Crystalline form of bezuclastinib and pharmaceuticals containing this crystal form.

Abstract

The invention relates to a crystalline form of bezuclastinib and a method for preparing such a crystalline form, and a pharmaceutical composition containing such a crystalline form for use in inhibiting the KIT D816V mutation and in the treatment of gastrointestinal stromal tumors and progressive systemic mast cell disease.

Description

Bezuclastinib crystal form, preparation method and use thereof Technical Field

[0001] The present invention relates to the field of crystal chemistry, and more particularly to a crystal form of Bezuclastinib, a preparation method thereof, and uses thereof. Background Art

[0002] Bezuclastinib is an oral, selective tyrosine kinase inhibitor (TKI) developed by Cogent Biosciences. Bezuclastinib inhibits the KIT D816V mutation and has demonstrated promising clinical results in the treatment of gastrointestinal stromal tumors (GIST) and advanced systemic mastocytosis (AdvSM).

[0003] The chemical name of Bezuclastinib is 3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide (hereinafter referred to as "Compound I"), and its structural formula is as follows:

[0004] WO2014100620A3 and WO2021222442A1 disclose the synthesis method of Compound I, but do not disclose the crystalline form of Compound I.

[0005] A crystal is a solid formed by the orderly three-dimensional arrangement of compound molecules within a microscopic structure, forming a lattice. Polymorphism refers to the phenomenon of a single compound existing in multiple crystal forms. A compound may exist in one or more crystal forms, but their existence and properties cannot be precisely predicted. APIs in different crystal forms have varying physicochemical properties, which can lead to varying dissolution and absorption in the body, thereby impacting the drug's clinical efficacy to a certain extent. Crystal form is particularly crucial to product performance for poorly soluble oral solid or semisolid dosage forms. Furthermore, the physicochemical properties of the crystal form are crucial to the production process. Therefore, polymorphism is a crucial aspect of pharmaceutical research and quality control.

[0006] The development of pharmaceuticals containing Compound I requires new crystalline forms that meet pharmaceutical requirements. The inventors of this application unexpectedly discovered that the crystalline form of Compound I provided herein exhibits advantages in at least one of solubility, hygroscopicity, purification efficiency, stability, adhesion, compressibility, flowability, in vitro and in vivo dissolution, and bioavailability. In particular, it exhibits excellent stability, low hygroscopicity, and suitability for pharmaceutical use, which is of great significance for the development of pharmaceuticals containing Compound I.

[0007] Summary of the Invention

[0008] The present invention provides a crystalline solid of Compound I, a method for preparing the same, and a pharmaceutical composition comprising the crystalline solid.

[0009] According to the object of the present invention, the present invention provides a crystalline solid of Compound I.

[0010] According to the purpose of the present invention, the present invention provides a crystalline form CSI of Compound I (hereinafter referred to as "crystalline form CSI").

[0011] In one aspect, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at one, two, or three of the diffraction angles 2θ of 7.5°±0.2°, 13.7°±0.2°, and 16.8°±0.2°. Preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2θ of 7.5°±0.2°, 13.7°±0.2°, and 16.8°±0.2°.

[0012] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at one, two, or three of the diffraction angles 2θ of 13.0°±0.2°, 15.1°±0.2°, and 18.9°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2θ of 13.0°±0.2°, 15.1°±0.2°, and 18.9°±0.2°.

[0013] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at one, two, or three of the diffraction angles 2θ of 22.8°±0.2°, 23.6°±0.2°, and 25.6°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2θ of 22.8°±0.2°, 23.6°±0.2°, and 25.6°±0.2°.

[0014] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at one, or two, or three, or four, or five, or six, or seven, or eight, or nine of the diffraction angles 2θ of 7.5°±0.2°, 13.7°±0.2°, 14.7°±0.2°, 16.8°±0.2°, 13.0°±0.2°, 15.1°±0.2°, 18.9°±0.2°, 22.8°±0.2°, 23.6°±0.2°, and 25.6°±0.2°.

[0015] Without limitation, using Cu-Kα radiation, the X-ray powder diffraction pattern of Form CSI is substantially as shown in FIG1 .

