Crystal form of quinazoline derivative and preparation method thereof

Abstract

The invention relates to a crystal form of a quinazoline derivative and a preparation method thereof. Specifically, the invention provides an E crystal form, a D crystal form and an H crystal form of 1-(inner-3-((4-((4-([1, 2, 4] triazolo [1, 5-a] pyridine-7-yloxy)-2-fluoro-3-methylphenyl) amino) quinazoline-6-yl) oxy)-8-azabicyclo [3.2. 1] oct-8-yl) prop-2-en-1-one, and the E crystal form, the D crystal form and the H crystal form have good stability and can be better used for clinical treatment. Formula (I).

Description

Crystalline form of a quinazoline derivative and its preparation method

[0001] This application claims the following priority:

[0002] Application number: CN202311254943.2, application date: September 27, 2023.

[0003] This disclosure belongs to the field of pharmaceutical technology and relates to a crystalline form of a quinazoline derivative and its preparation method.

[0004] Human epidermal growth factor receptor 2 (HER2; Neu, ERBB2) is a member of the type I receptor tyrosine kinase family, which also includes EGFR (ERBB1), HER3 (ERBB3), and HER4 (ERBB4). To date, no ligand has been found in the human body that can directly bind to HER2. HER2 must form homodimers or heterodimers with other family members (such as HER3). After HER2 dimerization, its conformation changes, activating intracellular tyrosine kinase activity, which in turn activates downstream pathways (MAPK signaling pathway and PI3K / AKT signaling pathway), thereby exerting its corresponding physiological functions.

[0005] It is estimated that approximately 2-4% of lung cancer patients carry activating mutations in HER2 exon 20. Currently approved ERBB-targeting tyrosine kinase inhibitors are largely ineffective in these patients, primarily due to dose-limiting toxicity mediated by EGFR wild-type mutations. Afatinib, ibrutinib, neratinib, poziotinib, and pyrotinib are known broad-spectrum ERBB inhibitors targeting HER2 exon 20 mutations. However, clinically, due to effective dose limitations, afatinib and other broad-spectrum ERBB inhibitors have shown only limited efficacy in NSCLC patients with HER2 exon 20 mutations.

[0006] PCT / CN2023 / 084265 discloses a novel inhibitor selective for EGFR wild-type HER2 exon 20 mutations, chemically named 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one, having the structure shown in Formula 1.

[0007] The crystal form of a pharmaceutical active ingredient often affects its chemical stability. Different crystallization and storage conditions can lead to changes in the crystal structure of the compound, sometimes even resulting in other crystal forms. Generally, amorphous drug products lack regular crystal structures and often have other defects, such as poor product stability, fine crystals, difficulty in filtration, easy agglomeration, and poor flowability. Polymorphism of drugs places different requirements on product storage, production, and scale-up. Therefore, in-depth research on the crystal forms of the aforementioned compounds and the improvement of their various properties is essential.

[0008]

[0009] This disclosure provides a novel crystal form of the compound shown in Formula 1, which has good stability and can be better applied in clinical practice.

[0010] The crystal form A of the compound of Formula 1 provided in this disclosure has characteristic peaks at 8.905, 9.836, 12.375, 13.207, 17.814, 18.265, 19.863 and 26.491 in its X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0011] In some embodiments, the crystal form of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 1.

[0012] This disclosure also provides a method for preparing crystal form A of the compound shown in Formula 1, comprising dissolving the compound shown in Formula 1 in methanol / ethyl acetate = 1:10 (v / v) and evaporating the solvent to precipitate crystals.

[0013] The crystal form B of the compound shown in Formula 1, as provided in this disclosure, has a characteristic peak at 8.963, 9.926, 17.902, 18.404, 19.850 and 22.049 in its X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0014] In some embodiments, the crystal form B of the compound shown in Formula 1 has characteristic peaks at 8.963, 9.926, 12.368, 13.219, 17.902, 18.404, 19.850 and 22.049 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0015] In some embodiments, the X-ray powder diffraction pattern of crystal form B of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, is shown in Figure 2.

[0016] This disclosure also provides a method for preparing crystal form B of the compound shown in Formula 1, comprising adding crystal form A of the compound shown in Formula 1 to methanol and stirring.

[0017] The crystal form C of the compound shown in Formula 1, as provided in this disclosure, has an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, with characteristic peaks at 6.071, 8.758, 13.787, 15.348, 17.522, and 21.621.

[0018] In some embodiments, the crystal form C of the compound shown in Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles 2θ, has characteristic peaks at 6.071, 8.758, 9.708, 13.787, 15.348, 17.522, 18.228, and 21.621.

[0019] In some embodiments, the X-ray powder diffraction pattern of crystal form C of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 6.071, 8.758, 9.708, 13.787, 15.348, 17.522, 18.228, 18.695, 21.621, 24.874, and 25.724.

[0020] In some embodiments, the X-ray powder diffraction pattern of the crystal form C of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 3.

[0021] This disclosure also provides a method for preparing the crystal form C of the compound shown in Formula 1, comprising:

[0022] Method 1: Dissolve the compound shown in Formula 1 in solvent A and stir. Solvent A is selected from one of ethanol, n-propanol, ethyl acetate / ethanol = 1:1 (v / v), and tetrahydrofuran / ethanol = 2:1 (v / v).

[0023] Method 2: Dissolve the compound shown in Formula 1 in n-propanol, add n-heptane, and stir.

[0024] The crystal form D of the compound shown in Formula 1, as provided in this disclosure, has an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, with characteristic peaks at 6.989, 10.610, 13.927, 14.544, 18.332, 18.930 and 23.940.

[0025] In some embodiments, the crystal form D of the compound shown in Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles 2θ, has characteristic peaks at 6.989, 7.512, 10.223, 10.610, 11.281, 13.927, 14.544, 14.805, 16.535, 18.332, 18.930, and 23.940.

