Crystal forms of nitrogen-containing aryl phosphine oxide derivatives, processes for their preparation and uses thereof

Abstract

This invention relates to the crystal forms of nitrogen-containing aryl phosphorus oxide derivatives, their preparation methods, and applications. Specifically, it relates to crystal forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, and XII of compounds with structures as shown in Formula I, as well as the preparation methods and applications of the above crystal forms. The preparation methods of this invention are simple, easy to implement, and have good reproducibility, and can stably prepare the target crystal forms.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to the crystal form of a nitrogen-containing aryl phosphorus oxide derivative, its preparation method, and its application. Background Technology

[0002] EGFR (Epidermal Growth Factor Receptor) is a member of the ErbB family of transmembrane receptor tyrosine kinases, activated by binding to its ligands epidermal growth factor (EGF) or transforming growth factor α (TGFα). Activated EGFR forms homodimers on the cell membrane or heterodimers with other receptors in the family (such as ErbB-2, ErbB-3, or ErbB-4), leading to phosphorylation of key intracellular tyrosine residues of EGFR. This activates downstream signaling pathways, playing a crucial role in cell proliferation, survival, and anti-apoptosis. Activating mutations, overexpression, or gene amplification of EGFR can lead to excessive activation, promoting cell transformation into tumor cells and playing a vital role in tumor cell proliferation, invasion, metastasis, and angiogenesis. Therefore, EGFR is an important target for the development of anticancer drugs, particularly for lung cancer treatment.

[0003] First-generation EGFR small molecule inhibitors, including gefitinib (Iressa) and erlotinib (Tarceva), have shown good efficacy in the treatment of lung cancer and have been used as first-line drugs for the treatment of non-small cell lung cancer (NSCLC) with EGFR activating mutations (including L858R and delE746_A750). However, after 10-12 months of treatment with first-generation small molecule EGFR inhibitors, almost all NSCLC patients develop resistance to these inhibitors. More than half of these resistance mechanisms are due to secondary mutations in the EGFR gate gene residue T790M.

[0004] Osimertinib (AZD9291) is a third-generation EGFR TKI inhibitor with a high response rate and good therapeutic effect against EGFR T790M resistance. It received accelerated approval from the FDA in November 2015 and has proven effective in treating advanced non-small cell lung cancer (NSCLC) patients with EGFR T790M resistance mutations. Despite the significant success of osimertinib in treating EGFR T790M-mutant NSCLC, resistance inevitably develops after 9–14 months of treatment. Studies have shown that resistance in up to 20–40% of patients is due to the EGFR C797S mutation. The EGFR C797S mutation changes the cysteine ​​residue at position 797 to serine, preventing osimertinib from forming a covalent bond with the EGFR protein, thus leading to resistance. Currently, there are no effective inhibitors targeting the EGFR C797S resistance mutation. Therefore, there is an urgent need to develop novel, highly active EGFR inhibitors to address the drug resistance problem caused by EGFR C797S mutations.

[0005] Novartis reported EAI0450, a compound targeting EGFR C797S resistance. This EGFR allosteric inhibitor, when combined with EGFR monoclonal antibodies such as cetuximab, showed good antitumor efficacy in a mouse model with the L858R / T790M / C797S mutation. However, this compound was ineffective as a monotherapy and could not inhibit the C797S resistance mutation containing deIE746_A750, thus failing to enter clinical trials. In 2017, Ken Uchibori et al. reported that the combination of Brigatinib (AP26113) and EGFR monoclonal antibodies (such as cetuximab) could overcome resistance to third-generation EGFR inhibitors caused by the C797S mutation, showing good antitumor efficacy in a PC9 (EGFR-C797S / T790M / de119) mouse model. However, Brigatinib also faced the challenge of low in vitro activity as a monotherapy and no significant in vivo antitumor activity, and similarly, no further clinical studies were conducted.

[0006] Lung cancer is a major disease threatening human health, and its mortality rate ranks first among all malignant tumors. In my country, the incidence of lung cancer is rising year by year, with approximately 700,000 new cases annually. About 35% of all NSCLC cases in my country have EGFR activating mutations. While first- or third-generation EGFR inhibitors can achieve good therapeutic effects, new drug resistance mutations often develop later. Therefore, developing a new generation of anti-drug-resistant EGFR inhibitors has enormous clinical and market value. Summary of the Invention

[0007] To address the problems of existing technologies, the inventors conducted in-depth research on different aggregation states of Formula I compounds, obtaining various polymorphs of Formula I compounds. These polymorphs can significantly improve the physicochemical properties of amorphous Formula I compounds, such as crystallinity, solubility, hygroscopicity, and chemical stability, and enhance process operability. By comparing the hygroscopicity, physicochemical stability, fluidity, and interconversion relationships of each polymorph, the most suitable aggregation state, polymorph III, suitable for pharmaceutical acceptance, was selected, providing a scientific basis for drug development.

[0008] This invention provides polymorphs I, II, III, IV, V, VI, VII, VIII, IX, X, XI, and XII of compound (6-((5-bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azacyclobutane-1-yl)piperidin-1-yl)-5-methylphenyl]amino]pyrimidin-4(-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxane-5-yl)dimethylphosphine oxide, as well as methods for preparing the above polymorphs and their applications.

[0009]

[0010] The X-ray powder diffraction pattern of the compound of formula I, crystal form I, has a diffraction peak at 2θ of 15.9 ± 0.2°; or at 18.4 ± 0.2°; or at 20.6 ± 0.2°; or at 7.9 ± 0.2°; or at 9.2 ± 0.2°; or at 11.2 ± 0.2°; or at 14.5 ± 0.2°; or at 16.3 ± 0.2°; preferably, it includes any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks; more preferably, it includes any 6, 7, or 8 of them;

[0011] or,

[0012] The X-ray powder diffraction pattern of crystal form I includes at least one or more diffraction peaks located at 2θ of 15.9±0.2°, 18.4±0.2°, and 20.6±0.2°, preferably two, more preferably three; optionally, it may further include at least one peak located at 2θ of 7.9±0.2°, 9.2±0.2°, 11.2±0.2°, 14.5±0.2°, and 16.3±0.2°, preferably two, three, four, or five, for example,

[0013] 15.9±0.2°, 18.4±0.2°;

[0014] 18.4±0.2°, 20.6±0.2°;

[0015] 15.9±0.2°, 20.6±0.2°;

[0016] 15.9±0.2°, 7.9±0.2°;

[0017] 18.4±0.2°, 9.2±0.2°;

[0018] 20.6±0.2°, 11.2±0.2°;

[0019] 15.9±0.2°, 18.4±0.2°, 20.6±0.2°;

[0020] 15.9±0.2°, 7.9±0.2°, 9.2±0.2°;

[0021] 18.4±0.2°, 9.2±0.2°, 11.2±0.2°;

[0022] 20.6±0.2°, 11.2±0.2°, 14.5±0.2°;

[0023] 15.9±0.2°, 18.4±0.2°, 20.6±0.2°, 7.9±0.2°;

[0024] 15.9±0.2°, 7.9±0.2°, 9.2±0.2°, 11.2±0.2°;

[0025] 18.4±0.2°, 11.2±0.2°, 14.5±0.2°, 16.3±0.2°;

[0026] 20.6±0.2°, 11.2±0.2°, 14.5±0.2°, 16.3±0.2°;

[0027] 15.9±0.2°, 18.4±0.2°, 20.6±0.2°, 7.9±0.2°, 9.2±0.2°;

[0028] 18.4±0.2°, 20.6±0.2°, 9.2±0.2°, 11.2±0.2°, 14.5±0.2°;

[0029] 18.4±0.2°, 20.6±0.2°, 11.2±0.2°, 14.5±0.2°, 16.3±0.2°;

[0030] or,

[0031] The X-ray powder diffraction pattern of crystal form I optionally includes one or more diffraction peaks located at 2θ of 8.4±0.2°, 12.8±0.2°, 19.5±0.2°, 5.5±0.2°, 17.7±0.2°, 21.2±0.2°, 21.7±0.2°, and 23.0±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks; for example,

[0032] 8.4±0.2°, 12.8±0.2°, 19.5±0.2°, 5.5±0.2°;

[0033] 12.8±0.2°, 19.5±0.2°, 5.5±0.2°, 17.7±0.2°;

[0034] 12.8±0.2°, 19.5±0.2°, 5.5±0.2°, 17.7±0.2°, 21.2±0.2°;

[0035] 8.4±0.2°, 17.7±0.2°, 21.2±0.2°, 21.7±0.2°, 23.0±0.2°;

[0036] 8.4±0.2°, 12.8±0.2°, 19.5±0.2°, 5.5±0.2°, 17.7±0.2°, 21.2±0.2°;

[0037] 8.4±0.2°, 19.5±0.2°, 5.5±0.2°, 21.2±0.2°, 21.7±0.2° and 23.0±0.2°;

[0038] 12.8±0.2°, 19.5±0.2°, 5.5±0.2°, 17.7±0.2°, 21.2±0.2°, 21.7±0.2°, 23.0±0.2°;

[0039] 8.4±0.2°, 12.8±0.2°, 19.5±0.2°, 5.5±0.2°, 17.7±0.2°, 21.2±0.2°, 21.7±0.2°.

[0040] Further preferred, the X-ray powder diffraction pattern of crystal form I is basically as follows: Figure 1 As shown, its DSC spectrum is basically as follows: Figure 1A As shown, its TGA spectrum is as follows: Figure 1B As shown.

[0041] More preferably, the compound of formula I has crystal form I as an anhydrous substance with a melting point of around 144°C and essentially no weight loss before decomposition.

