A her2 inhibitor fumarate crystal form and preparation method and application thereof

Abstract

This invention provides a HER2 inhibitor and its salt crystal form and preparation method. Specifically, this invention provides crystal forms VIII, IX, and X of the compound Zongertinib and their fumarate salt crystal forms and preparation methods. More specifically, this invention provides crystal forms and preparation methods of the salt formed by N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazido[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide and fumaric acid. The fumarate crystal forms provided by this invention, especially fumarate crystal form C, have low hygroscopicity, high crystal stability, high solubility, and are simple to prepare, making them suitable for subsequent drug formulation development and industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a HER2 inhibitor fumarate crystal form, its preparation method and application, and particularly to crystal forms A, B and C of the fumarate compound shown in formula (I), its preparation method, pharmaceutical compositions containing it and its use in the treatment or prevention of HER2-related diseases. Background Technology

[0002] N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]-diazino[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide (hereinafter referred to as "Compound (I)") is a selective HER2 (ErbB2) tyrosine kinase inhibitor disclosed in WO2021 / 213800. It exhibits potent inhibitory activity against both wild-type and mutant HER2, while having no significant effect on wild-type EGFR. Therefore, it can be used to treat or prevent tumors and hyperproliferative diseases that inhibit wild-type and / or mutant HER2, especially non-small cell lung cancer (NSCLC).

[0003] Currently marketed formulations are spray-dried solid dispersion (SDD) film-coated tablets, 60 mg / tablet. This process converts crystalline active pharmaceutical ingredients (APIs) into stable amorphous solid dispersions via spray drying, which are then used to prepare tablets using direct powder compression technology. The aim is to improve the compound's dissolution across a wide pH range and its oral bioavailability. However, amorphous systems are in a highly metastable state with a large surface area and strong hygroscopicity. They are prone to recrystallization during long-term storage or under fluctuating temperature and humidity conditions, leading to altered dissolution behavior and decreased bioavailability. To inhibit recrystallization, the API mass fraction in SDD is typically ≤30%, resulting in low drug loading, large tablet size, and increased swallowing burden for patients. Furthermore, the spray drying process has a narrow window; slight shifts in parameters such as outlet temperature, atomizing pressure, and feed viscosity can cause shifts in particle size distribution and glass transition temperature (Tg), leading to significant differences in dissolution on scale. In addition, to maintain the physical stability of the amorphous form, a large amount of carrier excipients (approximately 50% of the formulation) is required, further increasing excipient costs and shortening the product's shelf life. Therefore, recrystallization risk, high hygroscopicity, low drug loading (≤30%), large tablet weight load, poor process robustness, and high cost have become key pain points that must be continuously monitored for this formulation route.

[0004] Different solid forms of active pharmaceutical ingredients (APIs) exhibit significant differences in physicochemical properties, chemical stability, solubility, and dissolution rate. WO2024 / 133302 discloses seven crystal forms (Form I–VII) of compound (I), among which Forms I, III, and IV show one or more advantages in terms of chemical / physical stability, melting point, hygroscopicity, crystallinity, crystallinity, flowability, and compressibility, with Form IV exhibiting the best overall performance. Form IV is a thermodynamically stable anhydrous form with high crystallinity, high melting point, and low hygroscopicity, which can significantly reduce the risk of phase transitions during production and storage. However, compared to amorphous SDDs, Form IV still has lower solubility in FeSSIF (pH 5.0) and HCl (pH 2.0), limiting its direct use in later-stage formulation development. For poorly soluble drugs, salt formation is a classic strategy to improve solubility, dissolution rate, and bioavailability. Therefore, it is urgent to conduct systematic salt form screening of compound (I) to obtain a salt form that combines high solubility, low hygroscopicity and thermodynamic stability, thereby solving the inherent defects of existing SDD formulations and meeting the needs of subsequent commercial development.

[0005] Summary of the Invention

[0006] The present invention aims to provide the crystalline forms and preparation methods of the compound of formula (I) N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazido[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide and its salts. In addition to the seven crystal forms disclosed in WO2024 / 133302, other crystal forms of the compound of formula (I) have been found, including crystal forms VIII, IX, and X. The salts of the compound of formula (I) include salts formed with fumaric acid.

