Crystalline form of quinazoline derivative and preparation method therefor

Abstract

A crystalline form of a quinazoline derivative and a preparation method therefor. Specifically, provided is an E crystal form, D crystal form, and H crystal form of 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, which have good stability and can be better used for clinical treatment. Formula (I).

Description

A crystalline form of a quinazoline derivative and a preparation method thereof

[0001] This application claims priority to:

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

[0003] The present disclosure belongs to the field of medical technology and relates to a crystalline form of a quinazoline derivative and a preparation method thereof. Background Art

[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 homo- or heterodimers with other family members (such as HER3). Upon dimerization, HER2 undergoes conformational changes, activating intracellular tyrosine kinase activity and, subsequently, downstream pathways (MAPK signaling and PI3K / AKT signaling), thereby exerting its corresponding physiological effects.

[0005] According to statistics, approximately 2-4% of lung cancer patients carry activating mutations in HER2 exon 20. Currently approved ERBB-targeted tyrosine kinase inhibitors are rarely effective for these patients, primarily due to dose-limiting toxicities mediated by wild-type EGFR. Alectinib, ibrutinib, neratinib, poziotinib, and pyrotinib are known broad-spectrum ERBB inhibitors for HER2 exon 20 mutations. However, clinically, afatinib and other broad-spectrum ERBB inhibitors have shown only limited efficacy in NSCLC patients with HER2 exon 20 mutations due to limited effective doses.

[0006] PCT / CN2023 / 084265 provides a new inhibitor of HER2 exon 20 mutation that is selective for EGFR wild type. Its chemical name is 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, and it has the structure shown in Formula 1.

[0007] The crystal form of a pharmaceutically active ingredient often affects the chemical stability of the drug. Differences in crystallization and storage conditions can lead to variations in the compound's crystal structure, sometimes resulting in the formation of alternative crystal forms. Generally speaking, amorphous drug products lack a regular crystal structure and often exhibit other drawbacks, such as poor product stability, fine crystallization, difficulty in filtration, susceptibility to agglomeration, and poor flowability. Polymorphic drug forms impose varying requirements on product storage, production, and scale-up. Therefore, in-depth research into the crystal forms of these compounds is essential to improve their various properties.

[0008] Summary of the Invention

[0009] The present disclosure provides a new crystalline form of the compound represented by Formula 1, which has good stability and can be better applied in clinical practice.

[0010] The crystalline form A of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 8.905, 9.836, 12.375, 13.207, 17.814, 18.265, 19.863 and 26.491.

[0011] In some embodiments, the crystalline form of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in FIG1 .

[0012] The present disclosure also provides a method for preparing Form A of the compound represented by Formula 1, comprising dissolving the compound represented by Formula 1 in methanol / ethyl acetate = 1:10 (v / v), evaporating the solvent and crystallizing.

[0013] The present disclosure also provides Form B of the compound represented by Formula 1, which has an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2θ, with characteristic peaks at 8.963, 9.926, 17.902, 18.404, 19.850 and 22.049.

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

[0015] In some embodiments, the X-ray powder diffraction pattern of Form B of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG2 .

[0016] The present disclosure also provides a method for preparing the crystalline form B of the compound represented by Formula 1, comprising adding the crystalline form A of the compound represented by Formula 1 into methanol and stirring.

[0017] The present disclosure also provides Form C of the compound represented by Formula 1, which has an X-ray powder diffraction pattern expressed in terms of a 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 crystalline form C of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 6.071, 8.758, 9.708, 13.787, 15.348, 17.522, 18.228 and 21.621.

[0019] In some embodiments, Form C of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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 Form C of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG3 .

[0021] The present disclosure also provides a method for preparing Form C of the compound represented by Formula 1, comprising:

[0022] Method 1: dissolving the compound represented by Formula 1 in solvent A and stirring, wherein the 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 represented by formula 1 in n-propanol, add n-heptane, and stir.

[0024] The present disclosure also provides a crystalline form D of the compound represented by Formula 1, which has an X-ray powder diffraction pattern expressed in terms of a 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, Form D of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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, Form D of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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 Form D of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG4 .

