 is shown in Figure 54.

[0531] In the X-ray powder diffraction pattern at room temperature (25°C) and Cu-kα radiation, the crystalline form 22 of the compound Plinabulin sulfuric acid will show at least 20 of the following diffraction peaks, 38 2θ values ​​are provided, and the peak positions are as follows:

[0532] 4.3±0.2, 8.4±0.2, 10.5±0.2, 12.4±0.2, 14.4±0.2, 14.7±0.2, 15.3±0.2, 16.4±0.2, 16.8±0.2, 17.2±0.2, 18.3±0.2, 19.1±0.2, 19.3±0.2, 20.5±0.2, 21.0±0.2, 21.8±0.2, 22.2±0.2, 23.0±0.2, 23.5±0.2 , 23.8±0.2, 24.1±0.2, 24.7±0.2, 24.9±0.2, 25.8±0.2, 26.4±0.2, 27.6±0.2, 28.1±0.2, 29±0.2, 29.9±0.2, 30.8±0.2, 31.5±0.2, 31.8±0.2, 32.1±0.2, 33.8±0.2, 34.6±0.2, 35.9±0.2, 36.5±0.2, 38±0.2.

[0533] 4. TG data analysis

[0534] The TG curve of Form 22 is shown in Figure 55. The first stage: gradual weight loss from the beginning of heating, ending at around 220°C; the second stage continues until complete decomposition.

[0535] Example 23: Preparation and Characterization of Plinabulin Phosphate Compound (Form 23)

[0536] 1. Experimental methods

[0537] 50.1 mg of Plinabulin was dissolved in 17 ml of methanol (or other solvent systems such as acetonitrile and dichloromethane). The solution became clear under stirring. After adding 3 drops of phosphoric acid and continuing to stir, there was no significant change.

[0538] 2. Nuclear Magnetic Resonance Data

[0539] The NMR spectrum of Form 23 is shown in Figure 56.

[0540] 1H NMR(400MHz, DMSO-d6)δ7.81(t,J=0.9Hz,1H),7.52-7.45(m,2H),7.38(t,J=7.7 Hz,2H),7.29(d,J=7.4Hz,1H),6.82(d,J=0.6Hz,1H),6.71(s,1H),1.35(s,9H).

[0541] 3. XRD data

[0542] The powder XRD spectrum of Form 23 is shown in Figure 57.

[0543] In the X-ray powder diffraction pattern at room temperature (25°C) and Cu-kα radiation, the crystalline form 23 of the compound Plinabulin Phosphate will show at least 9 of the following diffraction peaks, 17 2θ values ​​are provided, and the peak positions are as follows:

[0544] 8.0±0.2, 9.1±0.2, 12.0±0.2, 16.0±0.2, 16.6±0.2, 17.8±0.2, 18.2±0.2, 18.5±0.2, 19.8±0.2, 21.5±0.2, 24.1±0.2, 24.4±0.2, 24.8±0.2, 25.8±0.2, 27.8±0.2, 28.6±0.2, 30.4±0.2.

[0545] 4. TG data analysis

[0546] The TG curve of Form 23 is shown in Figure 58. The first stage: gradual weight loss from the beginning of heating, ending at around 300°C; the second stage continues until complete decomposition.

[0547] Example 24: Preparation and Characterization of Plinabulin Nitrate Compound (Form 24)

[0548] 1. Experimental methods

[0549] 50 mg of Plinabulin was dissolved in 15 ml of methanol (or other solvent systems such as dichloromethane, acetonitrile, acetone, etc.). The solution became clear under stirring. After adding 2 drops of nitric acid and continuing to stir, if there was no obvious change, the sample was evaporated.

[0550] 2. Nuclear Magnetic Resonance Data

[0551] The NMR spectrum of Form 24 is shown in Figure 59.

[0552] 1H NMR (400MHz, DMSO-d6) δ10.21(s,1H),7.53-7.46(m,2H),7.39(dd,J=8.4,6.8Hz,2H),7.34-7.26(m,1H),6.75(s,1H),6.68(s,1H),1.32(s,9H).

[0553] 3. XRD data

[0554] The powder XRD spectrum of Form 24 is shown in Figure 60.

[0555] In the X-ray powder diffraction pattern at room temperature (25°C) and Cu-kα radiation, the crystalline form 24 of the compound Plinabulin nitric acid will show at least 23 of the following diffraction peaks, 31 2θ values ​​are provided, and the peak positions are as follows:

[0556] 4.3±0.2, 8.6±0.2, 12.4±0.2, 12.9±0.2, 13.9±0.2, 14.4±0.2, 16.2±0.2, 16.8±0.2, 17.4±0.2, 18.0±0.2, 19.0±0.2, 19.3±0.2, 19.6±0.2, 20.4±0.2, 20.8±0.2, 22.1± 0.2, 22.5±0.2, 23.4±0.2, 23.8±0.2, 24.6±0.2, 24.9±0.2, 25.3±0.2, 26.9±0.2, 27.9±0.2, 28.3±0.2, 30.2±0.2, 31.4±0.2, 32.7±0.2, 33.8±0.2, 34.7±0.2, 36.2±0.2.