[0042] The X-ray powder diffraction pattern of the compound of formula I, crystal form II, has a diffraction peak at 2θ of 10.8 ± 0.2°; or at 19.9 ± 0.2°; or at 13.9 ± 0.2°; or at 14.7 ± 0.2°; or at 8.6 ± 0.2°; or at 6.5 ± 0.2°; or at 9.9 ± 0.2°; or at 16.5 ± 0.2°; preferably, it includes any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks; more preferably, it includes any 6, 7, or 8 of them;

[0043] or,

[0044] The X-ray powder diffraction pattern of crystal form II contains at least one or more diffraction peaks located at 2θ of 10.8±0.2°, 19.9±0.2°, and 13.9±0.2°, preferably two, more preferably three; optionally, it may further contain at least one diffraction peak located at 2θ of 14.7±0.2°, 8.6±0.2°, 6.5±0.2°, 9.9±0.2°, and 16.5±0.2°, preferably two, three, four, or five, for example,

[0045] 10.8±0.2°, 19.9±0.2°;

[0046] 19.9±0.2°, 13.9±0.2°;

[0047] 10.8±0.2°, 13.9±0.2°;

[0048] 10.8±0.2°, 14.7±0.2°;

[0049] 19.9±0.2°, 6.5±0.2°;

[0050] 13.9±0.2°, 9.9±0.2°;

[0051] 10.8±0.2°, 19.9±0.2°, 13.9±0.2°;

[0052] 10.8±0.2°, 14.7±0.2°, 8.6±0.2°;

[0053] 13.9±0.2°, 8.6±0.2°, 16.5±0.2°;

[0054] 10.8±0.2°, 19.9±0.2°, 13.9±0.2°, 14.7±0.2°;

[0055] 10.8±0.2°, 14.7±0.2°, 8.6±0.2°, 6.5±0.2°;

[0056] 19.9±0.2°, 8.6±0.2°, 6.5±0.2°, 9.9±0.2°;

[0057] 13.9±0.2°, 6.5±0.2°, 9.9±0.2°, 16.5±0.2°;

[0058] 10.8±0.2°, 19.9±0.2°, 13.9±0.2°, 14.7±0.2°, 8.6±0.2°;

[0059] 10.8±0.2°, 14.7±0.2°, 8.6±0.2°, 6.5±0.2°, 9.9±0.2°;

[0060] 19.9±0.2°, 8.6±0.2°, 6.5±0.2°, 9.9±0.2°, 16.5±0.2°;

[0061] or,

[0062] The X-ray powder diffraction pattern of crystal form II optionally includes one or more diffraction peaks located at 2θ of 12.1±0.2°, 11.0±0.2°, 15.1±0.2°, 15.9±0.2°, 18.5±0.2°, 19.2±0.2°, 20.3±0.2°, 20.7±0.2°, 21.1±0.2°, 21.7±0.2°, 4.8±0.2°, 7.0±0.2°, 17.0±0.2°, 22.8±0.2°, 23.8±0.2°, and 24.6±0.2°; preferably, it includes at least any 2-3 peaks, or 4-5 peaks, or 6-7 peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks; for example,

[0063] 12.1±0.2°, 11.0±0.2°, 15.1±0.2°, 15.9±0.2°;

[0064] 18.5±0.2°, 19.2±0.2°, 20.3±0.2°, 20.7±0.2°;

[0065] 21.1±0.2°, 21.7±0.2°, 4.8±0.2°, 7.0±0.2°;

[0066] 17.0±0.2°, 22.8±0.2°, 23.8±0.2° and 24.6±0.2°;

[0067] 12.1±0.2°, 18.5±0.2°, 19.2±0.2°, 20.3±0.2°, 20.7±0.2°;

[0068] 15.1±0.2°, 15.9±0.2°, 18.5±0.2°, 19.2±0.2°, 20.3±0.2°;

[0069] 7.0±0.2°, 17.0±0.2°, 22.8±0.2°, 23.8±0.2°, 24.6±0.2°;

[0070] 15.9±0.2°, 18.5±0.2°, 19.2±0.2°, 20.3±0.2°, 20.7±0.2°, 21.1±0.2°;

[0071] 12.1±0.2°, 11.0±0.2°, 15.1±0.2°, 22.8±0.2°, 23.8±0.2°, 24.6±0.2°;

[0072] 11.0±0.2°, 15.9±0.2°, 4.8±0.2°, 7.0±0.2°, 22.8±0.2°, 23.8±0.2°;

[0073] 21.7±0.2°, 4.8±0.2°, 7.0±0.2°, 17.0±0.2°, 22.8±0.2°, 23.8±0.2°, 24.6±0.2°;

[0074] 12.1±0.2°, 11.0±0.2°, 15.1±0.2°, 15.9±0.2°, 18.5±0.2°, 19.2±0.2°, 20.3±0.2°;

[0075] 15.9±0.2°, 18.5±0.2°, 19.2±0.2°, 20.3±0.2°, 20.7±0.2°, 21.1±0.2°, 21.7±0.2°.

[0076] Further preferred, the X-ray powder diffraction pattern of crystal form II is basically as follows: Figure 2 As shown, its DSC spectrum is basically as follows: Figure 2A As shown, its TGA spectrum is as follows: Figure 2B As shown.

[0077] More preferably, the compound of formula I with crystal form II is a hydrate, with a TGA weight loss of about 2.4% and a KF moisture content of about 2.5%, indicating it is a monohydrate.

[0078] The X-ray powder diffraction pattern of the compound of formula I, crystal form III, has a diffraction peak at 2θ of 16.3 ± 0.2°; or at 21.1 ± 0.2°; or at 8.1 ± 0.2°; or at 13.1 ± 0.2°; or at 16.0 ± 0.2°; or at 16.6 ± 0.2°; or at 24.3 ± 0.2°; or at 17.7 ± 0.2°; preferably, it includes any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks; more preferably, it includes any 6, 7, or 8 of them;

[0079] or,

[0080] The X-ray powder diffraction pattern of crystal form III contains at least one or more diffraction peaks located at 2θ of 16.3±0.2°, 21.1±0.2°, and 8.1±0.2°, preferably two, more preferably three; optionally, it may further contain at least one diffraction peak located at 2θ of 13.1±0.2°, 16.0±0.2°, 16.6±0.2°, 24.3±0.2°, and 17.7±0.2°, preferably two, three, four, or five, for example,

[0081] 16.3±0.2°, 21.1±0.2°;

[0082] 21.1±0.2°, 8.1±0.2°;

[0083] 16.3±0.2°, 8.1±0.2°;

[0084] 16.3±0.2°, 13.1±0.2°;

[0085] 21.1±0.2°, 16.0±0.2°;

[0086] 8.1±0.2°, 16.6±0.2°;

[0087] 16.3±0.2°, 21.1±0.2°, 8.1±0.2°;

[0088] 16.3±0.2°, 21.1±0.2°, 13.1±0.2°

[0089] 21.1±0.2°, 24.3±0.2°, 17.7±0.2°;

[0090] 8.1±0.2°, 16.6±0.2°, 24.3±0.2°;

[0091] 16.3±0.2°, 21.1±0.2°, 8.1±0.2°, 13.1±0.2°;

[0092] 16.3±0.2°, 8.1±0.2°, 16.0±0.2°, 16.6±0.2°;

[0093] 21.1±0.2°, 16.0±0.2°, 16.6±0.2°, 24.3±0.2°;

[0094] 16.3±0.2°, 21.1±0.2°, 8.1±0.2°, 13.1±0.2°, 16.0±0.2°;

[0095] 21.1±0.2°, 16.0±0.2°, 16.6±0.2°, 24.3±0.2°, 17.7±0.2°;

[0096] 16.3±0.2°, 8.1±0.2°, 13.1±0.2°, 16.6±0.2°, 17.7±0.2°;

[0097] or,

[0098] The X-ray powder diffraction pattern of crystal form III optionally includes one or more diffraction peaks located at 2θ of 10.6±0.2°, 25.4±0.2°, 25.9±0.2°, 5.3±0.2°, 9.5±0.2°, 11.5±0.2°, 6.5±0.2°, 18.1±0.2°, 19.7±0.2°, 20.2±0.2°, 26.9±0.2°, and 27.7±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks; for example,

[0099] 10.6±0.2°, 25.4±0.2°, 25.9±0.2°, 5.3±0.2°;

[0100] 9.5±0.2°, 11.5±0.2°, 6.5±0.2°, 18.1±0.2°;

[0101] 19.7±0.2°, 20.2±0.2°, 26.9±0.2°, 27.7±0.2°;

[0102] 10.6±0.2°, 9.5±0.2°, 6.5±0.2°, 19.7±0.2°;

[0103] 25.4±0.2°, 25.9±0.2°, 5.3±0.2°, 9.5±0.2°, 11.5±0.2°;

[0104] 6.5±0.2°, 18.1±0.2°, 19.7±0.2°, 20.2±0.2°, 26.9±0.2°;

[0105] 10.6±0.2°, 5.3±0.2°, 9.5±0.2°, 20.2±0.2°, 26.9±0.2°;

[0106] 25.4±0.2°, 25.9±0.2°, 5.3±0.2°, 9.5±0.2°, 11.5±0.2°, 6.5±0.2°;

[0107] 10.6±0.2°, 6.5±0.2°, 18.1±0.2°, 19.7±0.2°, 26.9±0.2°, 27.7±0.2°;

[0108] 25.9±0.2°, 5.3±0.2°, 6.5±0.2°, 18.1±0.2°, 20.2±0.2°, 27.7±0.2°;

[0109] 10.6±0.2°, 25.4±0.2°, 25.9±0.2°, 5.3±0.2°, 9.5±0.2°, 11.5±0.2°, 6.5±0.2°;

[0110] 25.4±0.2°, 25.9±0.2°, 11.5±0.2°, 6.5±0.2°, 19.7±0.2°, 20.2±0.2°, 26.9±0.2°;

[0111] 10.6±0.2°, 25.9±0.2°, 9.5±0.2°, 11.5±0.2°, 18.1±0.2°, 20.2±0.2°, 27.7±0.2°.

[0112] Further preferred, the X-ray powder diffraction pattern of crystal form III is basically as follows: Figure 3 As shown, its DSC spectrum is basically as follows: Figure 3A As shown, its TGA spectrum is as follows: Figure 3B As shown.

[0113] More preferably, the compound of formula I, crystal form III, is a hydrate, with a TGA weight loss of approximately 2.6% and a KF moisture content of approximately 2.7%, indicating it is a monohydrate.