[0028] The present disclosure also provides a method for preparing the crystalline form D of the compound represented by Formula 1, the method comprising:

[0029] Method 1: Add the compound represented by Formula 1 to a solvent V and stir, wherein the 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: dissolving the compound represented by Formula 1 in solvent VI and stirring, wherein the 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: dissolving the compound represented by Formula 1 in solvent VII, adding solvent VIII, and stirring; when the VII is selected from one of n-propanol, propylene glycol methyl ether, and tetrahydrofuran, the added solvent VIII is water; when the VII is selected from dichloromethane, the added solvent VIII is selected from one of ethyl acetate and methyl tert-butyl ether.

[0032] Method 4: dissolving the compound represented by formula 1 in a solvent IX, volatilizing and crystallizing; the IX is selected from one or more of propylene glycol methyl ether and N,N-dimethylformamide.

[0033] The present disclosure also provides a crystalline form E of the compound represented by Formula 1, which has an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2θ, with characteristic peaks at 10.080, 14.012, 17.465, 18.635, 20.135 and 24.921.

[0034] In some embodiments, Form E of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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, Form E of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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 Form E of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG5 .

[0037] The present disclosure also provides a method for preparing the crystalline form E of the compound represented by Formula 1, the method comprising:

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

[0039] Method 2: dissolving the compound represented by Formula 1 in solvent II, adding solvent III, and stirring; when the II is selected from n-propanol, the added solvent III is selected from one of ethyl acetate, acetonitrile, methyl tert-butyl ether, and methyl isobutyl ketone; when the II is selected from propylene glycol methyl ether or tetrahydrofuran, the added solvent III is selected from one of ethyl acetate, acetonitrile, methyl tert-butyl ether, methyl isobutyl ketone, and n-heptane; when the II is selected from dichloromethane, the added solvent III is selected from one of isopropyl ether, methyl isobutyl ketone, and n-heptane;

[0040] The present disclosure also provides a crystalline form F of the compound represented by Formula 1, which has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 10.529, 12.617, 13.759, 17.919 and 18.778.

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

[0042] In some embodiments, Form F of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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 Form F of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG6 .

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

[0045] The present disclosure also provides a crystalline form G of the compound represented by Formula 1, which has an X-ray powder diffraction pattern expressed in terms of a 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 crystalline form G of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 10.437, 11.093, 13.989, 17.124, 17.620, 19.601, 19.929, 21.374 and 22.677.

[0047] In some embodiments, the crystalline form G of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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 Form G of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG7 .

[0049] The present disclosure also provides a method for preparing the crystalline form G of the compound represented by Formula 1, the method comprising adding the crystalline form F of the compound represented by Formula 1 to a solvent C and stirring; the solvent C is selected from one of tetrahydrofuran, 2-butanone, and methyl isobutyl ketone.

[0050] The present disclosure also provides a crystalline form H of the compound represented by Formula 1, which has an X-ray powder diffraction pattern expressed in terms of a 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 crystalline form H of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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 crystalline form H of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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 Form H of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG8 .

[0054] The present disclosure also provides a method for preparing the crystalline form H of the compound represented by Formula 1, the method comprising:

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

[0056] Method 2: Dissolve the compound represented by formula 1 in dichloromethane, add acetonitrile and stir.

[0057] The present disclosure also provides a crystalline form I of the compound represented by Formula 1, which has an X-ray powder diffraction pattern expressed in terms of a 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 crystalline form I of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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 Form I of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG9 .

[0060] The present disclosure also provides a method for preparing the crystalline form I of the compound represented by Formula 1, the method comprising adding the compound represented by Formula 1 to water / methanol = 8:2 (v / v) and stirring.

[0061] The present disclosure also provides a crystalline form J of the compound represented by Formula 1, which has an X-ray powder diffraction pattern expressed in terms of a 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, Form J of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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 Form J of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG10 .

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

[0065] The present disclosure also provides a crystalline form K of the compound represented by Formula 1, which has an X-ray powder diffraction pattern expressed in terms of a 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 Form K of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG11 .

[0067] The present disclosure also provides a method for preparing a crystalline form K of the compound represented by Formula 1, comprising dissolving the compound represented by Formula 1 in acetonitrile and volatilizing and crystallizing.