[0007] The compound of formula (I), N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazido[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide crystal form VIII, has characteristic peaks in its X-ray powder diffraction pattern at 2θ angles of 9.2±0.2, 9.6±0.2, 13.1±0.2, 13.5±0.2, and 14.2±0.2.

[0008] The compound of formula (I), N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazido[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide crystal form VIII, has characteristic peaks in its X-ray powder diffraction pattern at 2θ angles of 9.2±0.2, 9.6±0.2, 13.1±0.2, 13.5±0.2, 14.2±0.2, 15.9±0.2, 17.4±0.2, 19.0±0.2, 21.6±0.2, 22.1±0.2, and 22.6±0.2.

[0009] The compound of formula (I) N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazino[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide crystal form VIII, has essentially the same Figure 1 The X-ray powder diffraction pattern shown is shown.

[0010] This invention also provides a method for preparing the compound of formula (I) N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazido[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide crystal form VIII, comprising the following steps: (a) Add the compound of formula (I) to an ethanol solvent, stir at 15-35 °C for 20-25 h, then filter, and vacuum dry the filter cake at 15-35 °C overnight to obtain the crystal form VIII of the compound of formula (I).

[0011] (b) According to the method for preparing crystal form VIII of compound of formula (I) of the present invention, the reaction temperature is preferably 25-35 °C and the drying temperature is preferably 20-25 °C.

[0012] The compound of formula (I), N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazido[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide crystal form IX, has characteristic peaks in its X-ray powder diffraction pattern at 2θ angles of 7.0±0.2, 8.2±0.2, and 16.3±0.2.

[0013] The compound of formula (I), N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazido[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide crystal form IX, has characteristic peaks in its X-ray powder diffraction pattern at 2θ angles of 7.0±0.2, 8.2±0.2, 14.1±0.2, 16.3±0.2, and 22.7±0.2.

[0014] The compound of formula (I), N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazido[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide crystal form IX, has characteristic peaks in its X-ray powder diffraction pattern at 2θ angles of 7.0±0.2, 8.2±0.2, 12.1±0.2, 13.4±0.2, 14.1±0.2, 14.6±0.2, 16.3±0.2, 19.2±0.2, 20.0±0.2, 20.7±0.2, and 22.7±0.2.

[0015] The compound of formula (I) N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazino[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide crystal form IX has essentially the following Figure 3 The X-ray powder diffraction pattern shown is shown.

[0016] This invention also provides a method for preparing the N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazido[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide crystal form IX of formula (I), comprising the following steps: (a) Add the compound of formula (I) to acetone / water 95 / 5, stir at 15-35 °C for 20-25 h, then filter, and vacuum dry the filter cake at 15-35 °C overnight to obtain the crystal form IX of the compound of formula (I).

[0017] (b) According to the method for preparing the crystal form IX of the compound of formula (I) of the present invention, the reaction temperature is preferably 25-35 °C and the drying temperature is preferably 20-25 °C.

[0018] The compound of formula (I), N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazido[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide crystal form X, has characteristic peaks in its X-ray powder diffraction pattern at 2θ angles of 8.3±0.2, 14.7±0.2, and 22.9±0.2.

[0019] The compound of formula (I), N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazido[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide crystal form X, has characteristic peaks in its X-ray powder diffraction pattern at 2θ angles of 8.3±0.2, 13.6±0.2, 14.7±0.2, 16.7±0.2, and 22.9±0.2.

[0020] The compound of formula (I), N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazido[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide crystal form X, has characteristic peaks in its X-ray powder diffraction pattern at 2θ angles of 8.3±0.2, 10.4±0.2, 12.0±0.2, 13.6±0.2, 14.7±0.2, 15.1±0.2, 16.7±0.2, 17.7±0.2, 22.9±0.2, 24.8±0.2, and 27.5±0.2.

[0021] The compound of formula (I) N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazino[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide crystal form X has essentially the following Figure 5 The X-ray powder diffraction pattern shown is shown.

[0022] This invention also provides a method for preparing the compound of formula (I) N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazido[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide crystal form X, comprising the following steps: (a) Add the compound of formula (I) to acetonitrile / water 95 / 5, stir at 15-35 °C for 20-25 h, then filter, and vacuum dry the filter cake at 15-35 °C overnight to obtain the crystal form X of compound (I).

[0023] (b) According to the method for preparing compound crystal form X of formula (I) of the present invention, the reaction temperature is preferably 25-35 °C and the drying temperature is preferably 20-25 °C.