[0114] The X-ray powder diffraction pattern of the compound of formula I, crystal form IV, has a diffraction peak at 2θ of 21.0 ± 0.2°; or at 14.6 ± 0.2°; or at 12.9 ± 0.2°; or at 8.5 ± 0.2°; or at 9.2 ± 0.2°; or at 20.2 ± 0.2°; or at 13.5 ± 0.2°; or at 10.5 ± 0.2°; preferably, it includes any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks; more preferably, it includes any 6, 7, or 8 of them;

[0115] or,

[0116] The X-ray powder diffraction pattern of crystal form IV contains at least one or more diffraction peaks located at 2θ of 21.0±0.2°, 14.6±0.2°, and 12.9±0.2°, preferably two, more preferably three; optionally, it may further contain at least one diffraction peak located at 2θ of 8.5±0.2°, 9.2±0.2°, 20.2±0.2°, 13.5±0.2°, and 10.5±0.2°, preferably two, three, four, or five, for example,

[0117] 21.0±0.2°, 14.6±0.2°;

[0118] 14.6±0.2°, 12.9±0.2°;

[0119] 21.0±0.2°, 12.9±0.2°;

[0120] 21.0±0.2°, 8.5±0.2°;

[0121] 14.6±0.2°, 9.2±0.2°;

[0122] 12.9±0.2°, 20.2±0.2°;

[0123] 21.0±0.2°, 14.6±0.2°, 12.9±0.2°;

[0124] 14.6±0.2°, 12.9±0.2°, 20.2±0.2°;

[0125] 12.9±0.2°, 9.2±0.2°, 20.2±0.2°;

[0126] 21.0±0.2°, 13.5±0.2°, 10.5±0.2°;

[0127] 21.0±0.2°, 9.2±0.2°, 20.2±0.2°;

[0128] 21.0±0.2°, 14.6±0.2°, 12.9±0.2°, 8.5±0.2°;

[0129] 14.6±0.2°, 20.2±0.2°, 13.5±0.2°, 10.5±0.2°;

[0130] 12.9±0.2°, 8.5±0.2°, 20.2±0.2°, 10.5±0.2°;

[0131] 21.0±0.2°, 14.6±0.2°, 9.2±0.2°, 20.2±0.2°, 13.5±0.2°;

[0132] 21.0±0.2°, 14.6±0.2°, 12.9±0.2°, 8.5±0.2°, 10.5±0.2°;

[0133] 14.6±0.2°, 12.9±0.2°, 9.2±0.2°, 20.2±0.2°, 13.5±0.2°;

[0134] or,

[0135] The X-ray powder diffraction pattern of crystal form IV optionally includes one or more diffraction peaks located at 2θ of 5.0±0.2°, 11.4±0.2°, 23.7±0.2°, 18.5±0.2°, 19.8±0.2°, 17.2±0.2°, and 25.6±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks; for example,

[0136] 5.0±0.2°, 11.4±0.2°, 23.7±0.2°, 18.5±0.2°;

[0137] 18.5±0.2°, 19.8±0.2°, 17.2±0.2°, 25.6±0.2°;

[0138] 11.4±0.2°, 23.7±0.2°, 19.8±0.2°, 25.6±0.2°;

[0139] 5.0±0.2°, 11.4±0.2°, 23.7±0.2°, 18.5±0.2°, 19.8±0.2°;

[0140] 23.7±0.2°, 18.5±0.2°, 19.8±0.2°, 17.2±0.2°, 25.6±0.2°;

[0141] 5.0±0.2°, 11.4±0.2°, 18.5±0.2°, 19.8±0.2°, 17.2±0.2°;

[0142] 5.0±0.2°, 11.4±0.2°, 23.7±0.2°, 18.5±0.2°, 19.8±0.2°, 17.2±0.2°;

[0143] 11.4±0.2°, 23.7±0.2°, 18.5±0.2°, 19.8±0.2°, 17.2±0.2°, 25.6±0.2°;

[0144] 5.0±0.2°, 11.4±0.2°, 23.7±0.2°, 18.5±0.2°, 19.8±0.2°, 17.2±0.2°, 25.6±0.2°.

[0145] Further preferred, the X-ray powder diffraction pattern of crystal form IV is basically as follows: Figure 4 As shown, its DSC spectrum is basically as follows: Figure 4A As shown, its TGA spectrum is as follows: Figure 4B As shown.

[0146] More preferably, the compound of formula I has crystal form IV as a hydrate, with a TGA weight loss of about 7.7% and a KF moisture content of about 7.9%, indicating it is a trihydrate.

[0147] The X-ray powder diffraction pattern of the compound of formula I, crystal form V, has a diffraction peak at 2θ of 14.7 ± 0.2°; or at 9.8 ± 0.2°; or at 5.0 ± 0.2°; or at 11.3 ± 0.2°; or at 11.7 ± 0.2°; or at 19.7 ± 0.2°; or at 20.9 ± 0.2°; or at 24.6 ± 0.2°; preferably, it includes any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks; more preferably, it includes any 6, 7, or 8 of them;

[0148] or,

[0149] The X-ray powder diffraction pattern of crystal form V contains at least one or more diffraction peaks located at 2θ of 14.7±0.2°, 9.8±0.2°, and 5.0±0.2°, preferably two, more preferably three; optionally, it may further contain at least one diffraction peak located at 2θ of 11.3±0.2°, 11.7±0.2°, 19.7±0.2°, 20.9±0.2°, and 24.6±0.2°, preferably two, three, four, or five, for example,

[0150] 14.7±0.2°, 9.8±0.2°;

[0151] 9.8±0.2°, 5.0±0.2°;

[0152] 14.7±0.2°, 5.0±0.2°;

[0153] 14.7±0.2°, 11.3±0.2°;

[0154] 9.8±0.2°, 11.7±0.2°;

[0155] 5.0±0.2°, 19.7±0.2°;

[0156] 14.7±0.2°, 9.8±0.2°, 11.3±0.2°;

[0157] 9.8±0.2°, 5.0±0.2°, 19.7±0.2°;

[0158] 9.8±0.2°, 20.9±0.2°, 24.6±0.2°;

[0159] 5.0±0.2°, 11.3±0.2°, 19.7±0.2°;

[0160] 14.7±0.2°, 9.8±0.2°, 5.0±0.2°, 11.7±0.2°;

[0161] 14.7±0.2°, 5.0±0.2°, 19.7±0.2°, 20.9±0.2°;

[0162] 9.8±0.2°, 5.0±0.2°, 11.7±0.2°, 24.6±0.2°;

[0163] 14.7±0.2°, 9.8±0.2°, 5.0±0.2°, 11.7±0.2°, 19.7±0.2°;

[0164] 9.8±0.2°, 5.0±0.2°, 19.7±0.2°, 20.9±0.2°, 24.6±0.2°;

[0165] or,

[0166] The X-ray powder diffraction pattern of crystal form V optionally includes one or more diffraction peaks located at 2θ of 20.4±0.2°, 22.8±0.2°, 25.1±0.2°, and 25.5±0.2°; preferably, it includes at least 2-3 peaks, or 3-4 peaks; more preferably, it includes any 2, 3, or 4 peaks; for example,

[0167] 20.4±0.2°, 22.8±0.2°;

[0168] 22.8±0.2°, 25.1±0.2°;

[0169] 20.4±0.2°, 22.8±0.2°, 25.1±0.2°;

[0170] 22.8±0.2°, 25.1±0.2°, 25.5±0.2°;

[0171] 20.4±0.2°, 22.8±0.2°, 25.1±0.2°, 25.5±0.2°.

[0172] Further preferred, the X-ray powder diffraction pattern of crystal form V is basically as follows: Figure 5 As shown, its DSC spectrum is basically as follows: Figure 5A As shown, its TGA spectrum is as follows: Figure 5B As shown.

[0173] More preferably, the compound of formula I has crystal form V as a hydrate, with a TGA weight loss of about 5.4% and a KF moisture content of about 5.5%, indicating it is a dihydrate.

[0174] The X-ray powder diffraction pattern of the compound of formula I, crystal form VI, has a diffraction peak at 2θ of 10.7 ± 0.2°; or at 8.0 ± 0.2°; or at 14.6 ± 0.2°; or at 11.5 ± 0.2°; or at 21.7 ± 0.2°; or at 22.0 ± 0.2°; or at 24.2 ± 0.2°; or at 26.3 ± 0.2°; preferably, it includes any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks; more preferably, it includes any 6, 7, or 8 of them;

[0175] or,

[0176] The X-ray powder diffraction pattern of crystal form VI contains at least one or more diffraction peaks located at 2θ of 10.7±0.2°, 8.0±0.2°, and 14.6±0.2°, preferably two, more preferably three; optionally, it may further contain at least one peak located at 2θ of 11.5±0.2°, 21.7±0.2°, 8.0±0.2°, 24.2±0.2°, and 26.3±0.2°, preferably two, three, four, or five, for example,

[0177] 10.7±0.2°, 8.0±0.2°;

[0178] 8.0±0.2°, 14.6±0.2°;

[0179] 10.7±0.2°, 14.6±0.2°;

[0180] 14.7±0.2°, 11.5±0.2°;

[0181] 8.0±0.2°, 21.7±0.2°;

[0182] 10.7±0.2°, 8.0±0.2°, 11.5±0.2°;

[0183] 10.7±0.2°, 14.6±0.2°, 21.7±0.2°;

[0184] 8.0±0.2°, 14.6±0.2°, 22.0±0.2°;

[0185] 10.7±0.2°, 21.7±0.2°, 22.0±0.2°;

[0186] 8.0±0.2°, 22.0±0.2°, 24.2±0.2°;

[0187] 10.7±0.2°, 8.0±0.2°, 21.7±0.2°, 22.0±0.2°;

[0188] 8.0±0.2°, 14.6±0.2°, 24.2±0.2°, 26.3±0.2°;

[0189] 10.7±0.2°, 14.6±0.2°, 21.7±0.2°, 8.0±0.2°;

[0190] 10.7±0.2°, 8.0±0.2°, 21.7±0.2°, 8.0±0.2°, 24.2±0.2°;

[0191] 8.0±0.2°, 14.6±0.2°, 11.5±0.2°, 21.7±0.2°, 26.3±0.2°;

[0192] 10.7±0.2°, 8.0±0.2°, 14.6±0.2°, 24.2±0.2°, 26.3±0.2°;

[0193] or,

[0194] The X-ray powder diffraction pattern of crystal form VI optionally includes one or more diffraction peaks located at 2θ of 12.7±0.2°, 14.0±0.2°, 15.1±0.2°, 18.3±0.2°, 20.6±0.2°, 23.9±0.2°, and 32.4±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks; for example,

[0195] 12.7±0.2°, 14.0±0.2°, 15.1±0.2°, 18.3±0.2°;

[0196] 18.3±0.2°, 20.6±0.2°, 23.9±0.2°, 32.4±0.2°;

[0197] 14.0±0.2°, 15.1±0.2°, 23.9±0.2°, 32.4±0.2°;

[0198] 12.7±0.2°, 14.0±0.2°, 15.1±0.2°, 18.3±0.2°, 20.6±0.2°;

[0199] 14.0±0.2°, 15.1±0.2°, 18.3±0.2°, 20.6±0.2°, 23.9±0.2°;

[0200] 12.7±0.2°, 14.0±0.2°, 15.1±0.2°, 18.3±0.2°, 20.6±0.2°, 23.9±0.2°;

[0201] 4.0±0.2°, 15.1±0.2°, 18.3±0.2°, 20.6±0.2°, 23.9±0.2°, 32.4±0.2°;

[0202] 12.7±0.2°, 14.0±0.2°, 15.1±0.2°, 18.3±0.2°, 20.6±0.2°, 23.9±0.2°, 32.4±0.2°;

[0203] Further preferred, the X-ray powder diffraction pattern of crystal form VI is basically as follows: Figure 6 As shown, its DSC spectrum is basically as follows: Figure 6A As shown, its TGA spectrum is as follows: Figure 6B As shown.

[0204] More preferably, the compound of formula I, crystal form VI, is a methanol solvate, with a TGA weight loss of approximately 4.2% and a GC detection of 43,000 ppm methanol residue, indicating it is a mono-methanol solvate.