[0557] Test Example 1

[0558] The solubility test of the Plinabulin salt crystal form in the above example was performed. Methanol was gradually added to 1 mg of the above salt crystal form to detect the amount of methanol required to completely dissolve the above salt crystal form. The results are shown in Table 1 below.

[0559] Table 1 Solubility test results of the salt crystal forms in the examples

[0560] It can be seen that oxalate, trifluoroacetate, and hydrobromide salts have excellent solubility.

[0561] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A crystalline salt of a compound of formula I, in, The salt crystal form is selected from the following group: oxalate crystal form, maleate crystal form, fumarate crystal form, succinate crystal form, D-tartrate crystal form, L-tartrate crystal form, D-malate crystal form, L-malate crystal form, L-glutamate crystal form, citrate crystal form, benzoate crystal form, salicylate crystal form, methanesulfonate crystal form, ethanesulfonate crystal form, benzenesulfonate crystal form, p-toluenesulfonate crystal form, acetate crystal form, trifluoroacetate crystal form, propionate crystal form, hydrochloride crystal form, hydrobromide crystal form, sulfate crystal form, phosphate crystal form, and nitrate crystal form.

2. The salt crystal form according to claim 1, wherein The oxalate crystalline form is oxalate crystalline form Form 1, wherein the X-ray powder diffraction pattern of the crystalline form Form 1 includes 3 or more (e.g., 4 or 5) 2θ values ​​selected from the following group: 10.3±0.2, 12.5±0.2, 23.9±0.2, 25.4±0.2, 29.0±0.2; The maleate crystalline form is maleate crystalline form Form 2, wherein the X-ray powder diffraction pattern of the crystalline form Form 2 includes 2θ values ​​selected from the group consisting of: 6.7±0.2, 16.5±0.2, 22.3±0.2, and 25.4±0.2; The fumarate crystalline form is fumarate crystalline form Form 3, wherein the X-ray powder diffraction pattern of the crystalline form Form 3 includes 2θ values ​​selected from the group consisting of: 6.6±0.2, 16.4±0.2, 20.0±0.2, 22.2±0.2, and 25.3±0.2; The succinate salt crystal form is succinate salt crystal form Form 4, wherein the X-ray powder diffraction pattern of the crystal form Form 4 includes 3 or more (e.g., 4 or 5) 2θ values ​​selected from the following group: 8.2±0.2, 13.1±0.2, 20.1±0.2, 26.2±0.2, 31.6±0.2; The D-tartrate crystalline form is D-tartrate crystalline form Form 5, wherein the X-ray powder diffraction pattern of the crystalline form Form 5 includes 3 or more (e.g., 4 or 5) 2θ values ​​selected from the following group: 7.0±0.2, 18.5±0.2, 22.2±0.2, 25.07±0.2, and 26.0±0.2; The L-tartrate crystalline form is L-tartrate crystalline form Form 6, wherein the X-ray powder diffraction pattern of the crystalline form Form 6 includes 5 or more (e.g., 6, 7, 8, 9, 10) 2θ values ​​selected from the following group: 8.2±0.2, 13.1±0.2, 16.1±0.2, 19.2±0.2, 22.9±0.2, 23.8±0.2, 24.2±0.2, 25.4±0.2, 26.6±0.2, 29.3±0.2; The D-malate crystalline form is D-malate crystalline form Form 7, wherein the X-ray powder diffraction pattern of the crystalline form Form 7 includes 2θ values ​​selected from the group consisting of: 8.1±0.2, 23.8±0.2, 24.2±0.2, and 24.4±0.2; The L-malate crystalline form is L-malate crystalline form Form 8, wherein the X-ray powder diffraction pattern of the crystalline form Form 8 includes 3 or more (e.g., 4 or 5) 2θ values ​​selected from the following group: 10.2±0.2, 20.0±0.2, 20.6±0.2, 33.7±0.2, 35.7±0.2; The L-glutamate crystalline form is L-glutamate crystalline form Form 9, wherein the X-ray powder diffraction pattern of the crystalline form Form 9 includes 2θ values ​​selected from the group consisting of: 7.3±0.2, 17.2±0.2, 19.8±0.2, 22.5±0.2, and 23.1±0.2; The citrate salt crystalline form is citrate salt crystalline form Form 10, wherein the X-ray powder diffraction pattern of the crystalline form Form 10 includes 2θ values ​​selected from the group consisting of: 