[0024] This invention also relates to pharmaceutically acceptable salts of compounds of formula (I), specifically: The compound of formula (I), N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazido[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide fumarate crystal form A, has characteristic peaks in its X-ray powder diffraction pattern at 2θ angles of 6.6±0.2, 8.3±0.2, 14.8±0.2, 19.9±0.2, and 22.6±0.2.

[0025] The compound of formula (I), N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazido[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide fumarate crystal form A, has characteristic peaks in its X-ray powder diffraction pattern at 2θ angles of 6.6±0.2, 8.3±0.2, 9.9±0.2, 13.1±0.2, 14.8±0.2, 19.9±0.2, 22.6±0.2, 25.6±0.2, and 26.4±0.2.

[0026] The compound of formula (I) N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazido[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide fumarate crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 57.

[0027] This invention also provides a method for preparing the crystal form A of compound N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazido[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide fumarate of formula (I), comprising the following steps: (a) The compound of formula (I) and 1.1 eq of fumaric acid were added to ethyl acetate and stirred at 15-35 °C for 20-25 h to obtain a suspension. The suspension was filtered, and the filter cake was vacuum dried overnight at 15-35 °C to obtain fumarate form A of compound (I).

[0028] (b) According to the method for preparing fumarate crystal form A of compound (I) of the present invention, the reaction temperature is preferably 25-35 °C and the drying temperature is preferably 20-25 °C.

[0029] The compound of formula (I), N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazido[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide fumarate crystal form B, has characteristic peaks in its X-ray powder diffraction pattern at 2θ angles of 8.5±0.2, 12.7±0.2, 13.0±0.2, 17.0±0.2, and 18.0±0.2.

[0030] The compound of formula (I), N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazido[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide fumarate crystal form B, has characteristic peaks in its X-ray powder diffraction pattern at 2θ angles of 7.4±0.2, 8.5±0.2, 10.5±0.2, 12.2±0.2, 12.7±0.2, 13.0±0.2, 14.1±0.2, 17.0±0.2, 18.0±0.2, 18.5±0.2, and 22.1±0.2.

[0031] The compound of formula (I) N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazido[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide fumarate crystal form B has an X-ray powder diffraction pattern substantially as shown in Figure 59.

[0032] This invention also provides a method for preparing the crystal form B of compound N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazido[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide fumarate of formula (I), comprising the following steps: (a) Add the compound of formula (I) and 1.1 eq fumaric acid to tetrahydrofuran, stir at 15-35 °C for 20-25 h, filter, and vacuum dry the filter cake at 15-35 °C overnight to obtain the fumarate crystal form B of compound (I).

[0033] (b) According to the method for preparing phosphate crystal form B of compound (I) of the present invention, the reaction temperature is preferably 25-35°C and the drying temperature is preferably 20-25°C.

[0034] The present invention provides N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazido[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide fumarate crystal form C of formula (I), whose X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 8.9±0.2, 12.6±0.2, 16.6±0.2, and 17.8±0.2.

[0035] The compound of formula (I), N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazido[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide fumarate crystal form C, has characteristic peaks in its X-ray powder diffraction pattern at 2θ angles of 7.1±0.2, 8.9±0.2, 10.7±0.2, 12.6±0.2, 15.8±0.2, 16.6±0.2, 17.8±0.2, 19.2±0.2, 24.2±0.2, 24.9±0.2, 25.9±0.2, 26.9±0.2, and 30.2±0.2.

[0036] The compound of formula (I) N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazido[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide fumarate crystal form C has an X-ray powder diffraction pattern substantially as shown in Figure 62.

[0037] This invention also provides a method for preparing the crystal form C of compound N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazido[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide fumarate of formula (I), comprising the following steps: (a) Add the compound of formula (I) and 1.1 eq fumaric acid to acetonitrile / water 95 / 5, stir at 15-35 °C for 20-25 h, filter, and vacuum dry the filter cake at 15-35 °C overnight to obtain the fumarate crystal form C of compound (I).

[0038] (b) According to the method for preparing the phosphate crystal form C of the compound of formula (I) of the present invention, the reaction temperature is preferably 25-35°C and the drying temperature is preferably 20-25°C.