[0026] In some embodiments, the crystal form D of the compound shown in Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles 2θ, has characteristic peaks at 6.989, 7.512, 10.223, 10.610, 11.281, 13.310, 13.927, 14.544, 14.805, 16.535, 17.044, 18.332, 18.930, 20.617, 21.313, and 23.940.

[0027] In some embodiments, the X-ray powder diffraction pattern of the crystal form D of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 4.

[0028] This disclosure also provides a method for preparing the crystal form D of the compound shown in Formula 1, the method comprising:

[0029] Method 1: Add the compound shown in Formula 1 to solvent V and stir. Solvent V is selected from one or more of water, isopropyl acetate, toluene, and ethyl acetate / n-heptane = 1:1 (v / v).

[0030] Method 2: Dissolve the compound shown in Formula 1 in solvent VI and stir. Solvent VI is selected from one or more of dichloromethane, tetrahydrofuran, water / isopropanol = 1:9 (v / v), and water / acetone = 1:9 (v / v).

[0031] Method 3: Dissolve the compound shown in Formula 1 in solvent VII, add solvent VIII, and stir; when VII is selected from n-propanol, propylene glycol methyl ether, and tetrahydrofuran, the added solvent VIII is water; when VII is selected from dichloromethane, the added solvent VIII is selected from ethyl acetate and methyl tert-butyl ether.

[0032] Method 4: Dissolve the compound shown in Formula 1 in solvent IX and allow it to evaporate and crystallize; wherein IX is selected from one or more of propylene glycol methyl ether and N,N-dimethylformamide.

[0033] The crystal form E of the compound shown in Formula 1, as provided in this disclosure, has an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, with characteristic peaks at 10.080, 14.012, 17.465, 18.635, 20.135, and 24.921.

[0034] In some embodiments, the crystal form E of the compound shown in Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles 2θ, has characteristic peaks at 10.080, 11.701, 12.776, 14.012, 15.958, 17.465, 17.696, 20.135, 21.144, 23.088, and 24.921.

[0035] In some embodiments, the X-ray powder diffraction pattern of the crystal form E of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 10.080, 10.296, 11.701, 12.776, 14.012, 14.286, 15.958, 16.507, 17.177, 17.465, 17.696, 18.635, 19.111, 19.828, 20.135, 21.144, 23.088, 24.921, 26.493, and 31.991.

[0036] In some embodiments, the X-ray powder diffraction pattern of the crystal form E of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 5.

[0037] This disclosure also provides a method for preparing crystal form E of the compound shown in Formula 1, the method comprising:

[0038] Method 1: Add the compound shown in Formula 1 to solvent I and stir. Solvent I is selected from one or more of ethyl acetate, acetonitrile, n-heptane, methyl tert-butyl ketone, isopropanol, 1,4-dioxane, 2-methyltetrahydrofuran, acetone, methyl tert-butyl ether, cyclohexane, n-hexane, and isopropyl ether.

[0039] Method 2: Dissolve the compound shown in Formula 1 in solvent II, add solvent III, and stir; when II is selected from n-propanol, the added solvent III is selected from ethyl acetate, acetonitrile, methyl tert-butyl ether, and methyl isobutyl ketone; when II is selected from propylene glycol methyl ether or tetrahydrofuran, the added solvent III is selected from ethyl acetate, acetonitrile, methyl tert-butyl ether, methyl isobutyl ketone, and n-heptane; when II is selected from dichloromethane, the added solvent III is selected from isopropyl ether, methyl isobutyl ketone, and n-heptane.

[0040] The crystal form F of the compound shown in Formula 1, as provided in this disclosure, has a characteristic peak at 10.529, 12.617, 13.759, 17.919 and 18.778 in its X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0041] In some embodiments, the crystal form F of the compound shown in Formula 1 has characteristic peaks at 10.529, 12.617, 13.759, 17.919, 18.778, 22.566, 23.328, 24.788 and 25.666 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0042] In some embodiments, the X-ray powder diffraction pattern of the crystal form F of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 10.529, 12.617, 13.759, 17.919, 18.778, 20.887, 22.566, 23.328, 24.788, 25.666, 30.028, and 31.080.

[0043] In some embodiments, the X-ray powder diffraction pattern of the crystal form F of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 6.

[0044] This disclosure also provides a method for preparing the crystal form F of the compound shown in Formula 1, the method comprising adding the compound shown in Formula 1 to a solvent B and stirring, wherein the solvent B is selected from methanol, water / methanol = 1:1 (v / v), water / methanol = 1:9 (v / v), and acetonitrile / methanol = 1:1 (v / v).

[0045] The crystal form G of the compound shown in Formula 1, as provided in this disclosure, has an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, with characteristic peaks at 10.437, 11.093, 13.989, 17.124, 17.620, 21.374, and 22.677.

[0046] In some embodiments, the crystal form G of the compound shown in Formula 1 has characteristic peaks at 10.437, 11.093, 13.989, 17.124, 17.620, 19.601, 19.929, 21.374 and 22.677 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0047] In some embodiments, the crystal form G of the compound shown in Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles 2θ, has characteristic peaks at 10.437, 11.093, 11.362, 11.881, 12.161, 13.989, 17.124, 17.620, 19.601, 19.929, 21.374, and 22.677.

[0048] In some embodiments, the X-ray powder diffraction pattern of the crystal form G of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 7.

[0049] This disclosure also provides a method for preparing crystal form G of the compound shown in Formula 1, the method comprising adding crystal form F of the compound shown in Formula 1 to solvent C and stirring; wherein solvent C is selected from tetrahydrofuran, 2-butanone, and methyl isobutanone.

[0050] The crystal form H of the compound shown in Formula 1, as provided in this disclosure, has an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, with characteristic peaks at 10.963, 11.405, 17.174, 20.715, 21.265 and 24.600.

[0051] In some embodiments, the crystal form H of the compound shown in Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles 2θ, has characteristic peaks at 10.963, 11.405, 12.273, 14.569, 17.174, 20.715, 21.265, 21.328, 22.626, 22.834, and 24.600.