[0205] The X-ray powder diffraction pattern of the compound of formula I, crystal form VII, has a diffraction peak at 2θ of 17.4 ± 0.2°; or at 14.5 ± 0.2°; or at 23.6 ± 0.2°; or at 7.4 ± 0.2°; or at 12.8 ± 0.2°; or at 18.5 ± 0.2°; or at 21.2 ± 0.2°; or at 24.4 ± 0.2°; preferably, it includes any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks; more preferably, it includes any 6, 7, or 8 of them;

[0206] or,

[0207] The X-ray powder diffraction pattern of crystal form VII contains at least one or more diffraction peaks located at 2θ of 17.4±0.2°, 14.5±0.2°, and 23.6±0.2°, preferably two, more preferably three; optionally, it may further contain at least one diffraction peak located at 2θ of 7.4±0.2°, 12.8±0.2°, 18.5±0.2°, 21.2±0.2°, and 24.4±0.2°, preferably two, three, four, or five, for example,

[0208] 17.4±0.2°, 14.5±0.2°;

[0209] 14.5±0.2°, 23.6±0.2°;

[0210] 17.4±0.2°, 23.6±0.2°;

[0211] 17.4±0.2°, 7.4±0.2°;

[0212] 14.5±0.2°, 12.8±0.2°;

[0213] 23.6±0.2°, 18.5±0.2°;

[0214] 17.4±0.2°, 14.5±0.2°, 12.8±0.2°;

[0215] 14.5±0.2°, 23.6±0.2°, 18.5±0.2°;

[0216] 14.5±0.2°, 23.6±0.2°, 21.2±0.2°;

[0217] 17.4±0.2°, 14.5±0.2°, 12.8±0.2°, 18.5±0.2°;

[0218] 14.5±0.2°, 23.6±0.2°, 21.2±0.2°, 24.4±0.2°;

[0219] 17.4±0.2°, 14.5±0.2°, 12.8±0.2°, 18.5±0.2°, 21.2±0.2°;

[0220] 14.5±0.2°, 23.6±0.2°, 18.5±0.2°, 21.2±0.2°, 24.4±0.2°;

[0221] or,

[0222] The X-ray powder diffraction pattern of crystal form VII optionally includes one or more diffraction peaks located at 2θ of 11.7±0.2°, 12.1±0.2°, 15.0±0.2°, 15.8±0.2°, 22.3±0.2°, 26.7±0.2°, and 30.6±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks; for example,

[0223] 11.7±0.2°, 12.1±0.2°, 15.0±0.2°, 15.8±0.2°;

[0224] 15.8±0.2°, 22.3±0.2°, 26.7±0.2°, 30.6±0.2°;

[0225] 11.7±0.2°, 12.1±0.2°, 15.0±0.2°, 15.8±0.2°, 22.3±0.2°;

[0226] 15.0±0.2°, 15.8±0.2°, 22.3±0.2°, 26.7±0.2°, 30.6±0.2°;

[0227] 11.7±0.2°, 12.1±0.2°, 15.0±0.2°, 15.8±0.2°, 22.3±0.2°, 26.7±0.2°;

[0228] 12.1±0.2°, 15.0±0.2°, 15.8±0.2°, 22.3±0.2°, 26.7±0.2°, 30.6±0.2°;

[0229] 11.7±0.2°, 12.1±0.2°, 15.0±0.2°, 15.8±0.2°, 22.3±0.2°, 26.7±0.2°, 30.6±0.2°;

[0230] Further preferred, the X-ray powder diffraction pattern of crystal form VII is basically as follows Figure 7 As shown, its DSC spectrum is basically as follows: Figure 7A As shown, its TGA spectrum is as follows: Figure 7B As shown.

[0231] More preferably, the compound of formula I, crystal form VII, is anhydrous, has a melting point of around 215°C, and exhibits virtually no weight loss before decomposition.

[0232] The X-ray powder diffraction pattern of the compound of formula I, crystal form VII, has a diffraction peak at 2θ of 17.9 ± 0.2°; or at 20.3 ± 0.2°; or at 22.7 ± 0.2°; or at 7.5 ± 0.2°; or at 8.2 ± 0.2°; or at 12.1 ± 0.2°; or at 15.4 ± 0.2°; or at 17.6 ± 0.2°; preferably, it includes any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks; more preferably, it includes any 6, 7, or 8 of them;

[0233] or,

[0234] The X-ray powder diffraction pattern of crystal form VIII contains at least one or more diffraction peaks located at 2θ of 17.9±0.2°, 20.3±0.2°, and 22.7±0.2°, preferably two, more preferably three; optionally, it may further contain at least one diffraction peak located at 2θ of 7.5±0.2°, 8.2±0.2°, 12.1±0.2°, 15.4±0.2°, and 17.6±0.2°, preferably two, three, four, or five, for example,

[0235] 17.9±0.2°, 20.3±0.2°;

[0236] 20.3±0.2°, 22.7±0.2°;

[0237] 17.9±0.2°, 22.7±0.2°;

[0238] 17.9±0.2°, 7.5±0.2°;

[0239] 20.3±0.2°, 8.2±0.2°;

[0240] 22.7±0.2°, 12.1±0.2°;

[0241] 17.9±0.2°, 20.3±0.2°, 7.5±0.2°;

[0242] 20.3±0.2°, 22.7±0.2°, 8.2±0.2°;

[0243] 17.9±0.2°, 22.7±0.2°, 12.1±0.2°;

[0244] 20.3±0.2°, 22.7±0.2°, 15.4±0.2°;

[0245] 17.9±0.2°, 20.3±0.2°, 8.2±0.2°, 12.1±0.2°;

[0246] 20.3±0.2°, 22.7±0.2°, 12.1±0.2°, 15.4±0.2°;

[0247] 17.9±0.2°, 20.3±0.2°, 8.2±0.2°, 12.1±0.2°, 15.4±0.2°;

[0248] 20.3±0.2°, 22.7±0.2°, 12.1±0.2°, 15.4±0.2°, 17.6±0.2°;

[0249] or,

[0250] The X-ray powder diffraction pattern of crystal form VIII optionally includes one or more diffraction peaks located at 2θ of 7.0±0.2°, 14.9±0.2°, 16.1±0.2°, 19.2±0.2°, 20.7±0.2°, 22.4±0.2°, and 25.3±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks; for example,

[0251] 7.0±0.2°, 14.9±0.2°, 16.1±0.2°, 19.2±0.2°;

[0252] 16.1±0.2°, 19.2±0.2°, 20.7±0.2°, 22.4±0.2°;

[0253] 19.2±0.2°, 20.7±0.2°, 22.4±0.2°, 25.3±0.2°;

[0254] 7.0±0.2°, 14.9±0.2°, 16.1±0.2°, 19.2±0.2°, 20.7±0.2°;

[0255] 16.1±0.2°, 19.2±0.2°, 20.7±0.2°, 22.4±0.2°, 25.3±0.2°;

[0256] 7.0±0.2°, 14.9±0.2°, 16.1±0.2°, 19.2±0.2°, 20.7±0.2°, 22.4±0.2°;

[0257] 14.9±0.2°, 16.1±0.2°, 19.2±0.2°, 20.7±0.2°, 22.4±0.2°, 25.3±0.2°;

[0258] 7.0±0.2°, 14.9±0.2°, 16.1±0.2°, 19.2±0.2°, 20.7±0.2°, 22.4±0.2°, 25.3±0.2°;

[0259] Further preferred, the X-ray powder diffraction pattern of crystal form VIII is basically as follows Figure 8 As shown, its DSC spectrum is basically as follows: Figure 8A As shown, its TGA spectrum is as follows: Figure 8B As shown.

[0260] More preferably, the compound of formula I, crystal form VIII, is a hydrate, with a TGA weight loss of approximately 2.5% and a KF moisture content of approximately 2.6%, indicating it is a monohydrate.

[0261] The X-ray powder diffraction pattern of the compound of formula I, crystal form IX, has a diffraction peak at 2θ of 16.1 ± 0.2°; or at 16.4 ± 0.2°; or at 21.2 ± 0.2°; or at 8.1 ± 0.2°; or at 13.1 ± 0.2°; or at 17.7 ± 0.2°; or at 19.0 ± 0.2°; or at 24.2 ± 0.2°; preferably, it includes any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks; more preferably, it includes any 6, 7, or 8 of them;

[0262] or,

[0263] The X-ray powder diffraction pattern of crystal form IX contains at least one or more diffraction peaks located at 2θ of 16.1±0.2°, 16.4±0.2°, and 21.2±0.2°, preferably two, more preferably three; optionally, it may further contain at least one peak located at 2θ of 8.1±0.2°, 13.1±0.2°, 17.7±0.2°, 19.0±0.2°, and 24.2±0.2°, preferably two, three, four, or five, for example,

[0264] 16.1±0.2°, 16.4±0.2°;

[0265] 16.4±0.2°, 21.2±0.2°;

[0266] 16.1±0.2°, 21.2±0.2°;

[0267] 16.1±0.2°, 13.1±0.2°;

[0268] 16.4±0.2°, 17.7±0.2°;

[0269] 21.2±0.2°, 19.0±0.2°;

[0270] 16.1±0.2°, 16.4±0.2°, 8.1±0.2°;

[0271] 16.4±0.2°, 21.2±0.2°, 19.0±0.2°;

[0272] 16.1±0.2°, 21.2±0.2°, 24.2±0.2°;

[0273] 16.1±0.2°, 16.4±0.2°, 13.1±0.2°, 17.7±0.2°;

[0274] 16.4±0.2°, 21.2±0.2°, 19.0±0.2°, 24.2±0.2°;

[0275] 16.1±0.2°, 16.4±0.2°, 13.1±0.2°, 17.7±0.2°, 19.0±0.2°;

[0276] 16.4±0.2°, 21.2±0.2°, 17.7±0.2°, 19.0±0.2°, 24.2±0.2°;

[0277] or,

[0278] The X-ray powder diffraction pattern of crystal form IX optionally includes one or more diffraction peaks located at 2θ of 10.7±0.2°, 14.6±0.2°, 18.1±0.2°, 19.4±0.2°, 21.9±0.2°, 22.6±0.2°, and 25.9±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks; for example,

[0279] 10.7±0.2°, 14.6±0.2°, 18.1±0.2°, 19.4±0.2°;

[0280] 19.4±0.2°, 21.9±0.2°, 22.6±0.2°, 25.9±0.2°;

[0281] 10.7±0.2°, 14.6±0.2°, 18.1±0.2°, 19.4±0.2°, 21.9±0.2°;

[0282] 18.1±0.2°, 19.4±0.2°, 21.9±0.2°, 22.6±0.2°, 25.9±0.2°;

[0283] 10.7±0.2°, 14.6±0.2°, 18.1±0.2°, 19.4±0.2°, 21.9±0.2°, 22.6±0.2°;

[0284] 14.6±0.2°, 18.1±0.2°, 19.4±0.2°, 21.9±0.2°, 22.6±0.2°, 25.9±0.2°;

[0285] 10.7±0.2°, 14.6±0.2°, 18.1±0.2°, 19.4±0.2°, 21.9±0.2°, 22.6±0.2°, 25.9±0.2°;

[0286] Further preferred, the X-ray powder diffraction pattern of crystal form IX is basically as follows: Figure 9 As shown, its DSC spectrum is basically as shown in 9A, and its TGA spectrum is as shown in... Figure 9B As shown.