[0039] The measurement of the 2θ or diffraction peaks in the X-ray powder diffraction pattern of the crystal form is subject to experimental error. The measurement of the 2θ or diffraction peaks in the X-ray powder diffraction pattern may vary slightly between instrument parameters, equipment models, and sample preparation processes. The experimental error or difference may be ±0.2 units, ±0.1 units, or ±0.05 units. Therefore, the value of the 2θ or diffraction peaks cannot be considered absolute.

[0040] The differential scanning calorimetry (DSC) curves for the crystal form are subject to experimental error. The position and peak value of the endothermic peak may vary slightly depending on instrument parameters, equipment model, and sample preparation process. The experimental error or difference may be less than or equal to 5 °C, or slightly less. The peak position or value of the DSC endothermic peak is not absolute, as it is equal to or less than 4℃, or less than or equal to 3℃, or less than or equal to 2℃, or less than or equal to 1℃.

[0041] This invention provides different crystal forms of N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazido[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide of formula (I) and its salts. These crystal forms have simple preparation methods and good solid-state chemical properties, providing an alternative pharmaceutical form for later formulation development. In previous studies, this invention also discovered crystalline forms VIII, IX, and X of formula (I). Simultaneously, polymorphs of fumarate salts were discovered, including fumarate crystalline form A, fumarate crystalline form B, and fumarate crystalline form C. Among the various salt crystal forms, fumarate crystalline form C of formula (I) is anhydrous, exhibits low hygroscopicity, good solid-state chemical properties, and excellent solubility in FeSSIF, making it a suitable raw material for pharmaceutical formulations. Attached Figure Description

[0042] Figure 1 X-ray powder diffraction (XRPD) pattern of compound (I) crystal form VIII; Figure 2 Thermogravimetric analysis and differential scanning calorimetry (TGA & DSC) results for compound (I) crystal form VIII; Figure 3 X-ray powder diffraction (XRPD) pattern of crystal form IX of compound (I); Figure 4 Thermogravimetric analysis and differential scanning calorimetry (TGA & DSC) results for crystal form IX of compound (I); Figure 5 X-ray powder diffraction (XRPD) pattern of crystal form X of compound (I); Figure 6 Thermogravimetric analysis and differential scanning calorimetry (TGA & DSC) results for crystal form X of compound (I); Figure 7 X-ray powder diffraction (XRPD) pattern of fumarate crystal form A of compound (I); Figure 8 Thermogravimetric analysis and differential scanning calorimetry (TGA & DSC) results of compound (I) fumarate crystal form A; Figure 9 X-ray powder diffraction (XRPD) pattern of fumarate crystal form B of compound (I); Figure 10 1H NMR spectrum of fumarate crystal form B of compound (I) 1 H NMR (H NMR) detection map; Figure 11 Thermogravimetric analysis and differential scanning calorimetry (TGA & DSC) results for compound (I) fumarate crystal form B; Figure 12 X-ray powder diffraction (XRPD) pattern of fumarate crystal form C of compound (I); Figure 13 The 1H NMR spectrum of fumarate crystal form C of compound (I) 1 H NMR (H NMR) detection map; Figure 14 Thermogravimetric analysis and differential scanning calorimetry (TGA & DSC) results of compound (I) fumarate crystal form C; Figure 15 Adsorption kinetics curves of fumarate crystal form C of compound (I); Figure 16 Adsorption-desorption curves of fumarate crystal form C of compound (I); Figure 17 XRPD overlay images of the fumarate crystal form C of compound (I) before and after adsorption and desorption. Detailed Implementation

[0043] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. All technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. The preferred embodiments and materials shown herein are for illustrative purposes only.

[0044] The present invention employs the following general method for crystal form detection: A. X-ray powder diffraction (XRPD) detection method X-ray powder diffraction patterns were determined using a Bruker D2 Phaser X-ray diffractometer equipped with a LynxEye detector. In XRPD analysis, the 2θ scan angle of the sample was from 3... o up to 40 o The scan step size is 0.02. o The scanning rate was 0.1 seconds per step. The X-ray emitter was Cu Kα ( = 1.5418 Å), the phototube voltage and current are 30 kV and 10 mA respectively, the divergence slit is 0.6 mm, the anti-scattering slit is 8 mm, and the Sola slit is 2.5 mm. o .

