Crystalline salt and free base forms of kinase inhibitors

Abstract

The present invention provides crystalline salt forms and free base forms of kinase inhibitors. Specifically, the present invention provides crystalline salt forms formed by compounds as shown in Formula I with various acids, as well as the free base crystalline forms thereof. Formula I: JPEG2025503010000059.jpg51128

Description

[Technical field]

[0001] The present invention relates to the field of medicinal chemistry, and in particular to crystalline salt and free base forms of compounds and methods for their preparation. [Background technology]

[0002] The development and progression of malignant tumors is a complex process, and conventional therapeutic drugs mainly include the following major classes: alkylating agents, antimetabolites, natural products, and antibiotics. The drawbacks of these classes of drugs are their unclear efficacy and severe side effects. Currently, small molecule kinase inhibitors are a hot topic of potential cancer treatment. Protein kinases are catalysts that play a key role in almost all aspects of cell biology and biochemistry. These enzymes generate signaling modules that regulate cell cycle progression, proliferation, programmed cell death (apoptosis), cytoskeletal function, motility, differentiation, development, transcription, and translation. It is important to carefully regulate protein kinases, as they play several roles and their abnormal activity can lead to cancer, cardiovascular disease, inflammation, and neurological disorders. Dysregulation, overexpression, and mutations of protein kinases are reasons for the pathogenesis of human diseases, making these enzymes attractive drug targets. Growth factor receptors with protein tyrosine kinase (PTKs) activity are called receptor tyrosine kinases. Protein receptor tyrosine kinases are a class of tightly regulated enzymes, and aberrant activation of various members of the family is one of the markers of cancer. FLT3 belongs to the family of receptor tyrosine kinases, together with receptors such as KIT, FMS, and platelet-derived growth factor receptor (PDGFR), and plays an important role in regulating hematopoiesis.

[0003] FLT3 (FMS-like tyrosine kinase-3) is a specific cytokine receptor expressed on hematopoietic stem cells and regulates the survival and growth of hematopoietic stem and progenitor cells, maturation of dendritic cells, and maintenance of homeostasis of regulatory T cells. The high incidence and poor prognosis of FLT3 mutations suggest that they may be an important target for the treatment of AML.

[0004] In summary, there is an urgent need in the field to develop new FLT3 kinase inhibitors. Summary of the Invention [Problem to be solved by the invention]

[0005] It is an object of the present invention to provide crystalline salt and free base forms of the compound of formula I to meet the needs of drug research and development. [Means for solving the problem]

[0006] In a first aspect of the invention there is provided a crystalline form of a compound of formula I, Formula I: [ka] The crystalline form is free base crystalline Form T, which has characteristic X-ray powder diffraction peaks at 20.644°±0.2°, 17.233°±0.2°, 23.479°±0.2°, 15.867°±0.2°, and 20.091°±0.2°.

[0007] In another preferred embodiment, the free base crystalline Form T has an average molecular weight of 15.505°±0.2°, 26.036°±0.2°, 19.457°±0.2°, 14.223°±0.2°, 25.043°±0.2°, 16.205°±0.2°, 23.143°±0.2°, 11.843°±0.2°, 9.973°±0.2°, 14.944°±0.2°, 18.921 ... °, 26.36°±0.2°, 8.858°±0.2°, 17.69°±0.2°, 22.069°±0.2°, 12.867°±0.2°, 18.428°±0.2°, 5.403°±0.2°, 26.675°±0.2°, 10.788°±0.2°, 22.412°±0.2°, 27.533°±0.2°, 24.211°±0.2°, 32.856°±0.2°, 12.35 1°±0.2°, 27.321°±0.2°, 40.066°±0.2°, 35.91°±0.2°, 29.079°±0.2°, 31.878°±0.2°, 36.087°±0.2°, 37.559°±0.2°, 21.598°±0.2°, 28.468°±0.2°, 11.168°±0.2°, 34.799°±0.2°, 40.437°±0.2°, 30.249°±0.2° 0.2°, 33.551°±0.2°, 34.06°±0.2°, 7.753°±0.2°, 30.809°±0.2°, 35.509°±0.2°, 38.988°±0.2°, 29.487°±0.2°, and 38.282°±0.2°.

[0008] In another preferred embodiment, the free base crystalline Form T has three endothermic peaks in the DSC region at 90-95°C, 115-120°C, and 220-225°C.

[0009] In another preferred embodiment, the free base crystalline form T has an enthalpy value of 50.223 J / g for the first endothermic peak in the DSC region, 51.492 J / g for the second endothermic peak in the DSC region, and 80.538 J / g for the third endothermic peak in the DSC region.

[0010] In a second aspect of the invention, there is provided a crystalline form of a compound of formula I, Formula I: [ka] The crystalline form is free base crystalline Form B, which has characteristic X-ray powder diffraction peaks at 19.31°±0.2°, 23.059°±0.2°, 25.888°±0.2°, 12.805°±0.2°, and 17.188°±0.2°.

[0011] In another preferred embodiment, the crystalline form is free base crystalline Form B, and the free base crystalline Form B has the following molecular weights: 14.464°±0.2°, 20.6°±0.2°, 18.446°±0.2°, 6.337°±0.2°, 29.3°±0.2°, 16.155°±0.2°, 8.937°±0.2°, 9.29°±0.2°, 23.545°±0.2°, 32.361°±0.2°, 23.932°±0. and optionally further having one or more (e.g., 2, 3, 5, 8, or 10) characteristic X-ray powder diffraction peaks selected from the group consisting of: 10.227°±0.2°, 39.324°±0.2°, 15.042°±0.2°, 26.791°±0.2°, 30.37°±0.2°, 21.132°±0.2°, 24.448°±0.2°, 27.831°±0.2°, and 36.599°±0.2°.

[0012] In another preferred embodiment, the free base crystalline Form B has two endothermic peaks in the DSC region at 115-120°C and 225-230°C.

[0013] In another preferred embodiment, the free base crystalline form B has an enthalpy value of the first endothermic peak in the DSC region of 63.092 J / g and the enthalpy value of the second endothermic peak in the DSC region of 76.592 J / g.

[0014] In a third aspect of the present invention, there is provided a crystalline form of a compound of formula I, Formula I: [ka] The crystalline form is Crystalline salt forms IA, IB, and IC formed by the compound of formula I and parabenzenesulfonic acid; Crystalline salt forms II-A, II-B, and II-C formed by the compound of formula I and fumaric acid; Crystalline salt forms III-A, III-B, and III-C formed by the compound of formula I and methanesulfonic acid; A salt crystalline form IV-A formed by the compound of formula I and phosphoric acid; The salt crystalline forms VA and VB formed by the compound of formula I and maleic acid; The salt crystalline form VI-A formed by the compound of formula I and citric acid; Crystalline salt form VII-A formed by the compound of formula I and malic acid; Crystalline salt forms VIII-A, VIII-B, and VIII-C formed by the compound of formula I and salicylic acid; or selected from the group consisting of salt crystalline forms IX-A, IX-B, IX-C, IX-D, IX-E, and IX-F formed by the compound of formula I and hydrochloric acid; Alternatively, the crystalline form is a free base crystalline form selected from the group consisting of Form A, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, Form M, Form N, Form O, Form P, Form Q, Form R, and Form S.

