Crystal forms and application of pan-KIT kinase inhibitor compound and salt thereof

Abstract

The invention relates to a pan-KIT kinase inhibitor compound and a crystal form and application of salt of the pan-KIT kinase inhibitor compound. The invention relates to a polymorphic form of N-(4-((6, 7-dimethoxyquinoline-4-yl) oxy) phenyl)-2-(4-chloro-3-(trifluoromethyl) phenyl)-acetamide and tartrate thereof, a pharmaceutical composition and application of the polymorphic form and the pharmaceutical composition.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, and in particular to the crystal form of a pan-KIT kinase inhibitor compound, the crystal form of its salts, and the applications of these crystal forms. Background Technology

[0002] Chinese patent application CN111303024A discloses a class of pan-KIT kinase inhibitors and methods and uses thereof for treating, preventing or improving diseases, disorders or conditions regulated or affected by wild-type KIT and / or mutant KIT kinase activity or involving wild-type KIT and / or mutant KIT kinase activity.

[0003] As a type of pan-KIT kinase inhibitor compound, "N-(4-((6,7-dimethoxyquinoline-4-yl)oxy)phenyl)-2-(4-chloro-3-(trifluoromethyl)phenyl)-acetamide" with the structure of Formula I is known to have strong anti-proliferative activity against human gastrointestinal stromal tumor cell lines with different c-KIT mutations.

[0004]

[0005] In practical applications, the study of salt forms and crystal forms of active compounds plays a crucial role in drug development. Different salt forms or crystal forms of the same drug exhibit significant differences in physicochemical and biological properties. To better control drug quality and meet the requirements of formulation, production, storage, and transportation, there is a consistent need to develop salt forms and / or crystal forms with favorable properties for active compounds. Summary of the Invention

[0006] The purpose of this invention is to provide a polymorph of the salt of “N-(4-((6,7-dimethoxyquinoline-4-yl)oxy)phenyl)-2-(4-chloro-3-(trifluoromethyl)phenyl)-acetamide” (hereinafter referred to as “Compound I”) with improved solubility, stability, pharmacokinetics and bioavailability.

[0007] One aspect of the present invention is to provide a crystal form of a tartrate of formula I, wherein the tartrate is L-tartrate, D-tartrate, or DL-tartrate.

[0008]

[0009] In the X-ray powder diffraction patterns obtained using Cu-Kα radiation and expressed in terms of diffraction angle 2θ, the crystal form exhibits characteristic peaks at 2θ angles of 14.2±0.2°, 16.2±0.2°, 20.5±0.2°, 21.4±0.2°, and 22.6±0.2°.

[0010] Preferably, in the X-ray powder diffraction pattern obtained using Cu-Kα radiation and expressed in terms of diffraction angle 2θ, the crystal form also has a characteristic peak at at least one of 25.0±0.2° and 28.6±0.2°.

[0011] In some embodiments, the crystal form is crystal form α of D-tartrate.

[0012] In the X-ray powder diffraction patterns obtained using Cu-Kα radiation and expressed in terms of diffraction angle 2θ, the crystal form α of the D-tartrate exhibits characteristic peaks at 2θ angles of 14.2±0.2°, 16.2±0.2°, 20.5±0.2°, 21.4±0.2°, 22.6±0.2°, 25.0±0.2°, 25.5±0.2°, 26.1±0.2°, and 28.6±0.2°.

[0013] Preferably, in the X-ray powder diffraction pattern obtained using Cu-Kα radiation, the characteristic peak positions shown in the X-ray powder diffraction pattern of the α-crystal form are... Figure 25 The characteristic peaks shown are in basically the same position.

[0014] In the infrared spectrum, the α crystal form is at 3244±2 cm⁻¹. -1 3062±2cm -1 1730±2cm -1 1652±2cm -1 and 1479±2cm -1 The characteristic absorption peak is displayed at the wavenumber.

[0015] Preferably, in the infrared spectrum, the characteristic absorption peaks shown in the infrared spectrum of crystal form α are similar to... Figure 26 The characteristic absorption peaks shown are in basically the same position.

[0016] In some embodiments, the crystal form shows an endothermic peak at 220-221°C in differential scanning calorimetry.

[0017] Preferably, in the DSC spectrum, the endothermic peak shown by the DSC spectrum of the α-crystal form is similar to... Figure 27 Basically the same.

[0018] Another aspect of the present invention is to provide a crystal form B of a compound of formula I.

[0019]

[0020] In the X-ray powder diffraction patterns obtained using Cu-Kα radiation and expressed in terms of diffraction angle 2θ, crystal form B has characteristic peaks at 2θ angles of 11.4±0.2°, 14.3±0.2°, 15.1±0.2°, 17.1±0.2° and 19.1±0.2°.

[0021] Preferably, in the X-ray powder diffraction pattern obtained using Cu-Kα radiation, the crystal form B also has a characteristic peak at at least one of 19.9±0.2°, 23.3±0.2°, 24.7±0.2°, 25.3±0.2° and 26.7±0.2°.

[0022] More preferably, in the X-ray powder diffraction pattern obtained using Cu-Kα radiation, the characteristic peak positions shown in the X-ray powder diffraction pattern of crystal form B are similar to those of... Figure 3 The characteristic peaks shown are in basically the same position.

[0023] In some embodiments, crystal form B shows an endothermic peak at approximately 212°C in differential scanning calorimetry.

[0024] Another aspect of the present invention is to provide a pharmaceutical composition comprising the crystal form described above and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0025] Another aspect of the present invention is to provide the use of the above-described crystal form or the above-described pharmaceutical composition in the preparation of a medicament for treating cancer.

[0026] The cancer in question is a solid tumor or a hematologic malignancy.

[0027] The solid tumors are selected from: gastrointestinal stromal tumors, colorectal cancer, thyroid cancer, seminoma, dysgerminoma, mast cell tumors, lung cancer, bronchial cancer, testicular intraepithelial neoplasia, melanoma, breast cancer, neuroblastoma, malignant lymphoma, non-Hodgkin lymphoma, type 2 multiple endocrine neoplasia, pheochromocytoma, parathyroid hyperplasia / adenoma, colon cancer, colorectal adenoma, ovarian cancer, prostate cancer, glioblastoma, brain tumors, malignant glioma, pancreatic cancer, malignant pleural mesothelioma, angioblastoma, hemangioma, kidney cancer, liver cancer, adrenal cancer, bladder cancer, gastric cancer, rectal cancer, vaginal cancer, cervical cancer, endometrial cancer, multiple myeloma, and neck and head tumors.

[0028] The hematologic malignancies mentioned are selected from: myeloma, acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic neutrophilic leukemia, acute undifferentiated cell leukemia, degenerative large cell lymphoma, adult T-cell acute lymphoblastic leukemia, acute myeloid leukemia with tri-lineage spinal dysplasia, mixed lineage leukemia, spinal dysplasia syndrome, myelodysplastic syndrome, multiple myeloma, and spinal sarcoma.