[0068] The present disclosure also provides a crystalline form L of the compound represented by Formula 1, which has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 7.471, 10.514, 13.476, 16.708, 18.749, and 21.243.

[0069] In some embodiments, the crystalline form L of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2θ, with 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 crystalline form L of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with 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 Form L of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG13 .

[0072] The present disclosure also provides a method for preparing the crystalline form L of the compound represented by Formula 1, comprising the steps of dissolving the compound represented by Formula 1 in acetone and stirring.

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

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

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

[0076] The present disclosure also provides the use of the aforementioned crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F, crystalline form G, crystalline form H, crystalline form I, crystalline form J, crystalline form K or crystalline form L or the aforementioned composition in the preparation of a composition for preventing and / or treating cancer.

[0077] The use disclosed herein, 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 cancer, oral cancer, thyroid cancer, skin cancer, squamous cell carcinoma, synovium, 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 the present disclosure refers to the diffraction angle, θ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2θ is ±0.20 (including the case where the number exceeding 1 decimal place is rounded off), 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] Numerical values ​​in this disclosure, such as those related to substance content, are derived from measurements and calculations, and therefore inevitably have a certain degree of error. Generally speaking, ±10% is considered within a reasonable error range. While there may be some degree of error depending on the context in which they are used, this error may not exceed ±10% and may include ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%.

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

[0081] The drying temperature in the present disclosure is generally 25°C-100°C, preferably 40°C-70°C, and can be dried under normal pressure or reduced pressure.

[0082] The crystallization methods described in the present disclosure include room temperature crystallization, cooling crystallization, volatile solvent crystallization, adding seed crystals to induce crystallization, etc. The cooling temperature is selected from below 65°C, preferably -10°C to 60°C, and 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 a sample and a reference object during the process of heating or maintaining the sample at a constant temperature to characterize all physical and chemical changes related to thermal effects and obtain phase change information of the sample.

[0084] According to the description of hygroscopic characteristics and the definition of hygroscopic weight gain in the "9103 Guiding Principles for Hygroscopicity of Drugs" in Part IV of the 2015 edition of the Chinese Pharmacopoeia,

[0085] Deliquescent: Absorbs sufficient water to form a liquid;

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

[0087] Hygroscopic: weight gain due to moisture absorption is less than 15% but not less than 2%;

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

[0089] No or almost no hygroscopicity: weight gain due to moisture is less than 0.2%.

[0090] The "excipients" described in this disclosure include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent or emulsifier that has been approved by the U.S. Food and Drug Administration for use by humans or livestock animals. BRIEF DESCRIPTION OF THE DRAWINGS

[0091] Figure 1 is the XRPD spectrum of Compound 1 Form A.

[0092] Figure 2 is the XRPD spectrum of Compound 1 Form B.

[0093] Figure 3 is the XRPD spectrum of Compound 1 Form C.

[0094] Figure 4 is the XRPD spectrum of Compound 1 Form D.

[0095] Figure 5 is the XRPD spectrum of Compound 1 Form E.

[0096] Figure 6 is the XRPD spectrum of Compound 1 Form F.

[0097] Figure 7 is the XRPD spectrum of Compound 1 Form G.

[0098] Figure 8 is the XRPD spectrum of Compound 1 Form H.

[0099] Figure 9 is the XRPD spectrum of Compound 1 Form I.

[0100] Figure 10 is the XRPD spectrum of Compound 1 Form J.

[0101] Figure 11 is the XRPD spectrum of Compound 1 Form K.

[0102] FIG12 is an XRPD spectrum of the amorphous form of Compound 1.

[0103] Figure 13 is the XRPD spectrum of Compound 1 Form L. DETAILED DESCRIPTION

[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 essence and scope of the present disclosure.

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

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

[0107] MS was measured using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid spectrometer-mass spectrometer (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 Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatographs.

[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 preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0114] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0115] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

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

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

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

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

[0120] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0121] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

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

[0123] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0124] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

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

[0126] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0127] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the column chromatography eluent system used for purifying the compound, and the developing solvent system for thin layer chromatography 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 compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0128] XRPD is X-ray powder diffraction detection: the measurement is carried out using a BRUKER D8 X-ray diffractometer, specific collection information: Cu anode (40kV, 40mA), radiation: monochromatic Cu-Ka radiation Scanning mode: θ / 2θ, scanning range: 3-48°.