[0015] In another preferred embodiment, the crystalline form is a crystalline form selected from the group consisting of: the crystalline form is salt form IA, the powder X-ray diffraction pattern of salt form IA comprising two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 22.558°±0.2°, 6.153°±0.2°, 6.365°±0.2°, 11.62°±0.2°, and 23.392°±0.2°; the crystalline form is salt form IB, the powder X-ray diffraction pattern of the salt form IB comprising two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 6.349°±0.2°, 18.611°±0.2°, 20.111°±0.2°, 19.354°±0.2°, and 19.659°±0.2°; the crystalline form is salt crystalline form IC, the powder X-ray diffraction pattern of the salt crystalline form IC comprises two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 6.156°±0.2°, 19.228°±0.2°, 6.348°±0.2°, 18.607°±0.2°, and 24.203°±0.2°; the crystalline form is salt crystalline form II-A, and the powder X-ray diffraction pattern of the salt crystalline form II-A comprises two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 7.068°±0.2°, 22.629°±0.2°, 21.298°±0.2°, 18.108°±0.2°, and 19.312°±0.2°; the crystalline form is salt crystalline form II-B, and the powder X-ray diffraction pattern of the salt crystalline form II-B comprises two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 22.639°±0.2°, 8.057°±0.2°, 12.303°±0.2°, 5.666°±0.2°, and 18.977°±0.2°; the crystalline form is salt crystalline form II-C, and the powder X-ray diffraction pattern of the salt crystalline form II-C includes two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 22.482°±0.2°, 9.03°±0.2°, 7.668°±0.2°, 18.149°±0.2°, and 7.162°±0.2°; the crystalline form is salt crystalline form III-A, and the powder X-ray diffraction pattern of the salt crystalline form III-A comprises two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 9.199°±0.2°, 4.609°±0.2°, 23.106°±0.2°, 18.031°±0.2°, and 13.798°±0.2°; the crystalline form is salt crystalline form III-B, and the powder X-ray diffraction pattern of the salt crystalline form III-B comprises two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 16.693°±0.2°, 22.437°±0.2°, 22.187°±0.2°, 14.045°±0.2°, and 8.936°±0.2°; the crystalline form is salt crystalline form III-C, and the powder X-ray diffraction pattern of the salt crystalline form III-C comprises two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 19.533°±0.2°, 24.465°±0.2°, 17.496°±0.2°, 9.057°±0.2°, and 9.74°±0.2°; the crystalline form is salt form IV-A, and the powder X-ray diffraction pattern of the salt form IV-A contains two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 21.594°±0.2°, 12.749°±0.2°, 23.759°±0.2°, 19.944°±0.2°, and 27.501°±0.2°; the crystalline form is salt form VA, the powder X-ray diffraction pattern of the salt form VA comprising two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 19.511°±0.2°, 8.538°±0.2°, 26.084°±0.2°, 12.999°±0.2°, and 23.284°±0.2°; the crystalline form is salt form VB, and the powder X-ray diffraction pattern of salt form VB contains two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 22.48°±0.2°, 18.654°±0.2°, 17.31°±0.2°, 10.05°±0.2°, and 19.992°±0.2°; the crystalline form is salt form VI-A, and the powder X-ray diffraction pattern of salt form VI-A contains two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 17.502°±0.2°, 8.712°±0.2°, 17.012°±0.2°, 7.854°±0.2°, and 20.072°±0.2°; the crystalline form is salt crystalline form VII-A, and the powder X-ray diffraction pattern of the salt crystalline form VII-A contains two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 22.102°±0.2°, 17.149°±0.2°, 14.246°±0.2°, 19.119°±0.2°, and 22.613°±0.2°; the crystalline form is salt crystalline form VIII-A, and the powder X-ray diffraction pattern of the salt crystalline form VIII-A includes two or more (three, four, or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 3.834°±0.2°, 4.282°±0.2°, 7.593°±0.2°, 21.198°±0.2°, and 16.946°±0.2°; the crystalline form is salt crystalline form VIII-B, and the powder X-ray diffraction pattern of the salt crystalline form VIII-B includes two or more (three, four, or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 23.438°±0.2°, 14.857°±0.2°, 15.021°±0.2°, 24.138°±0.2°, and 20.337°±0.2°; the crystalline form is salt crystalline form VIII-C, the powder X-ray diffraction pattern of the salt crystalline form VIII-C includes two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 8.752°±0.2°, 19.298°±0.2°, 16.631°±0.2°, 17.601°±0.2°, and 25.289°±0.2°; the crystalline form is salt form IX-A, and the powder X-ray diffraction pattern of salt form IX-A contains two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 17.395°±0.2°, 21.697°±0.2°, 14.43°±0.2°, 13.765°±0.2°, and 22.166°±0.2°; the crystalline form is salt form IX-B, and the powder X-ray diffraction pattern of salt form IX-B comprises two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 20.835°±0.2°, 13.293°±0.2°, 17.98°±0.2°, 23.877°±0.2°, and 21.622°±0.2°; the crystalline form is salt form IX-C, and the powder X-ray diffraction pattern of salt form IX-C includes two or more (three, four, or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 20.232°±0.2°, 18.948°±0.2°, 23.486°±0.2°, 15.549°±0.2°, and 19.362°±0.2°; the crystalline form is salt form IX-D, and the powder X-ray diffraction pattern of salt form IX-D comprises two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 18.88°±0.2°, 22.356°±0.2°, 15.398°±0.2°, 21.954°±0.2°, and 9.411°±0.2°; the crystalline form is salt form IX-E, and the powder X-ray diffraction pattern of salt form IX-E contains two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 22.072°±0.2°, 17.415°±0.2°, 18.438°±0.2°, 18.002°±0.2°, and 11.596°±0.2°; the crystalline form is salt form IX-F, and the powder X-ray diffraction pattern of salt form IX-F comprises two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 19.477°±0.2°, 23.233°±0.2°, 16.372°±0.2°, 26.063°±0.2°, and 21.02°±0.2°; the crystalline form is free base crystalline Form A, the powder X-ray diffraction pattern of the free base crystalline Form A comprising two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 20.536°±0.2°, 16.957°±0.2°, 15.689°±0.2°, 19.34°±0.2°, and 9.858°±0.2°; the crystalline form is free base crystalline Form C, the powder X-ray diffraction pattern of the free base crystalline Form C comprising two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 20.503°±0.2°, 18.54°±0.2°, 17.404°±0.2°, 16.871°±0.2°, and 16.214°±0.2°; the crystalline form is free base crystalline Form D, the powder X-ray diffraction pattern of the free base crystalline Form D comprising two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 20.722°±0.2°, 14.963°±0.2°, 6.586°±0.2°, 12.967°±0.2°, and 17.286°±0.2°; the crystalline form is free base crystalline Form E, the powder X-ray diffraction pattern of the free base crystalline Form E comprising two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 8.559°±0.2°, 13.753°±0.2°, 20.533°±0.2°, 12.913°±0.2°, and 6.776°±0.2°; the crystalline form is free base crystalline Form F, the powder X-ray diffraction pattern of which comprises two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 19.324°±0.2°, 25.949°±0.2°, 12.82°±0.2°, 8.952°±0.2°, and 6.36°±0.2°; the crystalline form is free base crystalline Form G, the powder X-ray diffraction pattern of the free base crystalline Form G comprising two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 8.228°±0.2°, 19.529°±0.2°, 16.987°±0.2°, 5.253°±0.2°, and 24.365°±0.2°; the crystalline form is free base crystalline Form H, the powder X-ray diffraction pattern of the free base crystalline Form H comprising two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 19.327°±0.2°, 23.084°±0.2°, 25.903°±0.2°, 12.823°±0.2°, and 19.18°±0.2°; the crystalline form is free base crystalline Form I, the powder X-ray diffraction pattern of the free base crystalline Form I comprising two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 22.011°±0.2°, 20.226°±0.2°, 20.986°±0.2°, 13.416°±0.2°, and 13.033°±0.2°; the crystalline form is free base crystalline Form J, the powder X-ray diffraction pattern of the free base crystalline Form J comprising two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 6.403°±0.2°, 21.406°±0.2°, 11.755°±0.2°, 21.045°±0.2°, and 17.314°±0.2°; the crystalline form is free base crystalline Form K, the powder X-ray diffraction pattern of the free base crystalline Form K comprising two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 19.314°±0.2°, 23.064°±0.2°, 5.637°±0.2°, 11.396°±0.2°, and 17.197°±0.2°; the crystalline form is free base crystalline Form L, the powder X-ray diffraction pattern of the free base crystalline Form L comprising two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 21.963°±0.2°, 22.518°±0.2°, 20.943°±0.2°, 19.12°±0.2°, and 16.382°±0.2°; the crystalline form is free base crystalline Form M, the powder X-ray diffraction pattern of the free base crystalline Form M comprising two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 20.09°±0.2°, 15.616°±0.2°, 20.566°±0.2°, 9.241°±0.2°, and 16.989°±0.2°; the crystalline form is free base crystalline Form N, the powder X-ray diffraction pattern of the free base crystalline Form N comprising two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 20.569°±0.2°, 16.952°±0.2°, 19.507°±0.2°, 16.069°±0.2°, and 7.91°±0.2°; the crystalline form is free base crystalline Form O, the powder X-ray diffraction pattern of which comprises two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 21.72°±0.2°, 18.877°±0.2°, 17.769°±0.2°, 16.511°±0.2°, and 20.049°±0.2°; the crystalline form is free base crystalline Form P, the powder X-ray diffraction pattern of which comprises two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 8.249°±0.2°, 16.791°±0.2°, 15.796°±0.2°, 19.798°±0.2°, and 22.14°±0.2°; the crystalline form is free base crystalline form Q, the powder X-ray diffraction pattern of the free base crystalline form Q comprising two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 8.114°±0.2°, 19.767°±0.2°, 22.837°±0.2°, 12.949°±0.2°, and 21.397°±0.2°; the crystalline form is free base crystalline Form R, the powder X-ray diffraction pattern of the free base crystalline Form R comprising two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 22.248°±0.2°, 12.339°±0.2°, 19.597°±0.2°, 22.748°±0.2°, and 17.034°±0.2°; the crystalline form is free base crystalline Form S, the powder X-ray diffraction pattern of the free base crystalline Form S comprising two or more (three, four or five) characteristic powder X-ray diffraction peaks selected from the group consisting of 5.388°±0.2°, 18.299°±0.2°, 10.892°±0.2°, 16.589°±0.2°, and 20.774°±0.2°; In another preferred embodiment, the crystalline form is a crystalline form selected from the group consisting of ("having one or more characteristic X-ray powder diffraction peaks selected from the group consisting of" refers to the crystalline form having 5 or more, such as 6, 7, 8, 9, 10, 12, 15 or 20, characteristic X-ray powder diffraction peaks selected from the group consisting of): the crystalline form is salt form IA, which further has one or more characteristic X-ray powder diffraction peaks selected from the group consisting of 24.186°±0.2°, 19.235°±0.2°, 17.135°±0.2°, 16.848°±0.2°, 12.786°±0.2°, 24.743°±0.2°, 17.992°±0.2°, 18.56°±0.2°, 12.375°±0.2°, 5.584°±0.2°, 10.978°±0.2°, 21.829°±0.2°, 28.451°±0.2°, 21.034°±0.2°, and 19.832°±0.2°; The crystal form is salt form IB, and the salt form IB has the following crystal forms: 24.741°±0.2°, 13.702°±0.2°, 23.493°±0.2°, 12.931°±0.2°, 18.012°±0.2°, 23.206°±0.2°, 12.482°±0.2°, 27.48°±0.2°, 23.009°±0.2°, 24.5°±0.2°, 14.085°±0.2°, 12.002°±0.2°, 26.106°±0.2°, 20.379°±0.2°, 10.064°±0.2°, 22.71°±0.2°, 25.653°±0.2°, 24.151°± 0.2°, 8.967°±0.2°, 11.06°±0.2°, 6.56°±0.2°, 17.675°±0.2°, 20.886°±0.2°, 15.52°±0.2°, 9.39°±0.2°, 30.381°±0.2°, 28.579°±0.2°, 5.902°±0.2°, 29.863°±0.2°, 22.001°±0.2°, 21.463°±0.2°, 16.3°±0.2°, 26.746°±0.2°, 32.347°±0.2°, and 35.995°±0.2°; The crystal form is salt crystal form IC, and the salt crystal form IC has the following crystal angles: 12.443°±0.2°, 22.553°±0.2°, 11.588°±0.2°, 12.764°±0.2°, 23.357°±0.2°, 10.93°±0.2°, 14.126°±0.2°, 16.8°±0.2°, 20.219°±0.2°, 18.114°±0.2°, 9.22°±0.2°. and further having one or more characteristic powder X-ray diffraction peaks selected from the group consisting of 17.146°±0.2°, 10.033°±0.2°, 21.797°±0.2°, 26.531°±0.2°, 20.676°±0.2°, 16.128°±0.2°, 21.078°±0.2°, 15.292°±0.2°, and 37.716°±0.2°; The crystal form is salt form II-A, and the crystal form II-A of the salt has the following inclination angles: 20.504°±0.2°, 6.404°±0.2°, 22.168°±0.2°, 24.809°±0.2°, 8.079°±0.2°, 12.049°±0.2°, 7.599°±0.2°, 14.156°±0.2°, 28.701°±0.2°, 19.947°±0. 2°, 25.28°±0.2°, 8.973°±0.2°, 16.494°±0.2°, 12.411°±0.2°, 11.643°±0.2°, 27.741°±0.2°, 12.804°±0.2°, 32.311°±0.2°, and 26.183°±0.2°; the crystalline form is salt form II-B, the salt form II-B further having one or more characteristic powder X-ray diffraction peaks selected from the group consisting of 20.904°±0.2°, 9.02°±0.2°, 14.963°±0.2°, 16.106°±0.2°, 18.159°±0.2°, and 4.093°±0.2°; The crystal form is salt form II-C, and the salt form II-C has the following inclination angles: 11.704°±0.2°, 16.564°±0.2°, 8.665°±0.2°, 19.939°±0.2°, 27.791°±0.2°, 20.587°±0.2°, 12.603°±0.2°, 15.285°±0.2°, 16.911°±0.2°, 19.336°±0.2°, and 1 and further having one or more characteristic X-ray powder diffraction peaks selected from the group consisting of 8.563°±0.2°, 26.158°±0.2°, 9.711°±0.2°, 25.703°±0.2°, 23.442°±0.2°, 14.203°±0.2°, 24.9°±0.2°, 28.92°±0.2°, 31.336°±0.2°, and 13.62°±0.2°; The crystal form is salt form III-A, and the salt form III-A has the following inclination angles: 16.97°±0.2°, 18.427°±0.2°, 24.243°±0.2°, 20.545°±0.2°, 20.124°±0.2°, 21.289°±0.2°, 14.368°±0.2°, 25.954°±0.2°, 21.976°±0.2°, 30.329°±0.2°, 28.621°±0.2°, 1 and further having one or more characteristic powder X-ray diffraction peaks selected from the group consisting of 0.253°±0.2°, 27.03°±0.2°, 32.555°±0.2°, 16.261°±0.2°, 30.07°±0.2°, 28.953°±0.2°, 19.523°±0.2°, 15.063°±0.2°, 27.784°±0.2°, 31.627°±0.2°, and 41.318°±0.2°; The crystal form is salt form III-B, and the salt form III-B has the following angles: 20.243°±0.2°, 23.628°±0.2°, 24.494°±0.2°, 19.827°±0.2°, 18.705°±0.2°, 23.096°±0.2°, 21.151°±0.2°, 29.191°±0.2°, 11.507°±0.2°, 10.076°±0.2°, 7.053°±0.2°, 30.258°±0.2°, 1 and further having one or more characteristic X-ray powder diffraction peaks selected from the group consisting of 7.86°±0.2°, 25.239°±0.2°, 4.442°±0.2°, 21.562°±0.2°, 15.847°±0.2°, 7.435°±0.2°, 13.474°±0.2°, 26.342°±0.2°, 19.309°±0.2°, 28.778°±0.2°, 27.626°±0.2°, and 38.331°±0.2°; The crystal form is salt form III-C, and the crystal form III-C of the salt has the following angles: 21.36°±0.2°, 22.78°±0.2°, 15.371°±0.2°, 28.275°±0.2°, 26.74°±0.2°, 31.615°±0.2°, 29.332°±0.2°, 4.507°±0.2°, 22.485°±0.2°, 17.935°±0.2°, 16.759°±0.2°, 18.25°±0.2°, 18.746°±0.2°, 25. and further having one or more characteristic X-ray powder diffraction peaks selected from the group consisting of 926°±0.2°, 12.932°±0.2°, 10.125°±0.2°, 15.807°±0.2°, 23.727°±0.2°, 34.512°±0.2°, 4.866°±0.2°, 20.415°±0.2°, 14.639°±0.2°, 39.286°±0.2°, 11.223°±0.2°, 30.33°±0.2°, and 35.619°±0.2°; The crystal form is salt form IV-A, and the salt form IV-A has the following inclination angles: 22.271°±0.2°, 24.681°±0.2°, 20.389°±0.2°, 7.866°±0.2°, 18.339°±0.2°, 25.842°±0.2°, 9.546°±0.2°, 19.184°±0.2°, 16.168°±0. 2°, 32.892°±0.2°, 17.538°±0.2°, 18.625°±0.2°, 21.014°±0.2°, 30.816°±0.2°, 17.09°±0.2°, 23.137°±0.2°, and 30.574°±0.2°; The crystal form is a salt crystal form VA, and the salt crystal form VA has the following angles: 17.104°±0.2°, 4.31°±0.2°, 17.374°±0.2°, 14.939°±0.2°, 21.4°±0.2°, 29.51°±0.2°, 6.319°±0.2°, 10.728°±0.2°, 6.524°±0.2°, 30.089°±0.2°, 27.924°± 0.2°, 18.693°±0.2°, 7.084°±0.2°, 32.535°±0.2°, 25.051°±0.2°, 14.103°±0.2°, 20.847°±0.2°, 20.158°±0.2°, 39.538°±0.2°, and 30.432°±0.2°; The crystal form is salt form VB, and the salt form VB has the following crystal angles: 11.711°±0.2°, 18.356°±0.2°, 15.916°±0.2°, 9.279°±0.2°, 26.763°±0.2°, 8.67°±0.2°, 13.883°±0.2°, 8.292°±0.2°, 12.729°±0.2°, 26.159°±0.2° , 20.643°±0.2°, 14.695°±0.2°, 21.578°±0.2°, 23.761°±0.2°, 32.047°±0.2°, 25.1°±0.2°, 4.659°±0.2°, 15.563°±0.2°, and 29.532°±0.2°; the crystalline form is salt form VI-A, the salt form VI-A further having one or more characteristic powder X-ray diffraction peaks selected from the group consisting of 8.39°±0.2°, 14.974°±0.2°, 16.728°±0.2°, 4.667°±0.2°, 4.884°±0.2°, 8.937°±0.2°, 25.416°±0.2°, 14.393°±0.2°, 10.9°±0.2°, 22.593°±0.2°, 18.275°±0.2°, 9.346°±0.2°, 26.405°±0.2°, 18.928°±0.2°, 26.006°±0.2°, and 22.013°±0.2°; The crystalline form is salt form VII-A, and the salt form VII-A has the following crystal orientations: 11.58°±0.2°, 14.468°±0.2°, 20.398°±0.2°, 13.667°±0.2°, 25.16°±0.2°, 18.032°±0.2°, 21.293°±0.2°, 20.145°±0.2°, 14.952°±0.2°, 12.439°±0.2°, 13.387°±0.2°, 23.299°±0.2°, 25.584°±0.2°, 9.577°±0.2°, 21.067°± 0.2°, 26.73°±0.2°, 27.7°±0.2°, 18.511°±0.2°, 7.514°±0.2°, 28.217°±0.2°, 16.773°±0.2°, 19.824°±0.2°, 33.282°±0.2°, 39.237°±0.2°, 15.864°±0.2°, 34.927°±0.2°, 37.048°±0.2°, 30.018°±0.2°, and 29.501°±0.2°; The crystal form is salt form VIII-A, and the salt form VIII-A has the following crystal angles: 3.834°±0.2°, 4.282°±0.2°, 7.593°±0.2°, 21.198°±0.2°, 16.946°±0.2°, 25.302°±0.2°, 8.451°±0.2°, 11.334°±0.2°, 17.526°±0.2°, 19.847°±0.2°, 15.02°±0.2°, 16.946°±0.2°, 25.02°±0.2°, 8.451°±0.2°, 11.334°±0.2°, 17.526°±0.2°, 19.847°±0.2°, 15.02°±0.2°, 16.02°±0.2°, 17.02°±0.2°, 16 ... 