[0029] The crystal forms of the Formula I compound and its salts prepared by the method of this invention can be identified and distinguished from other crystal forms using characteristic X-ray powder diffraction (XRPD) patterns, DSC curves, TGA curves, and Fourier transform-infrared spectroscopy (FT-IR). Through comprehensive comparison of the polymorphic samples of the obtained Formula I compound and its salts from the perspectives of solubility, hygroscopicity, and physicochemical stability, the tartrate salt crystal form of Formula I compound exhibits the best performance in terms of solubility, hygroscopicity, physicochemical stability, bioavailability, and pharmacokinetics, making this crystal form a promising candidate for drug development.

[0030] Other aspects and advantages of the invention will be readily apparent to those skilled in the art from the following detailed description. Only exemplary embodiments of the invention are shown and described in the following detailed description. As will be appreciated by those skilled in the art, the content of this invention enables them to make modifications to the disclosed specific embodiments without departing from the spirit and scope of the invention. Accordingly, the descriptions in the accompanying drawings and specification are merely exemplary and not restrictive. Attached Figure Description

[0031] The specific features of the invention are shown in the appended claims. The characteristics and advantages of the invention can be better understood by referring to the exemplary embodiments and accompanying drawings described in detail below. A brief description of the drawings is as follows:

[0032] Figure 1 The X-ray powder diffraction (XRPD) pattern of crystal form A of the compound of formula I obtained in Example 1;

[0033] Figure 2 The differential scanning calorimetry (DSC) spectrum of crystal form A of the compound of formula I obtained in Example 1;

[0034] Figure 3 The X-ray powder diffraction (XRPD) pattern of crystal form B of the compound of formula I obtained in Example 2;

[0035] Figure 4 The differential scanning calorimetry (DSC) spectrum of crystal form B of the compound of formula I obtained in Example 2;

[0036] Figure 5 The X-ray powder diffraction (XRPD) pattern of crystal form C of the compound of formula I obtained in Example 3;

[0037] Figure 6 The differential scanning calorimetry (DSC) spectrum of crystal form C of the compound of formula I obtained in Example 3;

[0038] Figure 7 The X-ray powder diffraction (XRPD) pattern of crystal form D of the compound of formula I obtained in Example 4;

[0039] Figure 8 The differential scanning calorimetry (DSC) spectrum of crystal form D of the compound of formula I obtained in Example 4;

[0040] Figure 9 The X-ray powder diffraction (XRPD) pattern of crystal form E of the compound of formula I obtained in Example 5;

[0041] Figure 10 The differential scanning calorimetry (DSC) spectrum of crystal form E of the compound of formula I obtained in Example 5;

[0042] Figure 11 The X-ray powder diffraction (XRPD) pattern of the hydrochloride salt of the compound of formula I obtained in Example 7;

[0043] Figure 12 The TGA / DSC spectrum of the hydrochloride salt of the compound of formula I obtained in Example 7;

[0044] Figure 13 The X-ray powder diffraction (XRPD) pattern of the hydrobromide of the compound of formula I obtained in Example 7;

[0045] Figure 14 The TGA / DSC spectrum of the hydrobromide of the compound of formula I obtained in Example 7;

[0046] Figure 15 The X-ray powder diffraction (XRPD) pattern of the benzenesulfonate of the compound of formula I obtained in Example 7;

[0047] Figure 16 The TGA / DSC spectrum of the benzenesulfonate of compound I obtained in Example 7;

[0048] Figure 17 The X-ray powder diffraction (XRPD) pattern of the maleate of the compound of formula I obtained in Example 7;

[0049] Figure 18The TGA / DSC spectrum of the maleate of the compound of formula I obtained in Example 7;

[0050] Figure 19 The X-ray powder diffraction (XRPD) pattern of the DL-tartrate of the compound of formula I obtained in Example 7;

[0051] Figure 20 The TGA / DSC spectrum of the DL-tartrate of the compound of formula I obtained in Example 7;

[0052] Figure 21 The X-ray powder diffraction (XRPD) pattern of the L-malate of the compound of formula I obtained in Example 7;

[0053] Figure 22 The TGA / DSC spectrum of the L-malate of the compound of formula I obtained in Example 7;

[0054] Figure 23 The X-ray powder diffraction (XRPD) pattern of the L-tartrate of the compound of formula I obtained in Example 7;

[0055] Figure 24 The TGA / DSC spectrum of the L-tartrate of the compound of formula I obtained in Example 7;

[0056] Figure 25 The X-ray powder diffraction (XRPD) pattern of the D-tartrate crystal form α of the compound of Formula I obtained in Example 9;

[0057] Figure 26 The infrared spectrum of the D-tartrate crystal form α of the compound of formula I obtained in Example 9;

[0058] Figure 27 The TGA / DSC spectrum of the D-tartrate crystal form α of the compound of Formula I obtained in Example 9;

[0059] Figure 28 The X-ray powder diffraction (XRPD) patterns of the D-tartrate α-micron powder of the compound shown in Formula I before and after processing. Detailed Implementation

[0060] The following specific embodiments illustrate the implementation of the present invention. Those skilled in the art can easily understand the advantages and effects of the present invention from the content disclosed in this specification.

[0061] Terminology Definition

[0062] In this invention, the term “N-(4-((6,7-dimethoxyquinoline-4-yl)oxy)phenyl)-2-(4-chloro-3-(trifluoromethyl)phenyl)-acetamide” with the chemical structural formula shown in Formula I is a class of pan-KIT kinase inhibitors.

[0063] The terms “polymorph,” “polymorphic product,” “crystal variation,” “crystal form,” “crystal variation,” “polymorphic form,” and “crystal form” as used in this invention are understood to be synonymous and refer to the solid crystalline form of a compound or complex, including but not limited to, single-component or multi-component crystals, and / or polymorphs, solvates, hydrates, inclusion compounds, eutectics, salts, solvates of salts, and hydrates of salts.

[0064] Polymorphs can be detected, identified, classified, and characterized using techniques well known to those skilled in the art, including, but not limited to: differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD), single-crystal X-ray diffraction, vibrational spectroscopy, solution calorimetry, solid-state nuclear magnetic resonance (SSNMR), Fourier transform-infrared spectroscopy (FT-IR), Raman spectroscopy, hot-stage optical microscopy, scanning electron microscopy (SEM), electron crystallography, as well as quantitative analysis, particle size analysis (PSA), surface area analysis, solubility, and dissolution rate. A polymorph can be described as the ability of a specific compound to crystallize in different crystalline forms while maintaining the same chemical structure. Polymorphs of a given substance are chemically equivalent, containing the same atoms bonded together in the same manner, but differing in their crystalline forms, which can affect one or more physical properties, such as dissolution rate, melting point, bulk density, stability, flow properties, etc. The graphical representation of such data can vary slightly (e.g., relative peak intensities and peak positions) due to factors such as changes in instrument response and sample concentration and purity, as is well known to those skilled in the art. Nevertheless, those skilled in the art can compare the graphical data in the figures of this invention with graphical data generated for unknown crystal forms and can confirm whether the two sets of graphical data characterize the same crystal form.