[0129] DSC is differential scanning calorimetry: the measurement was performed using a METTLER TOLEDO DSC 3+ differential scanning calorimeter with a heating rate of 10°C / min. The specific temperature range was referred to the corresponding spectrum (mostly 25-300 or 25-350°C), and a nitrogen purge rate of 50 mL / min.

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

[0131] DVS stands for dynamic moisture sorption: the test uses SMSDVS Advantage. At 25°C, 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 based on the corresponding spectrum, and the method listed here is mostly used). The judgment standard is dm / dt no more than 0.002%.

[0132] Example 1 Preparation of the compound represented by 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] Endo-3-((4-chloroquinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 1c

[0136] 4-Chloroquinazoline-6-ol 1b (20 mg, 110 μmol, prepared using the method disclosed in "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 azodicarboxylate (34 mg, 166 μmol) was added dropwise under ice-cooling. The mixture was allowed to cool to room temperature and allowed to react for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent C to obtain the title compound 1c (40 mg, 92.6% yield).

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

[0138] Step 2

[0139] Tert-butyl 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]octane-8-carboxylate 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 of patent application "WO2022003575A1") was added. The reaction was carried out 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 obtain the 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]octan-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 hydrogen chloride in dioxane 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 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] 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 then added under ice-cooling. The mixture was stirred for 1 hour, and the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (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 the title compound 1 (110 mg, yield: 39.7%). X-ray powder diffraction analysis revealed that the product was amorphous. The amorphous X-ray powder diffraction spectrum 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] Logarithmically growing EGFR wild-type Ba / F3 cells (Cobioer, Catalog No. CBP73110) were seeded into 96-well plates at a density of 2.5 × 10 cells / 100 μL of growth medium. Logarithmically growing HER2 wild-type Ba / F3 cells (Cobioer, Catalog No. CBP73110) or HER2 A775_G776insYVMA mutant Ba / F3 cells (Cobioer, Catalog No. CBP73184) were seeded into 96-well plates at a density of 5 × 10 cells / 100 μL of growth medium. The plates were incubated overnight at 37°C. The next day, 100 μL / well of compound, serially diluted threefold in culture medium, was added. All treatments were performed in triplicate. The plates were cultured at 37°C for 72 hours. Cell viability was then measured using the Celltiter-Glo Luminescent assay.

[0153] The cell proliferation rate for each well was calculated using the following formula: % Proliferation = (Average value of test compound wells G3 - G0) / (Average value of DMSO control wells G3 - Average value of G0) * 100. Prism GraphPad software was used to fit the cell proliferation gradient curve based on the proliferation rate and concentration of each gradient well, and the compound GI50 (GI50 is defined as the compound concentration that inhibits cell proliferation by 50%) was calculated.

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

[0155] Table 1

[0156] Conclusion: The disclosed compounds have a potent inhibitory effect on the proliferation of Ba / F3 cells harboring HER2 exon 20YVMA insertion mutations and HER2 wild-type-dependent cells, and have strong selectivity relative to EGFR wild-type-dependent Ba / F3 cells; moreover, the disclosed compounds have significantly better inhibitory activity on the proliferation of Ba / F3 cells harboring HER2 exon 20YVMA insertion mutations than tucatinib.

[0157] Example 2 Preparation of Form A

[0158] The compound represented by Formula 1 (39 g) was dissolved in methanol / ethyl acetate = 1:10 (v / v) and dried in vacuo to obtain a solid. X-ray powder diffraction analysis determined the product to be Form A. The XRPD spectrum is shown in FIG1 , and the positions of the characteristic peaks are shown in Table 2.

[0159] Table 2 XRPD data of Form A

[0160] Example 3 Preparation of Form B

[0161] Form A (200 mg) of the compound represented by Formula 1 was dissolved in 2 mL of methanol and stirred. The filter cake was collected, washed with methanol, and dried under vacuum to obtain a solid. X-ray powder diffraction analysis identified the product as Form B. The X-ray powder diffraction data are shown in Table 3, and the X-ray powder diffraction spectrum is shown in Figure 2.