[0016] Without limitation, the thermogravimetric analysis of Form CSI is substantially as shown in FIG2 , with a mass loss of about 0.01% upon heating to 100° C.

[0017] Without limitation, the crystalline form CSI is an anhydrate.

[0018] According to the purpose of the present invention, the present invention provides a crystalline form CSII of Compound I (hereinafter referred to as "crystalline form CSII").

[0019] In one aspect, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at one, two, or three of the diffraction angles 2θ of 8.6°±0.2°, 12.5°±0.2°, and 22.0°±0.2°. Preferably, the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at diffraction angles 2θ of 8.6°±0.2°, 12.5°±0.2°, and 22.0°±0.2°.

[0020] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at one, two, or three of the diffraction angles 2θ of 7.9°±0.2°, 10.9°±0.2°, and 26.1°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at diffraction angles 2θ of 7.9°±0.2°, 10.9°±0.2°, and 26.1°±0.2°.

[0021] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at one or two of the diffraction angles 2θ of 18.1°±0.2° and 28.8°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at diffraction angles 2θ of 18.1°±0.2° and 28.8°±0.2°.

[0022] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at one, or two, or three, or four, or five, or six, or seven, or eight, or nine of the diffraction angles 2θ of 8.6°±0.2°, 12.5°±0.2°, 22.0°±0.2°, 7.9°±0.2°, 10.9°±0.2°, 26.1°±0.2°, 18.1°±0.2°, 28.8°±0.2°, and 17.1°±0.2°.

[0023] Without limitation, using Cu-Kα radiation, the X-ray powder diffraction pattern of Form CSII is substantially as shown in FIG. 7 .

[0024] Without limitation, the thermogravimetric analysis of Form CSII is substantially as shown in FIG8 , with a mass loss of approximately 0.04% upon heating to 100° C.

[0025] Without limitation, Form CSII is an anhydrate.

[0026] According to the purpose of the present invention, the present invention provides a crystalline form CSIII of Compound I (hereinafter referred to as "crystalline form CSIII").

[0027] In one aspect, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSIII has characteristic peaks at one, two, or three of the diffraction angles 2θ of 7.4°±0.2°, 11.5°±0.2°, and 16.2°±0.2°. Preferably, the X-ray powder diffraction pattern of the crystalline form CSIII has characteristic peaks at diffraction angles 2θ of 7.4°±0.2°, 11.5°±0.2°, and 16.2°±0.2°.

[0028] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSIII has characteristic peaks at one, two, or three of the diffraction angles 2θ of 13.4°±0.2°, 14.9°±0.2°, and 18.0°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSIII has characteristic peaks at diffraction angles 2θ of 13.4°±0.2°, 14.9°±0.2°, and 18.0°±0.2°.

[0029] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSIII has a characteristic peak at a diffraction angle 2θ value of 13.7°±0.2°.

[0030] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSIII has characteristic peaks at 1, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9 of the diffraction angle 2θ values ​​of 7.4°±0.2°, 11.5°±0.2°, 16.2°±0.2°, 13.4°±0.2°, 14.9°±0.2°, 18.0°±0.2°, 13.7°±0.2°, 5.7°±0.2°, 8.9°±0.2°, 11.0°±0.2°, 17.2°±0.2°, and 22.4°±0.2°.

[0031] Without limitation, using Cu-Kα radiation, the X-ray powder diffraction pattern of Form CSIII is substantially as shown in FIG12 .

[0032] According to the purpose of the present invention, the present invention provides a method for preparing the crystalline form CSIII of compound I: dissolving compound I in a mixed solvent of dimethyl sulfoxide and water, filtering, and adding the filtrate to acetonitrile and stirring to obtain the crystalline form CSIII.

[0033] According to the purpose of the present invention, the present invention provides a pharmaceutical composition comprising an effective therapeutic amount of crystalline form CSI, crystalline form CSII or crystalline form CSIII of Compound I, and pharmaceutically acceptable excipients.

[0034] According to the purpose of the present invention, the present invention provides the use of Compound I crystalline form CSI, crystalline form CSII or crystalline form CSIII in the preparation of KIT D816V inhibitor drugs.