7.3±0.2, 17.1±0.2, 19.7±0.2, 23.1±0.2, and 23.8±0.2; The benzoate salt crystal form is benzoate salt crystal form 11, wherein the X-ray powder diffraction pattern of the crystal form 11 includes 2θ values ​​selected from the group consisting of: 7.3±0.2, 17.2±0.2, 23.1±0.2, and 23.8±0.2; The salicylate crystalline form is salicylate crystalline form Form 12, wherein the X-ray powder diffraction pattern of the crystalline form Form 12 comprises 2θ values ​​selected from the group consisting of: 7.3±0.2, 17.1±0.2, 19.7±0.2, 23.1±0.2, and 27.5±0.2; The mesylate salt crystalline form is mesylate salt crystalline form 13, wherein the X-ray powder diffraction pattern of the crystalline form 13 comprises 3 or more (e.g., 4 or 5) 2θ values ​​selected from the group consisting of: 12.1±0.2, 15.6±0.2, 19.8±0.2, 23.0±0.2, and 26.3±0.2; The ethanesulfonate crystalline form is ethanesulfonate crystalline form Form 14, wherein the X-ray powder diffraction pattern of the crystalline form Form 14 includes 3 or more (e.g., 4 or 5) 2θ values ​​selected from the following group: 5.5±0.2, 9.89±0.2, 20.9±0.2, 23.4±0.2, 25.4±0.2; The benzenesulfonate crystalline form is benzenesulfonate crystalline form Form 15, wherein the X-ray powder diffraction pattern of the crystalline form Form 15 includes 3 or more (e.g., 4 or 5) 2θ values ​​selected from the following group: 5.7±0.2, 16.2±0.2, 17.4±0.2, 18.4±0.2, 22.8±0.2; The p-toluenesulfonate crystalline form is p-toluenesulfonate crystalline form Form 16, wherein the X-ray powder diffraction pattern of the crystalline form Form 16 includes 3 or more (e.g., 4 or 5) 2θ values ​​selected from the following group: 6.6±0.2, 15.1±0.2, 16.2±0.2, 21.5±0.2, 24.5±0.2; The acetate salt crystalline form is acetate salt crystalline form 17, wherein the X-ray powder diffraction pattern of the crystalline form 17 comprises 6 or more (e.g., 7, 8, 9, 10) 2θ values ​​selected from the group consisting of 8.2±0.2, 13.1±0.2, 16.0±0.2, 22.8±0.2, 23.8±0.2, 24.2±0.2, 24.5±0.2, 25.3±0.2, 26.5±0.2, and 29.3±0.2; The trifluoroacetate crystalline form is trifluoroacetate crystalline form Form 18, wherein the X-ray powder diffraction pattern of the crystalline form Form 18 comprises 3 or more (e.g., 4) 2θ values ​​selected from the group consisting of: 9.3±0.2, 17.0±0.2, 18.6±0.2, and 25.4±0.2; The propionate salt crystalline form is propionate salt crystalline form Form 19, wherein the X-ray powder diffraction pattern of the crystalline form Form 19 includes 2θ values ​​selected from the group consisting of: 7.3±0.2, 17.2±0.2, 17.4±0.2, 22.5±0.2, and 23.1±0.2; The hydrochloride salt crystalline form is hydrochloride salt crystalline form Form 20, wherein the X-ray powder diffraction pattern of the crystalline form Form 20 includes 3 or more (e.g., 4 or 5) 2θ values ​​selected from the following group: 12.2±0.2, 13.7±0.2, 21.0±0.2, 21.6±0.2, 22.8±0.2; The hydrobromide salt crystalline form is hydrobromide salt crystalline form Form 21, wherein the X-ray powder diffraction pattern of the crystalline form Form 21 includes 3 or more (e.g., 4, 5, 6) 2θ values ​​selected from the following group: 11.2±0.2, 17.7±0.2, 19.7±0.2, 21.6±0.2, 22.9±0.2, 23.8±0.2, 24.7±0.2; The sulfate salt crystalline form is sulfate salt crystalline form Form 22, wherein the X-ray powder diffraction pattern of the crystalline form Form 22 includes 3 or more (e.g., 4) 2θ values ​​selected from the group consisting of: 4.3±0.2, 12.4±0.2, 20.5±0.2, and 23.5±0.2; The phosphate crystal form is phosphate crystal form Form 23, wherein the X-ray powder diffraction pattern of the crystal form Form 23 includes 3 or more (e.g., 4) 2θ values ​​selected from the group consisting of: 8.0±0.2, 18.5±0.2, 25.8±0.2, and 30.4±0.2; and / or The nitrate crystal form is nitrate crystal form 24, wherein the X-ray powder diffraction pattern of the crystal form 24 includes 3 or more (e.g., 4 or 5) 2θ values ​​selected from the following group: 12.4±0.2, 19.3±0.2, 20.8±0.2, 23.8±0.2, and 27.9±0.