[0287] More preferably, the compound of formula I, crystal form IX, is a hydrate, with a TGA weight loss of approximately 2.4% and a KF moisture content of approximately 2.4%, indicating it is a monohydrate.

[0288] The X-ray powder diffraction pattern of the compound of formula I, crystal form X, has a diffraction peak at 2θ of 4.7 ± 0.2°; or at 9.1 ± 0.2°; or at 14.0 ± 0.2°; or at 17.7 ± 0.2°; or at 18.7 ± 0.2°; or at 21.0 ± 0.2°; or at 22.0 ± 0.2°; or at 24.1 ± 0.2°; preferably, it includes any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks; more preferably, it includes any 6, 7, or 8 of them;

[0289] or,

[0290] The X-ray powder diffraction pattern of crystal form X contains at least one or more diffraction peaks located at 2θ of 4.7±0.2°, 9.1±0.2°, and 14.0±0.2°, preferably two, more preferably three; optionally, it may further contain at least one diffraction peak located at 2θ of 17.7±0.2°, 18.7±0.2°, 21.0±0.2°, 22.0±0.2°, and 24.1±0.2°, preferably two, three, four, or five, for example,

[0291] 4.7±0.2°, 9.1±0.2°;

[0292] 9.1±0.2°, 14.0±0.2°;

[0293] 4.7±0.2°, 14.0±0.2°;

[0294] 4.7±0.2°, 17.7±0.2°;

[0295] 9.1±0.2°, 18.7±0.2°;

[0296] 14.0±0.2°, 22.0±0.2°;

[0297] 4.7±0.2°, 9.1±0.2°, 21.0±0.2°;

[0298] 9.1±0.2°, 14.0±0.2°, 22.0±0.2°;

[0299] 4.7±0.2°, 9.1±0.2°, 18.7±0.2°, 21.0±0.2°;

[0300] 9.1±0.2°, 14.0±0.2°, 22.0±0.2°, 24.1±0.2°;

[0301] 4.7±0.2°, 9.1±0.2°, 18.7±0.2°, 21.0±0.2°, 22.0±0.2°;

[0302] 9.1±0.2°, 14.0±0.2°, 21.0±0.2°, 22.0±0.2°, 24.1±0.2°;

[0303] or,

[0304] The X-ray powder diffraction pattern of crystal form X optionally includes one or more diffraction peaks located at 2θ of 10.4±0.2°, 12.1±0.2°, 13.0±0.2°, 16.0±0.2°, 20.0±0.2°, 24.7±0.2°, and 26.3±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks; for example,

[0305] 10.4±0.2°, 12.1±0.2°, 13.0±0.2°, 16.0±0.2°;

[0306] 13.0±0.2°, 16.0±0.2°, 20.0±0.2°, 24.7±0.2°;

[0307] 12.1±0.2°, 13.0±0.2°, 16.0±0.2°, 20.0±0.2°, 24.7±0.2°;

[0308] 10.4±0.2°, 16.0±0.2°, 20.0±0.2°, 24.7±0.2°, 26.3±0.2°;

[0309] 10.4±0.2°, 12.1±0.2°, 13.0±0.2°, 16.0±0.2°, 20.0±0.2°, 24.7±0.2°;

[0310] 12.1±0.2°, 13.0±0.2°, 16.0±0.2°, 20.0±0.2°, 24.7±0.2°, 26.3±0.2°;

[0311] 10.4±0.2°, 12.1±0.2°, 13.0±0.2°, 16.0±0.2°, 20.0±0.2°, 24.7±0.2°, 26.3±0.2°;

[0312] Further preferred, the X-ray powder diffraction pattern of crystal form X is basically as follows: Figure 10 As shown, its DSC spectrum is basically as shown in 10A, and its TGA spectrum is as shown in [the image / image]. Figure 10B As shown.

[0313] More preferably, the compound of formula I, crystal form X, is a hydrate, with a TGA weight loss of approximately 7.6% and a KF moisture content of approximately 7.8%, indicating it is a trihydrate.

[0314] The X-ray powder diffraction pattern of the compound of formula I, crystal form XI, has a diffraction peak at 4.8 ± 0.2°; or at 9.1 ± 0.2°; or at 18.6 ± 0.2°; or at 9.5 ± 0.2°; or at 14.2 ± 0.2°; or at 18.1 ± 0.2°; or at 21.3 ± 0.2°; or at 26.4 ± 0.2°; preferably, it includes any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks; more preferably, it includes any 6, 7, or 8 of them;

[0315] or,

[0316] The X-ray powder diffraction pattern of crystal form XI contains at least one or more diffraction peaks located at 2θ of 4.8±0.2°, 9.1±0.2°, and 18.6±0.2°, preferably two, more preferably three; optionally, it may further contain at least one peak located at 2θ of 9.5±0.2°, 14.2±0.2°, 18.1±0.2°, 21.3±0.2°, and 26.4±0.2°, preferably two, three, four, or five, for example,

[0317] 4.8±0.2°, 9.1±0.2°;

[0318] 9.1±0.2°, 18.6±0.2°;

[0319] 4.8±0.2°, 18.6±0.2°;

[0320] 4.8±0.2°, 9.5±0.2°;

[0321] 9.1±0.2°, 14.2±0.2°;

[0322] 18.6±0.2°, 18.1±0.2°;

[0323] 4.8±0.2°, 9.1±0.2°, 14.2±0.2°;

[0324] 9.1±0.2°, 18.6±0.2°, 18.1±0.2°;

[0325] 4.8±0.2°, 9.1±0.2°, 14.2±0.2°, 18.1±0.2°;

[0326] 9.1±0.2°, 18.6±0.2°, 21.3±0.2°, 26.4±0.2°;

[0327] 21.3±0.2°, 26.4±0.2°, 9.5±0.2°, 14.2±0.2°, 18.1±0.2°;

[0328] 9.1±0.2°, 18.6±0.2°, 14.2±0.2°, 18.1±0.2°, 21.3±0.2°;

[0329] or,

[0330] The X-ray powder diffraction pattern of crystal form XI optionally includes one or more diffraction peaks located at 2θ of 12.1±0.2°, 14.4±0.2°, 16.1±0.2°, 17.7±0.2°, 20.5±0.2°, 22.2±0.2°, and 23.7±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks; for example,

[0331] 12.1±0.2°, 14.4±0.2°, 17.7±0.2°, 20.5±0.2°;

[0332] 14.4±0.2°, 16.1±0.2°, 22.2±0.2°, 23.7±0.2°;

[0333] 14.4±0.2°, 16.1±0.2°, 17.7±0.2°, 20.5±0.2°, 22.2±0.2°;

[0334] 12.1±0.2°, 17.7±0.2°, 20.5±0.2°, 22.2±0.2°, 23.7±0.2°;

[0335] 12.1±0.2°, 14.4±0.2°, 16.1±0.2°, 17.7±0.2°, 20.5±0.2°, 22.2±0.2°;

[0336] 14.4±0.2°, 16.1±0.2°, 17.7±0.2°, 20.5±0.2°, 22.2±0.2°, 23.7±0.2°;

[0337] 12.1±0.2°, 14.4±0.2°, 16.1±0.2°, 17.7±0.2°, 20.5±0.2°, 22.2±0.2°, 23.7±0.2°;

[0338] Further preferred, the X-ray powder diffraction pattern of crystal form XI is basically as follows: Figure 11 As shown, its DSC spectrum is basically as shown in 11A, and its TGA spectrum is as shown in [the image / image]. Figure 11B As shown.

[0339] More preferably, the compound of formula I has crystal form XI as a hydrate, with a TGA weight loss of about 5.1% and a KF moisture content of about 5.2%, indicating it is a dihydrate.

[0340] The X-ray powder diffraction pattern of the compound of formula I, crystal form XII, has a diffraction peak at 6.8 ± 0.2°; or at 16.4 ± 0.2°; or at 18.8 ± 0.2°; or at 13.6 ± 0.2°; or at 14.5 ± 0.2°; or at 17.5 ± 0.2°; or at 20.3 ± 0.2°; or at 22.8 ± 0.2°; preferably, it includes any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks; more preferably, it includes any 6, 7, or 8 of them;

[0341] or,

[0342] The X-ray powder diffraction pattern of crystal form XII contains at least one or more diffraction peaks located at 2θ of 6.8±0.2°, 16.4±0.2°, and 18.8±0.2°, preferably two, more preferably three; optionally, it may further contain at least one diffraction peak located at 2θ of 13.6±0.2°, 14.5±0.2°, 17.5±0.2°, 20.3±0.2°, and 22.8±0.2°, preferably two, three, four, or five, for example,

[0343] 6.8±0.2°, 16.4±0.2°;

[0344] 16.4±0.2°, 18.8±0.2°;

[0345] 6.8±0.2°, 18.8±0.2°;

[0346] 6.8±0.2°, 14.5±0.2°;

[0347] 16.4±0.2°, 17.5±0.2°;

[0348] 6.8±0.2°, 16.4±0.2°, 14.5±0.2°;

[0349] 16.4±0.2°, 18.8±0.2°, 17.5±0.2°;

[0350] 6.8±0.2°, 16.4±0.2°, 17.5±0.2°, 20.3±0.2°;

[0351] 16.4±0.2°, 18.8±0.2°, 20.3±0.2°, 22.8±0.2°;

[0352] 6.8±0.2°, 16.4±0.2°, 13.6±0.2°, 14.5±0.2°, 17.5±0.2°;

[0353] 16.4±0.2°, 18.8±0.2°, 17.5±0.2°, 20.3±0.2°, 22.8±0.2°;

[0354] or,

[0355] The X-ray powder diffraction pattern of crystal form XII optionally includes one or more diffraction peaks located at 2θ of 7.5±0.2°, 8.4±0.2°, 15.2±0.2°, 21.9±0.2°, 24.6±0.2°, 26.8±0.2°, and 28.3±0.2°; preferably, it includes at least 2-3, 4-5, or 6-7 peaks; more preferably, it includes any 2, 3, 4, 5, 6, or 7 peaks; for example,

[0356] 7.5±0.2°, 8.4±0.2°, 15.2±0.2°, 21.9±0.2°;

[0357] 8.4±0.2°, 15.2±0.2°, 21.9±0.2°, 24.6±0.2°;

[0358] 21.9±0.2°, 24.6±0.2°, 26.8±0.2°, 28.3±0.2°;

[0359] 7.5±0.2°, 8.4±0.2°, 15.2±0.2°, 21.9±0.2°, 24.6±0.2°;

[0360] 15.2±0.2°, 21.9±0.2°, 24.6±0.2°, 26.8±0.2°, 28.3±0.2°;

[0361] 7.5±0.2°, 8.4±0.2°, 15.2±0.2°, 21.9±0.2°, 24.6±0.2°, 26.8±0.2°;

[0362] 8.4±0.2°, 15.2±0.2°, 21.9±0.2°, 24.6±0.2°, 26.8±0.2°, 28.3±0.2°;

[0363] 7.5±0.2°, 8.4±0.2°, 15.2±0.2°, 21.9±0.2°, 24.6±0.2°, 26.8±0.2°, 28.3±0.2°;

[0364] Further preferred, the X-ray powder diffraction pattern of crystal form XII is basically as follows Figure 12 As shown, its DSC spectrum is basically as shown in 12A, and its TGA spectrum is as shown in [the image / image]. Figure 12B As shown.