[0035] According to the purpose of the present invention, the present invention provides the use of Compound I crystal form CSI, crystal form CSII or crystal form CSIII in the preparation of drugs for gastrointestinal stromal tumors and progressive systemic mastocytosis.

[0036] The crystal forms CSI, CSII, and CSIII provided by the present invention have the following advantages:

[0037] (1) Crystal forms CSI, CSII, and CSIII have low hygroscopicity.

[0038] On the one hand, high hygroscopicity can easily cause chemical degradation and crystal transformation of APIs, thereby affecting their physicochemical stability. Furthermore, high hygroscopicity can reduce API flowability, thus impacting API processing. Furthermore, highly hygroscopic drugs require low humidity during production and storage, placing higher production requirements and incurring high costs. More importantly, high hygroscopicity can easily cause variations in the active ingredient content of the drug, impacting drug quality.

[0039] The crystal forms CSI, CSII and CSIII provided by the present invention have low hygroscopicity, are not demanding on drug production and storage, reduce drug production, storage and quality control costs, and have strong economic value.

[0040] (2) Crystal forms CSI, CSII, and CSIII have good stability.

[0041] Crystal forms CSI, CSII, and CSIII are stable for at least three months under 40°C / 75% RH and 60°C / 75% RH conditions, and their purity remains basically unchanged, indicating that the three crystal forms have good stability under accelerated conditions and more stringent conditions.

[0042] At the same time, the crystal forms CSI, CSII, and CSIII have good humidity stability. After one cycle of 0% RH-95% RH-0% RH, the crystal forms CSI, CSII, and CSIII did not change in crystalline form.

[0043] High temperatures and humidity caused by seasonal variations, regional climate differences, and environmental factors can impact the storage, transportation, and production of APIs and drug products. Therefore, the stability of APIs and drug products under accelerated and even more stringent conditions is crucial. Crystal forms CSI, CSII, and CSIII exhibit enhanced stability under these harsh conditions, helping to prevent drug quality from devitalization or purity loss during storage.

[0044] The excellent physical and chemical stability of the API crystal form ensures that the drug will not undergo crystal transformation and is essentially free of impurities during production and storage. Crystal forms CSI, CSII, and CSIII exhibit excellent physical and chemical stability, ensuring consistent and controllable quality of the API and drug product, and minimizing changes in drug quality, bioavailability, and toxic side effects caused by changes in crystal form or impurities. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 is the XRPD pattern of crystal form CSI

[0046] Figure 2 is the TGA diagram of crystal form CSI

[0047] Figure 3 is the TGA diagram of crystal form CSI

[0048] Figure 4 is the DVS diagram of crystal form CSI

[0049] Figure 5 is a comparison of XRPD images of crystal form CSI before and after DVS.

[0050] Figure 6 is a comparison of XRPD patterns of Form CSI placed under different conditions (from top to bottom: before placement, after being placed in the open at 40°C / 75% RH for 3 months, after being sealed (with desiccant) at 40°C / 75% RH for 3 months, after being placed in the open at 60°C / 75% RH for 3 months, and after being sealed (with desiccant) at 60°C / 75% RH for 3 months).

[0051] Figure 7 is the XRPD pattern of Form CSII

[0052] Figure 8 is the TGA diagram of crystal form CSII

[0053] Figure 9 is a DVS diagram of crystal form CSII

[0054] Figure 10 is a comparison of XRPD images of crystalline form CSII before and after DVS.

[0055] FIG11 is a comparison of XRPD patterns of Form CSII placed under different conditions (from top to bottom: before placement, after being placed in the open at 40°C / 75% RH for 3 months, after being sealed (with desiccant) at 40°C / 75% RH for 3 months, after being placed in the open at 60°C / 75% RH for 3 months, and after being sealed (with desiccant) at 60°C / 75% RH for 3 months).

[0056] Figure 12 is the XRPD pattern of Form CSIII

[0057] Figure 13 is a DVS diagram of Form CSIII

[0058] Figure 14 is a comparison of XRPD images of Form CSIII before and after DVS.