[0052] In some embodiments, the crystal form H of the compound shown in Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles 2θ, has characteristic peaks at 10.963, 11.405, 12.273, 14.569, 17.174, 20.715, 21.265, 21.328, 22.626, 22.834, 24.600, 27.581, and 30.944.

[0053] In some embodiments, the X-ray powder diffraction pattern of the crystal form H of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 8.

[0054] This disclosure also provides a method for preparing the crystal form H of the compound shown in Formula 1, the method comprising:

[0055] Method 1: Dissolve the compound shown in Formula 1 in water / ethanol = 0.7:9.3 (v / v), isopropanol, or 2-butanone, and stir.

[0056] Method 2: Dissolve the compound shown in Formula 1 in dichloromethane, add acetonitrile and stir.

[0057] The present disclosure also provides crystal form I of the compound of formula 1, and X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, with characteristic peaks at 8.451, 9.371, 12.950, 15.468, 24.693 and 26.353.

[0058] In some embodiments, the X-ray powder diffraction pattern of crystal form I of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 8.451, 9.371, 12.950, 13.556, 15.468, 17.911, 19.681, 24.693, and 26.353.

[0059] In some embodiments, the X-ray powder diffraction pattern of crystal form I of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, is shown in Figure 9.

[0060] This disclosure also provides a method for preparing crystal form I of the compound shown in Formula 1, the method comprising adding the compound shown in Formula 1 to water / methanol = 8:2 (v / v) and stirring.

[0061] The crystal form J of the compound shown in Formula 1, as provided in this disclosure, has an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, with characteristic peaks at 9.020, 10.008, 17.472, 18.631, 20.232, 24.977, and 26.623.

[0062] In some embodiments, the crystal form J of the compound shown in Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles 2θ, has characteristic peaks at 9.020, 10.008, 13.149, 15.973, 17.472, 18.631, 20.232, 23.333, 24.977, and 26.623.

[0063] In some embodiments, the X-ray powder diffraction pattern of the crystal form J of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 10.

[0064] This disclosure also provides a method for preparing the compound J of Formula 1, the method comprising adding the compound of Formula 1 to water / methanol = 8:2 (v / v) and stirring.

[0065] The crystal form K of the compound shown in Formula 1, as provided in this disclosure, has an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, with characteristic peaks at 5.814, 11.642, 13.010, 15.159, 20.326, and 23.543.

[0066] In some embodiments, the X-ray powder diffraction pattern of the crystal form K of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 11.

[0067] This disclosure also provides a method for preparing the crystal form K of the compound shown in Formula 1, the method comprising dissolving the compound shown in Formula 1 in acetonitrile and then volatilizing and crystallizing it.

[0068] The crystal form L of the compound shown in Formula 1, as provided in this disclosure, has a characteristic peak at 7.471, 10.514, 13.476, 16.708, 18.749, and 21.243 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0069] In some embodiments, the crystal form L of the compound shown in Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles 2θ, has characteristic peaks at 5.350, 7.471, 10.514, 13.476, 13.876, 16.708, 18.749, 21.243, 23.202, and 26.097.

[0070] In some embodiments, the X-ray powder diffraction pattern of the crystal form L of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 5.350, 7.471, 10.514, 12.171, 13.476, 13.876, 15.802, 16.708, 17.950, 18.749, 21.243, 21.932, 23.202, 24.826, and 26.097.

[0071] In some embodiments, the X-ray powder diffraction pattern of the crystal form L of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 13.

[0072] This disclosure also provides a method for preparing crystal form L of the compound shown in Formula 1, the method comprising the steps of dissolving the compound shown in Formula 1 in acetone and stirring.

[0073] This disclosure also provides a pharmaceutical composition comprising the aforementioned crystal form A, B, C, D, E, F, G, H, I, J, K, or L, and a pharmaceutical excipient optionally selected from pharmaceutically acceptable excipients.

[0074] This disclosure also provides a pharmaceutical composition prepared from the aforementioned crystal forms A, B, C, D, E, F, G, H, I, J, K, or L, and optionally a pharmaceutically acceptable excipient.

[0075] This disclosure also provides a method for preparing a pharmaceutical composition, comprising the step of mixing the aforementioned crystal form A, B, C, D, E, F, G, H, I, J, K, or L with a pharmaceutically acceptable excipient.

[0076] This disclosure also provides the use of the aforementioned crystal forms A, B, C, D, E, F, G, H, I, J, K, or L, or the aforementioned compositions, in the preparation for the prevention and / or treatment of cancer.

[0077] The uses described in this disclosure, wherein the cancer is selected from breast cancer, ovarian cancer, gastric cancer, colorectal cancer, cervical cancer, endometrial cancer, bladder cancer, brain cancer, epithelial cancer, esophageal cancer, mesothelioma, nasopharyngeal carcinoma, oral cancer, thyroid cancer, skin cancer, squamous cell carcinoma, synovoma, and sweat gland cancer; preferably, the cancer is selected from breast cancer, ovarian cancer, cervical cancer, endometrial cancer, gastric cancer, colorectal cancer, and lung cancer.

[0078] The "2θ or 2θ angle" mentioned in this disclosure refers to the diffraction angle, where θ is the Bragg angle, and the unit is ° or degree; the error range of 2θ for each characteristic peak is ±0.20 (including the case where the number has more than one decimal place after rounding), specifically -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.

[0079] The numerical values ​​in this disclosure, such as those relating to the content of certain substances, are calculated data and inevitably contain a certain degree of error. Generally, ±10% is within the reasonable error range. The error may vary to some extent depending on the context in which it is used, but this variation shall not exceed ±10%, and may be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%.

[0080] The starting material used in the crystal form preparation method disclosed herein can be any form of compound, including but not limited to: amorphous, arbitrary crystal form, hydrate, solvate, etc.