[0045] B. Differential Scanning Calorimetry (DSC) Detection Method The instrument used for differential scanning calorimetry was a DSC 3 (METTLER TOLEDO). 1-5 mg samples were weighed and placed in the perforated aluminum crucible of the DSC, and then... o The heating rate of C / min starts from 0 o C. Heat to the final temperature.

[0046] C. Thermogravimetric analysis (TGA) testing method The instrument used for thermogravimetric analysis was a TGA 2 SF (METTLER TOLEDO). 1-5 mg of sample was placed in an open aluminum sample dish, and incubated at 10... o The rate of C / min is from 30 o C. Heat to the final temperature.

[0047] D. Dynamic vapor adsorption (DVS) detection method Dynamic vapor adsorption measurements were performed using a TA SA, US water vapor adsorption analyzer at 25 ± 0.5°C. Approximately 8 mg of sample was equilibrated at 0% relative humidity (RH) before the test was initiated with a predetermined humidity protocol (0-90-0% RH, undergoing one adsorption-desorption cycle).

[0048] E. Proton nuclear magnetic resonance spectrum (NMR) 1 H NMR detection method 1H NMR spectroscopy was performed using a Bruker AVANCE III HD 400 instrument equipped with a SampleXpress 60 autosampler. Deuterated DMSO was used as the deuterated solvent to dissolve the samples.

[0049] F. High-performance liquid chromatography (HPLC) detection method A Waters XBridge C18, 150*4.6mm, 3.5µm HPLC column was used at a flow rate of 1.0 mL / min and a column temperature of 40 °C. o C. Detection wavelength: 210 nm. The mobile phase consisted of chromatographic grade acetonitrile (mobile phase A) and water (0.1% phosphoric acid) (mobile phase B) eluted according to a gradient program, as shown in the table below:

[0050] Example 1: Preparation of crystal form VIII of compound (I) Approximately 30 mg of the free form of compound (I) was added to 1.6 mL of ethanol to form a suspension. The suspension was stirred at room temperature for 20-25 h. The mixture was then filtered, and the filter cake was vacuum dried overnight at room temperature to obtain crystal form VIII of compound (I).

[0051] X-ray powder diffraction was performed on the crystal form VIII of compound (I), and the diffraction pattern is shown in the appendix. Figure 1 The diffraction peak data are as follows:

[0052]

[0053] Other test and analysis results are attached. Figure 2 The TGA results for crystal form VIII of compound (I) show a weight loss of 0.9% from 30.0 to 127.9 °C, which should be due to the loss of surface ethanol and water. The DSC results show four endothermic / exothermic peaks with onset values ​​of 167.9, 196.2 (exo), 229.4, and 233.6 °C (exo), respectively, suggesting that crystal form VIII of compound (I) is a metastable crystal form.

[0054] Example 2: Preparation of crystal form IX of compound (I) Approximately 30 mg of the free form of compound (I) was added to 1 mL of acetone / water (95 / 5) to form a suspension. The suspension was stirred at room temperature for 20-25 h. The mixture was then filtered, and the filter cake was vacuum dried overnight at room temperature to obtain the crystal form IX of compound (I).

[0055] X-ray powder diffraction was performed on the crystal form IX of compound (I), and the diffraction pattern is shown in the appendix. Figure 3 The diffraction peak data are as follows:

[0056]

[0057] Other test and analysis results are attached. Figure 4The TGA results for crystal form IX of compound (I) show a weight loss of 5.6% from 30.0 to 117.6 °C, which should be due to the loss of acetone and water. DSC analysis reveals five endothermic and exothermic peaks with onset values ​​of 69.8, 156.5, 174.0 (exo), 228.1, and 235.2 °C (exo), respectively. 228.1 °C is the melting point of free alkali crystal form A; therefore, crystal form IX of compound (I) is a metastable crystal form.

[0058] Example 3: Preparation of crystal form X of compound (I) Approximately 30 mg of the free form of compound (I) was added to 1 mL of acetonitrile / water 95 / 5 to form a suspension. The suspension was stirred at room temperature for 20-25 h, and then the mixture was filtered. The filter cake was vacuum dried overnight at room temperature to obtain the crystal form X of compound (I).