[0162] Table 3 XRPD data of Form B

[0163] Example 4 Preparation of Form C

[0164] 8 mg of the compound represented by Formula 1 was dissolved in 0.08 mL of ethanol, stirred, centrifuged, and vacuum dried to obtain a solid. X-ray powder diffraction analysis identified the product as 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 revealed endothermic peaks at 86.81°C and 132.29°C. The TGA spectrum showed a weight loss of 6.36% between 30°C and 160°C.

[0165] Table 4 XRPD data of Form C

[0166] Example 5 Preparation of Form C

[0167] 8 mg of the compound represented by Formula 1 was dissolved in a solvent as shown in Table 5 below, stirred, centrifuged, and vacuum dried to obtain a solid. X-ray powder diffraction analysis showed that the product was Form C.

[0168] Table 5

[0169] Example 6 Preparation of Form C

[0170] 8 mg of the compound of Formula 1 was dissolved in 0.08 mL of n-propanol, and then 0.24 mL of n-heptane was added for dissolution and crystallization. The mixture was centrifuged, and the solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was Form C.

[0171] Example 7 Preparation of Form D

[0172] 100 mg of the compound represented by Formula 1 was added to 5 mL of water, stirred, centrifuged, and the solid was collected and vacuum dried to obtain the product. X-ray powder diffraction analysis identified the product as 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 showed an endothermic peak at 145.09°C. The TGA spectrum showed a weight loss of 3.06% from 36°C to 180°C. DVS analysis showed that under normal storage conditions (i.e., 25°C, 60% RH), the sample had a moisture absorption weight gain of approximately 3.07%; under accelerated experimental conditions (i.e., 70% RH), the moisture absorption weight gain was approximately 3.23%; and under extreme conditions (90% RH), the moisture absorption weight gain was approximately 3.52%. After DVS analysis, the crystal form was retested and no change in form was observed.

[0173] Table 6 XRPD data of Form D

[0174] Example 8 Preparation of Form D

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

[0176] Table 7

[0177] Example 9 Preparation of Form D

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

[0179] Table 8

[0180] Example 10 Preparation of Form D

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

[0182] Table 9

[0183] Example 11 Preparation of Form D

[0184] 8 mg of the compound of Formula 1 was dissolved in 0.08 mL of dichloromethane. 0.40 mL of a solvent was added to precipitate a solid, as shown in Table 10 below. The solid was collected by centrifugation and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was Form D.

[0185] Table 10

[0186] Example 12 Preparation of 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, and the product was evaporated and crystallized to obtain the product. The product was crystal form D according to X-ray powder diffraction.

[0188] Table 11

[0189] Example 13 Preparation of Form D

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

[0191] Example 14 Preparation of Form E

[0192] 100 mg of the compound represented by Formula 1 was dissolved in 1 mL of n-propanol, and 5 mL of methyl tert-butyl ether was added. The mixture was dissolved and crystallized, centrifuged, and the solid was collected and vacuum dried to obtain the product. X-ray powder diffraction analysis identified the product as Form E. The XRPD spectrum is shown in Figure 5, and the positions of its characteristic peaks 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 (i.e., 25°C, 60% RH), the sample had a moisture weight gain of approximately 0.11%; under accelerated experimental conditions (i.e., 70% RH), the moisture weight gain was approximately 0.15%; and under extreme conditions (90% RH), the moisture weight gain was approximately 0.25%. After DVS analysis, the crystal form was retested and no change in form was observed.

[0193] Table 12 XRPD data of Form E

[0194] Example 15 Preparation of Form E

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

[0196] Table 13

[0197] Example 16 Preparation of Form E

[0198] 8 mg of the compound of Formula 1 was dissolved in 0.08 mL of solvent II, and 0.40 mL of solvent III was added and stirred. The solvent combination is shown in Table 14 below. The mixture was centrifuged, and the solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was Form E.

[0199] Table 14

[0200] Example 17 Preparation of Form E

[0201] 8 mg of the compound represented by Formula 1 was dissolved in 0.08 mL of dichloromethane, and 0.24 mL of a solvent was added and stirred. The solvent was listed in Table 15 below. The mixture was then centrifuged, and the solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis confirmed that the product was Form E.