[0081] The drying temperature described in this disclosure is generally 25℃-100℃, preferably 40℃-70℃, and can be dried under normal pressure or reduced pressure.

[0082] The crystallization methods described in this disclosure include room temperature crystallization, cooling crystallization, solvent evaporation crystallization, and seed crystallization induction. The cooling temperature is selected from below 65°C, preferably from -10°C to 60°C. Stirring can also be performed during the crystallization process.

[0083] The “differential scanning calorimetry or DSC” described in this disclosure refers to measuring the temperature difference and heat flow difference between the sample and the reference material during the sample heating or isothermal process, in order to characterize all physical and chemical changes related to thermal effects and obtain phase transition information of the sample.

[0084] According to the description of hygroscopic characteristics and the definition of hygroscopic weight gain in the "Guiding Principles on Hygroscopicity of Drugs" in Part IV of the 2015 edition of the Chinese Pharmacopoeia,

[0085] Deliquescence: Absorbs sufficient moisture to form a liquid;

[0086] Extremely hygroscopic: the weight gain due to hygroscopic absorption is not less than 15%;

[0087] It has hygroscopic properties: the weight gain due to hygroscopic absorption is less than 15% but not less than 2%;

[0088] Slightly hygroscopic: the weight gain due to moisture absorption is less than 2% but not less than 0.2%;

[0089] It has little or no hygroscopicity: the weight gain due to moisture absorption is less than 0.2%.

[0090] The “excipients” described in this disclosure include, but are not limited to, any adjuvants, carriers, flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, or emulsifiers that have been approved by the U.S. Food and Drug Administration for use in humans or livestock.

[0091] Figure 1 shows the XRPD spectrum of crystal form A of compound 1.

[0092] Figure 2 shows the XRPD spectrum of crystal form B of compound 1.

[0093] Figure 3 shows the XRPD spectrum of crystal form C of compound 1.

[0094] Figure 4 shows the XRPD spectrum of crystal form D of compound 1.

[0095] Figure 5 shows the XRPD spectrum of crystal form E of compound 1.

[0096] Figure 6 shows the XRPD spectrum of crystal form F of compound 1.

[0097] Figure 7 shows the XRPD spectrum of crystal form G of compound 1.

[0098] Figure 8 shows the XRPD spectrum of crystal form H of compound 1.

[0099] Figure 9 shows the XRPD spectrum of crystal form I of compound 1.

[0100] Figure 10 shows the XRPD spectrum of crystal form J of compound 1.

[0101] Figure 11 shows the XRPD spectrum of crystal form K of compound 1.

[0102] Figure 12 shows the XRPD spectrum of the amorphous compound 1.

[0103] Figure 13 shows the XRPD spectrum of crystal form L of compound 1.

[0104] The present disclosure will be explained in more detail below with reference to embodiments or experimental examples. The embodiments or experimental examples in the present disclosure are only used to illustrate the technical solutions in the present disclosure and are not intended to limit the substance and scope of the present disclosure.

[0105] Test conditions of the instruments used in the experiment:

[0106] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰. -6 The unit (ppm) is given. NMR determination was performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0107] MS measurements were performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometry system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0108] waters ACQuity UPLC-QD / SQD (Manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector)

[0109] THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS Model: THERMO Q Exactive)

[0110] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 high-performance liquid chromatograph.

[0111] Chiral HPLC analysis was performed using an Agilent 1260 DAD high-performance liquid chromatograph.

[0112] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0113] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0114] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0115] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0116] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0117] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0118] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0119] Unless otherwise specified in the examples, the reactions can be carried out under an argon or nitrogen atmosphere.

[0120] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0121] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0122] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0123] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0124] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0125] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0126] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0127] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system, and D: ethyl acetate / methanol system. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0128] XRPD (X-ray Powder Diffraction) was used for analysis. Measurements were performed using a BRUKER D8 X-ray diffractometer. Specific data acquisition information included: Cu anode (40 kV, 40 mA), and monochromatic Cu-Ka rays. Scanning mode: θ / 2θ, scanning range: 3-48°.

[0129] DSC stands for Differential Scanning Calorimetry: Measurements were performed using a METTLER TOLEDO DSC 3+ differential scanning calorimeter with a heating rate of 10℃ / min. The specific temperature range was referenced from the corresponding spectra (mostly 25-300 or 25-350℃). Nitrogen purging rate was 50mL / min.

[0130] TGA is thermogravimetric analysis: the test was performed using a METTLER TOLEDO TGA 2 thermogravimetric analyzer, with a heating rate of 10℃ / min, and the specific temperature range was referenced from the corresponding spectrum (mostly 30-400℃). The nitrogen purging rate was 50mL / min.

[0131] DVS stands for Dynamic Moisture Adsorption: The detection method is SMSDVS Advantage. At 25℃, the humidity changes from 50% to 95% to 0% to 95% to 50%, with a step of 10% (the last step is 5%). (The specific humidity range is subject to the corresponding spectrum. The methods listed here are the most commonly used methods.) The judgment standard is that dm / dt is not greater than 0.002%.

[0132] Example 1: Preparation of the compound shown in Formula 1

[0133] 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 1

[0134] first step

[0135] 3-((4-chloroquinazoline-6-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 1c

[0136] 4-Chloroquinazoline-6-phenol 1b (20 mg, 110 μmol, prepared according to the method disclosed in the European Journal of Medicinal Chemistry, 2018, vol. 147, pp. 130-149), compound 1a (30 mg, 133 μmol), and triphenylphosphine (58 mg, 221 μmol) were dissolved in tetrahydrofuran (5 mL). Diisopropyl azodicarbonate (34 mg, 166 μmol) was added dropwise under ice bath conditions, and the reaction was allowed to return to room temperature for 16 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography using elution system C to give the title compound 1c (40 mg, yield: 92.6%).

[0137] MS m / z (ESI): 390.2 [M+1].