2.

3. The salt crystal form according to claim 2, wherein The X-ray powder diffraction pattern of the crystalline form Form 1 includes 5 or more (e.g., 6, 7, 8, 9) 2θ values ​​selected from the group consisting of 5.2±0.2, 10.3±0.2, 12.5±0.2, 16.1±0.2, 18.3±0.2, 19.4±0.2, 22.7±0.2, 23.1±0.2, 23.9±0.2, 25.4±0.2, 25.8±0.2, and 29.0±0.2; The X-ray powder diffraction pattern of the crystalline form Form 2 includes 2θ values ​​selected from the group consisting of: 6.7±0.2, 16.5±0.2, 18.5±0.2, 19.4±0.2, 19.8±0.2, 20.1±0.2, and 29.4±0.2; The X-ray powder diffraction pattern of the crystalline form Form 3 includes 7 or more 2θ values ​​selected from the following group: 6.6±0.2, 12.4±0.2, 15.9±0.2, 16.4±0.2, 18.5±0.2, 19.7±0.2, 20.0±0.2, 22.2±0.2, 23.4±0.2, 24.8±0.2, 25.3±0.2, 28.5±0.2, 29.4±0.2; The X-ray powder diffraction pattern of the crystalline form Form 4 includes 5 or more (e.g., 6, 7, 8, 9, 10) 2θ values ​​selected from the group consisting of 8.2±0.2, 13.1±0.2, 20.1±0.2, 23.9±0.2, 24.3±0.2, 26.2±0.2, 26.6±0.2, 29.4±0.2, and 31.6±0.2; The X-ray powder diffraction pattern of the crystalline form Form 5 includes 5 or more (e.g., 6, 7, 8, 9, 10) 2θ values ​​selected from the group consisting of 7.0±0.2, 9.1±0.2, 12.9±0.2, 17.6±0.2, 18.1±0.2, 18.5±0.2, 20.1±0.2, 22.2±0.2, 25.07±0.2, and 26.0±0.2; The X-ray powder diffraction pattern of the crystalline form Form 7 includes 5 or more (e.g., 6, 7, 8, 9) 2θ values ​​selected from the group consisting of 8.1±0.2, 13.0±0.2, 16.2±0.2, 22.8±0.2, 23.8±0.2, 24.2±0.2, 24.4±0.2, 26.5±0.2, and 29.3±0.2; The X-ray powder diffraction pattern of the crystalline form Form 8 includes 5 or more (e.g., 6, 7, 8, 9, 10) 2θ values ​​selected from the group consisting of 10.2±0.2, 20.0±0.2, 20.6±0.2, 21.5±0.2, 22.1±0.2, 24.3±0.2, 26.2±0.2, 28.9±0.2, 33.7±0.2, and 35.7±0.2; The X-ray powder diffraction pattern of the crystalline form Form 9 includes 2θ values ​​selected from the group consisting of 7.3±0.2, 11.2±0.2, 14.7±0.2, 17.2±0.2, 17.5±0.2, 19.8±0.2, 20.6±0.2, 22.5±0.2, 23.1±0.2, 23.8±0.2, and 27.5±0.2; The X-ray powder diffraction pattern of the crystalline form Form 10 includes 2θ values ​​selected from the group consisting of 7.3±0.2, 8.1±0.2, 17.1±0.2, 17.4±0.2, 19.7±0.2, 22.4±0.2, 23.1±0.2, 23.8±0.2, 27.5±0.2, and 29.2±0.2; The X-ray powder diffraction pattern of the crystalline form Form 11 includes 2θ values ​​selected from the group consisting of 7.3±0.2, 17.2±0.2, 17.5±0.2, 19.7±0.2, 20.6±0.2, 22.4±0.2, 23.1±0.2, 23.8±0.2, and 27.5±0.2; The X-ray powder diffraction pattern of the crystalline form Form 12 includes 2θ values ​​selected from the group consisting of 7.3±0.2, 17.1±0.2, 17.4±0.2, 19.7±0.2, 20.6±0.2, 22.4±0.2, 23.1±0.2, 23.8±0.2, 27.5±0.2, and 29.2±0.2; The X-ray powder diffraction pattern of the crystalline form Form 13 includes 6 or more (e.g., 7, 8, 10, 12) 