0.123°±0.2°, 23.412°±0.2°, 24.234°±0.2°, 12.73°±0.2°, 19.367°±0.2°, 27.174°±0.2°, 10.128°±0.2°, 13.942°±0.2°, 28.858°±0.2°, and 14.369°±0.2°; The crystal form is salt form VIII-B, and the salt form VIII-B has the following crystal angles: 9.887°±0.2°, 14.008°±0.2°, 18.024°±0.2°, 14.638°±0.2°, 7.013°±0.2°, 26.786°±0.2°, 7.43°±0.2°, 11.851°±0.2°, 9.133°±0.2°, 19.462°±0.2°, 9.364°±0.2°, 22.721°±0.2°, 16.517°±0.2°, 22. 0.23°±0.2°, 6.089°±0.2°, 20.958°±0.2°, 24.636°±0.2°, 17.356°±0.2°, 15.702°±0.2°, 26.053°±0.2°, 18.609°±0.2°, 33.042°±0.2°, 12.943°±0.2°, 13.338°±0.2°, 19.81°±0.2°, and 12.564°±0.2°; The crystalline form is salt form VIII-C, and the salt form VIII-C has the following inclination angles: 4.296°±0.2°, 16.981°±0.2°, 21.325°±0.2°, 19.842°±0.2°, 13.995°±0.2°, 8.468°±0.2°, 12.953°±0.2°, 23.516°±0.2°, 26.44°±0.2°, 12.733°±0.2°, 24.186°±0.2°, 21.759°±0.2°, and further having one or more characteristic X-ray powder diffraction peaks selected from the group consisting of 14.942°±0.2°, 3.343°±0.2°, 27.226°±0.2°, 22.526°±0.2°, 10.151°±0.2°, 28.815°±0.2°, 11.717°±0.2°, 7.66°±0.2°, 6.606°±0.2°, 14.69°±0.2°, 28.114°±0.2°, and 10.855°±0.2°; The crystal form is salt form IX-A, and the salt form IX-A has the following crystal orientations: 18.824°±0.2°, 9.694°±0.2°, 7.013°±0.2°, 27.369°±0.2°, 20.086°±0.2°, 22.964°±0.2°, 16.176°±0.2°, 24.522°±0.2°, 12.558°±0.2°, 21.268°±0.2°, 24.93°±0. 0.2°, 11.528°±0.2°, 18.08°±0.2°, 28.083°±0.2°, 16.532°±0.2°, 28.307°±0.2°, 20.459°±0.2°, 40.496°±0.2°, 25.827°±0.2°, 35.1°±0.2°, and 32.649°±0.2°; The crystal form is salt form IX-B, and the crystal form IX-B has the following inclination angles: 11.265°±0.2°, 24.592°±0.2°, 14.698°±0.2°, 6.767°±0.2°, 6.283°±0.2°, 24.307°±0.2°, 12.566°±0.2°, 17.252°±0.2°, 21.169°±0.2°, 22.434°±0.2°, 15.562°±0.2°, 8.826°±0.2°, 19.852°±0.2°, 26.598°±0.2°, 25.069°±0.2°, 22.904°±0.2°, 14.075°±0. 2°, 14.285°±0.2°, 20.468°±0.2°, 25.677°±0.2°, 27.967°±0.2°, 10.209°±0.2°, 16.935°±0.2°, 27.314°±0.2°, 13.651°±0.2°, 19.027°±0.2°, 9.608°±0.2°, 16.506°±0.2°, 31.547°±0.2°, 26.026°±0.2°, 28.35°±0.2°, 29.367°±0.2°, and 34.221°±0.2°; The crystal form is salt form IX-C, and the crystal form IX-C has the following inclination angles: 10.123°±0.2°, 9.772°±0.2°, 24.632°±0.2°, 15.856°±0.2°, 7.962°±0.2°, 18.366°±0.2°, 6.476°±0.2°, 12.023°±0.2°, 24.033°±0.2°, 13.145°±0.2°, 27.497°±0.2°, 16.832°±0.2°, 26.629°±0.2°, and 12. and further having one or more characteristic X-ray powder diffraction peaks selected from the group consisting of 631°±0.2°, 21.536°±0.2°, 6.052°±0.2°, 24.943°±0.2°, 14.943°±0.2°, 25.899°±0.2°, 6.984°±0.2°, 16.419°±0.2°, 14.218°±0.2°, 22.661°±0.2°, 13.743°±0.2°, 11.453°±0.2°, and 28.746°±0.2°; the crystalline form is salt form IX-D, which further has one or more characteristic powder X-ray diffraction peaks selected from the group consisting of 19.966°±0.2°, 14.067°±0.2°, 24.809°±0.2°, 25.866°±0.2°, 8.338°±0.2°, 17.595°±0.2°, 28.502°±0.2°, 27.737°±0.2°, 13.596°±0.2°, and 11.512°±0.2°; The crystal form is salt form IX-E, and the crystal form IX-E has the following inclination angles: 23.237°±0.2°, 25.721°±0.2°, 16.1°±0.2°, 9.191°±0.2°, 8.322°±0.2°, 24.92°±0.2°, 27.119°±0.2°, 13.894°±0.2°, 19.383°±0.2°, 22.862°±0.2°, 24.401°±0.2°, 29.059°±0.2°, 16. and further having one or more characteristic X-ray powder diffraction peaks selected from the group consisting of 686°±0.2°, 9.99°±0.2°, 12.063°±0.2°, 26.392°±0.2°, 28.021°±0.2°, 15.79°±0.2°, 12.411°±0.2°, 32.014°±0.2°, 13.014°±0.2°, 14.366°±0.2°, 14.94°±0.2°, and 29.918°±0.2°; The crystal form is salt form IX-F, and the crystal form IX-F has the following inclination angles: 22.74°±0.2°, 10.901°±0.2°, 15.633°±0.2°, 17.35°±0.2°, 12.98°±0.2°, 21.762°±0.2°, 23.625°±0.2°, 14.101°±0.2°, 24.702°±0.2°, 24.398°±0.2°, 7.543°±0.2°, 13.187°±0.2°, 14.686°±0.2°, 29.425°±0.2°, 8.95°±0. 2°, 16.965°±0.2°, 5.441°±0.2°, 19.89°±0.2°, 9.46°±0.2°, 28.127°±0.2°, 27.504°±0.2°, 29.188°±0.2°, 18.622°±0.2°, 11.528°±0.2°, 28.477°±0.2°, 12.672°±0.2°, 15.141°±0.2°, 39.475°±0.2°, and 32.522°±0.2°; The crystalline form is free base crystalline Form A, and the free base crystalline Form A has the following angles: 11.738°±0.2°, 15.33°±0.2°, 16.072°±0.2°, 19.858°±0.2°, 14.126°±0.2°, 8.676°±0.2°, 23.15°±0.2°, 12.77°±0.2°, 14.805°±0.2°, 25.859°±0.2°, 18.855°±0.2°, 5.29°±0.2°, 1 and further having one or more characteristic X-ray powder diffraction peaks selected from the group consisting of 8.263°±0.2°, 8.445°±0.2°, 10.682°±0.2°, 21.863°±0.2°, 26.213°±0.2°, 24.796°±0.2°, 12.323°±0.2°, 28.899°±0.2°, 26.538°±0.2°, 31.755°±0.2°, 7.602°±0.2°, and 32.581°±0.2°; The crystalline form is free base crystalline Form C, and the free base crystalline Form C has the following crystal orientations: 11.736°±0.2°, 15.654°±0.2°, 22.017°±0.2°, 19.347°±0.2°, 22.166°±0.2°, 8.954°±0.2°, 9.835°±0.2°, 19.874°±0.2°, 18.853°±0.2°, 23.06°±0.2°, 25.8°±0.2°, 18.129°±0.2°, 14.094°±0.2°, 28.368°±0.2°, 14.724°±0.2°, 8.601 ... and further having one or more characteristic X-ray powder diffraction peaks selected from the group consisting of 15.353°±0.2°, 12.754°±0.2°, 24.977°±0.2°, 11.035°±0.2°, 24.57°±0.2°, 5.254°±0.2°, 8.395°±0.2°, 14.996°±0.2°, 12.273°±0.2°, 27.18°±0.2°, 40.473°±0.2°, 23.782°±0.2°, 32.539°±0.2°, 41.542°±0.2°, and 31.819°±0.2°; The crystalline form is free base crystalline Form D, and the free base crystalline Form D has the following rotation angles: 10.025°±0.2°, 25.554°±0.2°, 19.364°±0.2°, 8.401°±0.2°, 11.974°±0.2°, 19.86°±0.2°, 8.191°±0.2°, 13.312°±0.2°, 14.52°±0.2°, 25.035°±0.2°, 24.033°±0.2°, 26.213°±0.2°, 16.529°±0.2°, 23.323°±0.2°, 26.933°±0.2°, and further having one or more characteristic X-ray powder diffraction peaks selected from the group consisting of 15.982°±0.2°, 18.898°±0.2°, 17.711°±0.2°, 7.882°±0.2°, 21.949°±0.2°, 32.042°±0.2°, 22.526°±0.2°, 33.893°±0.2°, 27.981°±0.2°, 32.821°±0.2°, 41.062°±0.2°, 11.008°±0.2°, 27.218°±0.2°, 33.206°±0.2°, and 39.812°±0.2°; The crystalline form is free base crystalline form E, and the free base crystalline form E has the following rotation angles: 18.511°±0.2°, 13.521°±0.2°, 15.128°±0.2°, 11.724°±0.2°, 4.23°±0.2°, 24.687°±0.2°, 21.235°±0.2°, 16.27°±0.2°, 17.677°±0.2°, 23.693°±0.2°, 20.014°±0.2°, 15.483°±0.2° , 16.887°±0.2°, 7.482°±0.2°, 22.342°±0.2°, 24.031°±0.2°, 9.838°±0.2°, 18.137°±0.2°, 22.826°±0.2°, 19.427°±0.2°, 35.733°±0.2°, 41.301°±0.2°, 39.689°±0.2°, and 30.603°±0.2°; The crystalline form is free base crystalline Form F, and the free base crystalline Form F has the following crystal orientations: 39.352°±0.2°, 23.083°±0.2°, 17.224°±0.2°, 16.746°±0.2°, 20.632°±0.2°, 9.31°±0.2°, 18.407°±0.2°, 17.04°±0.2°, 14.49°±0.2°, 16.186°±0.2°, 32.354°±0.2°, 33.337°±0.2°, 35.404°±0.2°, 10.229°±0.2°, 18.753°±0.2°, 30.373°±0.2°, 36.67°±0.2°, 37.7°±0.2°, 38.7°±0.2°, 39.352°±0.2°, 23.083°±0.2°, 17.224°±0.2°, 16.746°±0.2°, 20.632°±0.2°, 9.31°±0.2°, 18.407°±0.2°, 17.04°±0.2°, 14.49°±0.2°, 16.186°±0.2°, 32.354°±0.2°, 33.337°±0.2°, 35.404°±0.2°, 10.229°±0.2°, 18.753°±0.2°, 30.373°±0.2°, 36.67° 9°±0.2°, 8.413°±0.2°, 15.142°±0.2°, 17.446°±0.2°, 17.87°±0.2°, 18.054°±0.2°, 23.348°±0.2°, 23.658°±0.2°, 24.109°±0.2°, 25.216°±0.2°, 26.831°±0.2°, 28.946°±0.2°, 29.351°±0.2°, 32.555°±0.2°, 33.903°±0.2°, 38.715°±0.2°, and 38.9°±0.2°; The crystalline form is free base crystalline Form G, and the free base crystalline Form G has the following angles: 21.414°±0.2°, 22.713°±0.2°, 15.917°±0.2°, 8.418°±0.2°, 18.689°±0.2°, 19.376°±0.2°, 23.137°±0.2°, 23.553°±0.2°, 9.86°±0.2°, 15.116°±0.2°, 20.615°±0.2°, 22.229°±0.2°, 15.462°±0.2°, 11.505°±0.2°, 28.21°±0.2°, 12.367°±0.2°, and further having one or more characteristic X-ray powder diffraction peaks selected from the group consisting of 25.112°±0.2°, 24.068°±0.2°, 13.687°±0.2°, 25.59°±0.2°, 10.954°±0.2°, 29.506°±0.2°, 27.964°±0.2°, 13.981°±0.2°, 26.905°±0.2°, 33.657°±0.2°, 34.776°±0.2°, 26.667°±0.2°, 14.35°±0.2°, 36.659°±0.2°, 17.671°±0.2°, and 30.615°±0.2°; The crystalline form is free base crystalline Form H, and the free base crystalline Form H has the following crystal orientations: 20.628°±0.2°, 17.222°±0.2°, 14.497°±0.2°, 16.169°±0.2°, 8.961°±0.2°, 17.01°±0.2°, 18.425°±0.2°, 9.229°±0.2°, 5.278°±0.2°, 16.826°±0.2°, 29.316°±0.2°, 10.67°±0.2°, 23.972°±0.2°, 15.318°±0.2°, 15.6 98°±0.2°, 23.639°±0.2°, 26.846°±0.2°, 6.353°±0.2°, 14.113°±0.2°, 15.054°±0.2°, 9.854°±0.2°, 11.773°±0.2°, 24.476°±0.2°, 24.963°±0.2°, 10.241°±0.2°, 13.111°±0.2°, 8.699°±0.2°, 39.333°±0.2°, 19.862°±0.2°, 21.147°±0.2°, 25.584°±0.2°, 26.519° ±0.2°, 32.396°±0.2°, 26.134°±0.2°, 27.909°±0.2°, 14.765°±0.2°, 18.846°±0.2°, 21.522°±0.2°, 3.68°±0.2°, 24.769°±0.2°, 28.977°±0.2°, 30.354°±0.2°, 25.208°±0.2°, 30.091°±0.2°, 38.922°±0.2°, 27.214°±0.2°, 20.272°±0.2°, 21.902°±0.2°, 35.705°±0 0.2°, 36.765°±0.2°, 38.715°±0.2°, 37.543°±0.2°, 8.435°±0.2°, 28.386°±0.2°, 7.593°±0.2°, 17.851°±0.2°, 31.755°±0.2°, 30.955°±0.2°, 31.366°±0.2°, 34.492°±0.2°, 34.827°±0.2°, 40.054°±0.2°, and 40.438°±0.2°; The crystalline form is free base crystalline Form I, and the free base crystalline Form I has the following angles: 17.029°±0.2°, 14.962°±0.2°, 19.141°±0.2°, 22.563°±0.2°, 22.769°±0.2°, 11.299°±0.2°, 16.466°±0.2°, 5 .593°±0.2°, 26.548°±0.2°, 8.231°±0.2°, 25.139°±0.2°, 6.617°±0.2°, 15.768°±0.2°, 23.72°±0.2°, 15.292°±0.2°, 23.975°±0.2°, 18.006°±0.2°, 21.324 and further having one or more characteristic X-ray powder diffraction peaks selected from the group consisting of 24.849°±0.2°, 24.623°±0.2°, 40.591°±0.2°, 26.263°±0.2°, 27.121°±0.2°, 27.369°±0.2°, 18.441°±0.2°, 19.907°±0.2°, 10.011°±0.2°, 14.558°±0.2°, 28.997°±0.2°, 23.286°±0.2°, 9.288°±0.2°, 14.109°±0.2°, 29.31°±0.2°, 32.007°±0.2°, and 30.722°±0.2°; The crystalline form is free base crystalline Form J, and the free base crystalline Form J has the following inclination angles: 9.63°±0.2°, 9.118°±0.2°, 5.655°±0.2°, 8.351°±0.2°, 16.869°±0.2°, 15.439°±0.2°, 9.895°±0.2°, 16.151°±0.2°, 19.388°±0.2°. and further having one or more characteristic powder X-ray diffraction peaks selected from the group consisting of 12.415°±0.2°, 19.789°±0.2°, 25.318°±0.2°, 13.448°±0.2°, 10.481°±0.2°, 18.763°±0.2°, 11.187°±0.2°, and 14.2°±0.2°; The crystalline form is free base crystalline form K, and the free base crystalline form K has the following crystal orientations: 20.625°±0.2°, 22.089°±0.2°, 14.482°±0.2°, 25.895°±0.2°, 18.418°±0.2°, 12.808°±0.2°, 9.272°±0.2°, 8.948°±0.2°, 16.154°±0.2°, 21.14°±0.2°, 20.21°±0.2°, 16.539°±0.2°, 22.61°±0.2°, 18.109°±0.2°, 29.288°±0.2°, 7.931°±0.2°, 23.92°±0.2°, 19.98°± 0.2°, 15.512°±0.2°, 8.35°±0.2°, 26.836°±0.2°, 15.867°±0.2°, 23.606°±0.2°, 26.668°±0.2°, 24.888°±0.2°, 32.296°±0.2°, 29.096°±0.2°, 10.215°±0.2°, 11.757°±0.2°, 24.467°±0.2°, 15.029°±0.2°, 39.238°±0.2°, 28.325°±0.2°, 27.845°±0.2°, and 40.494°±0.2°; The crystalline form is free base crystalline Form L, and the free base crystalline Form L has the following crystal orientations: 16.978°±0.2°, 15.741°±0.2°, 20.074°±0.2°, 11.225°±0.2°, 22.736°±0.2°, 15.252°±0.2°, 17.989°±0.2°, 5.574°±0.2°, 26.461°±0.2°, 8.088°±0.2°, 18.437°±0.2°, 21.277°±0.2°, 18.632°±0.2°, 23.539°±0.2°, 10.961°±0.2 20.459°±0.2°, 25.703°±0.2°, 9.279°±0.2°, 23.91°±0.2°, 14.018°±0.2°, 28.958°±0.2°, 24.86°±0.2°, 32.879°±0.2°, 27.314°±0.2°, 35.773°±0.2°, 33.542°±0.2°, 29.252°±0.2°, and 40.574°±0.2°; The crystalline form is free base crystalline form M, and the free base crystalline form M has the following angles: 21.173°±0.2°, 9.041°±0.2°, 8.828°±0.2°, 15.34°±0.2°, 16.449°±0.2°, 26.113°±0.2°, 16.099°±0.2°, 19.436°±0.2°, 26.406°±0.2° , 9.717°±0.2°, 5.282°±0.2°, 21.946°±0.2°, 14.107°±0.2°, 23.263°±0.2°, 10.669°±0.2°, 24.735°±0.2°, 11.76°±0.2°, and 18.278°±0.2°; The crystalline form is free base crystalline Form N, and the free base crystalline Form N has the following crystal orientations: 19.353°±0.2°, 15.677°±0.2°, 18.461°±0.2°, 23.017°±0.2°, 18.837°±0.2°, 23.23°±0.2°, 9.851°±0.2°, 10.726°±0.2°, 24.261°±0.2°, 21.615°±0.2°, 25.889°±0.2°, 26.902°±0.2°, 18.255°±0.2°, 23.903°±0.2°, 15.371°±0.2°, 22.713°±0.2°, 19.864°±0.2 25.661°±0.2°, 14.112°±0.2°, 14.798°±0.2°, 12.769°±0.2°, 29.013°±0.2°, 12.46°±0.2°, 24.799°±0.2°, 26.464°±0.2°, 11.751°±0.2°, 13.143°±0.2°, 5.108°±0.2°, 30.667°±0.2°, 34.665°±0.2°, 33.332°±0.2°, 28.357°±0.2°, 8.608°±0.2°, and 39.721°±0.2°; The crystalline form is free base crystalline form O, and the free base crystalline form O has the following crystal orientations: 9.294°±0.2°, 22.47°±0.2°, 11.139°±0.2°, 22.635°±0.2°, 15.11°±0.2°, 19.334°±0.2°, 20.676°±0.2°, 16.21°±0.2°, 26.024°±0. .2°, 18.318°±0.2°, 8.19°±0.2°, 13.891°±0.2°, 22.05°±0.2°, 23.086°±0.2°, 5.499°±0.2°, 15.632°±0.2°, 16.053°±0.2°, 24.463°±0.2°, 8.501°±0.2°, 12.827°±0.2°, 28.113° ±0.2°, 28.729°±0.2°, 17.216°±0.2°, 28.978°±0.2°, 20.921°±0.2°, 10.828°±0.2°, 14.485°±0.2°, 30.779°±0.2°, 27.64°±0.2°, 29.609°±0.2°, 23.81°±0.2°, 32.367°±0.2°, 23 and further having one or more characteristic powder X-ray diffraction peaks selected from the group consisting of 0.654°±0.2°, 33.6°±0.2°, 31.634°±0.2°, 25.085°±0.2°, 37.002°±0.2°, 11.83°±0.2°, 36.126°±0.2°, 40.712°±0.2°, and 41.521°±0.2°; The crystalline form is free base crystalline Form P, and the free base crystalline Form P has the following crystal orientations: 24.844°±0.2°, 22.643°±0.2°, 23.927°±0.2°, 15.998°±0.2°, 5.413°±0.2°, 11.243°±0.2°, 19.109°±0.2°, 15.204°±0.2°, 26.032°±0.2°, 20.313°±0.2°, 23.474°±0.2°, 18.855°±0.2°, 11.485°±0.2°, 19.5°±0.2°, 27.044°±0.2°, 30.158°±0.2°, 10.949 ... and further having one or more characteristic X-ray powder diffraction peaks selected from the group consisting of 25.584°±0.2°, 35.902°±0.2°, 28.805°±0.2°, 26.693°±0.2°, 27.751°±0.2°, 35.669°±0.2°, 9.756°±0.2°, 12.331°±0.2°, 34.452°±0.2°, 14.013°±0.2°, 32.583°±0.2°, 33.313°±0.2°, 39.326°±0.2°, 13.376°±0.2°, 31.555°±0.2°, and 17.643°±0.2°; The crystalline form is free base crystalline form Q, and the free base crystalline form Q has the following rotation angles: 19.354°±0.2°, 18.995°±0.2°, 11.472°±0.2°, 8.367°±0.2°, 18.593°±0.2°, 16.688°±0.2°, 9.591°±0.2°, 8.825°±0.2°, 26.164°±0.2°, 26.57 ... °±0.2°, 17.931°±0.2°, 24.918°±0.2°, 11.864°±0.2°, 17.354°±0.2°, 5.679°±0.2°, 17.66°±0.2°, 20.677°±0.2°, 15.589°±0.2°, 32.45°±0.2°, 27.084°±0.2°, 11.151°±0.2°, 31.897°±0.2° , 23.703°±0.2°, 35.188°±0.2°, 14.914°±0.2°, 15.758°±0.2°, 30.14°±0.2°, 27.238°±0.2°, 6.581°±0.2°, 23.209°±0.2°, 28.785°±0.2°, 34.05°±0.2°, 7.724°±0.2°, 14.273°±0.2°, 28.179 and further having one or more characteristic powder X-ray diffraction peaks selected from the group consisting of 29.984°±0.2°, 35.767°±0.2°, 24.539°±0.2°, 25.337°±0.2°, 39.77°±0.2°, 29.683°±0.2°, 31.355°±0.2°, 32.727°±0.2°, and 38.588°±0.2°; The crystalline form is free base crystalline Form R, and the free base crystalline Form R has the following inclination angles: 6.579°±0.2°, 17.62°±0.2°, 13.831°±0.2°, 25.901°±0.2°, 24.013°±0.2°, 9.447°±0.2°, 28.991°±0.2°, 8.241°±0.2 °, 13.556°±0.2°, 23.343°±0.2°, 20.822°±0.2°, 13.345°±0.2°, 16.664°±0.2°, 20.571°±0.2°, 19.406°±0.2°, 24.358°±0.2°, 24.919°±0.2°, 8.897°±0.2°, 39.905°±0.2° °±0.2°, 15.257°±0.2°, 28.601°±0.2°, 20.063°±0.2°, 33.028°±0.2°, 30.525°±0.2°, 21.408°±0.2°, 25.383°±0.2°, 36.219°±0.2°, 40.32°±0.2°, 30.27°±0.2°, 33 and further having one or more characteristic powder X-ray diffraction peaks selected from the group consisting of 0.741°±0.2°, 32.489°±0.2°, 31.21°±0.2°, 26.826°±0.2°, 34.552°±0.2°, 12.777°±0.2°, 18.963°±0.2°, and 31.607°±0.2°; The crystalline form is free base crystalline Form S, and the free base crystalline Form S has the following rotation angles: 18.103°±0.2°, 15.674°±0.2°, 7.917°±0.2°, 17.512°±0.2°, 21.377°±0.2°, 19.485°±0.2°, 16.025°±0.2°, 11.055°±0.2°, 18.622°±0.2°, 20.009°±0.2°, 23.269°±0.2° , 17.015°±0.2°, 12.162°±0.2°, 15.002°±0.2°, 8.735°±0.2°, 27.664°±0.2°, 8.239°±0.2°, 19.758°±0.2°, 24.248°±0.2°, 36.703°±0.2°, 25.547°±0.2°, and 12.903°±0.2°.