[0365] More preferably, the compound of formula I has crystal form XII as a hydrate, with a TGA weight loss of about 7.7% and a KF moisture content of about 7.6%, indicating it is a trihydrate.

[0366] On the other hand, the present invention provides a method for preparing crystal forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI and XII of the compound of formula I.

[0367] The method for preparing crystal form I of compound I includes the following steps:

[0368] ① Mix the compound of formula I with a good solvent to prepare a solution;

[0369] ② Add a poor solvent to the above solution system to induce crystallization;

[0370] ③ Stir, filter, and collect the solid to obtain crystal form I of compound I;

[0371] Preferred,

[0372] In step ①, the good solvent is selected from ethanol and methanol, with methanol being preferred;

[0373] Preferred,

[0374] The unsuitable solvent in step ② is water.

[0375] The method for preparing crystal form II of compound I includes the following steps:

[0376] ① Mix the compound of formula I with a good solvent to prepare a solution;

[0377] ② Add a poor solvent to the above solution system to induce crystallization;

[0378] ③ Stir, filter, and collect the solid to obtain crystal form II of compound I;

[0379] Preferred,

[0380] Step ① The good solvent is selected from tetrahydrofuran, isopropanol, and 1,4-dioxane, with isopropanol and 1,4-dioxane being preferred, and isopropanol being the most preferred.

[0381] Preferred,

[0382] The unsuitable solvent in step ② is water.

[0383] The method for preparing crystal form III of compound I includes the following steps:

[0384] ① Under certain temperature conditions, the compound of formula I is mixed with a poor solvent to prepare a suspension;

[0385] ② Stir, filter, and collect the solid to obtain crystal form III of compound I;

[0386] Preferably, the temperature in step ① is 70–100°C, more preferably 75–95°C, and most preferably 75–80°C;

[0387] Water is an unsuitable solvent.

[0388] The method for preparing crystal form IV of compound I includes the following steps:

[0389] ① Under certain temperature conditions, the compound of formula I is mixed with a poor solvent to prepare a suspension;

[0390] ② Stir, filter, and collect the solid to obtain crystal form IV of compound I;

[0391] Preferably, the temperature in step ① is 40-60℃, more preferably 45-55℃, and most preferably 45-50℃;

[0392] Water is an unsuitable solvent.

[0393] The method for preparing crystal form V of compound I includes the following steps:

[0394] ① Under certain temperature conditions, the compound of formula I is mixed with a poor solvent to prepare a suspension;

[0395] ② Stir, filter, and collect the solid to obtain crystal form V of compound I;

[0396] Preferably, the temperature in step ① is 0–25°C, more preferably 5–20°C, and most preferably 10–15°C;

[0397] Water is an unsuitable solvent.

[0398] The method for preparing crystal form VI of compound I includes the following steps:

[0399] ① Mix the compound of formula I with a good solvent to prepare a solution;

[0400] ② Add a poor solvent to the above solution system to induce crystallization;

[0401] ③ Stir, filter, and collect the solid to obtain crystal form VI of compound I;

[0402] Preferred,

[0403] Step ① The good solvent is methanol;

[0404] Preferred,

[0405] In step ②, the undesirable solvent is selected from methyl tert-butyl ether and isopropyl ether, with methyl tert-butyl ether being preferred.

[0406] The method for preparing crystal form VII of compound I includes the following steps:

[0407] ① Under certain temperature conditions, the compound of formula I is mixed with a solvent to prepare a suspension;

[0408] ② Stir, filter, and collect the solid to obtain crystal form VII of compound I;

[0409] Preferably, the temperature in step ① is 40-60℃, more preferably 45-55℃, and most preferably 45-50℃;

[0410] The solvent is selected from cyclic ethers, preferably tetrahydrofuran, 1,4-dioxane and 2-methyltetrahydrofuran, with tetrahydrofuran being the most preferred.

[0411] The method for preparing crystal form VIII of compound I includes the following steps:

[0412] ① Mix the compound of formula I with a solvent to prepare a solution;

[0413] ② Stir to induce crystallization;

[0414] ③ Filter and collect the solid to obtain the crystal form VIII of compound I;

[0415] Preferably, the solvent in step ① is ethyl formate.

[0416] The method for preparing crystal form IX of compound I includes the following steps:

[0417] ① Mix the compound of formula I with a solvent to prepare a solution;

[0418] ② Stir to induce crystallization;

[0419] ③ Filter and collect the solid to obtain the crystal form IX of compound I;

[0420] Preferably, the solvent in step ① is anisole.

[0421] The method for preparing crystal form X of compound I includes the following steps:

[0422] ① Mix the compound of formula I with a solvent to prepare a solution;

[0423] ② Stir to induce crystallization;

[0424] ③ Filter and collect the solid to obtain the crystal form X of compound I;

[0425] Preferably, the solvent in step ① is ethylene glycol diethyl ether.

[0426] The method for preparing crystal form XI of compound I includes the following steps:

[0427] ① Mix the compound of formula I with a solvent to prepare a solution;

[0428] ② Stir to induce crystallization;

[0429] ③ Filter and collect the solid to obtain the crystal form XI of compound I;

[0430] Preferably, the solvent in step ① is butyl formate.

[0431] The method for preparing crystal form XII of compound I includes the following steps:

[0432] ① At a certain temperature, the compound of formula I is mixed with a solvent to prepare a solution;

[0433] ② Add a poor solvent to the above solution system to induce crystallization;

[0434] ③ Filter and collect the solid to obtain the crystal form XII of compound I;

[0435] Preferred,

[0436] The temperature conditions in step ① are 55–80℃, preferably 60–75℃, and most preferably 65–70℃; the solvent used is ethyl formate.

[0437] In step ②, the undesirable solvent is selected from methyl tert-butyl ether, isopropyl ether, and n-heptane, with isopropyl ether and methyl tert-butyl ether being preferred, and methyl tert-butyl ether being the most preferred.

[0438] On the other hand, the present invention relates to a pharmaceutical composition comprising a therapeutically effective dose of a compound of formula I, crystal form III, and one or more pharmaceutically acceptable carriers, diluents, or excipients. A pharmaceutically acceptable carrier refers to one or more compatible solid or liquid fillers or gelling substances suitable for human use and possessing sufficient purity and sufficiently low toxicity. Compatibility here refers to the ability of the components in the composition to mix with and with the active ingredient of the present invention without significantly reducing the efficacy of the active ingredient. Pharmaceutically acceptable carriers include cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, etc.; solid lubricants such as stearic acid, magnesium stearate, etc.; vegetable oils such as soybean oil, castor oil, peanut oil, olive oil, etc.; polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.; emulsifiers such as the Tween series; wetting agents such as sodium dodecyl sulfate, gelatin, talc; colorants, flavoring agents, stabilizers, etc.

[0439] The pharmaceutical composition may be a tablet or a capsule.

[0440] On the other hand, the present invention relates to the use of compound of formula I crystal form III or a pharmaceutically acceptable composition thereof in a cancer-related medicament, wherein the cancer is selected from breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, pancreatic cancer, brain cancer, liver cancer, solid tumor, glioma, glioblastoma, leukemia, lymphoma or myeloma; preferably non-small cell lung cancer.

[0441] The preparation method involved in this invention is simple to operate, has good reproducibility, and can stably prepare the target crystal form. By comparing the hygroscopicity, physicochemical stability, and flowability of crystal forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, and XII, crystal form III was found to have significant advantages. Furthermore, the interconversion relationships show that crystal form III is the most stable; all crystal forms can transform into crystal form III in water, while crystal form III will not transform into other crystal forms. Attached Figure Description

[0442] Figure 1 The image shows the X-ray diffraction pattern of crystal form I of compound I.

[0443] Figure 1A The image shows the DSC spectrum of crystal form I of compound I.

[0444] Figure 1B The TGA spectrum is for crystal form I of compound of formula I.

[0445] Figure 2 The image shows the X-ray diffraction pattern of crystal form II of compound I.

[0446] Figure 2A The image shows the DSC spectrum of crystal form II of compound I.

[0447] Figure 2B The TGA spectrum is for crystal form II of compound I.

[0448] Figure 3 The X-ray diffraction pattern is shown for crystal form III of compound I.

[0449] Figure 3A This is the DSC spectrum of crystal form III of compound I.

[0450] Figure 3B The TGA spectrum is for crystal form III of compound I.

[0451] Figure 4 The X-ray diffraction pattern is shown for crystal form IV of compound I.

[0452] Figure 4A The image shows the DSC spectrum of crystal form IV of compound I.

[0453] Figure 4B The TGA spectrum is for crystal form IV of compound I.

[0454] Figure 5 The X-ray diffraction pattern of crystal form V of compound I is shown.

[0455] Figure 5A The image shows the DSC spectrum of crystal form V of compound I.

[0456] Figure 5B The TGA spectrum is for crystal form V of compound I.

[0457] Figure 6 The X-ray diffraction pattern is for crystal form VI of compound I.

[0458] Figure 6A The image shows the DSC spectrum of crystal form VI of compound I.

[0459] Figure 6B The TGA spectrum is for crystal form VI of compound I.

[0460] Figure 7 The X-ray diffraction pattern is for crystal form VII of compound I.

[0461] Figure 7A The image shows the DSC spectrum of crystal form VII of compound I.

[0462] Figure 7B The TGA spectrum is for crystal form VII of compound I.

[0463] Figure 8 The X-ray diffraction pattern is for crystal form VIII of compound I.

[0464] Figure 8A The image shows the DSC spectrum of crystal form VIII of compound I.

[0465] Figure 8B The TGA spectrum is for crystal form VIII of compound I.