2θ values ​​selected from the group consisting of 9.9±0.2, 12.1±0.2, 15.6±0.2, 16.5±0.2, 18.0±0.2, 18.9±0.2, 19.8±0.2, 20.5±0.2, 21.0±0.2, 23.0±0.2, 23.9±0.2, 24.9±0.2, and 26.3±0.2; The X-ray powder diffraction pattern of the crystalline form Form 14 includes 6 or more (e.g., 8, 10, 12, 13) 2θ values ​​selected from the group consisting of 5.5±0.2, 8.7±0.2, 9.89±0.2, 11.7±0.2, 15.1±0.2, 16.6±0.2, 17.3±0.2, 18.4±0.2, 20.9±0.2, 21.9±0.2, 23.4±0.2, 25.4±0.2, and 27.6±0.2; The X-ray powder diffraction pattern of the crystalline form Form 15 includes 6 or more (e.g., 8, 9, 10, 12) 2θ values ​​selected from the group consisting of 5.7±0.2, 13.7±0.2, 14.9±0.2, 16.2±0.2, 16.6±0.2, 17.4±0.2, 18.4±0.2, 22.4±0.2, 22.8±0.2, 23.9±0.2, 24.6±0.2, and 25.2±0.2; The X-ray powder diffraction pattern of the crystalline form Form 16 includes 6 or more (e.g., 7, 8, 9, 10) 2θ values ​​selected from the group consisting of 6.6±0.2, 8.5±0.2, 8.8±0.2, 14.3±0.2, 15.1±0.2, 16.2±0.2, 21.5±0.2, 23.6±0.2, 24.5±0.2, and 27.4±0.2; The X-ray powder diffraction pattern of the crystalline form Form 18 includes 6 or more (e.g., 7, 8, 9) 2θ values ​​selected from the group consisting of 9.3±0.2, 10.5±0.2, 17.0±0.2, 18.6±0.2, 20.5±0.2, 21.1±0.2, 23.9±0.2, 25.4±0.2, and 29.2±0.2; The X-ray powder diffraction pattern of the crystalline form Form 19 includes 2θ values ​​selected from the group consisting of 7.3±0.2, 11.2±0.2, 14.6±0.2, 17.2±0.2, 17.4±0.2, 19.7±0.2, 22.5±0.2, 23.1±0.2, 23.8±0.2, and 27.5±0.2; The X-ray powder diffraction pattern of the crystalline form Form 20 includes 6 or more (e.g., 7, 8, 9, 10) 2θ values ​​selected from the group consisting of 4.6±0.2, 9.1±0.2, 12.2±0.2, 13.7±0.2, 21.0±0.2, 21.6±0.2, 22.8±0.2, 23.3±0.2, 24.1±0.2, and 28.8±0.2; The X-ray powder diffraction pattern of the crystalline form Form 21 includes 6 or more (e.g., 8, 10, 12, or 13) 2θ values ​​selected from the group consisting of 11.2±0.2, 11.4±0.2, 14.8±0.2, 17.7±0.2, 19.7±0.2, 21.6±0.2, 22.9±0.2, 23.8±0.2, 24.7±0.2, 26.1±0.2, 27.6±0.2, 28.3±0.2, and 29.9±0.2; The X-ray powder diffraction pattern of the crystalline form Form 22 includes 6 or more (e.g., 7, 8, 9, 10) 2θ values ​​selected from the group consisting of 4.3±0.2, 8.4±0.2, 12.4±0.2, 14.4±0.2, 16.8±0.2, 20.5±0.2, 23.5±0.2, 23.8±0.2, 25.8±0.2, and 33.8±0.2; The X-ray powder diffraction pattern of the crystalline form Form 23 includes 6 or more (e.g., 7, 8, 9, 10) 2θ values ​​selected from the group consisting of 8.0±0.2, 16.0±0.2, 17.8±0.2, 18.5±0.2, 19.8±0.2, 24.1±0.2, 24.4±0.2, 24.8±0.2, 25.8±0.2, and 30.4±0.2; and / or The X-ray powder diffraction pattern of the crystalline form Form 24 includes 6 or more (e.g., 7, 8, 10, 12) 2θ values ​​selected from the group consisting of 12.4±0.2, 14.4±0.2, 19.0±0.2, 19.3±0.2, 19.6±0.2, 20.8±0.2, 22.5±0.2, 23.4±0.2, 23.8±0.2, 24.6±0.2, 24.9±0.2, and 27.9±0.