[0059] FIG15 is a comparison of XRPD patterns of Form CSIII stored under different conditions (from top to bottom: before storage, after being exposed at 40°C / 75% RH for 3 months, after being sealed (with desiccant) at 40°C / 75% RH for 3 months, after being exposed at 60°C / 75% RH for 3 months, and after being sealed (with desiccant) at 60°C / 75% RH for 3 months). DETAILED DESCRIPTION

[0060] The present invention is described in detail with reference to the following examples, which describe in detail the preparation and use of the crystalline forms of the present invention. It will be apparent to those skilled in the art that many variations in both materials and methods may be made without departing from the scope of the present invention.

[0061] The abbreviations used in the present invention are explained as follows:

[0062] XRPD: X-ray powder diffraction

[0063] TGA: Thermogravimetric analysis

[0064] DVS: Dynamic Water Sorption

[0065] HPLC: High Performance Liquid Chromatography

[0066] 1 H NMR: nuclear magnetic resonance

[0067] RH: relative humidity

[0068] Instruments and methods used to collect data:

[0069] The XRPD patterns described in the present invention were collected on a Bruker D8 ADVANCE X-ray powder diffractometer. The X-ray powder diffraction method parameters described in the present invention are as follows:

[0070] X-ray source: Cu, Kα

[0071] Kα1( ):1.54060;Kα2( ):1.54439

[0072] Kα2 / Kα1 intensity ratio: 0.50

[0073] Voltage: 40kV

[0074] Current: 40mA

[0075] Scanning range: from 4.0 to 40.0°

[0076] The TGA graphs of the present invention were collected on a TA Q500. The method parameters for thermogravimetric analysis (TGA) of the present invention are as follows:

[0077] Scan rate: 10℃ / min

[0078] Shielding gas: N2

[0079] The DVS graphs described herein were collected using an Intrinsic dynamic moisture sorption instrument manufactured by SMS (Surface Measurement Systems Ltd.). The instrument control software was DVS-Intrinsic control software. The method parameters for the dynamic moisture sorption instrument were as follows:

[0080] Temperature: 25℃

[0081] Carrier gas, flow rate: N2, 200mL / min

[0082] Relative humidity range: 0%RH-95%RH

[0083] The present invention 1 H NMR data were collected on a Bruker Avance II DMX 400M HZ NMR spectrometer. 1-5 mg of sample was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to prepare a 2-10 mg / mL solution.

[0084] The related substance detection methods involved in the present invention are shown in Table 1.

[0085] Table 1

[0086] In the present invention, the "crystalline solid" refers to a solid substance with different molecular arrangements and / or conformations in the crystal lattice.

[0087] The term "anhydrate" refers to a crystalline substance that does not contain water of crystallization or a crystallization solvent.

[0088] The "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50-1800 rpm, wherein the magnetic stirring is preferably 300-900 rpm and the mechanical stirring is preferably 100-300 rpm.

[0089] The separation is accomplished by conventional methods in the art, such as centrifugation or filtration. The centrifugation operation is as follows: the sample to be separated is placed in a centrifuge tube and centrifuged at a rate of 10,000 rpm until all solids settle to the bottom of the centrifuge tube.

[0090] The "drying" is accomplished using conventional methods in the art, such as vacuum drying, forced air drying, or air drying. The drying temperature can be room temperature or higher, preferably room temperature to about 60°C, or to 50°C, or to 40°C. The drying time can be 0.5-48 hours, or overnight. Drying is performed in a fume hood, forced air oven, or vacuum oven. The "room temperature" is not a specific temperature value, but refers to a temperature range of 10-30°C.

[0091] The "evaporation" is accomplished by conventional methods in the art, such as slow evaporation or fast evaporation. Slow evaporation involves sealing the container with a sealing film, puncturing a hole, and allowing the container to evaporate; fast evaporation involves leaving the container open for evaporation.

[0092] The “characteristic peak” refers to a representative diffraction peak used to identify crystals. When tested using Cu-Kα radiation, the peak position can usually have an error of ±0.2°.