[0065] Unless otherwise stated, when this invention refers to spectra or data presented in graphical form (e.g., XRPD, IR, Raman, and NMR spectra), the term "peak" refers to a peak or other special feature that is not caused by background noise and can be identified by a person skilled in the art.

[0066] As is well known in the field of X-ray powder diffraction (XRPD), for any given crystal form, the apparatus used to obtain the X-ray powder diffraction pattern, humidity, temperature, powder crystal orientation, and other parameters can all cause some variability in the appearance, intensity, and position of peaks in the diffraction pattern. In the present case, a variability of ±0.2°2θ peak positions takes into account these possible variations without hindering the clear identification of the indicated crystal form. Crystal form identification can be based on any unique difference peaks (in °2θ units) or combinations thereof, typically more prominent peaks. Therefore, in some embodiments, the crystalline compounds of the present invention are characterized by XRPD patterns with certain peak positions that have substantially the same characteristics as the XRPD patterns provided in the accompanying drawings. With the instrumentation used according to the present invention, an error tolerance of ±0.2° may exist for the diffraction peak positions. For example, an X-ray powder diffraction pattern “substantially consistent” with the pattern provided in the present invention may be identical to the XRPD pattern in the accompanying drawings, or more likely it may be slightly different. Such XRPD plots may not necessarily show every peak in the diffraction pattern presented in this invention, and / or may show slight variations in the appearance, intensity, or shift of said peaks due to differences in the conditions involved in obtaining the data. Those skilled in the art can determine whether a sample of the crystalline compound has the same or different crystal form as that of this invention by comparing their XRPD plots. Similarly, those skilled in the art can determine whether the given diffraction peak positions (expressed in °2θ) derived from the XRPD plot are at approximately the same positions as the values ​​presented in this invention. In the context of this invention, 2θ values ​​in X-ray powder diffraction patterns are all in degrees (°).

[0067] Similarly, as is well known in the field of differential scanning calorimetry (DSC), the melting peak height of a DSC curve depends on many related factors, such as sample preparation and instrument conditions, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystalline compounds of the present invention are characterized by DSC plots with characteristic peak positions, possessing substantially the same properties as the DSC plots provided in the accompanying drawings. Depending on the instrument used in this experiment, the melting temperature has an error tolerance of ±3°C, ±4°C, or ±5°C.

[0068] As is well known in the field of Fourier transform-infrared spectroscopy (FT-IR), the position and shape of the absorption peaks in an infrared spectrum depend on the transitions of the covalent bond energy levels in the sample molecule. Therefore, in some embodiments, the crystalline compounds of the present invention are characterized by Fourier transform-infrared spectra with characteristic peak positions and shapes, possessing substantially the same properties as the Fourier transform-infrared spectra provided in the accompanying drawings of the present invention. According to Appendix IV C of the Chinese Pharmacopoeia (2010 edition) – Infrared Spectrophotometry, and based on the instrumentation used in this experiment, the absorption peak is at 3000 cm⁻¹. -1 There is ±5cm nearby-1 The error tolerance is within 1000cm. -1 There is ±2cm nearby -1 Error tolerance.

[0069] The phrase "substantially identical" or "essentially identical" in X-ray powder diffraction patterns, DSC curves, TGA curves, and Fourier transform-infrared spectra generally means that at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about 95%, or at least about 99% of the peaks are shown in the X-ray powder diffraction pattern, DSC curve, Raman spectrum, and infrared spectrum.

[0070] The terms “about” and “approximately” as used in this invention generally mean within ±10% of a given value or range, appropriately within ±5%, and particularly within ±1%. Alternatively, to those skilled in the art, the terms “about” and “approximately” mean within an acceptable standard error of the average value.

[0071] As used in this invention, the term "solution" generally refers to a mixture containing at least one solvent and at least one compound, which is at least partially dissolved in the solvent.

[0072] Hygroscopicity is an important physical property of active pharmaceutical ingredients (APIs), directly affecting their storage stability, processability, and manufacturing process. Table A defines the hygroscopicity of drugs after equilibration at 25°C and 80% RH, according to the 2020 edition of the Chinese Pharmacopoeia.

[0073] Table A

[0074] deliquescence Absorb enough water to form a liquid Extremely hygroscopic The weight gain due to moisture absorption should not be less than 15%. Hygroscopic The weight gain due to moisture absorption is less than 15% but not less than 2%. Slightly hygroscopic The weight gain due to moisture absorption is less than 2% but not less than 0.2%. None or almost none hygroscopic The weight gain due to moisture absorption is less than 0.2%.

[0075] The term "pharmaceutical composition" generally refers to a mixture of one or more crystal forms of the compounds described in this invention, or crystal forms of physiologically / pharmaceutically acceptable salts thereof, with other chemical components, such as physiologically / pharmaceutical acceptable excipients, excipients, diluents, adjuvants, carriers, and additional therapeutic agents. The purpose of a pharmaceutical composition is to facilitate the administration of the compound to a living organism.

[0076] Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffering substances, such as phosphates; glycine; sorbic acid; potassium sorbate; mixtures of partial glycerides of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as carboxymethyl cellulose. Sodium cellulose, ethyl cellulose, and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate; colorants; release agents; coatings; sweeteners; flavorings; fragrances; preservatives and antioxidants.

[0077] The pharmaceutical compositions of the present invention can be administered orally, by injection, topically, sublingually, or via an implantable cartridge. The term "injection" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intramembranous, intraocular, intrahepatic, intralesional, and intracranial injection or infusion techniques. For example, the pharmaceutical compositions of the present invention can be administered orally in any acceptable oral dosage form, including, but not limited to, capsules, tablets, aqueous suspensions, or solutions. As another example, the aseptic injection method of the pharmaceutical compositions of the present invention can be an aqueous or oil-based suspension, which can be formulated according to known techniques using suitable dispersants, wetting agents, and suspending agents.

[0078] The term "cancer" refers to a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. Cancers are classified according to the type of cells that resemble tumor cells and are therefore presumed to be the origin of the tumor. These types include carcinomas, sarcomas, lymphomas and leukemias, germ cell tumors, and blastomas. The term "carcinoma" is used to refer to cancers that originate from epithelial cells. This group includes many of the most common cancers and includes almost all cancers that develop in the breast, prostate, lung, pancreas, and colon.