[0466] Figure 9 The X-ray diffraction pattern is for crystal form IX of compound I.

[0467] Figure 9A The image shows the DSC spectrum of crystal form IX of compound I.

[0468] Figure 9B The TGA spectrum is for crystal form IX of compound I.

[0469] Figure 10 The X-ray diffraction pattern of crystal form X of compound I is shown.

[0470] Figure 10A The image shows the DSC spectrum of crystal form X of compound I.

[0471] Figure 10B The TGA spectrum is for crystal form X of compound I.

[0472] Figure 11 The X-ray diffraction pattern is for crystal form XI of compound I.

[0473] Figure 11A The image shows the DSC spectrum of crystal form XI of compound I.

[0474] Figure 11B The TGA spectrum is for crystal form XI of compound I.

[0475] Figure 12 The X-ray diffraction pattern is for crystal form XII of compound I.

[0476] Figure 12A The image shows the DSC spectrum of crystal form XII of compound I.

[0477] Figure 12B The TGA spectrum is for crystal form XII of compound I. Detailed Implementation

[0478] The specific embodiments of the present invention will be described in further detail below with reference to the accompanying drawings and examples. The following examples are for illustrative purposes only and are not intended to limit the scope of the invention.

[0479] Example 1: Preparation of Crystal Form I of Compound I

[0480] Weigh 1g of compound I and mix it with 10mL of methanol. Control the system temperature at 35℃ and start stirring. The system becomes clear. Under the condition of keeping warm, add 40mL of water to the above system, stir for 12h, filter, and place the product at 45℃ for drying in a forced air for 24h to obtain compound I of crystal form I with a mass yield of 90% and a purity of 99.2%.

[0481] Example 2: Preparation of Crystal Form I of Compound I

[0482] Weigh 1g of compound I and mix it with 10mL of ethanol. Control the system temperature at 45℃ and start stirring. The system becomes clear. Under the condition of keeping warm, add 30mL of water to the above system, stir for 16h and then filter. Place the product at 40℃ and dry it in a forced air for 20h to obtain compound I, crystal form I, with a mass yield of 91% and a purity of 99.4%.

[0483] Example 3: Preparation of Crystal Form II of Compound I

[0484] Weigh 1g of compound I and mix it with 10mL of isopropanol. Control the system temperature at 30℃ and start stirring. The system becomes clear. Under the condition of keeping warm, add 30mL of water to the above system, stir for 15h and then filter. Place the product at 45℃ and dry it in a forced air for 22h to obtain crystal form II of compound I. The mass yield is 92% and the purity is 99.5%.

[0485] Example 4: Preparation of Crystal Form II of Compound I

[0486] Weigh 1g of compound I and mix it with 8mL of 1,4-dioxane. Control the system temperature at 40℃ and start stirring. The system becomes clear. Under the condition of keeping warm, add 32mL of water to the above system, stir for 15h and then filter. Place the product at 40℃ and dry it in a forced air for 24h to obtain compound I, crystal form II, with a mass yield of 91% and a purity of 99.3%.

[0487] Example 5: Preparation of Crystal Form III of Compound I

[0488] Weigh 1g of compound I and mix it with 25mL of water. Control the system temperature at 75℃ and start stirring to obtain a suspension. Stir for 15h under the temperature keeping condition and then filter. Place the product in a blast dryer at 45℃ for 22h to obtain crystal form III of compound I, with a mass yield of 91% and a purity of 99.4%.

[0489] Example 6: Preparation of Crystal Form III of Compound I

[0490] Weigh 1g of compound I and mix it with 30mL of water. Control the system temperature at 85℃ and start stirring to obtain a suspension. Stir for 20h under the temperature keeping condition and then filter. Place the product in a 40℃ forced air drying environment for 20h to obtain crystal form III of compound I, with a mass yield of 90% and a purity of 99.1%.

[0491] Example 7: Preparation of Crystal Form III of Compound I

[0492] Weigh 1g of compound I and mix it with 35mL of water. Control the system temperature at 70℃ and start stirring to obtain a suspension. Stir for 16h under the temperature keeping condition and then filter. Place the product in a blast dryer at 45℃ for 24h to obtain crystal form III of compound I, with a mass yield of 92% and a purity of 99.3%.

[0493] Example 8: Preparation of Crystal Form III of Compound I

[0494] Weigh 1g of compound I and mix it with 40mL of water. Control the system temperature at 90℃ and start stirring to obtain a suspension. Stir for 15h under the temperature control and then filter. Place the product in a blast dryer at 40℃ for 22h to obtain crystal form III of compound I, with a mass yield of 90% and a purity of 99.2%.

[0495] Example 9: Preparation of Crystal Form IV of Compound I

[0496] Weigh 1g of compound I and mix it with 30mL of water. Control the system temperature at 45℃ and start stirring to obtain a suspension. Stir for 16h under the temperature keeping condition and then filter. Place the product in a 35℃ forced air drying environment for 16h to obtain compound I crystal form IV with a mass yield of 92% and a purity of 99.5%.

[0497] Example 10: Preparation of Crystal Form IV of Compound I

[0498] Weigh 1g of compound I and mix it with 25mL of water. Control the system temperature at 55℃ and start stirring to obtain a suspension. Stir for 18h under the temperature condition and then filter. Place the product at 40℃ and dry it in a forced air for 20h to obtain crystal form IV of compound I. The yield is 91% and the purity is 99.2%.

[0499] Example 11: Preparation of crystal form V of compound of formula I

[0500] Weigh 1g of compound I and mix it with 20mL of water. Control the system temperature at 15℃ and start stirring to obtain a suspension. Stir for 20h under the heat preservation condition and then filter. Place the product in a 40℃ forced air drying environment for 18h to obtain compound I with crystal form V, with a mass yield of 93% and a purity of 99.5%.

[0501] Example 12: Preparation of crystal form V of compound of formula I

[0502] Weigh 1g of compound I and mix it with 15mL of water. Control the system temperature at 5℃ and start stirring to obtain a suspension. Stir for 24h under the temperature keeping condition and then filter. Place the product in a 35℃ forced air drying oven for 20h to obtain compound I with crystal form V, with a mass yield of 92% and a purity of 99.4%.

[0503] Example 13: Preparation of crystal form VI of compound I

[0504] Weigh 1g of compound I and mix it with 10mL of methanol. Control the system temperature at 35℃ and start stirring. The system becomes clear. Under the condition of keeping warm, add 30mL of methyl tert-butyl ether to the above system, stir for 12h and filter. Place the product at 45℃ and dry it in a forced air for 24h to obtain compound I, crystal form VI, with a mass yield of 89% and a purity of 99.2%.

[0505] Example 14: Preparation of crystal form VI of compound I

[0506] Weigh 1g of compound I and mix it with 5mL of methanol. Control the system temperature at 30℃ and start stirring. The system becomes clear. Under the condition of keeping warm, add 15mL of isopropyl ether to the above system, stir for 15h and then filter. Place the product at 40℃ and dry it in a forced air for 20h to obtain compound I, crystal form VI, with a mass yield of 90% and a purity of 99.3%.

[0507] Example 15: Preparation of Crystal Form VII of Compound I

[0508] Weigh 1g of compound I and mix it with 5mL of tetrahydrofuran. Control the system temperature at 45℃ and start stirring to obtain a suspension. Stir for 24h under the temperature condition and then filter. Place the product at 35℃ and dry it in a forced air for 20h to obtain compound I crystal form VII with a mass yield of 91% and a purity of 99.4%.

[0509] Example 16: Preparation of crystal form VII of compound I

[0510] Weigh 1g of compound I and mix it with 5mL of 1,4-dioxane. Control the system temperature at 50℃ and start stirring to obtain a suspension. Stir for 20h under the heat preservation condition and then filter. Place the product in a 45℃ forced air drying chamber for 18h to obtain compound I crystal form VII with a mass yield of 88% and a purity of 99.1%.

[0511] Example 17: Preparation of crystal form VIII of compound I

[0512] Weigh 1g of compound I and mix it with 5mL of ethyl formate. Control the system temperature at 25℃ and start stirring. The system becomes clear. After 10min, the system begins to crystallize. After stirring for 12h, filter the mixture. Place the product in a forced-air drying chamber at 25℃ for 24h to obtain compound I in crystal form VIII, with a yield of 88% and a purity of 99.3%.

[0513] Example 18: Preparation of crystal form VIII of compound I

[0514] Weigh 1g of compound I and mix it with 8mL of ethyl formate. Control the system temperature at 30℃ and start stirring. The system becomes clear. After 10min, the system begins to crystallize. After stirring for 10h, filter the mixture. Place the product at 35℃ and dry it in a forced-air dryer for 20h to obtain compound I in crystal form VIII. The yield is 85% and the purity is 99.2%.

[0515] Example 19: Preparation of crystal form IX of compound I

[0516] Weigh 1g of compound I and mix it with 6mL of anisole. Control the system temperature at 25℃ and start stirring. The system becomes clear, and crystals begin to precipitate after 8 minutes. After stirring for 20 hours, filter the mixture and dry it in a forced-air dryer at 45℃ for 24 hours to obtain compound I in crystal form IX, with a yield of 87% and a purity of 99.3%.

[0517] Example 20: Preparation of crystal form IX of compound I

[0518] Weigh 1g of compound I and mix it with 8mL of anisole. Control the system temperature at 30℃ and start stirring. The system becomes clear. After 10min, the system begins to crystallize. After stirring for 15h, filter the mixture. Place the product at 45℃ and dry it in a forced-air environment for 24h to obtain compound I in crystal form IX, with a yield of 85% and a purity of 99.4%.

[0519] Example 21: Preparation of crystal form X of compound I

[0520] Weigh 1g of compound I and mix it with 10mL of ethylene glycol diethyl ether. Control the system temperature at 30℃ and start stirring. The system becomes clear. After 10min, the system begins to crystallize. After stirring for 18h, filter the mixture. Place the product in a 30℃ oven and dry for 20h to obtain compound I in crystal form X, with a yield of 91% and a purity of 99.4%.

[0521] Example 22: Preparation of crystal form X of compound I

[0522] Weigh 1g of compound I and mix it with 15mL of ethylene glycol diethyl ether. Control the system temperature at 25℃ and start stirring. The system becomes clear, and crystals begin to precipitate after 10 minutes. After stirring for 20 hours, filter the mixture and dry it in a forced-air dryer at 35℃ for 18 hours to obtain compound I in crystal form X with a yield of 88% and a purity of 99.3%.

[0523] Example 23: Preparation of crystal form XI of compound I

[0524] Weigh 1g of compound I and mix it with 5mL of butyl formate. Control the system temperature at 25℃ and start stirring. The system becomes clear. After 10min, the system begins to crystallize. After stirring for 15h, filter the mixture. Place the product at 35℃ and dry it in a forced-air dryer for 24h to obtain compound I in crystal form XI. The yield is 89% and the purity is 99.2%.