[0059] X-ray powder diffraction was performed on crystal form X of compound (I), and the diffraction pattern is shown in the appendix. Figure 5 The diffraction peak data are as follows:

[0060]

[0061] Other test and analysis results are attached. Figure 6 The TGA results for crystal form X of compound (I) show a weight loss of 4.0% from 30.0 to 114.5 °C, which should be due to the loss of water. The DSC shows five endothermic and exothermic peaks with onset values ​​of 72.7, 160.8, 173.4 (exo), 228.9, and 235.1 °C (exo), respectively. Among them, 228.9 °C is the melting point of the free state crystal form A. Therefore, crystal form X of compound (I) is a metastable crystal form.

[0062] Example 4: Preparation of fumarate crystal form A of compound (I) Approximately 30 mg of compound (I) and 1.1 eq of fumaric acid were added to 1.5 mL of ethyl acetate to form a suspension. The suspension was stirred at room temperature for 20-25 h. The suspension was filtered, and the filter cake was vacuum dried overnight at room temperature to obtain fumaric salt crystal form A of compound (I).

[0063] X-ray powder diffraction was performed on fumarate crystal form A of compound (I). The diffraction pattern is shown in the appendix. Figure 7 The diffraction peak data are as follows:

[0064] Other test and analysis results are attached. Figure 8The TGA results of compound (I) fumarate crystal form A showed a weight loss of 1.1% from 30.0 to 127.1 °C, which should be due to the loss of surface water. The DSC results showed endothermic peaks at 37.8 °C and 152 °C (50.4 J / g), corresponding to desolvation and melting, suggesting that fumarate crystal form A is an anhydrous product.

[0065] Example 5: Preparation of fumarate crystal form B of compound (I) Approximately 30 mg of compound (I) and 1.1 eq of fumaric acid were added to 1 mL of tetrahydrofuran to form a suspension. The suspension was stirred at room temperature for 20-25 h. The suspension was filtered, and the filter cake was vacuum dried overnight at room temperature to obtain fumarate form B of compound (I).

[0066] X-ray powder diffraction was performed on fumarate crystal form B of compound (I). The diffraction pattern is shown in the appendix. Figure 9 The diffraction peak data are as follows:

[0067] Other test and analysis results are attached. Figure 10-11 The NMR results of compound (I) fumarate form B showed no obvious solvent residue, and the TGA results showed a weight loss of 0.8% from 30.0 to 120.8 °C, which should be due to the loss of water. The DSC results showed endothermic peaks at 37.6 °C and 157.4 °C (53.2 J / g), corresponding to solvent removal and melting, suggesting that fumarate form B is an anhydrous product.

[0068] Example 6: Preparation of fumarate crystal form C of compound (I) Approximately 30 mg of compound (I) and 1.1 eq of fumaric acid were added to 1 mL of acetonitrile / water (95 / 5) to form a suspension. The suspension was stirred at room temperature for 20-25 h. The suspension was filtered, and the filter cake was vacuum dried overnight at room temperature to obtain fumarate form C of compound (I).

[0069] X-ray powder diffraction was performed on the fumarate crystal form C of compound (I). The diffraction pattern is shown in the appendix. Figure 12 The diffraction peak data are as follows:

[0070]

[0071] Other test and analysis results are attached. Figure 13-14The NMR results of compound (I) fumarate crystal form C showed no obvious solvent residue, and the TGA results showed a weight loss of 0.9% from 30.0 to 130.1 °C, which should be due to the loss of surface water. The DSC results showed endothermic peaks at 36.8 °C and 200.3 °C, corresponding to desolvation and melting, suggesting that fumarate crystal form C is an anhydrous product.

[0072] Example 7: Preparation of fumarate crystal form C of compound (I) Approximately 240 mg of compound (I) and 1.1 eq of fumaric acid were added to 10 mL of acetonitrile / water (95 / 5) to form a suspension. The suspension was stirred at 50 °C for 5-6 h. After filtration, the filter cake was vacuum dried overnight at room temperature to obtain 230.5 mg of dry product, with a yield of 78.9% (based on the free state). X-ray powder diffraction analysis showed that the crystal form was the same as in Example 6.

[0073] Test Example 1: Hygroscopicity

[0074] Dynamic vapor adsorption analysis was performed on fumarate crystal form C of compound (I). The relevant results are shown in the appendix. Figure 15-17 The results showed that the adsorption-desorption curve of the initial sample was at 25°C. o The moisture adsorption at C / 80% RH (relative humidity) is 2.016%. The hygroscopicity data of the solid dispersion reported in patent WO2024133325 were collected and compared, showing that the fumarate crystal form C has lower hygroscopicity, and the crystal form remains unchanged after DVS test.