2.

4. The salt crystal form according to claim 2, wherein The X-ray powder diffraction pattern of the crystalline form Form 1 includes 10 or more (e.g., 12, 14, 15, 16, 18) 2θ values ​​selected from the group consisting of 5.2±0.2, 8.4±0.2, 10.3±0.2, 12.5±0.2, 14.2±0.2, 14.6±0.2, 15.3±0.2, 16.1±0.2, 17.2±0.2, 18.3±0.2, 19.1±0.2, 19.4±0.2, 22.7±0.2, 23.1±0.2, 23.5±0.2, 23.9±0.2, 25.4±0.2, 25.8±0.2, and 29.0±0.2; The X-ray powder diffraction pattern of the crystalline form Form 4 includes 10 or more 2θ values ​​(e.g., 11, 12, 13, 14, 15) selected from the group consisting of 8.2±0.2, 13.1±0.2, 16.3±0.2, 17.7±0.2, 19.2±0.2, 20.1±0.2, 22.9±0.2, 23.9±0.2, 24.3±0.2, 24.6±0.2, 25.4±0.2, 26.2±0.2, 26.6±0.2, 29.4±0.2, and 31.6±0.2; The X-ray powder diffraction pattern of the crystalline form Form 5 includes 10 or more (e.g., 11, 12, 13, 14, 15) 2θ values ​​selected from the group consisting of 7.0±0.2, 9.1±0.2, 11.8±0.2, 12.3±0.2, 12.9±0.2, 17.3±0.2, 17.6±0.2, 18.1±0.2, 18.5±0.2, 20.1±0.2, 22.2±0.2, 25.07±0.2, 26.0±0.2, and 27.9±0.2; The X-ray powder diffraction pattern of the crystalline form Form 6 includes 16 or more 2θ values ​​selected from the following group: 8.2±0.2, 13.1±0.2, 14.8±0.2, 15.5±0.2, 16.1±0.2, 16.3±0.2, 17.6±0.2, 19.2±0.2, 19.4±0.2, 22.4±0.2, 22.9±0.2, 23.8±0.2, 24.2±0.2, 24.5±0.2, 25.4±0.2, 26.6±0.2, 27.5±0.2, 29.3±0.2, 31.8±0.2, and 33.0±0.2; The X-ray powder diffraction pattern of the crystalline form Form 7 includes 10 or more (e.g., 12, 14, 15, 16, 17) 2θ values ​​selected from the group consisting of 8.1±0.2, 13.0±0.2, 16.0±0.2, 16.2±0.2, 17.6±0.2, 19.1±0.2, 19.7±0.2, 20.8±0.2, 22.4±0.2, 22.8±0.2, 23.8±0.2, 24.2±0.2, 24.4±0.2, 25.3±0.2, 26.5±0.2, and 29.3±0.2; The X-ray powder diffraction pattern of the crystalline form Form 8 includes 10 or more (e.g., 12, 13, 14, 15, 16) 2θ values ​​selected from the group consisting of 10.2±0.2, 20.0±0.2, 20.6±0.2, 21.5±0.2, 22.1±0.2, 23.8±0.2, 24.3±0.2, 25.7±0.2, 26.2±0.2, 28.9±0.2, 30.1±0.2, 31.1±0.2, 33.1±0.2, 33.7±0.2, 35.7±0.2, and 38.0±0.2; The X-ray powder diffraction pattern of the crystalline form Form 9 includes 2θ values ​​selected from the group consisting of 7.3±0.2, 11.2±0.2, 14.7±0.2, 15.4±0.2, 17.2±0.2, 17.5±0.2, 18.1±0.2, 19.8±0.2, 20.6±0.2, 22.1±0.2, 22.5±0.2, 23.1±0.2, 23.8±0.2, 24.9±0.2, 26.4±0.2, 27.5±0.2, 28.6±0.2, and 29.2±0.2; The X-ray powder diffraction pattern of the crystalline form Form 10 includes 18 or more 2θ values ​​selected from the group consisting of 7.3±0.2, 8.1±0.2, 11.2±0.2, 13.0±0.2, 14.6±0.2, 15.4±0.2, 17.1±0.2, 17.4±0.2, 18.1±0.2, 19.2±0.2, 19.7±0.2, 20.6±0.2, 22.0±0.2, 22.4±0.2, 23.1±0.2, 23.8±0.2, 24.2±0.2, 24.8±0.2, 26.6±0.2, 27.5±0.2, and 29.2±0.2; The X-ray powder diffraction pattern of the crystalline form Form 11 includes 18 or more 2θ values ​​selected from the group consisting of 7.3±0.2, 11.0±0.2, 11.2±0.2, 14.6±0.2, 15.4±0.2, 17.2±0.2, 17.5±0.2, 18.1±0.2, 19.7±0.2, 20.6±0.2, 21.4±0.2, 22.0±0.2, 22.4±0.2, 23.1±0.2, 23.8±0.2, 24.4±0.2, 24.8±0.2, 27.5±0.2, and 29.2±0.2; The X-ray powder diffraction pattern of the crystalline form Form 12 includes 2θ values ​​selected from the group consisting of: 7.3±0.2, 11.2±0.2, 12.3±0.2, 14.6±0.2, 15.4±0.2, 17.1±0.2, 17.4±0.2, 18.1±0.2, 19.7±0.2, 20.6±0.2, 22.0±0.2, 22.4±0.2, 23.1±0.2, 23.8±0.2, 24.8±0.2, 25.7±0.2, 27.5±0.2, and 29.2±0.2; The X-ray powder diffraction pattern of the crystalline form Form 13 includes 10 or more 2θ values ​​(e.g., 12, 14, 15, 16, 18) selected from the group consisting of 9.9±0.2, 12.1±0.2, 15.6±0.2, 16.5±0.2, 18.0±0.2, 18.9±0.2, 19.8±0.2, 20.5±0.2, 21.0±0.2, 21.9±0.2, 23.0±0.2, 23.5±0.2, 23.9±0.2, 24.9±0.2, 26.3±0.2, 26.7±0.2, 27.9±0.2, 28.3±0.2, 28.8±0.2, and 31.6±0.2; The X-ray powder diffraction pattern of the