[0525] Example 24: Preparation of crystal form XI of compound I

[0526] 1 g of compound I was weighed and mixed with 7 mL of butyl formate. The system temperature was controlled at 25 °C and stirring was started. The system became clear, and crystals began to precipitate after 10 min. After stirring for 12 h, the mixture was filtered. The product was dried in a forced-air dryer at 30 °C for 20 h to obtain compound I in crystal form XI, with a yield of 85% and a purity of 99.1%.

[0527] Example 25: Preparation of crystal form XII of compound I

[0528] Weigh 1g of compound I and mix it with 10mL of ethyl formate. Control the system temperature at 65℃ and start stirring. The system becomes clear. Under the condition of keeping warm, add 30mL of methyl tert-butyl ether to the above system, stir for 22h and then filter. Place the product at 45℃ and dry it in a forced air for 24h to obtain compound I, crystal form XII, with a mass yield of 88% and a purity of 99.4%.

[0529] Example 26: Preparation of Crystal Form XII of Compound I

[0530] Weigh 1g of compound I and mix it with 12mL of ethyl formate. Control the system temperature at 70℃ and start stirring. The system becomes clear. Under the condition of keeping warm, add 30mL of isopropyl ether to the above system, stir for 24h, filter, and place the product at 35℃ for 20h to dry in a forced air to obtain compound I, crystal form XII, with a mass yield of 86% and a purity of 99.2%.

[0531] Experiment Example 1: Hygroscopicity Experiment

[0532] The specific experimental procedure is as follows:

[0533] ① Take a stoppered vial and place it in a constant temperature desiccator (with a saturated solution of NH4Cl at the bottom and a relative humidity of 80%) the day before, weigh it accurately, and record it as M1.

[0534] ② Weigh approximately 100 mg of each crystal form (crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, crystal form VI, crystal form VII, crystal form VIII, crystal form IX, crystal form X, crystal form XI and crystal form XII) of the compound of formula I and place them in the above-mentioned vial. Weigh accurately and record the weight as M2.

[0535] ③ Leave the vial open and place it, along with the cap, under the above-mentioned constant temperature and humidity conditions for 24 hours.

[0536] ④ Close the lid, weigh accurately, and record it as M3.

[0537] Weight gain percentage of each crystal form = (M3-M2) / (M2-M1)×100%

[0538] The results are shown in the table below:

[0539]

[0540]

[0541] The results show that for each crystal form (crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, crystal form VI, crystal form VII, crystal form VIII, crystal form IX, crystal form X, crystal form XI and crystal form XII) of the compound of formula I prepared in this invention, crystal form III is non-hygroscopic, crystal forms IV, V, VIII and XI are slightly hygroscopic, crystal forms VI, VII and XII are hygroscopic, and crystal forms IX and X are highly hygroscopic.

[0542] Experiment Example 2: Stability Experiment

[0543] The stability of each crystal form of the compound of formula I (crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, crystal form VI, crystal form VII, crystal form VIII, crystal form IX, crystal form X, crystal form XI and crystal form XII) was investigated under high temperature (60℃), high humidity (RH 92.5%) and light exposure (5500 lux). The results are shown in the table below:

[0544]

[0545] The results show that, in terms of crystal stability, all crystal forms of the compound of formula I prepared in this invention (crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, crystal form VI, crystal form VII, crystal form VIII, crystal form IX, crystal form X, crystal form XI and crystal form XII) underwent crystal transformation except for crystal form III. In terms of chemical stability, all crystal forms were stable under high temperature and high humidity conditions, but degraded to varying degrees under light conditions. Among them, crystal form III had the lowest degree of degradation and was relatively stable.

[0546] Experiment Example 3: Liquidity Experiment

[0547] Angle of repose: The angle of repose is determined using the fixed funnel method. The sample to be tested is poured into the funnel and allowed to fall gently and evenly into the center of the disk, forming a cone. The feeding is stopped when the material falls freely from the inclined edge of the powder along the edge of the disk. The angle of repose is measured using a protractor. Each sample is measured three times and the average value is taken.

[0548] Filtration time: Connect the Buchner funnel lined with filter paper to the vacuum filtration flask, turn on the vacuum water pump, pour in the prepared crystal form, and start vacuum filtration (the same vacuum filtration parameters are used for all 12 crystal forms). Calculate the time required for complete filtration.

[0549] Crystal forms of Formula I compounds Angle of repose ° Filtering time / min Crystal form I 29 4 Crystal form II 35 8 Crystal form III 25 2 Crystal form IV 37 9 Crystal form V 39 10 Crystal form VI 40 11 Crystal form VII 39 10 Crystal form VIII 37 9 Crystal form IX 30 6 Crystal form X 34 7 Crystal form XI 38 10 Crystal form XII 35 8

[0550] The results show that among the various crystal forms (crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, crystal form VI, crystal form VII, crystal form VIII, crystal form IX, crystal form X, crystal form XI and crystal form XII) of the compound of formula I prepared in this invention, crystal form III has the best fluidity and is more conducive to industrial preparation and production.

[0551] Experiment Example 4: Experiment on the Interconversion Relationship

[0552] The interconversion relationships of various crystal forms (crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, crystal form VI, crystal form VII, crystal form VIII, crystal form IX, crystal form X, crystal form XI, and crystal form XII) of compound of formula I in water were investigated, and the results are shown in the table below:

[0553]

[0554] The results showed that crystal form III was the most stable. All crystal forms could transform into crystal form III in water, while crystal form III would not transform into other crystal forms.

[0555] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the technical principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A crystal form of the compound shown in Formula I, Its features are, It is crystal form III. The X-ray powder diffraction pattern of crystal form III has diffraction peaks at 2θ of 16.3±0.2°, 21.1±0.2°, 8.1±0.2°, 13.1±0.2°, 16.0±0.2°, 16.6±0.2°, 24.3±0.2° and 17.7±0.2°.

2. The crystal form of the compound according to claim 1, characterized in that, The X-ray powder diffraction pattern of crystal form III may optionally include one or more diffraction peaks located at 2θ of 10.6±0.2°, 25.4±0.2°, 25.9±0.2°, 5.3±0.2°, 9.5±0.2°, 11.5±0.2°, 6.5±0.2°, 18.1±0.2°, 19.7±0.2°, 20.2±0.2°, 26.9±0.2°, and 27.7±0.2°.

3. The crystal form of the compound according to claim 2, characterized in that, The X-ray powder diffraction pattern of crystal form III may optionally include 2-3, 4-5, or 6-7 diffraction peaks located at any of the following 2θ values: 10.6±0.2°, 25.4±0.2°, 25.9±0.2°, 5.3±0.2°, 9.5±0.2°, 11.5±0.2°, 6.5±0.2°, 18.1±0.2°, 19.7±0.2°, 20.2±0.2°, 26.9±0.2°, and 27.7±0.2°.

4. The crystal form of the compound according to claim 2, characterized in that, The X-ray powder diffraction pattern of crystal form III can optionally include diffraction peaks at any 2, 3, 4, 5, 6, or 7 locations within the range of 2θ values ​​of 10.6±0.2°, 25.4±0.2°, 25.9±0.2°, 5.3±0.2°, 9.5±0.2°, 11.5±0.2°, 6.5±0.2°, 18.1±0.2°, 19.7±0.2°, 20.2±0.2°, 26.9±0.2°, and 27.7±0.2°.

5. The crystal form of the compound according to claim 2, characterized in that, The optional X-ray powder diffraction pattern of crystal form III also includes those located in 10.6±0.2°、25.4±0.2°、25.9±0.2°、5.3±0.2°； 9.5±0.2°、11.5±0.2°、6.5±0.2°、18.1±0.2°； 19.7±0.2°、20.2±0.2°、26.9±0.2°、27.7±0.2°； 10.6±0.2°、9.5±0.2°、6.5±0.2°、19.7±0.2°； 25.4±0.2°、25.9±0.2°、5.3±0.2°、9.5±0.2°、11.5±0.2°； 6.5±0.2°、18.1±0.2°、19.7±0.2°、20.2±0.2°、26.9±0.2°； 10.6±0.2°、5.3±0.2°、9.5±0.2°、20.2±0.2°、26.9±0.2°； 25.4±0.2°、25.9±0.2°、5.3±0.2°、9.5±0.2°、11.5±0.2°、6.5±0.2°； 10.6±0.2°、6.5±0.2°、18.1±0.2°、19.7±0.2°、26.9±0.2°、27.7±0.2°； 25.9±0.2°、5.3±0.2°、6.5±0.2°、18.1±0.2°、20.2±0.2°、27.7±0.2°； 10.6±0.2°、25.4±0.2°、25.9±0.2°、5.3±0.2°、9.5±0.2°、11.5±0.2°、6.5±0.2°； 25.4±0.2°、25.9±0.2°、11.5±0.2°、6.5±0.2°、19.7±0.2°、20.2±0.2°、26.9±0.2°； Diffraction peaks are observed at 10.6±0.2°, 25.9±0.2°, 9.5±0.2°, 11.5±0.2°, 18.1±0.2°, 20.2±0.2°, and 27.7±0.2°.

6. The crystal form of the compound according to claim 1, characterized in that, The X-ray powder diffraction pattern of crystal form III is shown in Figure 3.

7. The crystal form of the compound according to any one of claims 1 to 6, characterized in that, The preparation method of crystal form III includes the following steps: Step 1: Mix the compound of formula I with a poor solvent under certain temperature conditions to prepare a suspension; Step 2: Stir, filter, and collect the solid to obtain crystal form III of compound I; The unsuitable solvent is selected from water or methanol.

8. The crystal form of the compound according to claim 7, characterized in that, The preparation method of crystal form III also includes a temperature condition of 70-100℃ in step one.

9. The crystal form of the compound according to claim 7, characterized in that, The preparation method of crystal form III also includes a temperature condition of 75–95°C in step one.

10. The crystal form of the compound according to claim 7, characterized in that, The preparation method of crystal form III also includes a temperature condition of 75-80℃ in step one.

11. The crystal form of the compound according to claim 7, characterized in that, The preparation method of crystal form III also includes using water as a poor solvent.

12. A pharmaceutical composition comprising a therapeutically effective amount of the crystal form of a compound of formula I according to any one of claims 1 to 6, and one or more pharmaceutically acceptable carriers, diluents or excipients.

13. The use of the crystal form of the compound according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 12 in the preparation of a medicament for treating cancer-related diseases, wherein the cancer is selected from breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, pancreatic cancer, brain cancer, liver cancer, solid tumors, glioma, glioblastoma, leukemia, lymphoma, or myeloma.

14. The use of the crystal form of the compound according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 12 in the preparation of a medicament for treating cancer-related diseases, wherein the cancer is selected from non-small cell lung cancer.

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