[0075] Test Example 2: Solubility

[0076] The fumarate crystal form C of formula (1) was suspended in the appropriate buffer solution and equilibrated in a constant-temperature shaker at 37°C for 24 hours. After filtration, the supernatant was analyzed by HPLC to determine the saturation concentration, and the solubility was calculated based on a standard curve. Compared with the amorphous solid dispersion reported in US2024 / 0226103A1 and form IV of formula (1), fumarate crystal form C exhibited superior solubility characteristics in FeSSIF. These results indicate that fumarate crystal form C has the potential to be used as a pharmaceutical crystal form for formulation development, providing a feasible option for subsequent formulation strategies.

Claims

1. A crystal form of the fumarate salt of the compound shown in formula (I), characterized in that, ； The crystal form is selected from at least one of the following groups: 1) Fumarate crystal form C, wherein the X-ray powder diffraction pattern of fumarate crystal form C has characteristic peaks at 2θ angles of 8.9±0.2, 12.6±0.2, 16.6±0.2, and 17.8±0.2; 2) Fumarate crystal form A, wherein the X-ray powder diffraction pattern of fumarate crystal form A has characteristic peaks at 2θ angles of 6.6±0.2, 8.3±0.2, 14.8±0.2, 19.9±0.2, and 22.6±0.2; 3) Fumarate crystal form B, wherein the X-ray powder diffraction pattern of fumarate crystal form B has characteristic peaks at 2θ angles of 8.5±0.2, 12.7±0.2, 13.0±0.2, 17.0±0.2, and 18.0±0.

2.

2. The crystal form according to claim 1, characterized in that, The X-ray powder diffraction pattern of the fumarate crystal form C has characteristic peaks at 2θ angles of 7.1±0.2, 8.9±0.2, 10.7±0.2, 12.6±0.2, 15.8±0.2, 16.6±0.2, 17.8±0.2, 19.2±0.2, 24.2±0.2, 24.9±0.2, 25.9±0.2, 26.9±0.2, and 30.2±0.

2.

3. The crystal form according to claim 1, characterized in that, The X-ray powder diffraction pattern of the fumarate crystal form A has characteristic peaks at 2θ angles of 6.6±0.2, 8.3±0.2, 9.9±0.2, 13.1±0.2, 14.8±0.2, 19.9±0.2, 22.6±0.2, 25.6±0.2, and 26.4±0.

2.

4. The crystal form according to claim 1, characterized in that, The X-ray powder diffraction pattern of the fumarate crystal form B has characteristic peaks at 2θ angles of 7.4±0.2, 8.5±0.2, 10.5±0.2, 12.2±0.2, 12.7±0.2, 13.0±0.2, 14.1±0.2, 17.0±0.2, 18.0±0.2, 18.5±0.2, and 22.1±0.

2.

5. A method for preparing the crystal form of the fumarate of formula (I) according to any one of claims 1-4, characterized in that, The fumarate crystal form C is prepared by the following steps: the compound of formula (I) and fumaric acid are added to an acetonitrile / water mixed solvent to form a salt crystallization, and the resulting solid is dried under vacuum after filtration to obtain the fumarate crystal form C. And / or, The fumarate crystal form A is prepared by the following steps: adding the compound of formula (I) and fumaric acid to ethyl acetate to form a salt crystal, filtering and then drying the resulting solid under vacuum to obtain the fumarate crystal form A; And / or, The fumarate crystal form B is prepared by the following steps: adding the compound of formula (I) and fumaric acid to tetrahydrofuran for salt crystallization, filtering and then vacuum drying the resulting solid to obtain the fumarate crystal form B.

6. A pharmaceutical composition of a compound of formula (I), characterized in that, It comprises the crystal form of the fumarate as described in any one of claims 1-4 and one or more pharmaceutically acceptable excipients.

7. The pharmaceutical composition according to claim 6, characterized in that, The pharmaceutical composition is in the form of tablets, capsules, granules, or powder.

8. The crystal form of the fumarate according to any one of claims 1-4, or the use of the pharmaceutical composition according to claim 6 in the preparation of a medicament for treating or preventing HER2-related diseases.

9. The use according to claim 8, characterized in that, The HER2-related disease is non-small cell lung cancer.

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