[0016] In another preferred embodiment, (IA) The crystalline form is salt form IA, which further comprises one or more of the following characteristics: (1) the salt form IA has XRPD data essentially as shown in Table 1; and / or (2) the salt form IA has an XRPD pattern essentially as shown in FIG. 1; (IB) The crystalline form is salt form IB, which further has one or more of the following characteristics: (1) the salt form IB has XRPD data essentially as shown in Table 2; and / or (2) The salt crystalline form IB has an XRPD pattern essentially as shown in FIG. 2. (IC) The crystalline form is a salt crystalline form IC, the salt crystalline form IC further comprising one or more of the following features: (1) the salt crystalline form IC has XRPD data essentially as set forth in Table 3; and / or (2) The salt crystalline form IC has an XRPD pattern essentially as shown in FIG. 3; (II-A) The crystalline form is salt form II-A, which further has one or more of the following characteristics: (1) the salt form II-A has XRPD data essentially as shown in Table 4; and / or (2) The salt crystalline form II-A has an XRPD pattern essentially as shown in FIG. 4. (II-B) The crystalline form is salt form II-B, which further comprises one or more of the following characteristics: (1) the salt form II-B has XRPD data essentially as shown in Table 5; and / or (2) The salt crystalline form II-B has an XRPD pattern essentially as shown in FIG. 5. (II-C) The crystalline form is salt form II-C, which further comprises one or more of the following characteristics: (1) the salt form II-C has XRPD data essentially as shown in Table 6; and / or (2) The salt crystalline form II-C has an XRPD pattern essentially as shown in FIG. 6. (III-A) The crystalline form is salt form III-A, which further comprises one or more of the following characteristics: (1) the salt form III-A has XRPD data essentially as shown in Table 7; and / or (2) The salt crystalline form III-A has an XRPD pattern essentially as shown in FIG. 7. (III-B) The crystalline form is salt form II-B, which further comprises one or more of the following characteristics: (1) the salt form III-B has XRPD data essentially as shown in Table 8; and / or (2) The salt crystalline form III-B has an XRPD pattern essentially as shown in FIG. 8. (III-C) The crystalline form is salt form II-C, which further comprises one or more of the following characteristics: (1) the salt form III-C has XRPD data essentially as shown in Table 9; and / or (2) The salt crystalline form III-C has an XRPD pattern essentially as shown in FIG. 9. (IV-A) The crystalline form is salt form IV-A, which further comprises one or more of the following characteristics: (1) the salt form IV-A has XRPD data essentially as shown in Table 10; and / or (2) The salt crystalline form IV-A has an XRPD pattern essentially as shown in FIG. 10. (VA) The crystalline form is a salt crystalline form VA, which further comprises one or more of the following characteristics: (1) the salt crystalline form VA has XRPD data essentially as shown in Table 11; and / or (2) The salt crystalline form VA has an XRPD pattern essentially as shown in FIG. 11. (VB) The crystalline form is salt form VB, which further comprises one or more of the following characteristics: (1) the salt form VB has XRPD data essentially as shown in Table 12; and / or (2) The salt form VB has an XRPD pattern essentially as shown in FIG. 12. (VI-A) The crystalline form is salt form VI-A, which further comprises one or more of the following characteristics: (1) the salt form VI-A has XRPD data essentially as shown in Table 13; and / or (2) The salt crystalline form VI-A has an XRPD pattern essentially as shown in FIG. 13. (VII-A) The crystalline form is salt form VII-A, which further comprises one or more of the following characteristics: (1) the salt form VII-A has XRPD data essentially as shown in Table 14; and / or (2) The salt crystalline form VII-A has an XRPD pattern essentially as shown in FIG. 14. (VIII-A) The crystalline form is salt form VIII-A, which further comprises one or more of the following characteristics: (1) the salt Form VIII-A has XRPD data essentially as shown in Table 15; and / or (2) The salt crystalline form VIII-A has an XRPD pattern essentially as shown in FIG. 15. (VIII-B) The crystalline form is salt form VIII-B, which further comprises one or more of the following characteristics: (1) the salt Form VIII-B has XRPD data essentially as shown in Table 16; and / or (2) The salt crystalline form VIII-B has an XRPD pattern essentially as shown in FIG. 16. (VIII-C) The crystalline form is salt form VIII-C, which further comprises one or more of the following features: (1) the salt Form VIII-C has XRPD data essentially as shown in Table 17; and / or (2) The salt form VIII-C has an XRPD pattern essentially as shown in FIG. 17. (IX-A) The crystalline form is salt form IX-A, which further has one or more of the following characteristics: (1) the salt form IX-A has XRPD data essentially as shown in Table 18; and / or (2) The salt crystalline form IX-A has an XRPD pattern essentially as shown in FIG. 18. (IX-B) The crystalline form is salt form IX-B, which further has one or more of the following characteristics: (1) the salt form IX-B has XRPD data essentially as shown in Table 19; and / or (2) The salt crystalline form IX-B has an XRPD pattern essentially as shown in FIG. 19. (IX-C) The crystalline form is salt form IX-C, which further has one or more of the following characteristics: (1) the salt form IX-C has XRPD data essentially as shown in Table 20; and / or (2) The salt crystalline form IX-C has an XRPD pattern essentially as shown in FIG. 20. (IX-D) The crystalline form is salt form IX-D, which further has one or more of the following characteristics: (1) the salt form IX-D has XRPD data essentially as shown in Table 21; and / or (2) The salt crystalline form IX-D has an XRPD pattern essentially as shown in FIG. 21. (IX-E) The crystalline form is salt form IX-E, which further has one or more of the following characteristics: (1) the salt form IX-E has XRPD data essentially as shown in Table 22; and / or (2) The salt crystalline form IX-E has an XRPD pattern essentially as shown in FIG. 22. (IX-F) The crystalline form is salt form IX-F, which further has one or more of the following characteristics: (1) the salt form IX-F has XRPD data essentially as shown in Table 23; and / or (2) The salt crystalline form IX-F has an XRPD pattern essentially as shown in FIG. 23. (A) The crystalline form is free base crystalline Form A, and the free base crystalline Form A further has one or more of the following characteristics: (1) the free base crystalline Form A has XRPD data essentially as set forth in Table 0; and / or (2) the free base crystalline Form A has an XRPD pattern essentially as shown in Figure 24; (B) The crystalline form is free base crystalline Form B, which further has one or more of the following characteristics: (1) the free base crystalline Form B has XRPD data essentially as shown in Table 27; and / or (2) the free base crystalline Form B has an XRPD pattern essentially as shown in Figure 25; (C) The crystalline form is free base crystalline Form C, which free base crystalline Form C further has one or more of the following characteristics: (1) the free base crystalline Form C has XRPD data essentially as set forth in Table 28; and / or (2) the free base crystalline Form C has an XRPD pattern essentially as shown in Figure 26; (D) The crystalline form is free base crystalline Form D, and the free base crystalline Form D further has one or more of the following characteristics: (1) the free base crystalline Form D has XRPD data essentially as set forth in Table 29; and / or (2) the free base crystalline Form D has an XRPD pattern essentially as shown in Figure 27; (E) The crystalline form is free base crystalline Form E, which free base crystalline Form E further has one or more of the following characteristics: (1) the free base crystalline Form E has XRPD data essentially as set forth in Table 30; and / or (2) the free base crystalline Form E has an XRPD pattern essentially as shown in FIG. 28; (F) The crystalline form is free base crystalline Form F, the free base crystalline Form F further having one or more of the following characteristics: (1) the free base crystalline Form F has XRPD data essentially as set forth in Table 31; and / or (2) the free base crystalline Form F has an XRPD pattern essentially as shown in FIG. 29; (G) The crystalline form is free base crystalline Form G, which free base crystalline Form G further has one or more of the following characteristics: (1) the free base crystalline Form G has XRPD data essentially as shown in Table 32; and / or (2) the free base crystalline Form G has an XRPD pattern essentially as shown in Figure 30; (H) The crystalline form is free base crystalline Form H, which free base crystalline Form H further has one or more of the following characteristics: (1) the free base crystalline Form H has XRPD data essentially as set forth in Table 33; and / or (2) the free base crystalline Form H has an XRPD pattern essentially as shown in Figure 31; (I) The crystalline form is free base crystalline Form I, which further has one or more of the following characteristics: (1) the free base crystalline Form I has XRPD data essentially as set forth in Table 34; and / or (2) the free base crystalline Form I has an XRPD pattern essentially as shown in Figure 32; (J) The crystalline form is free base crystalline Form J, and the free base crystalline Form J further has one or more of the following features: (1) the free base crystalline Form J has XRPD data essentially as set forth in Table 35; and / or (2) the free base crystalline Form J has an XRPD pattern essentially as shown in Figure 33; (K) The crystalline form is free base crystalline Form K, which further has one or more of the following characteristics: (1) the free base crystalline Form K has XRPD data essentially as set forth in Table 36; and / or (2) the free base crystalline Form K has an XRPD pattern essentially as shown in Figure 34; (L) The crystalline form is free base crystalline Form L, which further has one or more of the following characteristics: (1) the free base crystalline Form L has XRPD data essentially as shown in Table 37; and / or (2) the free base crystalline Form L has an XRPD pattern essentially as shown in Figure 35; (M) The crystalline form is free base crystalline Form M, which further has one or more of the following characteristics: (1) the free base crystalline Form M has XRPD data essentially as set forth in Table 38; and / or (2) the free base crystalline Form M has an XRPD pattern essentially as shown in Figure 36; (N) The crystalline form is free base crystalline Form N, which further has one or more of the following characteristics: (1) the free base crystalline Form N has XRPD data essentially as set forth in Table 39; and / or (2) the free base crystalline Form N has an XRPD pattern essentially as shown in Figure 37; (O) The crystalline form is free base crystalline Form O, which free base crystalline Form O further has one or more of the following characteristics: (1) the free base crystalline Form O has XRPD data essentially as set forth in Table 40; and / or (2) the free base crystalline Form O has an XRPD pattern essentially as shown in Figure 38; (P) The crystalline form is free base crystalline Form P, which further has one or more of the following characteristics: (1) the free base crystalline Form P has XRPD data essentially as set forth in Table 41; and / or (2) the free base crystalline Form P has an XRPD pattern essentially as shown in Figure 39; (Q) The crystalline form is free base crystalline Form Q, which further has one or more of the following characteristics: (1) the free base crystalline Form Q has XRPD data essentially as set forth in Table 42; and / or (2) the free base crystalline form Q has an XRPD pattern essentially as shown in Figure 40; (R) the crystalline form is free base crystalline Form R, which free base crystalline Form R further has one or more of the following characteristics: (1) the free base crystalline Form R has XRPD data essentially as set forth in Table 43; and / or (2) the free base crystalline Form R has an XRPD pattern essentially as shown in Figure 41; (S) The crystalline form is free base crystalline Form S, which free base crystalline Form S further has one or more of the following characteristics: (1) the free base crystalline Form S has XRPD data essentially as set forth in Table 44; and / or (2) the free base crystalline Form S has an XRPD pattern essentially as shown in Figure 42; (T) The crystalline form is free base crystalline Form T, which free base crystalline Form T further has one or more of the following characteristics: (1) the free base crystalline Form T has XRPD data essentially as set forth in Table 45; and / or (2) The free base crystalline Form T has an XRPD pattern essentially as shown in FIG.