[0079] For example, the term "cancer" includes, but is not limited to, solid tumors, hematologic cancers (e.g., leukemia, lymphoma, myeloma (such as multiple myeloma)), and metastatic lesions. In one embodiment, cancer is a solid tumor. Examples of solid tumors include malignant tumors such as sarcomas and carcinomas, such as gastrointestinal stromal tumors, colorectal cancer, thyroid cancer, seminoma, dysgerminoma, mast cell tumors, lung cancer, bronchial cancer, testicular intraepithelial neoplasia, melanoma, breast cancer, neuroblastoma, malignant lymphoma, non-Hodgkin lymphoma, type 2 multiple endocrine neoplasia, pheochromocytoma, parathyroid hyperplasia / adenoma, colon cancer, colorectal adenoma, ovarian cancer, prostate cancer, glioblastoma, brain tumors, malignant gliomas, pancreatic cancer, malignant pleural mesothelioma, angioblastoma, hemangioma, kidney cancer, liver cancer, adrenal cancer, bladder cancer, stomach cancer, rectal cancer, vaginal cancer, cervical cancer, endometrial cancer, multiple myeloma, neck and head tumors, etc. In another embodiment, the cancer is a hematologic malignancy, such as myeloma, acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic neutrophilic leukemia, acute undifferentiated leukemia, degenerative large cell lymphoma, adult T-cell acute lymphoblastic leukemia, acute myeloid leukemia with tri-lineage spinal dysplasia, mixed-lineage leukemia, spinal dysplasia syndrome, myelodysplastic syndrome, multiple myeloma, and spinal sarcoma. In a preferred embodiment, the cancer is a gastrointestinal stromal tumor. The cancer may be in the early, middle, or late stages, or it may be metastatic.

[0080] As used in this invention, the term "treatment" refers to any disease or condition, and in some embodiments, it means improving the disease or condition (i.e., slowing down or stopping or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" means alleviating and / or improving at least one bodily parameter, including bodily parameters that may not be perceived by the patient. In still other embodiments, "treatment" means regulating the disease or condition from a physical (e.g., stabilizing perceptible symptoms), physiological (e.g., stabilizing bodily parameters), or both. In still other embodiments, "treatment" means preventing or delaying the onset, occurrence, or worsening of the disease or condition.

[0081] The term "combination" refers to a fixed combination, or combination administration, of a dosage unit, in which a crystalline form of a compound having Formula I or a salt thereof and a combination partner (i.e., an immunotherapeutic agent) can be administered independently at the same time or separately at time intervals, particularly where these time intervals allow the combination partner to exhibit synergy, such as a co-existing effect. Individual components may be packaged in a single box or separately. One or both components (e.g., powder or liquid) may be reconstituted or diluted to the desired dose prior to administration.

[0082] The term "drug combination" refers to a fixed combination or a non-fixed combination or kit for combined administration in the form of a single dose unit, wherein two or more therapeutic agents may be administered independently at the same time or separately at time intervals, particularly where these time intervals allow the combination couple to exhibit synergistic effects, such as a co-occurrence. The term "fixed combination" means a crystalline form of a compound having Formula I or a salt thereof, and a combination couple (i.e., an immunotherapeutic agent), administered simultaneously to a patient as a single entity or dose. The term "non-fixed combination" means a crystalline form of a compound having Formula I or a salt thereof, and a combination couple (i.e., an immunotherapeutic agent), administered simultaneously, in parallel, or sequentially to a patient as separate entities (without a specific time limit), wherein such administration provides a therapeutically effective level of the two compounds in the patient's body. The latter also applies to cocktail therapies, such as the administration of three or more therapeutic agents. In a non-limiting example, the drug combination is a non-fixed combination.

[0083] The terms “co-administration” or “combination administration” are intended to cover the administration of a selected combination of couples (i.e., immunotherapeutic agents) to a single subject (e.g., a patient) in need, and are intended to include treatment regimens in which the agents are not necessarily administered via the same route of administration or administered simultaneously.

[0084] In one aspect of the present invention, a crystal form B of the compound of formula I is provided.

[0085]

[0086] In the X-ray powder diffraction patterns obtained using Cu-Kα radiation and expressed in terms of diffraction angle 2θ, crystal form B exhibits characteristic peaks at 2θ angles of 11.4±0.2°, 14.3±0.2°, 15.1±0.2°, 17.1±0.2°, and 19.1±0.2°.

[0087] In some embodiments, in the X-ray powder diffraction pattern obtained using Cu-Kα radiation, the crystal form B of compound I also has a characteristic peak at at least one of 19.9±0.2°, 23.3±0.2°, 24.7±0.2°, 25.3±0.2° and 26.7±0.2°.

[0088] In some embodiments, the characteristic peak positions shown in the X-ray powder diffraction pattern of crystal form B are... Figure 3 The characteristic peaks shown are in basically the same position.

[0089] In some embodiments, crystal form B shows an endothermic peak at approximately 212°C in differential scanning calorimetry.

[0090] On the other hand, the present invention provides a salt of a compound of formula I:

[0091] The salt comprises a free base portion and an acid portion;

[0092] The free alkali portion has the structure shown in Formula I;

[0093]

[0094] The acid portion is selected from any one of hydrobromic acid, hydrochloric acid, benzenesulfonic acid, maleic acid, L-tartaric acid, D-tartaric acid, DL-tartaric acid, and L-malic acid.

[0095] In some embodiments, the salt has a crystalline form.

[0096] In some embodiments, the acid portion is L-tartaric acid, D-tartaric acid, or DL-tartaric acid.

[0097] On the other hand, the present invention provides a crystal form of a compound of formula I, wherein the tartrate is L-tartrate, D-tartrate, or DL-tartrate.

[0098] In the X-ray powder diffraction patterns obtained using Cu-Kα radiation and expressed in terms of diffraction angle 2θ, the crystal form exhibits characteristic peaks at 2θ angles of 14.2±0.2°, 16.2±0.2°, 20.5±0.2°, 21.4±0.2°, and 22.6±0.2°.

[0099] Preferably, in the X-ray powder diffraction pattern obtained using Cu-Kα radiation, the crystal form also has a characteristic peak at at least one of 25.0±0.2° and 28.6±0.2°.

[0100] In some embodiments, the crystal form of the tartrate salt of Formula I compound shows an endothermic peak at 220-221 °C in differential scanning calorimetry.

[0101] In some embodiments, the crystal form is that of DL-tartrate, and in X-ray powder diffraction patterns obtained using Cu-Kα radiation, the crystal form exhibits characteristic peaks at 2θ angles of 14.3±0.2°, 16.2±0.2°, 20.5±0.2°, 21.5±0.2°, and 22.6±0.2°.

[0102] Preferably, in the X-ray powder diffraction pattern obtained using Cu-Kα radiation, the crystal form also has a characteristic peak at at least one of 25.2±0.2°, 26.1±0.2° and 28.6±0.2°.

[0103] In some embodiments, the crystal form of the Formula I compound DL-tartrate shows an endothermic peak at approximately 220°C in differential scanning calorimetry.

[0104] In some embodiments, the crystal form is crystal form α of D-tartrate, and in X-ray powder diffraction patterns obtained using Cu-Kα radiation, expressed in terms of diffraction angles 2θ, crystal form α has characteristic peaks at 2θ angles of 14.2±0.2°, 16.2±0.2°, 20.5±0.2°, 21.4±0.2°, 22.6±0.2°, 25.0±0.2°, 25.5±0.2°, 26.1±0.2°, and 28.6±0.2°.