[0138] Step 2

[0139] 3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 1d

[0140] Compound 1c (1.2 g, 3 mmol) was dissolved in isopropanol (5 mL), and 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylaniline (845 mg, 3.27 mmol, prepared by the method disclosed in Example 95 on page 143 of the specification in patent application "WO2022003575A1") was added. The mixture was reacted at 80 °C for 2 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give title compound 1d (1.05 g, yield: 55.7%).

[0141] MS m / z (ESI): 612.2 [M+1].

[0142] Step 3

[0143] 6-((endo-8-azabicyclo[3.2.1]oct-3-yl)oxy)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)quinazolin-4-amine hydrochloride 1e

[0144] Compound 1d (1.05 g, 1.7 mmol) was dissolved in methanol (10 mL), and 0.1 mL of 4 M dioxane hydrochloride solution was added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain the crude title compound 1e (940 mg). The crude product was used directly in the next step of the reaction without purification.

[0145] MS m / z (ESI): 512.2 [M+1].

[0146] Step 4

[0147] 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 1

[0148] The crude compound 1e (250 mg, 488.7 μmol) was dissolved in 5 mL of dichloromethane, and N,N-diisopropylethylamine (126 mg, 974 μmol) was added. Acryloyl chloride (50 mg, 552.4 μmol) was added under ice bath conditions. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to obtain title compound 1 (110 mg, yield: 39.7%). X-ray powder diffraction analysis showed that the product was amorphous, and the amorphous X-ray powder diffraction pattern is shown in Figure 12.

[0149] MS m / z (ESI): 566.2 [M+1].

[0150] 1 H NMR (500MHz, MeOD): δ8.80-8.78(d,1H),8.41(s,1H),8.33(s,1H),7.84-7. 82(m,1H),7.77(s,1H),7.60-7.56(m,2H),7.14-7.10(m,2H),7.02-7.01(m ,1H),6.79-6.74(m,1H),6.35(dd,1H),5.81(dd,1H),4.97-4.93(m,1H),4. 76-4.73(m,1H),4.61-4.59(m,1H),2.44-2.17(m,10H),2.06-2.02(m,1H).

[0151] Test Example 1: Ba / F3 Cell Proliferation Experiment

[0152] Log-growing EGFR wild-type Ba / F3 cells (Cobioer, catalog number: CBP73110) were seeded into 96-well plates at 2.5 × 10³ cells / 100 μL of growth medium. Log-growing HER2 wild-type Ba / F3 cells (Cobioer, catalog number: CBP73110) or HER2 A775_G776insYVMA mutant Ba / F3 cells (Cobioer, catalog number: CBP73184) were seeded into 96-well plates at 5 × 10³ cells / 100 μL of growth medium. The plates were incubated overnight at 37°C. The next day, 100 μL / well of the compound, serially diluted 3-fold with culture medium, was added. All treatments were performed in triplicate. Cells were then cultured at 37°C for another 72 hours. Celltiter-Glo Luminescent cell viability was then measured.

[0153] The cell proliferation rate for each well was calculated using the following formula: Proliferation % = (average value of G3-G0 in wells containing the test compound) / (average value of G3 in wells containing DMSO control - average value of G0 in wells) * 100. Based on the proliferation rate and concentration of each well with a gradient concentration, a gradient curve of cell proliferation was fitted using Prism Graphpad software, and the GI50 of the compound was calculated (GI50 is defined as the compound concentration corresponding to a cell proliferation inhibition rate of 50%).

[0154] The structure of tucatinib (synthesized according to Example 11 of patent WO2007059257A2), a selective HER2 inhibitor, is as follows:

[0155] Table 1

[0156] Conclusion: The compound disclosed herein exhibits potent inhibitory activity against HER2 exon 20YVMA insertion mutation and HER2 wild-type dependent Ba / F3 cells, and shows strong selectivity relative to EGFR wild-type dependent Ba / F3 cells; furthermore, the inhibitory activity of the compound disclosed herein against HER2 exon 20YVMA insertion mutation Ba / F3 cells is significantly superior to that of tucatinib.

[0157] Example 2 Preparation of crystal form A

[0158] The compound shown in Formula 1 (39g) was dissolved in methanol / ethyl acetate = 1:10 (v / v), and dried under vacuum to obtain a solid. The product was identified as crystal form A by X-ray powder diffraction. The XRPD spectrum is shown in Figure 1, and the positions of its characteristic peaks are shown in Table 2.

[0159] Table 2 XRPD Data for Crystal Form A

[0160] Example 3 Preparation of crystal form B

[0161] 200 mg of the compound in crystal form A shown in Formula 1 was dissolved in 2 mL of methanol, stirred, and the filter cake was collected, washed with methanol, and dried under vacuum to obtain a solid. X-ray powder diffraction analysis determined the product to be crystal form B. The X-ray powder diffraction data are shown in Table 3, and the X-ray powder diffraction pattern is shown in Figure 2.

[0162] Table 3 XRPD data for crystal form B

[0163] Example 4: Preparation of Crystal Form C

[0164] 8 mg of the compound shown in Formula 1 was dissolved in 0.08 mL of ethanol, then stirred, centrifuged, and vacuum dried to obtain a solid. X-ray powder diffraction analysis identified the product as crystal form C. The XRPD spectrum is shown in Figure 3, and the positions of its characteristic peaks are shown in Table 4. The DSC spectrum shows endothermic peaks at 86.81 °C and 132.29 °C. The TGA spectrum shows a weight loss of 6.36% from 30 °C to 160 °C.

[0165] Table 4 XRPD data for crystal form C

[0166] Example 5 Preparation of Crystal Form C

[0167] 8 mg of the compound shown in Formula 1 was dissolved in a solvent listed in Table 5 below. The solution was then stirred, centrifuged, and vacuum dried to obtain a solid. X-ray powder diffraction analysis confirmed that the product was crystalline form C.