[0017] In a fourth aspect of the present invention, there is provided a method for preparing a crystalline form according to the first aspect of the present invention, the crystalline form being Form T, the method comprising the steps of: (i) dissolving free base Form A in a fifth solvent, adding trifluoroacetic acid, and filtering; (ii) maintaining the filtrate at 35-45° C. for 1-2 hours, and then adjusting the pH of the filtrate to 7-8; (iii) keeping the filtrate at 35 to 45°C for 1 to 3 hours, continuously dropping an alkaline solution thereinto, and then continuously keeping the filtrate at 35 to 45°C for 1 to 3 hours; (v) slowly cooling to 0-10° C., keeping warm and stirring for 1-3 hours, thereby obtaining the free base crystalline Form T.

[0018] In another preferred embodiment, the fifth solvent is water.

[0019] In another preferred embodiment, in step (ii), the pH adjustment is performed using an alkaline solution, which is a sodium carbonate solution.

[0020] In a fifth aspect of the present invention, there is provided a process for preparing the crystalline form according to the second aspect of the present invention, wherein the crystalline form is free base crystalline form B, the process comprising any of the steps (a), (b), (c), (d) and (e): (a) Suspension crystallization method: Free base Form A is dissolved in a first solvent to prepare a suspension, which is then placed at 25°C to 50°C, optionally stirred, and then filtered to obtain free base crystalline Form B. In another preferred embodiment, when suspension stirring is not performed, the mixture is left to stand for 6 to 8 days and then filtered.

[0021] In another preferred embodiment, when suspension stirring is performed, filtration is performed after suspension stirring is performed for 2 to 4 days.

[0022] (b) Gas-liquid diffusion: Free base Form A is dissolved in a liquid vial containing a first good solvent, which is then kept open and placed in a larger flask containing a first poor solvent, the large flask is sealed and allowed to stand at room temperature for one week to obtain free base crystalline Form B. In another preferred embodiment, in step (b), the concentration of Form A in the liquid vial is 40-60 mg / mL.

[0023] (c) Gas-solid diffusion: Free base Form A is placed in a liquid vial, which is then kept open and placed in a larger flask containing a third solvent, the large flask is sealed and allowed to stand at room temperature for one week to obtain free base crystalline Form B; (d) Slow evaporation: Free base Form A is placed in a liquid vial and a fourth solvent is added to dissolve it clear, then the solvent is slowly evaporated at room temperature (N2 protection) to obtain free base crystalline Form B. In another preferred embodiment, the fourth solvent is THF, MIBK, or a combination thereof.

[0024] (e) Dissolution crystallization: Free base Form A is placed in a vial and dissolved by adding a second good solvent. A second poor solvent is quickly added, stirred overnight, and then filtered to obtain free base crystalline Form B.

[0025] In another preferred embodiment, the starting compound of formula I is the free base crystalline Form A of the compound of formula I.

[0026] In another preferred embodiment, when the method employs step (a), the first solvent is selected from the group consisting of EtOH, IPA, MTBE, EA, heptane, IPAC, ethyl formate, anisole, MIBK, a mixed solvent of IPA and ACN, a mixed solvent of DMSO and HO, and a mixed solvent of EtOH and HO.

[0027] In another preferred embodiment, when the temperature is 25° C., the first solvent is selected from the group consisting of EtOH, IPA, MTBE, EA, IPAC, ethyl formate, MIBK, a mixed solvent of IPA and ACN, and a mixed solvent of DMSO and HO.

[0028] In another preferred embodiment, when the temperature is 50° C., the first solvent is selected from the group consisting of EtOH, MTBE, EA, heptane, IPAC, ethyl formate, MIBK, anisole, a mixed solvent of DMSO and HO, and a mixed solvent of EtOH and HO.

[0029] In another preferred embodiment, when the method employs step (b), the first good solvent is NPA and the first poor solvent is selected from the group consisting of ACN, acetone, EA, and combinations thereof; When the process employs step (c), the third solvent is ethyl formate; When the method employs step (d), the fourth solvent is THF, MIBK, or a combination thereof; When the method employs step (e), the second good solvent is selected from the group consisting of THF, NPA, and combinations thereof, and the second poor solvent is selected from the group consisting of ACN, EA, IPAC, MTBE, n-heptane, and combinations thereof.

[0030] In a sixth aspect of the present invention, there is provided a pharmaceutical composition comprising (a) a crystalline form according to the first, second or third aspect of the present invention as an active ingredient, and (b) a pharma- ceutically acceptable carrier.

[0031] In another preferred embodiment, the dosage form of the pharmaceutical composition or preparation is selected from the group consisting of powder, capsule, granule, tablet, pill, and injection. Effect of the Invention

[0032] It should be understood that within the scope of the present invention, the above technical features of the present invention and the technical features specifically described below (e.g., in the Examples) can be combined with each other to constitute new or preferred technical solutions, which will not be repeated here due to space limitations. [Brief description of the drawings]

[0033] [Figure 1] 1 is an XRPD pattern of crystalline form IA of a salt of the present invention. [Diagram 2] 1 is an XRPD pattern of crystalline form IB of the salt of the present invention. [Diagram 3] 1 is an XRPD pattern of crystalline form IC of a salt of the present invention. [Figure 4] 1 is an XRPD pattern of crystalline form II-A of the salt of the present invention. [Diagram 5] 1 is an XRPD pattern of crystalline form II-B of the salt of the present invention. [Figure 6] 1 is an XRPD pattern of crystalline form II-C of the salt of the present invention. [Figure 7] 1 is an XRPD pattern of crystalline form III-A of the salt of the present invention. [Figure 8] 1 is an XRPD pattern of crystalline form III-B of the salt of the present invention. [Figure 9] 1 is an XRPD pattern of crystalline form III-C of a salt of the present invention. [Figure 10] 1 is an XRPD pattern of crystalline form IV-A of the salt of the present invention. [Figure 11]1 is an XRPD pattern of the crystalline form VA of a salt of the present invention. [Figure 12] 1 is an XRPD pattern of the salt of the present invention, crystalline form VB. [Figure 13] 1 is an XRPD pattern of crystalline form VI-A of the salt of the present invention. [Figure 14] 1 is an XRPD pattern of crystalline form VII-A of the salt of the present invention. [Figure 15] 1 is an XRPD pattern of crystalline form VIII-A of a salt of the present invention. [Figure 16] 1 is an XRPD pattern of crystalline form VIII-B of a salt of the present invention. [Figure 17] 1 is an XRPD pattern of crystalline form VIII-C of a salt of the present invention. [Figure 18] 1 is an XRPD pattern of crystalline form IX-A of a salt of the present invention. [Figure 19] 1 is an XRPD pattern of crystalline form IX-B of a salt of the present invention. [Figure 20] 1 is an XRPD pattern of crystalline form IX-C of a salt of the present invention. [Figure 21] 1 is an XRPD pattern of crystalline form IX-D of a salt of the present invention. [Figure 22] 1 is an XRPD pattern of crystalline form IX-E of a salt of the present invention. [Figure 23] 1 is an XRPD pattern of crystalline form IX-F of a salt of the present invention. [Figure 24] 1 is an XRPD pattern of the free base crystalline form Form A of the present invention. [Diagram 25] 1 is an XRPD pattern of the free base crystalline Form B of the present invention. [Figure 26] 1 is an XRPD pattern of the free base crystalline Form C of the present invention. [Figure 27] 1 is an XRPD pattern of the free base crystalline Form D of the present invention. [Figure 28] 1 is an XRPD pattern of the free base crystalline Form E of the present invention. [Figure 29] 1 is an XRPD pattern of the free base crystalline Form F of the present invention. [Diagram 30]1 is an XRPD pattern of the free base crystalline Form G of the present invention. [Diagram 31] 1 is an XRPD pattern of the free base crystalline Form H of the present invention. [Diagram 32] 1 is an XRPD pattern of the free base crystalline Form I of the present invention. [Diagram 33] 1 is an XRPD pattern of the free base crystalline Form J of the present invention. [Diagram 34] 1 is an XRPD pattern of the free base crystalline Form K of the present invention. [Diagram 35] 1 is an XRPD pattern of the free base crystalline Form L of the present invention. [Diagram 36] 1 is an XRPD pattern of the free base crystalline Form M of the present invention. [Figure 37] 1 is an XRPD pattern of the free base crystalline Form N of the present invention. [Figure 38] 1 is an XRPD pattern of the free base crystalline Form O of the present invention. [Figure 39] 1 is an XRPD pattern of the free base crystalline Form P of the present invention. [Diagram 40] 1 is an XRPD pattern of the free base crystalline form Form Q of the present invention. [Diagram 41] 1 is an XRPD pattern of the free base crystalline Form R of the present invention. [Diagram 42] 1 is an XRPD pattern of the free base crystalline Form S of the present invention. [Diagram 43] 1 is an XRPD pattern of the free base crystalline Form T of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] After a long and thorough study, the present inventors have provided a salt crystal form and a free base crystal form of the compound of formula I. These crystal forms have advantages in stability, solubility, hygroscopicity, mechanical stability, tableting stability, flowability, process development, formulation development and powder processing performance, etc. In particular, crystal form B and crystal form T have significant advantages in preparation process and stability. Based on the above findings, the present inventors have completed the present invention.

[0035] term In this specification, unless stated otherwise, all abbreviations have the common meaning understood by those of ordinary skill in the art.

[0036] As used herein, unless otherwise specified, the method of adding a solvent or solution is by direct injection or constant rate addition.

[0037] As used herein, "room temperature" refers to approximately 4 to 30°C, preferably 20±5°C.

[0038] As used herein, "slow addition" methods include, but are not limited to, dropwise, slow addition down the wall of a container.

[0039] Compounds of Formula I As used herein, the term "compound of formula I" refers to a compound as shown in the following formula (i.e., 3-ethyl-8-(4-(4-(4-ethylpiperazin-1-yl)piperidin-1-yl)-3-methoxyphenyl)-N2-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-b]pyrazine-2,5-diamine). Formula I: [ka]

[0040] The above compound was first reported in International Application No. PCT / CN2021 / 107759 and can be prepared using the methods described therein. In this specification, unless otherwise specified, the term "raw material of the compound of Formula I" refers to the free base crystalline form Form A of the compound of Formula I, whose XRPD data is as shown in Table 0 and whose XRPD pattern is shown in Figure 24. The crystalline form is the free base synthesized and isolated according to the preparation method of International Application No. PCT / CN2021 / 107759, and in the examples, Form A and API are interchangeable. [Table 1]

[0041] Pharmaceutical Compositions Containing Crystalline Forms of the Compound of Formula I Another aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of the compound of formula I according to the present invention, and optionally one or more pharma- ceutically acceptable carriers, excipients, adjuvants, vehicles and / or diluents, such as odorants, flavorings, sweeteners, etc.

[0042] The pharmaceutical composition provided by the present invention preferably contains 1-99% by weight of the active ingredient, and the preferred ratio is that the compound of general formula I as the active ingredient accounts for 65wt%-99wt% of the total weight, with the remaining portion being a pharma- ceutically acceptable carrier, diluent or solution or salt solution. The compounds and pharmaceutical compositions provided by the present invention may be in various forms, such as tablets, capsules, powders, syrups, liquids, suspensions and aerosols, and may be present in suitable solid or liquid carriers or diluents, and in suitable sterilizers for injection or infusion.

[0043] Various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field.The unit dosage of the preparation contains 1mg-700mg of the compound of formula I, preferably, the unit dosage of the preparation contains 25mg-300mg of the compound of formula I.

[0044] The compounds and pharmaceutical compositions of the present invention can be used clinically in mammals, including humans and animals, through routes of administration such as oral, nasal, dermal, pulmonary or gastrointestinal tract. The most preferred route of administration is oral administration. The optimal daily dose is 50-1400 mg / kg body weight taken in a single dose or 25-700 mg / kg body weight taken in multiple doses. Regardless of the method of administration, the optimal dose for an individual must be determined based on the specific treatment. Usually, a small dose is started and gradually increased until the optimal dose is found.

[0045] In the present invention, unless otherwise specified, the method used for drying is a conventional drying method in the art. For example, in the embodiment of the present invention, drying refers to vacuum drying or normal pressure drying using a conventional drying oven. Drying is generally performed for 0.1 to 50 hours or 1 to 30 hours.

[0046] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to describe the present invention, and do not limit the scope of the present invention. In the following embodiments, the experimental methods without specific conditions are usually based on conventional conditions or conditions recommended by manufacturers. Unless otherwise specified, percentages and parts are calculated by weight.

[0047] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Furthermore, any methods and materials similar or equivalent to those described can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0048] General methods and reagents All the solvents used in the present invention are analytically pure, and the water content is about 0.1%. All the compounds of formula (I) used as raw materials in the examples were purchased.

[0049] All the test methods of the present invention are general methods, and the test parameters are as follows:

[0050] Measurement method by powder X-ray diffractometer: The crystal form of the raw material is analyzed using a powder X-ray diffractometer. The 2θ scanning angle of the sample is 3°~42°, the scanning step size is 0.02°, and the scanning time per step is 0.2 seconds. The voltage and current of the arc tube are 40kv and 40mA, respectively. When preparing the sample, place an appropriate amount of sample on the sample tray and flatten it with a tool such as a spoon or glass plate to ensure that the surface is smooth and flat.

[0051] Determination of TGA pattern: The samples are analyzed using a TA Instruments TGA Discovery 550. The samples are placed in a tared aluminum plate, which is automatically weighed by the system. The samples are then heated to 300° C. at a rate of 10° C. / min under nitrogen protection.

[0052] Method for determining the DSC pattern: The samples are analyzed using a TA Instruments Discovery DSC 25. A weighed sample is placed on a sample tray and the sample is heated to 300° C. at a rate of 10° C. / min under nitrogen gas (50 ml / min) protection.

[0053] Proton Nuclear Magnetic Resonance Data (1H NMR): The instrument used for 1H NMR analysis is a Bruker Ascend 400MH NMR analyzer.

[0054] Method for determining DSV patterns: Dynamic moisture sorption was performed using Intrinsic DVS. In step mode, the samples are subjected to a loop test from 0 to 90% relative ambient humidity. The samples are analyzed at 10% RH. The dm / dt is set to 0.002 to achieve equilibrium between the sample and the room environment.