[0105] In some embodiments, in the infrared spectrum obtained using infrared spectroscopy characterization, the crystal form α is at 3244±2 cm⁻¹. -1 3062±2cm -1 1730±2cm -1 1652±2cm -1 and 1479±2cm -1 The characteristic absorption peak is displayed at the wavenumber.

[0106] In some embodiments, the characteristic peak positions shown in the X-ray powder diffraction pattern of crystal form α of compound I, D-tartrate, are similar to... Figure 25 The characteristic peaks shown are in basically the same position.

[0107] In some embodiments, the crystal form α of the compound of formula I, D-tartrate, shows an endothermic peak at approximately 221°C in differential scanning calorimetry.

[0108] On the other hand, the present invention provides a method for preparing crystal form α of the aforementioned compound of formula I, D-tartrate.

[0109] In some embodiments, the method includes: weighing a certain amount of free alkali and adding an appropriate amount of solvent to dissolve it; dissolving the solid acid in an appropriate amount of solvent, then adding the acid solution to the free alkali solution to precipitate the solid, filtering, and drying to obtain pharmaceutical salt.

[0110] On the other hand, the present invention provides a pharmaceutical composition comprising a crystal form of the aforementioned compound of formula I, or a salt of the aforementioned compound of formula I or a crystal form of a salt thereof, and a pharmaceutically acceptable excipient.

[0111] In some embodiments, the pharmaceutical composition comprises the crystal form α of D-tartaric acid of Formula I, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0112] On the other hand, the present invention provides the use of the crystal form of the aforementioned Formula I compound, or the crystal form of a salt of the aforementioned Formula I compound or a salt thereof, in the preparation of a medicament for treating a disease, wherein the disease is cancer.

[0113] In some embodiments, the present invention provides the use of the crystal form α of the D-tartrate of Formula I compound or the aforementioned pharmaceutical composition in the preparation of a medicament for treating a disease, said disease being cancer.

[0114] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that the following detailed description of the technical solutions of the present invention using embodiments will help to further understand the advantages and effects of the technical solutions of the present invention. The embodiments do not limit the scope of protection of the present invention, which is determined by the claims.

[0115] The abbreviations used in this invention are explained as follows:

[0116] XRPD: X-ray powder diffraction;

[0117] IR: Infrared spectrum;

[0118] DSC: Differential Scanning Calorimetry;

[0119] TGA: Thermogravimetric analysis;

[0120] HPLC: High Performance Liquid Chromatography;

[0121] RH: Relative humidity.

[0122] Instruments and methods

[0123] X-ray powder diffraction (XRPD)

[0124] XRPD images were acquired using a DX-2700BH X-ray diffractometer, with the following scanning parameters:

[0125] Equipment parameters: Cu-Kα rays, scattering slit #2: 1°, anti-scattering slit #3: 1°, receiving slit #4: 0.2mm;

[0126] Detection parameters: tube current: 40mA, tube voltage: 40kV, step rate: 0.02° / 0.5 seconds; starting angle: 3°, ending angle: 40°.

[0127] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)

[0128] TGA and DSC spectra were acquired using a TA Q5000 / Discovery 5500 thermogravimetric analyzer and a TA Q2000 / Discovery 2500 differential scanning calorimeter, respectively. The test parameters are shown in Table 1.

[0129] Table 1. TGA and DSC Test Parameters

[0130] parameter TGA DSC method linear heating linear heating Sample tray Aluminum disc, open Aluminum disc, pressure cap Temperature range Room temperature ~ target temperature 25℃~Target Temperature Scan rate 10℃ / min 10℃ / min Protective gas Nitrogen Nitrogen

[0131] Unless otherwise specified in the examples, the room temperature is 20℃~30℃.

[0132] Infrared spectroscopy (IR)

[0133] Samples for IR spectroscopy were prepared using a potassium bromide pellet method and analyzed using a transmission FTIR spectrometer. The infrared spectrometer was an Infrared Spectrometer Thermo Scientific Nicolet iS5+iD1 or similar instrument.

[0134] The starting materials used in the following examples can be prepared according to the prior art, for example, according to the method described in patent application CN111303024A, but the starting materials are not a limiting condition for preparing the crystal form of the present invention.

[0135] Example 1: Preparation of crystal form A of compound of formula I

[0136] 50 mg of the compound shown in Formula I was added to 4 mL of cyclohexane, heated to 50 °C, and stirred for 9 days. The mixture was filtered, and the filter cake was collected. The product was then dried under vacuum to obtain a solid. X-ray powder diffraction analysis identified the product as crystal form A; the XRPD pattern is attached. Figure 1 As shown in the figure. The DSC spectrum shows that the endothermic peak has a peak value of approximately 176℃. Figure 2 As shown.

[0137] Example 2: Preparation of crystal form B of compound of formula I

[0138] 50 mg of the compound shown in Formula I was added to 2 mL of acetonitrile, heated to 50 °C, and stirred for 9 days. The mixture was filtered, and the filter cake was collected. The product was then vacuum dried to obtain a solid. X-ray powder diffraction analysis identified the product as crystal form B; the XRPD pattern is attached. Figure 3 As shown in the figure. The DSC spectrum shows that the endothermic peak has a peak value of approximately 212℃. Figure 4 As shown.

[0139] Example 3: Preparation of Crystal Form C of Compound I

[0140] 50 mg of the compound shown in Formula I was added to 2 mL of methanol, heated to 50 °C, and stirred until dissolved. The solution was then cooled to 5 °C and stirred to induce crystallization for 2 h. The mixture was filtered, and the filter cake was collected. The solid was obtained by vacuum drying. X-ray powder diffraction analysis identified the product as crystal form C. The XRPD pattern is shown in the attached figure. Figure 5 As shown in Figure 6, the DSC spectrum shows an endothermic peak with a peak value of approximately 127℃. It is speculated that the endothermic peak at approximately 201℃ in the spectrum is generated by the transformation of crystal form C during the heating process.

[0141] Example 4: Preparation of crystal form D of compound of formula I

[0142] 50 mg of the compound shown in Formula I was added to 2 mL of ethanol, heated to 50 °C, and stirred until dissolved. The solution was then cooled to 5 °C and stirred to induce crystallization for 2 h. The mixture was filtered, and the filter cake was collected. The solid was obtained by vacuum drying. X-ray powder diffraction analysis identified the product as crystal form D. The XRPD pattern is attached. Figure 7 As shown in Figure 8, the DSC spectrum shows an endothermic peak with a peak value of approximately 121℃. It is speculated that the endothermic peak at approximately 200℃ in the spectrum is generated by crystal transformation of crystal form D during the heating process.

[0143] Example 5: Preparation of crystal form E of compound of formula I

[0144] 50 mg of the compound shown in Formula I was added to 2 mL of tetrahydrofuran and stirred until dissolved. The solution was slowly added dropwise to 20 mL of water, and the mixture was stirred to induce crystallization for 2 h. The solution was filtered, and the filter cake was collected. The product was dried under vacuum to obtain a solid. X-ray powder diffraction analysis identified the product as crystal form E, and the XRPD pattern is attached. Figure 9 As shown in Figure 10, the DSC spectrum shows an endothermic peak with a peak value of approximately 207℃.