[0168] Table 5

[0169] Example 6 Preparation of Crystal Form C

[0170] 8 mg of the compound shown in Formula 1 was dissolved in 0.08 mL of n-propanol, followed by the addition of 0.24 mL of n-heptane. Crystals were precipitated, centrifuged, and the solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis confirmed that the product was crystalline form C.

[0171] Example 7 Preparation of crystal form D

[0172] 100 mg of the compound shown in Formula 1 was added to 5 mL of water, stirred, centrifuged, and the solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as crystal form D. The XRPD spectrum is shown in Figure 4, and the positions of its characteristic peaks are shown in Table 6. The DSC spectrum shows an endothermic peak at 145.09 °C. The TGA spectrum shows a weight loss of 3.06% from 36 °C to 180 °C. DVS analysis showed that under normal storage conditions (25 °C, 60% RH), the sample gained approximately 3.07% weight due to moisture absorption; under accelerated experimental conditions (70% RH), the weight gain was approximately 3.23%; and under extreme conditions (90% RH), the weight gain was approximately 3.52%. Furthermore, retesting after DVS analysis showed no change in crystal form.

[0173] Table 6 XRPD Data for Crystal Form D

[0174] Example 8 Preparation of crystal form D

[0175] 8 mg of the compound shown in Formula 1 was dissolved in a solvent listed in Table 7 below; the mixture was then stirred, centrifuged, and the solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was crystal form D.

[0176] Table 7

[0177] Example 9 Preparation of crystal form D

[0178] 8 mg of the compound shown in Formula 1 was added to 0.8 mL of solvent, as shown in Table 8 below. The mixture was stirred, centrifuged, and the solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was crystal form D.

[0179] Table 8

[0180] Example 10 Preparation of crystal form D

[0181] 8 mg of the compound shown in Formula 1 was dissolved in 0.08 mL of solvent, as shown in Table 9 below. After adding 0.40 mL of water, a solid precipitated. The solid was centrifuged, collected, and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was crystal form D.

[0182] Table 9

[0183] Example 11 Preparation of crystal form D

[0184] 8 mg of the compound shown in Formula 1 was dissolved in 0.08 mL of dichloromethane, and after adding 0.40 mL of solvent (as shown in Table 10), a solid precipitated. The solid was centrifuged, collected, and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was crystal form D.

[0185] Table 10

[0186] Example 12 Preparation of crystal form D

[0187] 8 mg of the compound shown in Formula 1 was dissolved in 0.08 mL of solvent, as shown in Table 11 below. The solution was then evaporated and crystallized to obtain the product. X-ray powder diffraction analysis showed that the product was of crystal form D.

[0188] Table 11

[0189] Example 13 Preparation of crystal form D

[0190] 200 mg of compound A (as shown in Formula 1) was dissolved in 0.6 mL of acetone, stirred, filtered, and the filter cake was collected. The cake was washed with acetone and dried under vacuum at 45 °C for 3 hours to obtain the product. X-ray powder diffraction analysis showed that the product was crystal form D.

[0191] Example 14 Preparation of crystal form E

[0192] 100 mg of the compound shown in Formula 1 was dissolved in 1 mL of n-propanol, followed by the addition of 5 mL of methyl tert-butyl ether. The solution was dissolved and crystallized, centrifuged, and the solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as crystal form E. The XRPD spectrum is shown in Figure 5, and the characteristic peak positions are shown in Table 12. The DSC spectrum showed endothermic peaks at 209.45 °C and 226.29 °C. The TGA spectrum showed no significant weight loss. DVS analysis showed that under normal storage conditions (25 °C, 60% RH), the sample gained approximately 0.11% weight due to moisture absorption; under accelerated experimental conditions (70% RH), the weight gain was approximately 0.15%; and under extreme conditions (90% RH), the weight gain was approximately 0.25%. Furthermore, retesting after DVS analysis showed no change in crystal form.

[0193] Table 12 XRPD Data for Crystal Form E

[0194] Example 15 Preparation of crystal form E

[0195] 8 mg of the compound shown in Formula 1 was added to 0.8 mL of solvent, as shown in Table 13 below. The mixture was stirred, centrifuged, and the solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was crystal form E.

[0196] Table 13

[0197] Example 16 Preparation of crystal form E

[0198] 8 mg of the compound shown in Formula 1 was dissolved in 0.08 mL of solvent II, followed by 0.40 mL of solvent III. The mixture was stirred, and the solvent combinations are shown in Table 14 below. After centrifugation, the solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was of crystal form E.

[0199] Table 14

[0200] Example 17 Preparation of crystal form E

[0201] Dissolve 8 mg of the compound shown in Formula 1 in 0.08 mL of dichloromethane, add 0.24 mL of solvent, and stir. The solvent is shown in Table 15 below. After centrifugation, collect the solid and dry it under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product is crystal form E.

[0202] Table 15

[0203] Example 18 Preparation of crystal form E

[0204] 8 mg of the compound shown in Formula 1 was added to 0.08 mL of solvent, as shown in Table 16 below, to dissolve and crystallize the compound. The crystals were then centrifuged, and the solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was of crystal form E.

[0205] Table 16

[0206] Example 19 Preparation of crystal form E

[0207] 50 mg of the compound in crystal form F shown in Formula 1 was added to 1 mL of 2-methyltetrahydrofuran, stirred, and the solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was in crystal form E.

[0208] Example 20 Preparation of crystal form E

[0209] 200 mg of compound A (as shown in Formula 1) was dissolved in 2 mL of isopropanol, and crystals were precipitated. The solid was collected, washed with isopropanol, and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was in crystal form E.

[0210] Example 21 Preparation of crystal form F

[0211] 8 mg of the compound shown in Formula 1 was added to 0.8 mL of water / methanol at a ratio of 1:1 (v / v), stirred, centrifuged, and the solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as crystal form F. The XRPD spectrum is shown in Figure 6, and the positions of its characteristic peaks are shown in Table 17. The DSC spectrum shows endothermic peaks at 140.45℃, 154.95℃, and 226.48℃. The TGA spectrum shows a weight loss of 4.56% from 30℃ to 180℃.