crystalline form Form 14 includes 10 or more (e.g., 12, 14, 15, 16, 18) 2θ values ​​selected from the group consisting of 5.5±0.2, 8.7±0.2, 9.89±0.2, 11.7±0.2, 13.6±0.2, 14.2±0.2, 15.1±0.2, 16.0±0.2, 16.6±0.2, 17.3±0.2, 17.9±0.2, 18.4±0.2, 19.8±0.2, 20.9±0.2, 21.9±0.2, 23.4±0.2, 24.4±0.2, 25.4±0.2, and 27.6±0.2; The X-ray powder diffraction pattern of the crystalline form Form 15 comprises 10 or more (e.g., 12, 14, 15, 16, 18) 2θ values ​​selected from the group consisting of 5.7±0.2, 6.8±0.2, 8.6±0.2, 10.9±0.2, 12.5±0.2, 13.7±0.2, 14.9±0.2, 16.2±0.2, 16.6±0.2, 17.4±0.2, 18.4±0.2, 19.5±0.2, 19.9±0.2, 22.4±0.2, 22.8±0.2, 23.9±0.2, 24.6±0.2, and 25.2±0.2; The X-ray powder diffraction pattern of the crystalline form Form 16 includes 10 or more (e.g., 12, 14, 15, 16, 17) 2θ values ​​selected from the group consisting of 6.6±0.2, 8.5±0.2, 8.8±0.2, 14.3±0.2, 15.1±0.2, 16.2±0.2, 17.0±0.2, 17.7±0.2, 18.5±0.2, 18.8±0.2, 20.0±0.2, 21.5±0.2, 23.6±0.2, 24.5±0.2, 27.4±0.2, 28.4±0.2, and 29.2±0.2; The X-ray powder diffraction pattern of the crystalline form Form 17 includes 15 or more 2θ values ​​selected from the group consisting of 8.2±0.2, 13.1±0.2, 14.8±0.2, 16.0±0.2, 17.6±0.2, 19.1±0.2, 19.8±0.2, 20.8±0.2, 22.4±0.2, 22.8±0.2, 23.8±0.2, 24.2±0.2, 24.5±0.2, 25.3±0.2, 26.5±0.2, and 29.3±0.2; The X-ray powder diffraction pattern of the crystalline form Form 18 includes 10 or more (e.g., 12, 14, 15, 16, 18) 2θ values ​​selected from the group consisting of 6.7±0.2, 9.3±0.2, 10.5±0.2, 13.6±0.2, 15.5±0.2, 17.0±0.2, 18.6±0.2, 20.0±0.2, 20.5±0.2, 21.1±0.2, 22.3±0.2, 23.5±0.2, 23.9±0.2, 24.7±0.2, 25.4±0.2, 26.1±0.2, 26.9±0.2, and 29.2±0.2; The X-ray powder diffraction pattern of the crystalline form Form 19 includes 16 or more 2θ values ​​selected from the group consisting of 7.3±0.2, 11.2±0.2, 14.6±0.2, 15.4±0.2, 17.2±0.2, 17.4±0.2, 18.0±0.2, 19.7±0.2, 20.6±0.2, 22.5±0.2, 23.1±0.2, 23.8±0.2, 24.8±0.2, 26.6±0.2, 27.5±0.2, 28.5±0.2, and 29.2±0.2; The X-ray powder diffraction pattern of the crystalline form Form 20 includes 10 or more (e.g., 12, 14, 15, 16, 18) 2θ values ​​selected from the group consisting of 4.6±0.2, 9.1±0.2, 12.2±0.2, 13.7±0.2, 14.5±0.2, 17.7±0.2, 19.0±0.2, 19.7±0.2, 21.0±0.2, 21.6±0.2, 22.8±0.2, 23.3±0.2, 24.1±0.2, 24.6±0.2, 26.2±0.2, 27.5±0.2, 28.8±0.2, and 32.2±0.2; The X-ray powder diffraction pattern of the crystalline form Form 21 includes 10 or more (e.g., 12, 15, 18, 20, 24) 2θ values ​​selected from the group consisting of 9.0±0.2, 11.2±0.2, 11.4±0.2, 12.1±0.2, 14.8±0.2, 15.9±0.2, 16.1±0.2, 17.7±0.2, 19.4±0 .2, 19.7±0.2, 20.2±0.2, 20.9±0.2, 21.6±0.2, 22.9±0.2, 23.8±0.2, 24.7±0.2, 26.1±0.2, 26.3±0.2, 27.6±0.2, 28.3±0.2, 29.9±0.2, 31.5±0.2, 33.4±0.2; The X-ray powder diffraction pattern of the crystalline form Form 22 comprises 10 or more (e.g., 12, 13, 15, 18, 20) 2θ values ​​selected from the group consisting of 4.3±0.2, 8.4±0.2, 12.4±0.2, 14.4±0.2, 16.8±0.2, 17.2±0.2, 18.3±0.2, 19.3±0.2, 20.5±0.2, 23.0±0.2, 23.5±0.2, 23.8±0.2, 24.1±0.2, 24.7±0.2, 24.9±0.2, 25.8±0.2, 26.4±0.2, 33.8±0.2, 34.6±0.2, and 35.9±0.2; The X-ray powder diffraction pattern of the crystalline form Form 23 includes 10 or more (e.g., 11, 12, 13, 14, 15) 2θ values ​​selected from the group consisting of 8.0±0.2, 9.1±0.2, 12.0±0.2, 16.0±0.2, 17.8±0.2, 18.2±0.2, 18.5±0.2, 19.8±0.2, 21.5±0.2, 24.1±0.2, 24.4±0.2, 24.8±0.2, 25.8±0.2, 27.8±0.2, and 30.4±0.2; and / or The X-ray powder diffraction pattern of the crystalline form Form 24 includes 10 or more 2θ values ​​(e.g., 12, 14, 15, 18, 20) selected from the group consisting of 4.3±0.2, 8.6±0.2, 12.4±0.2, 13.9±0.2, 14.4±0.2, 16.2±0.2, 16.8±0.2, 18.0±0.2, 19.0±0.2, 19.3±0.2, 196±0.2, 20.4±0.2, 20.8±0.2, 22.5±0.2, 23.4±0.2, 23.8±0.2, 24.6±0.2, 24.9±0.2, 25.3±0.2, and 27.9±0.