[0145] Example 6: Crystal form transformation relationship of compound I

[0146] Approximately 50 mg of each of the following crystal forms (A, B, C, D, and E) of the compound of formula I obtained in Examples 1-5 were weighed and suspended in approximately 1 ml of solvent. The mixture was magnetically stirred at room temperature (20-30°C) for 2 days. After filtration and drying, solids were obtained, and XRPD was tested. The results are shown in Table 2.

[0147] Table 2 Results of Crystal Form Transformation Investigation of Compound I

[0148]

[0149] The experimental results show that crystal form B is a stable crystal form in various systems, while other crystal forms tend to transform into crystal form B to varying degrees.

[0150] Example 7: Salt type screening of Formula I compounds

[0151] Experimental Procedure: Weigh approximately 200 mg of the free base sample of the compound shown in Formula I, add 5 mL of acetone or tetrahydrofuran, and heat to 50 °C while stirring until dissolved. Weigh the corresponding acid (1.05 eq, see Table 3), add 2 mL of water to dilute or heat to 50 °C to dissolve. Add the acid solution dropwise to the free base sample solution, and crystallize using the method shown in Table 3. Filter, vacuum dry to obtain the solid, and test XRPD and TGA / DSC.

[0152] The XRPD spectrum of the hydrochloride salt of compound I is attached. Figure 11 The TGA / DSC spectra are attached. Figure 12 The XRPD spectrum of compound I, hydrobromide, is shown in the appendix. Figure 13 The TGA / DSC spectra are attached. Figure 14 The XRPD spectrum of compound I, benzenesulfonate, is shown in the appendix. Figure 15 The TGA / DSC spectra are attached. Figure 16 The XRPD spectrum of maleate of Formula I is attached. Figure 17 The TGA / DSC spectra are attached. Figure 18 The XRPD spectrum of compound I, DL-tartrate, is attached. Figure 19 The TGA / DSC spectra are attached. Figure 20 The XRPD spectrum of compound I, L-malate, is shown in the appendix. Figure 21 The TGA / DSC spectra are attached. Figure 22 The XRPD spectrum of compound I, L-tartrate, is shown in the appendix. Figure 23 The TGA / DSC spectra are attached. Figure 24 .

[0153] Preliminary crystal form analysis of the obtained product is shown in Table 3:

[0154] Table 3 Salt formation process and crystal form analysis

[0155]

[0156]

[0157] The results showed that all acids could form crystalline substances with free bases, but most of them were likely mixed crystals and may contain hydrates. Only hydrochloride and tartrate had good crystallinity and were both monocrystalline.

[0158] Example 8: Evaluation of the salt stability of compound I

[0159] Approximately 40 mg of each salt type sample listed in Table 3 was weighed and placed at 90% RH and 60℃ for 5 days, respectively. Purity, XRPD, and DSC were measured, as well as the moisture gain under high humidity conditions, to investigate their stability under high humidity and high temperature conditions. The results are shown in Table 4.

[0160] Table 4. Stability test results for each salt type sample

[0161]

[0162] Table 4 shows that all salt forms exhibit good chemical stability under high temperature and high humidity conditions. From a crystal form perspective, hydrochloride, maleate, and tartrate are stable, while other salt forms tend to be unstable. However, hydrochloride, hydrobromide, benzenesulfonate, and maleate are highly hygroscopic. Overall, tartrate is considered an anhydrous crystal form with good crystallinity, low hygroscopicity, and good stability, making its preparation process feasible.

[0163] Example 9: Preparation of D-tartrate crystal form α of compound I

[0164] Approximately 25 g of the compound shown in Formula I was added to 375 mL of tetrahydrofuran, and the mixture was heated to 60 °C and stirred until dissolved. 7.6 g of D-tartaric acid was weighed and added to 125 mL of tetrahydrofuran, and the mixture was stirred until dissolved at room temperature. The D-tartaric acid solution was added dropwise to the solution of the compound shown in Formula I, and the mixture was stirred for 1 h after the addition was complete. The mixture was filtered, the filter cake was collected, and the solid was obtained by vacuum drying. The XRPD pattern obtained by X-ray powder diffraction is shown in the attached figure. Figure 25 As shown, it is defined as crystal form α. The spectral analysis data of the X-ray powder diffraction pattern are shown in Table 5. The infrared spectrum is attached. Figure 26 As shown, the TGA / DSC spectrum is as follows: Figure 27 As shown, the endothermic peak value is approximately 221℃.

[0165] Table 5. XRPD spectra analysis data of D-tartrate crystal form α of compound I.

[0166]

[0167]

[0168] Example 10: Preparation of D-tartrate crystal form α of compound I

[0169] Approximately 200 mg of the free base of the compound shown in Formula I was weighed and added to an appropriate amount of solvent (see Table 6), and the solution was heated to 50 °C and dissolved completely. A certain amount of D-tartaric acid (1.1 eq) was weighed and added to an appropriate amount of solvent (see Table 6), and the solution was stirred until dissolved completely. The D-tartaric acid solution was added to the solution of the free base of the compound shown in Formula I. After stirring for a certain period of time, the precipitated solid was filtered and dried. The XPRD of the dried product was tested, and the results are shown in Table 6.

[0170] Table 6 shows the stability of the D-tartrate crystal form α of compound I in different solvent preparation systems.

[0171]

[0172] As can be seen from the experimental results in Table 6, the D-tartrate salt of Formula I was obtained in various solvent systems, and the crystal form α is a stable crystal form in most solvent systems.

[0173] Example 11: Solubility experiment of free alkali crystal form B and D-tartrate crystal form α of compound I

[0174] 10 mg of the free alkali crystal form B of compound I obtained in Example 2 and 10 mg of the D-tartrate crystal form α obtained in Example 9 were weighed and added to 4 mL glass bottles, followed by 2 mL of solvent (see Table 7). The mixture was stirred at 37 °C for 24 h. The resulting sample solution was rapidly centrifuged, and the supernatant was diluted appropriately. The concentration (unit: mg / mL) was determined by HPLC, and the solubility results are shown in Table 7.

[0175] Table 7. Solubility of free alkali crystal form B and D-tartrate crystal form α of compound I.

[0176]

[0177]

[0178] The results showed that the free alkali crystal form B had low solubility in various solvents, while the solubility of the D-tartrate crystal form α was significantly improved in all solvents, which could meet the requirements for drug preparation.

[0179] Example 12: Stability study of the D-tartrate crystal form α of compound I

[0180] 1. Solvent pulping experiment

[0181] Weigh 100 mg of the D-tartrate α-form sample obtained in Example 9 and add 1 mL of solvent (see Table 8) to suspend it. Stir magnetically for 7 days at room temperature and 50°C, respectively. Filter to obtain a solid wet product. Dry to obtain a dry product, and test XRPD. The results are shown in Table 8.

[0182] Table 8 shows the crystal form changes of compound I's D-tartrate α under different solvents and temperatures during pulping.