[0055] Example 1: Preparation of p-Toluenesulfonate Crystalline Forms IA, IB, and IC At 0° C., approximately 25 mg of API was weighed out and ethanol (0.5 mL) was added, followed by 1.2 equivalents of p-toluenesulfonic acid. The mixture was reacted at 50° C. under magnetic stirring for 3 hours and then cooled to room temperature. After reacting overnight, the mixture was filtered to obtain phosphate salt crystalline form IA. At 0° C., approximately 25 mg of API was weighed out and THF (0.5 mL) was added, followed by 1.2 equivalents of p-toluenesulfonic acid. The mixture was reacted at 50° C. under magnetic stirring for 3 hours and then cooled to room temperature. After reacting overnight, the reaction was filtered to obtain phosphate salt crystal form IB. At 0° C., approximately 25 mg of API was weighed and ethyl formate (0.5 mL) (DCM:MeOH (1:1) (0.5 mL)) was added, followed by 1.2 equivalents of p-toluenesulfonic acid. The mixture was reacted at 50° C. under magnetic stirring for 3 hours and then cooled to room temperature. After reacting overnight, the mixture was filtered to obtain the phosphate salt crystal form IC. Various characterizations were carried out for each crystalline form. The analytical results showed that there were chemical shift deviations in the NMR spectrum, which indicated that the free base had undergone salt formation reactions. The XRPD data are shown in Tables 1 to 3, respectively, and the DSC results showed that the obtained p-toluenesulfonate salt had more than one endothermic peak, which may indicate that it is a mixed crystal. [Table 2] [Table 3] [Table 4]

[0056] Example 2: Preparation of Fumarate Crystalline Forms II-A, II-B, and II-C At 0° C., approximately 25 mg of API was weighed out and ethanol (0.5 mL) was added, followed by 1.2 equivalents of fumaric acid. The mixture was reacted at 50° C. under magnetic stirring for 3 hours and then cooled to room temperature. After reacting overnight, the mixture was filtered to obtain phosphate salt crystalline form II-A. At 0° C., approximately 25 mg of API was weighed out and THF (0.5 mL) was added, followed by 1.2 equivalents of fumaric acid. The mixture was reacted at 50° C. under magnetic stirring for 3 hours and then cooled to room temperature. After reacting overnight, the mixture was filtered to obtain phosphate salt crystal form II-B. At 0° C., approximately 25 mg of API was weighed out and ethyl formate (0.5 mL) was added, followed by 1.2 equivalents of fumaric acid. The mixture was reacted at 50° C. under magnetic stirring for 3 hours and then cooled to room temperature. After reacting overnight, the mixture was filtered to obtain phosphate salt crystalline form II-C. Various characterizations were performed on the crystal forms. The analytical results showed that there was a deviation in chemical shifts in the NMR spectrum, which indicated that the free base had undergone a salt formation reaction. The XRPD data was shown in Tables 4-6, and the DSC results showed that fumarate salt form II-A had two endothermic peaks, which may be a mixed crystal. The DSC and TGA results of fumarate salt form II-C showed that its melting point was 204.09°C, and the corresponding weight loss was 6.826%, and the DSC results showed that the XRPD of fumarate salt form II-C was examined after heating to 150°C. The results showed that the crystal form changed after the solvent removal treatment, which indicates that fumarate salt form II-C may be a solvate or hydrate. [Table 5] [Table 6] [Table 7]

[0057] Example 3: Preparation of methanesulfonate salt crystalline forms III-A, III-B, and III-C At 0° C., approximately 25 mg of API was weighed out and THF (0.5 mL) was added, followed by 1.2 equivalents of methanesulfonic acid. The mixture was reacted under magnetic stirring at 50° C. for 3 hours and then cooled to room temperature. After reacting overnight, the mixture was filtered to obtain methanesulfonate salt crystalline form III-A. At 0° C., approximately 25 mg of API was weighed out and ethyl formate (0.5 mL) was added, followed by 1.2 equivalents of methanesulfonic acid. The mixture was reacted at 50° C. under magnetic stirring for 3 hours and then cooled to room temperature. After reacting overnight, the mixture was filtered to obtain methanesulfonate salt crystalline form III-B. At 0° C., approximately 25 mg of API was weighed out and ethanol (0.5 mL) was added, followed by 2.2 equivalents of methanesulfonic acid. The mixture was reacted at 50° C. under magnetic stirring for 3 hours and then cooled to room temperature. After reacting overnight, the mixture was filtered to obtain methanesulfonate salt crystalline form III-C. Various characterizations were performed on each crystal form, and the results are shown in the following figures. The analytical results show that there are chemical shift deviations in the NMR spectrum, which indicates that the free base undergoes salt formation reaction. The XRPD data are shown in Tables 7 to 9, respectively, and the DSC results show that both methanesulfonate salt crystal forms III-B and III-C have two endothermic peaks, which indicates that they are mixed crystals. The DSC results show that the XRPD of methanesulfonate salt crystal form III-A was examined after heating to 150°C. The results show that the crystal form did not change after the solvent removal treatment, which indicates that methanesulfonate salt crystal form III-A is anhydrous. [Table 8] [Table 9] [Table 10]

[0058] Example 4: Preparation of Phosphate Crystalline Form IV-A At 0° C., approximately 25 mg of API was weighed out and methyl formate (0.5 mL) was added, followed by 1.2 equivalents of phosphoric acid. The mixture was reacted at 50° C. under magnetic stirring for 3 hours and then cooled to room temperature. After reacting overnight, the mixture was filtered to obtain phosphate crystalline form IV-A.

[0059] Various characterizations were performed on the crystalline form. The analytical results showed that there was a deviation in chemical shifts in the NMR spectrum, which indicates that the free base was undergoing a salt formation reaction. The XRPD data is shown in Table 10, and the DSC&TGA results showed that the melting point of phosphate crystalline form IV-A was 184.94°C, and the weight loss before 150°C was 3.361%. The DSC results showed that phosphate crystalline form IV-A was heated to 150°C and its XRPD was examined. The results showed that the crystalline form did not change after the solvent removal treatment, which indicates that phosphate crystalline form IV-A is anhydrous. [Table 11]

[0060] Example 5: Preparation of Maleate Crystal Forms VA and VB At 0° C., approximately 25 mg of API was weighed out and ethyl formate (0.5 mL) was added, followed by 1.2 equivalents of maleic acid. The mixture was reacted at 50° C. under magnetic stirring for 3 hours, then cooled to room temperature. After reacting overnight, the mixture was filtered to obtain the salt crystalline form VA. At 0° C., approximately 25 mg of API was weighed and DCM:MeOH (1:1) (0.5 mL) was added, followed by 1.2 equivalents of maleic acid. The mixture was reacted at 50° C. under magnetic stirring for 3 hours and then cooled to room temperature. After reacting overnight, the mixture was filtered to obtain salt crystalline form VB. Various characterizations were performed on each crystalline form. The analytical results showed that there were chemical shift deviations in the NMR spectrum, which indicated that the free base had undergone a salt formation reaction. The XRPD data are shown in Tables 11-12. [Table 12] [Table 13]

[0061] Example 6: Preparation of Citrate Crystalline Form VI-A At 0° C., approximately 25 mg of API was weighed out and ethanol (0.5 mL) was added, followed by 1.2 equivalents of citric acid. The mixture was reacted at 50° C. under magnetic stirring for 3 hours and then cooled to room temperature. After reacting overnight, the mixture was filtered to obtain citrate salt crystal form VI-A. Various characterizations were performed on the citrate salt crystalline form VI-A. From the analysis results, there was a deviation in chemical shifts in the NMR spectrum, which indicates that the free base had undergone a salt formation reaction. The XRPD data is shown in Table 13, and from the DSC results, it can be estimated that the melting point peak value of the citrate salt crystalline form VI-A is 191.36°C. From the DSC results, the XRPD of the citrate salt crystalline form VI-A was examined after heating to 150°C. The results showed that the crystal form changed to amorphous after the solvent removal treatment, which indicates that the citrate salt crystalline form VI-A may be a solvate or hydrate. [Table 14]

[0062] Example 7: Preparation of Malate Crystalline Form VII-A At 0° C., approximately 25 mg of API was weighed out and THF (0.5 mL) was added, followed by 1.2 equivalents of malic acid. The mixture was reacted at 50° C. under magnetic stirring for 3 hours and then cooled to room temperature. After reacting overnight, the mixture was filtered to obtain malate crystal form VII-A. Various characterizations were performed on the malate crystalline form, and the results are shown in the following figures. From the analytical results, there was a deviation in chemical shifts in the NMR spectrum, which indicates that the free base had undergone salt formation reaction. Its XRPD data is shown in Table 14. According to the DSC and DSC results, the melting point peak value of malate crystalline form VII-A is 183.96°C, and the weight loss before 150°C is 1.954%. According to the DSC results, the XRPD of malate crystalline form VII-A was examined after heating to 150°C. The results showed that the crystal form did not change after the solvent removal treatment, which indicates that malate crystalline form VII-A was made anhydrous. [Table 15]

[0063] Example 8: Preparation of Salicylate Crystalline Forms VIII-A, VIII-B, and VIII-C At 0° C., approximately 25 mg of API was weighed out and ethanol (0.5 mL) was added, followed by 1.2 equivalents of salicylic acid. The mixture was reacted at 50° C. under magnetic stirring for 3 hours and then cooled to room temperature. After reacting overnight, the mixture was filtered to obtain salicylate crystalline form VIII-A. At 0° C., approximately 25 mg of API was weighed out and THF (0.5 mL) was added, followed by 1.2 equivalents of salicylic acid. The mixture was reacted at 50° C. under magnetic stirring for 3 hours and then cooled to room temperature. After reacting overnight, the mixture was filtered to obtain salicylate crystalline form VIII-B. At 0° C., approximately 25 mg of API was weighed out and DCM:MeOH (0.5 mL) was added followed by 1.2 equivalents of salicylic acid. The mixture was reacted at 50° C. under magnetic stirring for 3 hours and then cooled to room temperature. After reacting overnight, the mixture was filtered to obtain salicylate crystalline form VIII-C. Various characterizations were performed on each of the crystalline forms, the XRPD data of which are shown in Tables 15-17, and the analysis revealed that there were chemical shift deviations in the NMR spectra, which indicated that the free base had undergone a salt formation reaction. [Table 16] [Table 17] [Table 18]

[0064] Example 9: Preparation of Hydrochloride Crystalline Forms IX-A, IX-B, IX-C, IX-D, IX-E, and IX-F At 0° C., approximately 25 mg of API was weighed out and ethanol (0.5 mL) was added, followed by 1.2 equivalents of hydrochloric acid. The mixture was reacted under magnetic stirring at 50° C. for 3 hours and then cooled to room temperature. After reacting overnight, the mixture was filtered to obtain hydrochloride crystalline form IX-A. At 0° C., approximately 25 mg of API was weighed out and tetrahydrofuran (0.5 mL) was added, followed by 1.2 equivalents of hydrochloric acid. The mixture was reacted at 50° C. under magnetic stirring for 3 hours and then cooled to room temperature. After reacting overnight, the mixture was filtered to obtain hydrochloride crystalline form IX-B. At 0° C., approximately 25 mg of API was weighed out and ethyl formate (0.5 mL) was added, followed by 1.2 equivalents of hydrochloric acid. The mixture was reacted at 50° C. under magnetic stirring for 3 hours and then cooled to room temperature. After reacting overnight, the mixture was filtered to obtain hydrochloride crystalline form IX-C. At 0° C., approximately 25 mg of API was weighed and DCM:MeOH (1:1) (0.5 mL) was added, followed by 1.2 equivalents of hydrochloric acid. The mixture was reacted at 50° C. under magnetic stirring for 3 hours and then cooled to room temperature. After reacting overnight, the mixture was filtered to obtain hydrochloride crystalline form IX-D. At 0° C., approximately 25 mg of API was weighed and tetrahydrofuran (1:1) (0.5 mL) was added, followed by 2.2 equivalents of hydrochloric acid. The mixture was reacted at 50° C. under magnetic stirring for 3 hours, then cooled to room temperature. After reacting overnight, the mixture was filtered to obtain hydrochloride crystalline form IX-E. At 0° C., approximately 25 mg of API was weighed and tetrahydrofuran (1:1) (0.5 mL) was added, followed by 4.0 equivalents of hydrochloric acid. The mixture was reacted under magnetic stirring at 50° C. for 3 hours and then cooled to room temperature. After reacting overnight, the mixture was filtered to obtain hydrochloride crystalline form IX-F. The crystalline form was subjected to various characterizations. The analytical results showed that there were chemical shift deviations in the NMR spectrum, which indicated that the free base had undergone a salt formation reaction. The XRPD data are shown in Tables 18 to 23.

[0065] From the DSC results, hydrochloride crystalline form IX-A, IX-B, and IX-D all have two endothermic peaks, which may be mixed crystals. According to the DSC and TGA results of hydrochloride crystalline form IX-C and hydrochloride crystalline form IX-E, the melting point of hydrochloride crystalline form IX-C is 270.82°C, and the weight loss before 230°C is 7.826%. The melting point of hydrochloride crystalline form IX-E is 289.17°C, and the weight loss before 230°C is 8.507%. According to the DSC results, the XRPD of hydrochloride crystalline form IX-E was examined after heating to 250°C, and the XRPD of hydrochloride crystalline form IX-F was examined after heating to 200°C. The results show that both hydrochloride crystalline form IX-E and hydrochloride crystalline form IX-F changed after the solvent removal treatment, which indicates that hydrochloride crystalline form IX-E and hydrochloride crystalline form IX-F may be solvates or hydrates. [Table 19] [Table 20] [Table 21] [Table 22] [Table 23] [Table 24]

[0066] Example 10: Repeated preparation of advantageous crystal forms Salt crystalline forms were repeatedly prepared using phosphoric acid, malic acid and methanesulfonic acid as ligands.

[0067] About 30mg of API was weighed out and solvent was added, then an appropriate amount of ligand was weighed out and added. The molar ratio of API to ligand was 1:1.2, and the reaction process was carried out at 0°C. The mixture was reacted at 50°C under magnetic stirring for 3 hours, and then cooled to room temperature. After overnight reaction, the solid sample obtained was filtered and analyzed. [Table 25]

[0068] Malate crystalline form VII-A can be stably prepared, and DSC and TGA characterization results showed that it has a high melting point of about 170° C. Therefore, the scale-up of malate crystalline form VII-A and its subsequent solubility and stability were evaluated.

[0069] 10.1. Scale-up preparation of malate crystalline form VII-A About 400mg of free base A was weighed into a round bottom flask and 8ml of ethyl formate was added. 1.2 equivalents of malic acid was weighed and added at 0°C. The mixture was reacted at 50°C for 3 hours under magnetic stirring and then cooled to room temperature. After overnight reaction and filtration, the obtained solid sample was dried at 50°C overnight and then subjected to various characterizations. According to the characterization results, malate crystalline form VII-A can be obtained stably.

[0070] 10.2. Stability A certain amount of API and malate crystalline form VII-A were weighed into liquid vials to prepare a total of nine batches. The nine batches were separately placed at 80°C (open), 25°C, 60% RH (open), 40°C, 75% RH (open) and in a light stability box (closed). The stability was tested at 80°C for 1 day, light exposure for 10 days, and at 25°C, 60% RH and 40°C, 75% RH for 1 week and 2 weeks, and the XRPD of the solids was measured. Under light exposure and 40°C, 75% RH conditions, both free base form A and malate crystalline form VII-A decomposed to various extents. [Table 26]

[0071] 10.3. Solubility Approximately 10 mg of malate crystal form VII-A and free base form A were weighed separately, and 1 ml of buffers with different pH were added to supersaturate the solutions, and stirred at 37° C. for 2 hours and 24 hours. The samples were filtered, and the concentration and pH value of the filtrate were measured and determined, and XRPD was performed on the remaining solid. The specific results were as follows: [Table 27]

[0072] Example 11: Preparation of Free Base Crystalline Form B Suspension crystallization method: Approximately 25 mg of API was weighed into a glass bottle, and EtOH (1 mL) was added to prepare a suspension. The suspension was placed at 25° C. and suspended and stirred for 3 days and / or 7 days, respectively, and then filtered to obtain the free base crystalline form B.

[0073] Approximately 25 mg of API was weighed into a glass bottle, and EtOH (1 mL) was added to prepare a suspension. The suspension was placed under 50° C. conditions, suspended and stirred for 3 days and / or 7 days, respectively, and then filtered to obtain the free base crystalline Form B.

[0074] Gas-Liquid Diffusion: A certain amount of API was weighed into a liquid vial and dissolved with a good solvent (NPA) to a concentration of 50 mg / mL. The vial was placed in the open position and placed into a large flask containing a poor solvent (ACN) of 30 mL. The flask was sealed with a lid and left at room temperature for a week to obtain the free base crystalline Form B.