[0212] Table 17 XRPD Data for Crystal Form F

[0213] Example 22 Preparation of crystal form F

[0214] 8 mg of the compound shown in Formula 1 was dissolved in 0.08 mL of solvent, as shown in Table 18 below. Crystals were precipitated, centrifuged, and the solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was in the F crystal form.

[0215] Table 18

[0216] Example 23 Preparation of crystal form G

[0217] 50 mg of the compound in crystal form F, as shown in Formula 1, was dispersed in 1 mL of tetrahydrofuran. The mixture was stirred, centrifuged, and vacuum dried to collect the solid. X-ray powder diffraction (XPD) analysis identified the product as crystal form G. The XPD data are shown in Table 19, and the XPD pattern is shown in Figure 7. The DSC spectrum shows endothermic peaks at 155.21 °C and 222.61 °C. The TGA spectrum shows a weight loss of 1.75% from 40 °C to 170 °C.

[0218] Table 19 XRPD Data for Crystal Form G

[0219] Example 24 Preparation of crystal form G

[0220] 50 mg of the compound in crystal form F shown in Formula 1 was dispersed in 1 mL of solvent, as shown in Table 20 below. The mixture was then stirred, centrifuged, and the solid was collected and dried under vacuum. X-ray powder diffraction analysis confirmed that the product was in crystal form G.

[0221] Table 20

[0222] Example 25 Preparation of crystal form H

[0223] 100 mg of the compound shown in Formula 1 was dissolved in 1 mL of 2-butanone, stirred, centrifuged, and the solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as crystal form H. The XRPD spectrum is shown in Figure 8, and the characteristic peak positions are shown in Table 21. The DSC spectrum shows endothermic peaks at 145.94 °C and 226.47 °C. The TGA spectrum shows a weight loss of 2.96% from 37 °C to 180 °C. DVS analysis showed that under normal storage conditions (i.e., 25 °C, 60% RH), the sample gained approximately 0.09% weight due to moisture absorption; under accelerated experimental conditions (i.e., 70% RH), the weight gain was approximately 0.12%; and under extreme conditions (90% RH), the weight gain was approximately 0.22%.

[0224] Table 21 XRPD Data for Crystal Form H

[0225] Example 26 Preparation of crystal form H

[0226] 8 mg of the compound shown in Formula 1 was dissolved in 0.08 mL of solvent, as shown in Table 22 below. Crystallization occurred, and the solution was centrifuged. The solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was of crystal form H.

[0227] Table 22

[0228] Example 27 Preparation of crystal form H

[0229] Dissolve 8 mg of the compound shown in Formula 1 in 0.08 mL of dichloromethane, add 0.40 mL of acetonitrile, allow crystals to precipitate, centrifuge, collect the solid and dry it under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product is crystalline form H.

[0230] Example 28 Preparation of Crystal Form I

[0231] 8 mg of the compound shown in Formula 1 was added to 0.8 mL of water / methanol at a ratio of 8:2 (v / v), and stirred to obtain the product. X-ray powder diffraction analysis determined the wet sample of this product to be crystal form I. The XRPD spectrum is shown in Figure 9, and the positions of its characteristic peaks are shown in Table 23.

[0232] Table 23 XRPD Data for Crystal Form I

[0233] Example 29 Preparation of crystal form J

[0234] 30 mg of the compound shown in Formula 1 was added to 3 mL of 80% water / methanol = 8:2 (v / v), stirred, centrifuged, and the solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as crystal form J. The XRPD spectrum is shown in Figure 10, and the positions of its characteristic peaks are shown in Table 24. The DSC spectrum shows endothermic peaks at 128.14 and 226.15 °C, and exothermic peaks at 207.16 °C. The TGA spectrum shows a weight loss of 5.08% from 31 °C to 160 °C. DVS analysis shows that under normal storage conditions (i.e., 25 °C, 60% RH), the sample's moisture absorption weight gain is approximately 2.44%; under accelerated experimental conditions (i.e., 70% RH), the moisture absorption weight gain is approximately 2.64%; and under extreme conditions (90% RH), the moisture absorption weight gain is approximately 8.10%.

[0235] Table 24 XRPD Data for Crystal Form J

[0236] Example 30 Preparation of crystal form K

[0237] 8 mg of the compound shown in Formula 1 was dissolved in 0.8 mL of acetonitrile, and the product was obtained by volatilization and crystallization. X-ray powder diffraction analysis identified the product as crystal form K. The XRPD spectrum is shown in Figure 11, and the positions of its characteristic peaks are shown in Table 25.

[0238] Table 25 XRPD Data for Crystal Form K

[0239] Example 31 Preparation of crystal form L

[0240] The compound shown in Formula 1 (0.5 g) was dissolved in acetone and stirred at room temperature for 16 h to obtain a solid. X-ray powder diffraction analysis identified the product as crystal form L. The XRPD spectrum is shown in Figure 13, and the positions of its characteristic peaks are shown in Table 26.

[0241] Table 26

[0242] Example 32: Stability Study of Influencing Factors

[0243] The D, E, and H crystal forms were laid out flat in the open, and the stability of the samples was investigated under light (4500 Lux), high temperature (40℃, 60℃), and high humidity (RH 75%, RH 92.5%) conditions. The sampling period was one month.

[0244] Table 27 Factors Affecting Crystal Form D Stability

[0245] Conclusion: Crystal form D exhibits good physical and chemical stability after being placed under light (4500 Lux), high temperature (40℃, 60℃), and high humidity (RH 75%, RH 92.5%) conditions for 30 days.

[0246] Table 28 Factors Affecting the Stability of Crystal Form E

[0247] Conclusion: Crystal form E exhibits good physical and chemical stability after being placed under light (4500 Lux), high temperature (40℃, 60℃), and high humidity (RH 75%, RH 92.5%) conditions for 30 days.