[0183]

[0184] The results show that the D-tartrate crystal form α of compound I is stable in most solvents at room temperature and 50°C, exhibiting excellent stability.

[0185] 2. Experiments on the D-tartrate crystal form α of compound I under high temperature, high humidity and light conditions.

[0186] Take an appropriate amount of the D-tartrate crystal form α sample obtained in Example 9, lay it flat in an open container, and examine the stability of the sample under conditions of high humidity, light, and high temperature. After 20 or 30 days, take it out to test XRPD and purity. The experimental results are shown in Table 9.

[0187] Table 9 shows the crystal form changes of D-tartrate α of compound I under high temperature, high humidity, and light conditions.

[0188]

[0189]

[0190] The results in Table 9 show that the chemical stability and crystal form stability of the α-crystalline sample are very high under high temperature, high humidity and light conditions.

[0191] 3. Tableting stability

[0192] Take 50 mg of the D-tartrate crystal form α sample of the compound of formula I obtained in Example 9, apply 20 N pressure to compress it into a tablet, and test the content of XRPD and related substances. The results are shown in Table 10.

[0193] Table 10 shows the changes in the content and crystal form of D-tartrate crystals of compound I before and after tableting.

[0194]

[0195] The results show that the crystal form of D-tartrate α of compound I remains consistent before and after tableting, and no increase in impurities is observed, indicating that D-tartrate α of compound I has good pressure stability.

[0196] 4. Pulverization stability

[0197] 4.1 Stability of the grinding process

[0198] A suitable amount of the D-tartrate crystal form α sample of the compound of formula I obtained in Example 9 was placed in a grinder (Ruian Yongli Pharmaceutical Machinery Co., Ltd., model: YF103B) and ground for 1 minute, 2 minutes and 3 minutes respectively. Then, samples were taken to test XRPD. The test results are shown in Table 11.

[0199] Table 11 Crystal form detection results during grinding process

[0200] deal with Crystal form Before grinding α crystal form Grind for 1 minute α crystal form Grind for 2 minutes α crystal form Grind for 3 minutes α crystal form

[0201] The results show that the D-tartrate crystal form α of compound I exhibits good crystal stability during the grinding process.

[0202] 4.2 Stability under air jet milling conditions

[0203] A suitable amount of the D-tartrate α-sample of the compound of formula I obtained in Example 9 was placed in an air jet mill (Masim, J-100 type) for pulverization. The particle size and XRPD were investigated under pulverization pressures of 0.8 and 1.0 MPa (feed rate of 2 kg / h), respectively. The results are shown in Table 12 and... Figure 28 .

[0204] Table 12 Particle size and crystal form of samples obtained under different pulverizing pressures

[0205]

[0206] like Figure 28 The position and relative intensity of the 2θ angle of the diffraction peak, as shown in Table 12, indicate that the crystal form of samples with different particle size distributions did not change after pulverization compared to before pulverization. The D-tartrate crystal form α sample of compound I showed good crystal form stability during pulverization.

[0207] 5. Packaging stability test

[0208] A suitable amount of the D-tartrate crystal form α sample obtained in Example 9 was packaged in a pharmaceutical low-density polyethylene bag (2 layers), and then covered with a pharmaceutical packaging polyester / aluminum / polyethylene pharmaceutical composite bag, and sealed for storage. Under the above packaging conditions, the sample was stored for 6 months under accelerated conditions (40℃±2℃, RH75%±5%) and 12 months under long-term conditions (25±2℃, RH60±5%) to investigate the effect of the packaging material on the sample. The results of the accelerated test are shown in Table 13, and the results of the long-term test are shown in Table 14.

[0209] Table 13 Results of stability testing under accelerated conditions

[0210]

[0211] Table 14 Results of stability study under long-term conditions

[0212]

[0213] The results showed that when the D-tartrate crystal form α sample of compound I was packaged in a low-density polyethylene bag (2 layers) as the inner packaging material and a polyester / aluminum / polyethylene pharmaceutical composite bag as the outer packaging material and sealed, there were no significant changes in properties, content of related substances and moisture content under accelerated conditions (6 months) and long-term conditions (12 months).

[0214] Example 13: Pharmacokinetic study of the D-tartrate crystal form α of compound I

[0215] 1. In vitro pharmacokinetics

[0216] Caco-2 cells (passage 45, purchased from Wuhan Shangen Biotechnology Co., Ltd.) were seeded into 96-well cell culture plates and cultured continuously for 21 days (culture medium: DMEM high glucose medium + 10% fetal bovine serum + 1% penicillin-streptomycin + 1% glutamine (purchased from Shanghai Enzyme-Linked Biotechnology Co., Ltd.), culture conditions: 37℃). The D-tartrate crystal form α sample of compound I was administered bidirectionally, with or without Eclairida (GF120918, an inhibitor of efflux transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), purchased from Shanghai Hanxiang Biotechnology Co., Ltd.), with final concentrations of 2.00 and 5.00 μM, respectively. After incubation for 120 minutes, the content of the test sample in the incubation system was determined by LC-MS / MS (API4000, chromatographic column ACQUITY UPLC BEH C18 (2.1×50mm, 1.7μm)). The results are shown in Table 15.

[0217] Table 15. Data on the bidirectional permeability of D-tartrate α form of compound I in Caco-2 cells.

[0218]

[0219] The results in Table 15 show that, under conditions with and without ectilida, at drug concentrations of 2.00 and 5.00 μM, the average apparent permeability coefficients in both the apex-to-basal (AB) and basal-to-apex (BA) directions, according to existing classification criteria, indicate that the test sample exhibits high permeability in Caco-2 cells; the efflux ratio (ER) is less than 2.00, indicating that no efflux transport was observed.

[0220] 2. In vivo pharmacokinetics: Pharmacokinetic studies of D-tartrate α-form of compound I in SD rats after single-dose and 7-day repeated administration.

[0221] Forty healthy SD rats (purchased from Beijing Vital River Laboratory Animal Co., Ltd., half male and half female) were randomly divided into five groups (intravenous injection group, low-, medium-, and high-dose gavage groups, and 7-day repeated administration group, n=4 per group). Each group received a single intravenous injection of 0.5 mg / kg, a single gavage of 2.5, 7.5, and 12.5 mg / kg, or a repeated 7-day gavage administration of 7.5 mg / kg / day of the test product (D-tartrate α-sample of compound I). Blood samples were collected from the intravenous injection group, the low-, medium-, and high-dose gavage groups, and the 7-day repeated administration group at the following time points. Intravenous injection group: Blood samples were collected 0 h before administration and 0.033, 0.083, 0.25, 0.5, 1, 3, 6, 9, 12, 24, 36, and 48 h after administration; Low, medium, and high dose gavage groups: Blood samples were collected 0 h before administration and 0.25, 0.5, 1, 3, 6, 9, 12, 24, 36, 48, and 72 h after administration; 7-day repeated administration group: Blood samples were collected 0 h before administration on days 3, 4, 5, and 6, 0 h before the last administration, and 0.25, 0.5, 1, 3, 6, 9, 12, 24, 36, 48, and 72 h after the last administration. After the blood samples were separated into plasma, the concentration of the test sample in the plasma was determined by LC-MS / MS (the analytical instrument used was API4000, and the chromatographic column was ACQUITY UPLC BEH C18 (2.1×50mm, 1.7μm)). The results are shown in Table 16.