2.

5. The salt crystal form according to claim 2, wherein The crystal form Form 1 has an X-ray powder diffraction pattern substantially as shown in FIG2 ; The crystal form Form 2 has an X-ray powder diffraction pattern substantially as shown in FIG5 ; The crystal form Form 3 has an X-ray powder diffraction pattern substantially as shown in FIG8 ; The crystalline form Form 4 has an X-ray powder diffraction pattern substantially as shown in FIG11 ; The crystalline form Form 5 has an X-ray powder diffraction pattern substantially as shown in FIG13 ; The crystalline form Form 6 has an X-ray powder diffraction pattern substantially as shown in FIG15 ; The crystalline Form 7 has an X-ray powder diffraction pattern substantially as shown in FIG17 ; The crystalline form Form 8 has an X-ray powder diffraction pattern substantially as shown in FIG19 ; The crystalline Form 9 has an X-ray powder diffraction pattern substantially as shown in FIG21 ; The crystalline form Form 10 has an X-ray powder diffraction pattern substantially as shown in FIG23 ; The crystalline Form 11 has an X-ray powder diffraction pattern substantially as shown in FIG25 ; The crystalline Form 12 has an X-ray powder diffraction pattern substantially as shown in FIG27 ; The crystalline Form 13 has an X-ray powder diffraction pattern substantially as shown in FIG29 ; The crystalline Form 14 has an X-ray powder diffraction pattern substantially as shown in FIG32 ; The crystalline Form 15 has an X-ray powder diffraction pattern substantially as shown in FIG35 ; The crystalline Form 16 has an X-ray powder diffraction pattern substantially as shown in FIG38 ; The crystalline Form 17 has an X-ray powder diffraction pattern substantially as shown in FIG41 ; The crystalline Form 18 has an X-ray powder diffraction pattern substantially as shown in FIG43 ; The crystalline Form 19 has an X-ray powder diffraction pattern substantially as shown in FIG46 ; The crystalline Form 20 has an X-ray powder diffraction pattern substantially as shown in FIG48 ; The crystalline Form 21 has an X-ray powder diffraction pattern substantially as shown in FIG51 ; The crystalline Form 22 has an X-ray powder diffraction pattern substantially as shown in FIG54 ; The crystalline Form 23 has an X-ray powder diffraction pattern substantially as shown in Figure 57; and / or The crystalline form Form 24 has an X-ray powder diffraction pattern substantially as shown in FIG60 .

6. The salt crystal form according to claim 2, wherein The molar ratio of the compound of formula I to oxalic acid in the crystalline form Form 1 is 0.8-1.5:0.8-1.5; The molar ratio of the compound of formula I to maleic acid in the crystalline form Form 2 is 0.8-1.2:0.8-1.2; The molar ratio of the compound of formula I to fumaric acid in the crystalline form Form 3 is 0.8-1.2:0.8-1.2; The molar ratio of the compound of formula I to succinic acid in the crystalline form Form 4 is 0.8-1.2:0.8-1.2; The molar ratio of the compound of formula I to D-tartaric acid in the crystalline form Form 5 is 0.8-1.2:0.8-1.2; The molar ratio of the compound of formula I to L-tartaric acid in the crystalline form Form 6 is 0.8-1.2:0.8-1.2; The molar ratio of the compound of formula I to D-malic acid in the crystalline form Form 7 is 0.8-1.2:0.8-1.2; The molar ratio of the compound of formula I to L-malic acid in the crystalline form Form 8 is 0.8-1.2:0.8-1.2; The molar ratio of the compound of formula I to L-glutamic acid in the crystalline form Form 9 is 0.8-1.2:0.8-1.2; The molar ratio of the compound of formula I to citric acid in the crystalline form Form 10 is 0.8-1.2:0.8-1.2; The molar ratio of the compound of formula I to benzoic acid in the crystalline form Form 11 is 0.8-1.2:0.8-1.2; The molar ratio of the compound of formula I to salicylic acid in the crystalline form Form 12 is 0.8-1.2:0.8-1.2; The molar ratio of the compound of formula I to methanesulfonic acid in the crystalline form Form 13 is 1:0.8-20; The molar ratio of the compound of formula I to ethanesulfonic acid in the crystalline form Form 14 is 1:0.8-20; The molar ratio of the compound of formula I to benzenesulfonic acid in the crystalline form Form 15 is 1:0.8-5; The molar ratio of the compound of formula I to p-toluenesulfonic acid in the crystalline form Form 16 is 1:0.8-2; The molar ratio of the compound of formula I to acetic acid in the crystalline form Form 17 is 1:0.8-2; The molar ratio of the compound of formula I to trifluoroacetic acid in the crystalline form Form 18 is 1:0.8-20; The molar ratio of the compound of formula I to propionic acid in the crystalline form Form 19 is 1:0.8-30; The molar ratio of the compound of formula I to hydrochloric acid in the crystalline form Form 20 is 1:0.8-40; The molar ratio of the compound of formula I to hydrobromic acid in the crystalline form Form 21 is 1:0.8-5; The molar ratio of the compound of formula I to sulfuric acid in the crystalline form Form 22 is 1:0.8-20; The molar ratio of the compound of formula I to phosphoric acid in the crystalline form Form 23 is 1:0.8-20; and / or The molar ratio of the compound of formula I to nitric acid in the crystalline form Form 24 is 1:0.8-20.

7. A method for preparing a crystalline salt of the compound of formula I according to claim 1, characterized in that: The method comprises the following steps: The compound of formula I is mixed with a solvent, and then a corresponding acid is added, followed by continued mixing to crystallize or evaporate to obtain the salt crystal form.

8. The preparation method according to claim 7, wherein The solvent is selected from the group consisting of methanol, dichloromethane, acetonitrile, ethyl acetate, acetone, or a combination thereof.

9. A pharmaceutical composition comprising the crystalline salt of the compound of formula I according to claim 1, and a pharmaceutically acceptable carrier.

10. A use of a crystalline salt of the compound of formula I according to claim 1, characterized in that: Used for preparing pharmaceutical compositions for preventing and / or treating cancer.

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