[0093] In the present invention, "crystals" or "crystal forms" can be characterized by X-ray powder diffraction. Those skilled in the art will appreciate that X-ray powder diffraction patterns can vary depending on instrument conditions, sample preparation, and sample purity. The relative intensities of diffraction peaks in an X-ray powder diffraction pattern may also vary with experimental conditions, so the diffraction peak intensities cannot be the sole or decisive factor in determining a crystal form. In fact, the relative intensities of diffraction peaks in an X-ray powder diffraction pattern are related to the preferred orientation of the crystal. The diffraction peak intensities shown herein are illustrative and not intended for absolute comparison. Therefore, those skilled in the art will appreciate that the X-ray powder diffraction patterns of the crystal forms claimed by the present invention do not necessarily have to be identical to those in the Examples described herein; any crystal form having an X-ray powder diffraction pattern with characteristic peaks identical or similar to those in these patterns falls within the scope of the present invention. Those skilled in the art can compare the X-ray powder diffraction patterns listed herein with those of an unknown crystal form to determine whether the two patterns reflect the same or different crystal forms.

[0094] In some embodiments, the crystalline forms CSI, CSII, and CSIII of the present invention are pure and substantially free of any other crystalline forms. As used herein, "substantially free" when referring to a new crystalline form means that the crystalline form contains less than 20% (by weight) of other crystalline forms, particularly less than 10% (by weight) of other crystalline forms, more particularly less than 5% (by weight) of other crystalline forms, and even more particularly less than 1% (by weight) of other crystalline forms.

[0095] The term "about" in the present invention, when used to refer to a measurable value, such as mass, time, temperature, etc., means that there is a certain floating range around the specific value, which can be ±10%, ±5%, ±1%, ±0.5%, or ±0.1%.

[0096] Unless otherwise specified, the following examples were all performed at room temperature.

[0097] According to the present invention, the compound I as the starting material includes but is not limited to solid form (crystalline or amorphous), oily form, liquid form and solution. Preferably, the compound I as the starting material is in solid form.

[0098] Compound I used in the following examples can be prepared according to existing technologies, for example, according to the method described in WO2014100620A3.

[0099] Example 1: Preparation method of crystalline CSI

[0100] Weigh 100.9 mg of Compound I into a glass vial, add 31.75 mL of tetrahydrofuran and 2.05 mL of water to yield a clear solution. The solution was filtered and rotary evaporated at 40°C to yield a solid. The solid was then vacuum dried at 50°C for 16 hours. The resulting solid was then heated at 10°C / min to 160°C, held for 10 minutes, and returned to room temperature to yield a crystalline solid.

[0101] The obtained crystalline solid was tested to be Form CSI of the present invention. Its X-ray powder diffraction data are shown in Table 2, and its X-ray powder diffraction pattern is shown in Figure 1. As shown in Figure 2, the TGA shows a mass loss of approximately 0.01% when heated to 100°C, indicating that Form CSI is anhydrous.

[0102] Table 2

[0103] Example 2: Preparation method of crystalline CSI

[0104] 13.7 mg of Compound I was weighed into a glass bottle, and 0.4 mL of benzonitrile was added thereto. After stirring at room temperature for 3 days, the sample was transferred to 50° C. and stirred for 3 days. The solid was separated and vacuum dried at 50° C. for 1.5 hours to obtain a crystalline solid.

[0105] The obtained crystalline solid was tested to be the crystal form CSI of the present invention, and its X-ray powder diffraction data are shown in Table 3. The TGA graph is shown in Figure 3, and when heated to 100°C, it has a mass loss of about 0.06%.

[0106] Table 3

[0107] Example 3: Hygroscopicity and stability of crystalline CSI

[0108] An appropriate amount of the present invention's crystalline form CSI was tested for moisture gain using a dynamic moisture sorption instrument. The system cycled from 0% RH to 95% RH and then back to 0% RH, recording the mass change at each humidity level. The DVS graph is shown in Figure 4 , demonstrating a hygroscopic weight gain of 0.91% at 80% RH. A comparison of XRPD patterns before and after DVS is shown in Figure 5 . These results demonstrate that the crystalline form remained unchanged before and after DVS, indicating that CSI exhibits excellent humidity stability.