[0222] Table 16. Absorption study of D-tartrate α-form of compound I in SD rats after single and repeated administration.

[0223]

[0224] Based on the results in Table 16, the absolute bioavailability (calculated using the formula: Absolute Bioavailability = (AUClast of the single-gavage group / dose of the single-gavage group) / (AUClast of the intravenous injection group / dose of the intravenous injection group) × 100%) of the D-tartrate crystal form α of compound I in SD rats after a single oral gavage administration of 2.5, 7.5, and 12.5 mg / kg of the test product, was positively correlated with the dose. Furthermore, no significant accumulation of the test product was observed after repeated administration of 7.5 mg / kg over 7 days, indicating that the risk of significant drug accumulation leading to safety issues in clinical practice is relatively low, which is beneficial for drug development.

[0225] It should be noted that the present invention is not limited to the above-described embodiments. The above embodiments are merely examples, and any embodiments that have the same structure and perform the same effects as the technical concept within the scope of the present invention are included within the scope of the present invention. Furthermore, various modifications that can be conceived by those skilled in the art to the embodiments, and other ways of constructing by combining some of the constituent elements of the embodiments, without departing from the spirit of the present invention, are also included within the scope of the present invention.

Claims

1. A crystalline form of a tartrate salt of a compound of Formula I, the tartrate salt being an L-tartrate salt, a D-tartrate salt, or a DL-tartrate salt, characterized by: an X-ray powder diffraction pattern, in terms of diffraction angles 2Q, obtained using Cu-Ka radiation, having characteristic peaks at 2Q angles of 14.2 ± 0.2°, 16.2 ± 0.2°, 20.5 ± 0.2°, 21.4 ± 0.2°, and 22.6 ± 0.2°.

2. The crystalline form of a tartrate salt of a compound of Formula I according to claim 1, characterized by: an X-ray powder diffraction pattern, in terms of diffraction angles 2Q, obtained using Cu-Ka radiation, further having characteristic peaks at at least one of 25.0 ± 0.2° and 28.6 ± 0.2°.

3. The crystalline form of a tartrate salt of a compound of Formula I according to claim 1 or 2, characterized by: the crystalline form being a crystalline form a of a D-tartrate salt.

4. The crystalline form of a tartrate salt of a compound of Formula I according to claim 3, characterized by: an X-ray powder diffraction pattern, in terms of diffraction angles 2Q, obtained using Cu-Ka radiation, the crystalline form a of a D-tartrate salt having characteristic peaks at 2Q angles of 14.2 ± 0.2°, 16.2 ± 0.2°, 20.5 ± 0.2°, 21.4 ± 0.2°, 22.6 ± 0.2°, 25.0 ± 0.2°, 25.5 ± 0.2°, 26.1 ± 0.2°, and 28.6 ± 0.2°.

5. The crystalline form of a tartrate salt of a compound of Formula I according to claim 3, characterized by: an X-ray powder diffraction pattern, in terms of diffraction angles 2Q, obtained using Cu-Ka radiation, the X-ray powder diffraction pattern of the crystalline form a of a D-tartrate salt having characteristic peaks at essentially the same positions as the characteristic peaks shown in FIG.

25.

6. The crystalline form of a tartrate salt of a compound of Formula I according to claim 3, characterized by: In an infrared spectrum, the crystal form a shows characteristic absorption peaks at wave numbers of 3244±2 cm -1 , 3062±2 cm -1 , 1730±2 cm -1 , 1652±2 cm -1 , and 1479±2 cm -1 .

7. The crystalline form of a tartrate salt of a compound of Formula I according to claim 1, characterized by: the crystalline form exhibiting an endothermic peak at 220-221 °C in a differential scanning calorimetry test.

8. A crystalline form B of a compound of Formula I, characterized by: an X-ray powder diffraction pattern, in terms of diffraction angles 2Q, obtained using Cu-Ka radiation, the crystalline form B having characteristic peaks at 2Q angles of 11.4 ± 0.2°, 14.3 ± 0.2°, 15.1 ± 0.2°, 17.1 ± 0.2°, and 19.1 ± 0.2°.

9. The crystalline form B of a compound of Formula I according to claim 8, characterized by: an X-ray powder diffraction pattern, in terms of diffraction angles 2Q, obtained using Cu-Ka radiation, the X-ray powder diffraction pattern of the crystalline form B having characteristic peaks at essentially the same positions as the characteristic peaks shown in FIG.

3.

10. The crystalline form B of a compound of Formula I according to claim 8 or 9, characterized by: the crystalline form B exhibiting an endothermic peak at about 212 °C in a differential scanning calorimetry test.

11. A pharmaceutical composition comprising a crystalline form of a tartrate salt of the compound of Formula I according to any one of claims 1 to 7 or crystalline Form B of the compound of Formula I according to any one of claims 8 to 10, and one or more pharmaceutically acceptable carriers, diluents or excipients.

12. Use of a crystalline form of a tartrate salt of the compound of Formula I according to any one of claims 1 to 7 or crystalline Form B of the compound of Formula I according to any one of claims 8 to 10 or a pharmaceutical composition according to claim 11 for the manufacture of a medicament for the treatment of cancer.

13. The use according to claim 12, wherein the cancer is a solid tumor or a hematological malignancy, the solid tumor is selected from the group consisting of gastrointestinal stromal tumor, colorectal cancer, thyroid cancer, seminoma, dysgerminoma, mast cell tumor, lung cancer, bronchial cancer, testicular intraepithelial neoplasia, melanoma, breast cancer, neuroblastoma, malignant lymphoma, non-Hodgkin's lymphoma, multiple endocrine neoplasia type 2, pheochromocytoma, parathyroid hyperplasia / adenoma, colon cancer, colorectal adenoma, ovarian cancer, prostate cancer, glioblastoma, brain tumor, malignant glioma, pancreatic cancer, malignant pleural mesothelioma, hemangioblastoma, hemangioma, renal cancer, liver cancer, adrenal cancer, bladder cancer, stomach cancer, rectal cancer, vaginal cancer, cervical cancer, endometrial cancer, multiple myeloma, tumor of the neck and head; the hematological malignancy is selected from the group consisting of myeloma, acute lymphoblastic leukemia, acute myelocytic leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic neutrophilic leukemia, acute undifferentiated cell leukemia, blastic NK cell lymphoma, adult T-cell acute lymphoblastic leukemia, acute myeloid leukemia with trilineage myelodysplasia, mixed lineage leukemia, myelodysplastic syndrome, myelodysplastic / myeloproliferative disease, multiple myeloma, and spinal cord sarcoma. ​

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