[0248] Table 29 Factors Affecting the Stability of Crystal Form H

[0249] Conclusion: Crystal form H exhibits good physical and chemical stability after being placed under light (4500 Lux), high temperature (40℃, 60℃), and high humidity (RH 75%, RH 92.5%) conditions for 30 days.

[0250] Example 33 Long-term / Accelerated Stability

[0251] The stability of crystal forms D, E, and H was investigated under conditions of 25℃ / 60%RH and 40℃ / 75%RH, respectively.

[0252] Table 30 Long-term / Accelerated Stability of Crystal Form D

[0253] Conclusion: Crystal form D exhibits good physical and chemical stability under long-term / accelerated conditions.

[0254] Table 31 Long-term / accelerated stability of crystal form E

[0255] Conclusion: Crystal form E exhibits good physical and chemical stability under long-term / accelerated conditions.

[0256] Table 32 Long-term / Accelerated Stability of Crystal Form H

[0257] Conclusion: Crystal form H exhibits good physical and chemical stability under long-term accelerated conditions.

Claims

A crystal form E of the compound shown in Formula 1, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 10.080, 14.012, 17.465, 18.635, 20.135, and 24.921, preferably at 10.080, 11.701, 12.776, 14.012, 15.958, 17.465, 17.696, 20.135, 21.144, 23.088, and 24.921, and more preferably at 10.080, 2θ. Characteristic peaks are found at 10.296, 11.701, 12.776, 14.012, 14.286, 15.958, 16.507, 17.177, 17.465, 17.696, 18.635, 19.111, 19.583, 19.828, 20.135, 21.144, 21.698, 23.088, 23.310, 24.921, 26.493, 28.563, and 31.

991. Crystal form E according to claim 1, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 5. A method for preparing crystal form E as described in claim 1 or 2, the method comprising: Method 1: Add the compound shown in Formula 1 to solvent I and stir. Solvent I is selected from one or more of ethyl acetate, acetonitrile, n-heptane, methyl tert-butyl ketone, isopropanol, 1,4-dioxane, 2-methyltetrahydrofuran, acetone, methyl tert-butyl ether, cyclohexane, n-hexane, and isopropyl ether. Method 2: Dissolve the compound shown in Formula 1 in solvent II, add solvent III, and stir. When solvent II is selected from n-propanol, solvent III is selected from ethyl acetate, acetonitrile, methyl tert-butyl ether, and methyl isobutyl ketone. When II is selected from propylene glycol methyl ether or tetrahydrofuran, solvent III is selected from ethyl acetate, acetonitrile, methyl tert-butyl ether, methyl isobutyl ketone, and n-heptane. When II is selected from dichloromethane, solvent III is selected from isopropyl ether, methyl isobutyl ketone, and n-heptane. A crystal form D of the compound shown in Formula 1, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 6.989, 10.610, 13.927, 14.544, 18.332, 18.930, and 23.940, with preferred peaks at 6.989, 7.512, 10.223, 10.610, 11.281, 13.927, 14.544, 14.805, 16.535, and 18. Characteristic peaks are present at 332, 18.930 and 23.940, and more preferably at 6.989, 7.512, 10.223, 10.610, 11.281, 13.310, 13.927, 14.544, 14.805, 16.535, 17.044, 18.332, 18.930, 20.617, 21.313 and 23.

940. Crystal form D according to claim 1, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 4. A method for preparing crystal form D as described in claim 4 or 5, the method comprising: Method 1: Add the compound shown in Formula 1 to solvent V and stir. Solvent V is selected from one or more of water, isopropyl acetate, toluene, and ethyl acetate / n-heptane = 1:1 (v / v). Method 2: Dissolve the compound shown in Formula 1 in solvent VI and stir. Solvent VI is selected from one or more of dichloromethane, tetrahydrofuran, water / isopropanol = 1:9 (v / v), and water / acetone = 1:9 (v / v). Method 3: Dissolve the compound shown in Formula 1 in solvent VII, add solvent VIII, and stir. When VII is selected from one of n-propanol, propylene glycol methyl ether, and tetrahydrofuran, the added solvent VIII is water. When VII is selected from dichloromethane, the added solvent VIII is selected from one of ethyl acetate and methyl tert-butyl ether. Method 4: Dissolve the compound shown in Formula 1 in solvent IX and allow it to evaporate and crystallize. Solvent IX is selected from one or more of propylene glycol methyl ether and N,N-dimethylformamide. A crystal form H of the compound shown in Formula 1, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 10.963, 11.405, 17.174, 20.715, 21.265, and 24.600, preferably at 10.963, 11.405, 12.273, 14.569, 17.174, 20.715, 21.265, 21.328, 22.626, 22.834, and 24.600, and more preferably at 10.963, 11.405, 12.273, 14.569, 17.174, 20.715, 21.265, 21.328, 22.626, 22.834, 24.600, 27.581, and 30.

944. According to claim 1, the crystal form H is characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 8. A method for preparing crystal form H as described in claim 7 or 8, the method comprising: Method 1: Dissolve the compound shown in Formula 1 in water / ethanol = 0.7:9.3 (v / v), isopropanol, or 2-butanone, and stir. Method 2: Dissolve the compound shown in Formula 1 in dichloromethane, add acetonitrile, and stir. According to any one of claims 1-2, 4-5, and 7-8, the 2θ angle error range is ±0.

20. A pharmaceutical composition comprising the crystal form as described in any one of claims 1-2, 4-5, 7-8 and optionally a pharmaceutically acceptable excipient. A method for preparing a pharmaceutical composition includes the step of mixing the crystal form according to any one of claims 1-2, 4-5, 7-8 with a pharmaceutically acceptable excipient. The use of the crystal form according to any one of claims 1-2, 4-5, 7-8, or the pharmaceutical composition according to claim 11 in the preparation of a medicament for treating and / or preventing cancer or tumors.

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