[0109] Appropriate amounts of the crystalline CSI prepared according to the present invention were placed under 40°C / 75% RH and 60°C / 75% RH, respectively, and the purity and crystalline form were determined using HPLC and XRPD. The results are shown in Table 4, and a comparative XRPD diagram is shown in Figure 6. These results demonstrate that crystalline CSI is stable for at least three months at both 40°C / 75% RH and 60°C / 75% RH, demonstrating its excellent stability under both accelerated and more stringent conditions.

[0110] Table 4

[0111] Example 4: Preparation of Crystalline Form CSII

[0112] 10.8 mg of Compound I was weighed into a glass vial, and 0.7 mL of N,N-dimethylacetamide was added to obtain a clear solution. The solution was filtered and evaporated at 50°C for 2 days and then at 80°C for 1 day to obtain a crystalline solid.

[0113] The obtained crystalline solid was tested to be Form CSII of the present invention. Its X-ray powder diffraction data are shown in Table 5, and its X-ray powder diffraction pattern is shown in Figure 7. The TGA analysis, as shown in Figure 8, showed a mass loss of approximately 0.04% upon heating to 100°C, indicating that Form CSII is anhydrous.

[0114] Table 5

[0115] Example 5: Hygroscopicity and stability of crystalline form CSII

[0116] An appropriate amount of the present invention's crystal form CSII was tested for moisture gain using a dynamic moisture sorption instrument. The system cycled from 0% RH to 95% RH and then back to 0% RH, recording the mass change at each humidity level. The DVS graph is shown in Figure 9 , demonstrating a hygroscopic weight gain of 0.22% at 80% RH. A comparison of XRPD patterns before and after DVS of the crystal form CSII is shown in Figure 10 . The results demonstrate that the crystal form remains unchanged before and after DVS, indicating that the crystal form CSII exhibits excellent humidity stability.

[0117] Appropriate amounts of Form CSII prepared according to the present invention were stored at 40°C / 75% RH and 60°C / 75% RH, respectively, and the purity and crystal form were determined using HPLC and XRPD. The results are shown in Table 6, and a comparative XRPD diagram is shown in Figure 11. These results demonstrate that Form CSII is stable for at least three months at both 40°C / 75% RH and 60°C / 75% RH, demonstrating its excellent stability under both accelerated and more stringent conditions.

[0118] Table 6

[0119] Example 6: Preparation of Crystalline Form CSIII

[0120] Weigh 19.8 mg of Compound I into a glass vial and add 2.6 mL of a 4:1, v / v, dimethyl sulfoxide / water mixture. Heat to obtain a clear solution, which is then filtered. Add 1.3 mL of the filtrate to 3 mL of acetonitrile at 5°C and stir at 5°C to obtain a crystalline solid.

[0121] After testing, the obtained crystalline solid was found to be the crystalline form CSIII of the present invention. Its X-ray powder diffraction data is shown in Table 7, and its X-ray powder diffraction pattern is shown in FIG12.

[0122] Table 7

[0123] Example 7: Hygroscopicity and stability of crystalline form CSIII

[0124] An appropriate amount of Form CSIII of the present invention was tested for moisture gain using a dynamic moisture sorption instrument. The system cycled from 0% RH to 95% RH and then back to 0% RH, with the mass change recorded at each humidity level. The DVS graph is shown in Figure 13 , demonstrating a hygroscopic weight gain of 0.56% at 80% RH. A comparison of XRPD patterns of Form CSIII before and after DVS is shown in Figure 14 . These results demonstrate that the crystal form remained unchanged before and after DVS, indicating that Form CSIII exhibits excellent humidity stability.

[0125] Appropriate amounts of Form CSIII prepared according to the present invention were stored at 40°C / 75% RH and 60°C / 75% RH, respectively, and the purity and crystal form were determined using HPLC and XRPD. The results are shown in Table 8, and a comparative XRPD diagram is shown in Figure 15. These results demonstrate that Form CSIII is stable for at least three months at both 40°C / 75% RH and 60°C / 75% RH, demonstrating its excellent stability under both accelerated and more stringent conditions.