[0075] Gas-Solid Diffusion: A suitable amount of API solid was collected in a liquid vial, the vial was placed in an open position and placed in a large 30 mL flask containing ethyl formate. The large flask was sealed and left at room temperature for 7 days to obtain the free base crystalline Form B.

[0076] Slow evaporation: Based on the solubility results, a certain amount of API was weighed into a liquid vial and dissolved clear by adding THF:MIBK (1:1).The vial was then placed at room temperature and the solvent (N2 protection) was slowly evaporated to obtain the free base crystalline Form B.

[0077] Dissolution crystallization: A certain amount of API was weighed into a 4 mL glass bottle, and the good solvent NPA (0.3 mL) was added to dissolve it, and the concentration was 66.7%. Then 0.9 mL of poor solvent ACN (EA) was quickly added, and the free base crystalline form B was obtained after stirring under magnetic force overnight and filtration.

[0078] A certain amount of API was weighed into a 4 mL glass bottle, and the good solvent THF (1 mL) was added to dissolve it, and the concentration was 20%. Then, 3 mL of poor solvent n-heptane (IPAC / MTBE) was quickly added, and the mixture was stirred under magnetic force overnight, and then filtered to obtain the free base crystalline form B.

[0079] Various characterizations were performed on each of the crystalline forms. The XRPD data are shown in Table 27. The TGA pattern showed that Form B had two stages of weight loss, the first stage being 4.478% and the second stage being 0.577%, and the DSC pattern showed two endothermic peaks, suggesting that Form B was a hydrate. The melting onset temperatures were 99.38° C. and 227.13° C., respectively, the peak temperatures were 118.25° C. and 228.55° C., respectively, and the enthalpy values ​​were 63.092 J / g and 76.592 J / g, respectively. [Table 28]

[0080] Example 12: Preparation of Free Base Crystalline Form C Suspension crystallization method: Approximately 25 mg of API was weighed into a glass bottle, and THF (1 mL) was added to prepare a suspension. The suspension was placed at 25° C. and stirred for 3 days and / or 7 days, respectively, and then filtered to obtain the free base crystalline form C.

[0081] Approximately 25 mg of API was weighed into a glass bottle, and IPA (1 mL) was added to prepare a suspension. The suspension was placed under 50° C. conditions and stirred for 3 days and / or 7 days, respectively, and then filtered to obtain the free base crystalline form C.

[0082] Gas-solid diffusion: An appropriate amount of API solid was weighed into a liquid vial, the vial was left open and placed into a 30 mL large flask containing THF. The large flask was sealed and left at room temperature for 7 days to obtain the free base crystalline Form C.

[0083] Slow evaporation: Based on the solubility results, a certain amount of API was weighed into a liquid vial and dissolved in THF to a clear solution.The solvent was then slowly evaporated at room temperature (under N2 protection) to obtain the free base crystalline Form C.

[0084] Various characterizations were performed on the crystalline form, and its XRPD data is shown in Table 28. The TGA pattern showed that Form C had a weight loss of 5.580% before 150° C., and the DSC pattern showed two endothermic peaks, suggesting that Form C had hydrated. The melting onset temperatures were 106.30° C. and 226.16° C., respectively, the peak temperatures were 120.04° C. and 228.10° C., respectively, and the enthalpy values ​​were 34.713 J / g and 79.591 J / g, respectively. [Table 29]

[0085] Example 13: Preparation of Free Base Crystalline Form D Suspension crystallization method: Approximately 25 mg of API was weighed into a glass bottle, and ACN (1 mL) was added to prepare a suspension. The suspension was placed at 25°C and stirred for 3 days and / or 7 days, respectively, and then filtered to obtain the free base crystalline form D.

[0086] Slow evaporation: Based on the solubility results, a certain amount of API was weighed into a liquid phase vial and dissolved clear by adding THF:MTBE (1:1).The vial was then placed at room temperature and the solvent was slowly evaporated (under N2 protection) to obtain the free base crystalline form D.

[0087] Dissolution crystallization: A certain amount of API was weighed into a 4 mL glass bottle, and dissolved in good solvent DCM:IPA (1:1) (0.6 mL) to a concentration of 33.3%, then 1.8 mL of poor solvent n-heptane was quickly added, stirred under magnetic force overnight, and filtered to obtain the free base crystalline form D.

[0088] Various characterizations were performed on the crystalline form, and its XRPD data is shown in Table 29. The TGA pattern showed that Form D had a weight loss of 5.817% before 150° C., and the DSC pattern showed three endothermic peaks and one exothermic peak, suggesting that Form D underwent a crystalline transition process during heating. [Table 30]

[0089] Example 14: Preparation of Free Base Crystalline Form E Suspension crystallization method: Approximately 25 mg of API was weighed into a glass bottle, and anisole (1 mL) was added to prepare a suspension. The suspension was placed at 25° C. and stirred for 3 and / or 7 days, and then filtered to obtain the free base crystalline form E.

[0090] Approximately 25 mg of API was weighed into a glass bottle, and DMSO (1 mL) was added to prepare a suspension. The suspension was placed under 50° C. conditions and stirred for 3 and / or 7 days, and then filtered to obtain the free base crystalline form E.

[0091] Various characterizations were performed on the crystalline form, the XRPD data of which is shown in Table 30, the TGA pattern showed that Form E had a weight loss of 18.075% before 150° C., and the DSC pattern showed three endothermic peaks, indicating the presence of solvent or water in Form E. [Table 31]

[0092] Example 15: Preparation of Free Base Crystalline Form F Gas-Liquid Diffusion: A certain amount of API was weighed into a liquid vial and dissolved by adding a good solvent (DMF) to a concentration of 10 mg / mL. The vial was placed in an open position and placed into a large flask containing a poor solvent (water) of 30 mL. The flask was sealed with a lid and left at room temperature for a week to obtain the free base crystalline Form F.

[0093] Gas-solid diffusion: An appropriate amount of API solid was taken and added to a liquid vial, the vial was left open and placed into a large flask containing 30 mL of ethanol. The flask was sealed and left at room temperature for 7 days to obtain the free base crystalline Form F.

[0094] Various characterizations were performed on the crystalline form, and its XRPD data is shown in Table 31. The TGA pattern showed that Form F had a weight loss of 4.796% before 220° C., and the DSC pattern showed one endothermic peak, which suggested that Form F had become a hydrate. The melting onset temperature was 228.76° C., the peak temperature was 229.65° C., and the enthalpy value was 55.214 J / g. [Table 32]

[0095] Example 16: Preparation of Free Base Crystalline Form G Gas-Liquid Diffusion: A certain amount of API was weighed into a liquid vial and dissolved by adding a good solvent (NPA) to a concentration of 50 mg / mL. The vial was placed in the open position and placed into a large flask containing a poor solvent (MeOH) of 30 mL. The flask was sealed with a lid and left at room temperature for a week to obtain the free base crystalline Form G.

[0096] Slow evaporation: Based on the solubility results, a certain amount of API was weighed into a liquid vial and dissolved clear by adding MeOH. The vial was then placed at room temperature and the solvent was slowly evaporated (under N2 protection) to obtain the free base crystalline Form G.

[0097] Dissolution crystallization: A certain amount of API was weighed into a 4 mL glass bottle, and dissolved in good solvent DCM:MeOH (1:1) (0.2 mL) to a concentration of 100%, then 0.6 mL of poor solvent MTBE was quickly added, stirred under magnetic force overnight, and filtered to obtain the free base crystalline form G.

[0098] Various characterizations were performed on the crystalline form, and its XRPD data is shown in Table 32. The TGA pattern showed that Form G had two stages of weight loss, the first stage being 1.645% and the second stage being 3.225%, and the DSC pattern showed two endothermic peaks, suggesting that Form G is a hydrate. The melting onset temperatures were 103.40° C. and 226.81° C., respectively, the peak temperatures were 124.31° C. and 228.18° C., respectively, and the enthalpy values ​​were 69.262 J / g and 80.651 J / g, respectively. [Table 33]

[0099] Example 17: Preparation of Free Base Crystalline Form H Gas-Liquid Diffusion: A certain amount of API was weighed into a liquid vial and dissolved by adding a good solvent (NPA) to a concentration of 50 mg / mL. The vial was placed in the open position and placed into a large flask containing a poor solvent (water) of 30 mL. The flask was sealed with a lid and left at room temperature for a week to obtain the free base crystalline Form H.

[0100] Various characterizations were performed on the crystalline form, and its XRPD data is shown in Table 33, the TGA pattern showed that Form H had a weight loss of 6.987% before 200° C., and the DSC pattern showed two endothermic peaks, suggesting that Form H was hydrated. [Table 34]

[0101] Example 18: Preparation of Free Base Crystalline Form I Gas-solid diffusion: An appropriate amount of API solid was taken and added to a liquid vial, the vial was left open and placed into a 30 mL large flask containing DCM. The large flask was sealed and left at room temperature for 7 days to obtain the free base crystalline Form I.

[0102] Various characterizations were performed on the crystalline form, and its XRPD data is shown in Table 34. The TGA pattern showed that Form I had a weight loss of 12.244% before 200° C., and the DSC pattern showed two endothermic peaks, which suggested that Form I was mixed crystal. The melting onset temperatures were 209.17° C. and 220.81° C., respectively, the peak temperatures were 217.16° C. and 224.35° C., respectively, and the enthalpy values ​​were 14.499 J / g and 33.294 J / g, respectively. [Table 35]

[0103] Example 19: Preparation of Free Base Crystalline Form J Gas-solid diffusion: An appropriate amount of API solid was taken and added to a liquid vial, the vial was left open and placed into a 30 mL large flask containing 1,4-dioxane. The flask was sealed and left at room temperature for 7 days to obtain the free base crystalline Form J.

[0104] Polymer derivatization: A certain amount of API was weighed into 0.5 mL of ethanol, and about 10% (by mass) of high polymer (20.88 mg) was added. The mixture was stirred at room temperature for 24 hours and then filtered to obtain the free base crystalline Form J.

[0105] Cooling Crystallization: 11.13 mg excess of API solid was added to 1 mL of 1,4-dioxane and dissolved clear at 50° C., then filtered to remove undissolved material. The filtrate was slowly cooled from 50° C. to 0° C. at a rate of 0.1° C. / min and kept at 0° C. for 10 hours. If no solid separated, the filtrate was continued to cool to −10° C. to obtain the free base crystalline Form J.

[0106] Various characterizations were performed on the crystalline form, and its XRPD data is shown in Table 35, the TGA pattern shows that Form J has two stages of weight loss, the first stage weight loss is 3.699% and the second stage weight loss is 3.272%, and the DSC pattern shows three endothermic peaks and one exothermic peak, indicating that Form J undergoes a crystalline transition process during heating. [Table 36]

[0107] Example 20: Preparation of Free Base Crystalline Form K Suspension crystallization method: Approximately 25 mg of API was weighed and added to a glass bottle, and IPA:ACN (1:1) (1 mL) was added to prepare a suspension. The suspension was placed at 50°C and stirred for 7 days, and then filtered to obtain the free base crystalline form K.

[0108] Various characterizations were performed on the crystalline form, and its XRPD data is shown in Table 36. The TGA pattern showed that Form K had a weight loss of 4.482% before 150° C., and the DSC pattern showed two endothermic peaks, suggesting that Form K had become a hydrate. The melting onset temperatures were 102.50° C. and 227.25° C., respectively, the peak temperatures were 115.47° C. and 228.34° C., respectively, and the enthalpy values ​​were 39.929 J / g and 80.766 J / g, respectively. [Table 37]

[0109] Example 21: Preparation of Free Base Crystalline Form L Slow evaporation: Based on the solubility results, a certain amount of API was weighed into a liquid vial and dissolved in DCM to clear.Then the vial was placed at room temperature and the solvent was evaporated slowly (under N2 protection) at room temperature to obtain the free base crystalline Form L.

[0110] Dissolution crystallization: A certain amount of API was weighed into a 4 mL glass bottle and dissolved in good solvent DCM:IPA (1:1) (0.6 mL) to a concentration of 33.3%. Then 1.8 mL of poor solvent CYH was quickly added, and the mixture was stirred under magnetic force overnight and then filtered to obtain the free base crystalline form L.

[0111] Cooling Crystallization: 22.27 mg excess API solid was added to 1 mL THF and dissolved clear at 50° C., then filtered to remove undissolved material. The filtrate was slowly cooled from 50° C. to 0° C. at a rate of 0.1° C. / min and kept at 0° C. for 10 hours. If no solid separated, the filtrate was continued to cool to −10° C. to obtain the free base crystalline Form L.

[0112] An excess of 51.95 mg of API solid was added to 0.5 mL of DCM and dissolved clear at 50° C., then filtered to remove undissolved material. The filtrate was slowly cooled from 50° C. to 0° C. at a rate of 0.1° C. / min and kept at 0° C. for 10 hours. If no solid separated, the filtrate was continued to be cooled to −10° C. to obtain the free base crystalline Form L.

[0113] Various characterizations were performed on the crystalline form, and its XRPD data is shown in Table 37, and the DSC pattern showed two endothermic peaks, suggesting that Form L was a hydrate. The melting onset temperatures were 109.88° C. and 225.72° C., respectively, the peak temperatures were 123.96° C. and 227.56° C., respectively, and the enthalpy values ​​were 63.617 J / g and 69.833 J / g, respectively. [Table 38]

[0114] Example 22: Preparation of Free Base Crystalline Form M Dissolution crystallization: A certain amount of API was weighed into a 4 mL glass bottle, and the good solvent NPA (0.3 mL) was added to dissolve it, and the concentration was 66.7%. Then 0.9 mL of poor solvent water was quickly added, and the mixture was stirred under magnetic force overnight and then filtered to obtain the free base crystalline form M.

[0115] Various characterizations were performed on the crystalline form, the XRPD data is shown in Table 38, and the TGA pattern showed that Form M had a weight loss of 10.717% before 150° C., which was assumed to be a solvate / hydrate. [Table 39]

[0116] Example 23: Preparation of Free Base Crystalline Form N Dissolution crystallization: A certain amount of API was weighed into a 4 mL glass bottle, and the good solvent NPA (0.3 mL) was added to dissolve it, and the concentration was 66.7%. Then 0.9 mL of the poor solvent DMSO was quickly added, and the mixture was stirred under magnetic force overnight and then filtered to obtain the free base crystalline form N.

[0117] Various characterizations were performed on the crystalline form, the XRPD data is shown in Table 39, and the TGA pattern showed that Form N had two stages of weight loss, the first stage being 7.259% and the second stage being 2.932%, which was assumed to be a solvate / hydrate. [Table 40]

[0118] Example 24: Preparation of Free Base Crystalline Form O Dissolution crystallization: A certain amount of API was weighed into a 4 mL glass bottle, and the good solvent NPA (0.3 mL) was added to dissolve it, and the concentration was 66.7%. Then 0.9 mL of the poor solvent acetone was quickly added, and the mixture was stirred under magnetic force overnight and then filtered to obtain the free base crystalline form O.

[0119] Various characterizations were performed on the crystalline form, and its XRPD data is shown in Table 40. The TGA pattern showed that Form O had a weight loss of 8.095% before 150° C., and the DSC pattern showed two endothermic peaks, suggesting that Form O was hydrated. The melting onset temperatures were 100.07° C. and 226.17° C., respectively, the peak temperatures were 113.53° C. and 227.77° C., respectively, and the enthalpy values ​​were 41.053 J / g and 76.278 J / g, respectively. [Table 41]

[0120] Example 25: Preparation of Free Base Crystalline Form P Dissolution crystallization: A certain amount of API was weighed into a 4 mL glass bottle and dissolved by adding good solvent DCM:MeOH (1:1) (0.2 mL) to reach a concentration of 66.7%. Then 0.6 mL of poor solvent EA was quickly added, and the mixture was stirred under magnetic force overnight and then filtered to obtain the free base crystalline Form P.

[0121] Various characterizations were performed on the crystalline form, and its XRPD data is shown in Table 41. The TGA pattern showed that Form P had two stages of weight loss, the first stage being 3.554% and the second stage being 0.751%, and the DSC pattern showed two endothermic peaks, suggesting that Form P was hydrated. The melting onset temperatures were 96.55° C. and 225.42° C., respectively, the peak temperatures were 115.25° C. and 227.56° C., respectively, and the enthalpy values ​​were 49.897 J / g and 79.541 J / g, respectively. [Table 42]

[0122] Example 26: Preparation of Free Base Crystalline Form Q Cooling Crystallization: An excess of 11.88 mg of API solid was added to 0.5 mL of ethanol and dissolved clear at 50° C., then filtered to remove undissolved material. The filtrate was slowly cooled from 50° C. to 0° C. at a rate of 0.1° C. / min and kept at 0° C. for 10 hours. If no solid separated, the filtrate was continued to cool to −10° C. to obtain the free base crystalline Form Q.

[0123] The crystalline form was subjected to various characterizations and its XRPD data is shown in Table 42. [Table 43]

[0124] Example 27: Preparation of Free Base Crystalline Form R The free base crystalline forms BQ prepared above were heated to 200° C., and all the crystalline forms were converted into the same crystalline form, which was named free base crystalline form R, and the area of ​​its XRPD data was shown in FIG. 41. [Table 44]

[0125] Example 28: Preparation of Free Base Crystalline Form S 1 g of API solid was added to a mixture of 10 mL of ethanol and 2 mL of water, and the mixture was heated to 50° C. and stirred while maintaining the temperature. 961 mg of trifluoroacetic acid was added to the solution and stirred to dissolve the API solid. After filtration, the filtrate was stirred at 45° C. Sodium carbonate solution was added to the solution until it became slightly turbid and the addition was stopped. The solution was stirred for 2 hours while maintaining the temperature at 45° C. The solution was continuously added dropwise to sodium carbonate solution and maintained at 40° C. for 1 hour. The solution was slowly cooled to 5° C. and stirred while maintaining the temperature overnight, then the solid was filtered and dried to obtain the free base crystalline form S.

[0126] The crystalline form was subjected to various characterizations and its XRPD data is shown in Table 44. [Table 45]

[0127] Example 29: Preparation of Free Base Crystalline Form T 90 g of API solid was added to 4.5 L of water, and 71.42 g of trifluoroacetic acid was added at room temperature. After filtration, the filtrate was placed at 40° C. and stirred while maintaining the temperature. The pH of the solution was adjusted to 7-8 using sodium carbonate solution to make the solution slightly turbid and the addition was stopped. The solution was stirred for 2 hours while maintaining the temperature at 40° C. The sodium carbonate solution was continuously added dropwise to the solution and maintained at 40° C. for 1-2 hours. The solution was slowly cooled to 5° C. and stirred while maintaining the temperature for 1-2 hours, then filtered and dried to obtain the free base crystalline form T.

[0128] Various characterizations were performed on the crystalline forms and their XRPD data are presented in Table 45. [Table 46]

[0129] Example 30: Scale-up of free base crystalline form B Approximately 250 mg of API was weighed into a 4 ml glass vial and 2.5 ml of ethyl acetate was added. The mixture was stirred overnight at 50° C. under magnetic stirring, cooled to room temperature, filtered, and the solid obtained was dried overnight in a 50° C. oven under vacuum. The solid obtained was free base crystalline form B. Various characterizations were performed on free base crystalline form B. The results showed that the scale-up free base crystalline form B was consistent with Example 11. The TGA pattern showed that form A had two stages of weight loss, with the first stage weight loss being 4.837% and the second stage weight loss being 0.998%, and the DSC pattern showed two endothermic peaks with melting onset temperatures of 105.17° C. and 223.07° C., respectively, and peak temperatures of 122.82° C. and 226.67° C., respectively. The DVS results showed that Form A was slightly hygroscopic with a 1.05% increase in water uptake weight at 80% RH humidity, a significant improvement compared to the API, which had a 11.12% increase in water uptake weight at 80% RH humidity. The crystalline form of Form B did not change before and after the DVS test.

[0130] Example 31: Competitive Slurrying A saturated solution of API (free base Form A) in DCM and water was prepared. Approximately 10 mg of API (free base Form A) and free base crystalline form B were weighed into a 4 ml glass bottle, and 1 mL of saturated solvent was added. The mixture was stirred at 50° C. for 3 and 7 days, and filtered. XRPD test was performed on the obtained solid. The results show that the solid crystalline form obtained by competitively slurrying API and Form B in DCM for 3 days tends to be close to Form L, but this crystalline form was not considered later because it became oily after beating treatment for 5 days. The crystalline form obtained by competitively slurrying in water for 3 days was a mixed crystal of Form B and API. [Table 47]

[0131] Example 32: Solubility and Stability Evaluation of Free Base Crystalline Form B 32.1. Solubility Approximately 10 mg of Form B sample was weighed, 1 ml of buffers with different pH were added, and the mixture was stirred at 37° C. for 2 and 24 hours. The samples were filtered, and the concentration and pH value of the filtrate were measured and determined, and XRPD test was performed on the remaining solid. The results showed that Form B was soluble at more than 10 mg / ml in pH 1.2, pH 3.0, pH 4.5, FeSSIF, and SGF buffers. In pH 6.8, pH 7.4, FaSSIF, and water, the solubility was improved compared to the API, and the crystalline form remained unchanged in the buffers. [Table 48]

[0132] 32.2. Stability A certain amount of crystalline form B was weighed into a liquid vial to prepare a total of nine batches. The nine batches were separately placed at 80°C, 25°C, 60% RH, 40°C, 75% RH and light stability boxes. Chemical stability at 80°C for 1 day and 10 days of light exposure, and at 25°C, 60% RH and 40°C, 75% RH for 1 week and 2 weeks was tested using liquid chromatography and solid-state XRPD. Specific results are shown below. The results showed that form B has good physical and chemical stability under various conditions. [Table 49]

[0133] Example 33. Solubility of Crystalline Form T Approximately 60 mg of sample was weighed into a 4 mL bottle and 2 mL of different solvents (water, pH 1.0, 3.0, 5.0, 7.0, 9.0, FaSSIF, FeSSIF and SGF) were added and the mixture was stirred at 37° C. for 24 hours after adding a magnetic stir bar. Samples were taken at 2 hours and 24 hours respectively. The sample concentration in the filtrate was tested by HPLC after filtration and the pH value of the filtrate and XRPD of the remaining solid were also measured. The solubility of the samples measured in various solutions was as follows:

[0134] The results showed that the solubility of the samples at 2 and 24 hours at 37°C was similar, and the solubility of the samples gradually decreased with increasing pH of the solution. The solubility in pH 1.0, pH 3.0, FeSSIF and SGF was high, all higher than 18 mg / mL, the solubility in pH 5.0 was slightly higher, about 8 mg / mL, and the solubility in water, pH 7.0, pH 9.0 and FaSSIF was relatively low, all lower than 0.7 mg / mL. Compared with the initial pH values ​​of the buffer solutions, the pH values ​​in pH 1.0, pH 3.0, pH 5.0, FeSSIF and SGF showed significant changes. In other solvents, the pH of the solution did not change much, and the crystal form did not change. [Table 50]

[0135] All documents mentioned in the present invention are incorporated by reference herein as if each document was individually incorporated by reference. Furthermore, it should be understood that after reading the above teachings of the present invention, a person skilled in the art may make various modifications or changes to the present invention, and the equivalents thereof are also included in the scope defined by the appended claims of this application.

Claims

1. A crystalline form of the compound of formula I, Formula I: 【Chemistry 1】 The crystalline form is a free base crystalline form T, the free base crystalline form T having characteristic X-ray powder diffraction peaks at 20.644°±0.2°, 17.233°±0.2°, 23.479°±0.2°, 15.867°±0.2°, and 20.091°±0.2°.

2. The crystalline forms are as follows: 15.505°±0.2°, 26.036°±0.2°, 19.457°±0.2°, 14.223°±0.2°, 25.043°±0.2°, 16.205°±0.2°, 23.143°±0.2°, 11.843°±0.2°, 9.973°±0.2°, 14.944°±0.2°, 18.921°±0.2°, 26.36°±0.2°, 8.85°±0.2°, 17 ...17.223°±0.2°, 17.223°±0.2°, 17.223°±0. 8°±0.2°, 17.69°±0.2°, 22.069°±0.2°, 12.867°±0.2°, 18.428°±0.2°, 5.403°±0.2°, 26.675°±0.2°, 10.788°±0.2°, 22.412°±0.2°, 27.533°±0.2°, 24.211°±0.2°, 32.856°±0.2°, 12.351°±0.2°, 27.3 21°±0.2°, 40.066°±0.2°, 35.91°±0.2°, 29.079°±0.2°, 31.878°±0.2°, 36.087°±0.2°, 37.559°±0.2°, 21.598°±0.2°, 28.468°±0.2°, 11.168°±0.2°, 34.799°±0.2°, 40.437°±0.2°, 30.249°±0.2°, 33 and optionally further having one or more (e.g., 2, 3, 5, 8, or 10) characteristic powder X-ray diffraction peaks selected from the group consisting of: 551°±0.2°, 34.06°±0.2°, 7.753°±0.2°, 30.809°±0.2°, 35.509°±0.2°, 38.988°±0.2°, 29.487°±0.2°, and 38.282°±0.2°; The crystalline form of claim 1.

3. The free base crystalline Form T has three endothermic peaks in the DSC region at 90-95°C, 115-120°C, and 220-225°C. The crystalline form of claim 1.

4. The free base crystalline form T has an enthalpy value of 50.223 J / g for the first endothermic peak in the DSC region, 51.492 J / g for the second endothermic peak in the DSC region, and 80.538 J / g for the third endothermic peak in the DSC region. The crystalline form of claim 1.

5. A crystalline form of the compound of formula I, Formula I: 【Chemistry 2】 The crystalline form is a free base crystalline Form B, the free base crystalline Form B having characteristic X-ray powder diffraction peaks at 19.31°±0.2°, 23.059°±0.2°, 25.888°±0.2°, 12.805°±0.2°, and 17.188°±0.2°.

6. The crystalline form is free base crystalline Form B, and the free base crystalline Form B has the following peaks: 14.464°±0.2°, 20.6°±0.2°, 18.446°±0.2°, 6.337°±0.2°, 29.3°±0.2°, 16.155°±0.2°, 8.937°±0.2°, 9.29°±0.2°, 23.545°±0.2°, 32.361°±0.2°, 23.932°±0.2°, 10.2 and optionally further having one or more (e.g., 2, 3, 5, 8, or 10) characteristic powder X-ray diffraction peaks selected from the group consisting of: 27°±0.2°, 39.324°±0.2°, 15.042°±0.2°, 26.791°±0.2°, 30.37°±0.2°, 21.132°±0.2°, 24.448°±0.2°, 27.831°±0.2°, and 36.599°±0.2°. The crystalline form of claim 5.

7. The DSC region of the crystalline form has two endothermic peaks at 115-120°C and 225-230°C. The crystalline form of claim 5.

8. The free base crystalline form B has an enthalpy value of 63.092 J / g for the first endothermic peak in the DSC region and 76.592 J / g for the second endothermic peak in the DSC region. The crystalline form of claim 5.

9. A crystalline form of the compound of formula I, Formula I: 【Chemistry 3】 The crystalline form is The salt crystalline forms IA, IB, and IC formed by the compound of formula I and paratoluenesulfonic acid; The salt crystalline forms II-A, II-B, and II-C formed by the compound of formula I and fumaric acid; The salt crystalline forms III-A, III-B, and III-C formed by the compound of formula I and methanesulfonic acid; A salt crystalline form IV-A formed by the compound of formula I and phosphoric acid; The salt crystalline forms VA and VB formed by the compound of formula I and maleic acid; The salt crystalline form VI-A formed by the compound of formula I and citric acid; A salt crystalline form VII-A formed by the compound of formula I and malic acid; Crystalline salt forms VIII-A, VIII-B, and VIII-C formed by the compound of formula I and salicylic acid; selected from the group consisting of salt crystalline forms IX-A, IX-B, IX-C, IX-D, IX-E, and IX-F formed by the compound of formula I and hydrochloric acid; Alternatively, the crystalline form is a free base crystalline form selected from the group consisting of Form A, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, Form M, Form N, Form O, Form P, Form Q, Form R, and Form S.

10. A process for preparing the crystalline form of claim 1, comprising the steps of: the crystalline form is Form T, and the method comprises: (i) dissolving the free base Form A in a fifth solvent, adding trifluoroacetic acid and filtering; (ii) maintaining the filtrate at 35-45° C. for 1-2 hours and then adjusting the pH of the filtrate to 7-8; (iii) keeping the filtrate at 35 to 45° C. for 1 to 3 hours, continuously dropping an alkaline solution thereinto, and then continuously keeping the filtrate at 35 to 45° C. for 1 to 3 hours; and (v) slowly cooling the filtrate to 0-10° C., incubating and stirring for 1-3 hours, thereby obtaining the free base crystalline Form T.

11. A process for preparing the crystalline form of claim 5, comprising the steps of: The method includes any one of steps (a), (b), (c), (d) and (e) of a preparation method: (a) Suspension crystallization method: dissolving free base Form A in a first solvent to prepare a suspension, then placing at 25° C. to 50° C., optionally stirring the suspension, and then filtering to obtain said free base crystalline Form B; (b) Gas-liquid diffusion: dissolving free base Form A in a liquid vial containing a first good solvent, then keeping the liquid vial open, placing it in a large flask containing a first poor solvent, sealing the large flask, and allowing to stand at room temperature for one week to obtain the free base crystalline Form B; (c) Gas-solid diffusion: Free base Form A is placed in a liquid vial, which is then kept open and placed in a larger flask containing a third solvent, the large flask is sealed and allowed to stand at room temperature for one week to obtain the free base crystalline Form B. (d) Slow Volatilization: Free base Form A is placed in a liquid vial and a fourth solvent is added until it dissolves clearly, then the solution is cooled to room temperature (N ２ and slowly evaporating the solvent under reduced pressure (under protection) to obtain the free base crystalline Form B. (e) Dissolution crystallization: Free base Form A is placed in a vial, dissolved by adding a second good solvent, quickly adding a second poor solvent, stirring overnight, and then filtering to obtain free base crystalline Form B.

12. When the method employs step (a), the first solvent is selected from the group consisting of EtOH, IPA, MTBE, EA, heptane, IPAC, ethyl formate, anisole, MIBK, a mixture of IPA and ACN, DMSO and H ２ Mixture of EtOH and H ２ and a mixture of the solvents with O; When the temperature is 25° C., the first solvent is EtOH, IPA, MTBE, EA, IPAC, ethyl formate, MIBK, a mixed solvent of IPA and ACN, and a mixed solvent of DMSO and H ２ and a mixture of the solvents with O; When the temperature is 50° C., the first solvent is EtOH, MTBE, EA, heptane, IPAC, ethyl formate, MIBK, anisole, DMSO and H ２ Mixture of EtOH and H ２ and a mixture of the solvents with O; When the method employs step (b), the first good solvent is NPA and the first poor solvent is selected from the group consisting of ACN, acetone, EA, and combinations thereof; When the process employs step (c), the third solvent is ethyl formate; When the method employs step (d), the fourth solvent is THF, MIBK, and combinations thereof; When the method employs step (e), the second good solvent is selected from the group consisting of THF, NPA, and combinations thereof, and the second poor solvent is selected from the group consisting of ACN, EA, IPAC, MTBE, n-heptane, and combinations thereof. The preparation method according to claim 11.

13. 1. A pharmaceutical composition comprising:

10. A pharmaceutical composition comprising: (a) the crystalline form according to any one of claims 1 to 9 as an active ingredient; and (b) a pharma- ceutically acceptable carrier.

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