[0126] Table 8

[0127] Example 8: NMR data of Form CSI, Form CSII, and Form CSIII

[0128] Take crystal form CSI for 1 H NMR detection, nuclear magnetic data are: 1 H NMR (400MHz, DMSO-d6) δ12.90(s,1H),12.04(s,1H),9.92(s,1H),8.51(d,J=2.1Hz,1H),8.36(d,J=2.1Hz,1H),7. 93(d,J=7.3Hz,2H),7.46(t,J=7.7Hz,2H),7.34(t,J=7.4Hz,1H),6.91(d,J=1.9Hz,1H),2.21(s,3H),2.18(s,3H).

[0129] Take crystal form CSII for 1 H NMR detection, nuclear magnetic data are: 1 H NMR (400MHz, DMSO-d6) δ12.90(s,1H),12.03(s,1H),9.91(s,1H),8.51(d,J=2.2Hz,1H),8.35(d,J=2.1Hz,1H),7. 93(d,J=7.3Hz,2H),7.46(t,J=7.7Hz,2H),7.34(t,J=7.4Hz,1H),6.91(d,J=2.0Hz,1H),2.21(s,3H),2.18(s,3H).

[0130] Take crystal form CSIII for 1 H NMR detection, nuclear magnetic data are: 1H NMR (400MHz, DMSO-d6) δ12.91(s,1H),12.05(s,1H),9.94(s,1H),8.51(d,J=2.1Hz,1H),8.36(d,J=2.1Hz,1H),7. 93(d,J=7.3Hz,2H),7.46(t,J=7.7Hz,2H),7.34(t,J=7.4Hz,1H),6.91(d,J=1.9Hz,1H),2.21(s,3H),2.18(s,3H).

[0131] The above embodiments are intended only to illustrate the technical concepts and features of the present invention. Their purpose is to enable those skilled in the art to understand the contents of the present invention and implement them accordingly. They are not intended to limit the scope of protection of the present invention. Any equivalent changes or modifications made in accordance with the spirit of the present invention are intended to be covered by the scope of protection of the present invention.

Claims

1. A compound I The crystalline form is characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 7.5°±0.2°, 13.7°±0.2°, and 16.8°±0.2°.

2. The crystal form according to claim 1, characterized in that Using Cu—Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at at least one of 2θ values ​​of 13.0°±0.2°, 15.1°±0.2°, and 18.9°±0.2°.

3. The crystal form according to claim 2, characterized in that: Using Cu-Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at at least one of 2θ values ​​of 22.8°±0.2°, 23.6°±0.2°, and 25.6°±0.2°.

4. The crystal form according to claim 1, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern is basically as shown in Figure 1.

5. A compound I The crystalline form is characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 8.6°±0.2°, 12.5°±0.2°, and 22.0°±0.2°.

6. The crystalline form of Compound I according to claim 5, characterized in that: Using Cu—Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at at least one of 2θ values ​​of 7.9°±0.2°, 10.9°±0.2°, and 26.1°±0.2°.

7. The crystalline form of Compound I according to claim 5, characterized in that: Using Cu-Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at at least one of 2θ values ​​of 18.1°±0.2° and 28.8°±0.2°.

8. The crystalline form of Compound I according to claim 5, characterized in that: Using Cu-Kα radiation, its X-ray powder diffraction pattern is substantially as shown in FIG7 .

9. A compound I The crystalline form is characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 7.4°±0.2°, 11.5°±0.2°, and 16.2°±0.2°.

10. The crystalline form of Compound I according to claim 9, characterized in that: Using Cu—Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at at least one of 2θ values ​​of 13.4°±0.2°, 14.9°±0.2°, and 18.0°±0.2°.

11. The crystalline form of Compound I according to claim 9, characterized in that: Using Cu-Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at a 2θ value of 13.7°±0.2°.

12. The crystalline form of Compound I according to claim 9, characterized in that: Using Cu-Kα radiation, its X-ray powder diffraction pattern is substantially as shown in FIG12 .

13. A pharmaceutical composition comprising a therapeutically effective amount of the crystal form according to claim 1, claim 5 or claim 9, and a pharmaceutically acceptable excipient.

14. Use of the crystal form according to claim 1, claim 5 or claim 9 in preparing a drug for inhibiting KIT D816V mutation.

15. Use of the crystal form according to claim 1, claim 5 or claim 9 in the preparation of a drug for treating gastrointestinal stromal tumors and progressive systemic mastocytosis.

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