[0202] Table 15

[0203] Example 18 Preparation of Form E

[0204] 8 mg of the compound of Formula 1 was added to 0.08 mL of a solvent as shown in Table 16 below, and the mixture was dissolved and crystallized. The mixture was centrifuged, and the solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was Form E.

[0205] Table 16

[0206] Example 19 Preparation of Form E

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

[0208] Example 20 Preparation of Form E

[0209] 200 mg of the crystalline form A of the compound represented by Formula 1 was dissolved in 2 mL of isopropanol, and crystallized. 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 crystalline form E.

[0210] Example 21 Preparation of Form F

[0211] 8 mg of the compound represented by Formula 1 was added to 0.8 mL of a 1:1 (v / v) mixture of water and methanol, stirred, centrifuged, and the solid collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as 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 showed endothermic peaks at 140.45°C, 154.95°C, and 226.48°C. The TGA spectrum showed a weight loss of 4.56% from 30°C to 180°C.

[0212] Table 17 XRPD data of Form F

[0213] Example 22 Preparation of Form F

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

[0215] Table 18

[0216] Example 23 Preparation of Form G

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

[0218] Table 19 XRPD data of Form G

[0219] Example 24 Preparation of Form G

[0220] 50 mg of Form F of the compound represented by Formula 1 was dispersed in 1 mL of a solvent as shown in Table 20 below, stirred, centrifuged, and the solid was collected and vacuum dried to obtain a solid. X-ray powder diffraction analysis showed that the product was Form G.

[0221] Table 20

[0222] Example 25 Preparation of Form H

[0223] 100 mg of the compound represented by Formula 1 was dissolved in 1 mL of 2-butanone, stirred, centrifuged, and the solid was collected and vacuum dried to obtain the product. X-ray powder diffraction analysis identified the product as Form H. The XRPD spectrum is shown in Figure 8, and the positions of its characteristic peaks are shown in Table 21. The DSC spectrum showed endothermic peaks at 145.94°C and 226.47°C. The TGA spectrum showed 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 had a moisture absorption weight gain of approximately 0.09%; under accelerated experimental conditions (i.e., 70% RH), the moisture absorption weight gain was approximately 0.12%; and under extreme conditions (90% RH), the moisture absorption weight gain was approximately 0.22%.

[0224] Table 21 XRPD data of Form H

[0225] Example 26 Preparation of Form H

[0226] 8 mg of the compound represented by Formula 1 was dissolved in 0.08 mL of a solvent as shown in Table 22 below, and the mixture was dissolved and crystallized. The mixture was centrifuged, and the solid was collected and dried under vacuum to obtain a product. X-ray powder diffraction analysis showed that the product was Form H.

[0227] Table 22

[0228] Example 27 Preparation of Form H

[0229] 8 mg of the compound represented by Formula 1 was dissolved in 0.08 mL of dichloromethane, and 0.40 mL of acetonitrile was added. The mixture was dissolved and crystallized, and the mixture was centrifuged. The solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was Form H.

[0230] Example 28 Preparation of Form I

[0231] 8 mg of the compound represented by Formula 1 was added to 0.8 mL of water / methanol (8:2, v / v) and stirred to obtain the product. X-ray powder diffraction analysis identified the wet sample of the product as 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 of Form I

[0233] Example 29 Preparation of Form J

[0234] 30 mg of the compound represented by Formula 1 was added to 3 mL of 80% water / methanol (8:2, v / v), stirred, centrifuged, and the solid collected and vacuum dried to obtain the product. X-ray powder diffraction analysis identified the product as 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 showed endothermic peaks at 128.14 and 226.15°C, and an exothermic peak at 207.16°C. The TGA spectrum showed a weight loss of 5.08% from 31°C to 160°C. DVS analysis showed that under normal storage conditions (i.e., 25°C, 60% RH), the sample had a moisture absorption weight gain of approximately 2.44%; under accelerated test conditions (i.e., 70% RH), the moisture absorption weight gain was approximately 2.64%; and under extreme conditions (90% RH), the moisture absorption weight gain was approximately 8.10%.

[0235] Table 24 XRPD data of Form J

[0236] Example 30 Preparation of Form K

[0237] 8 mg of the compound represented by Formula 1 was dissolved in 0.8 mL of acetonitrile and evaporated to obtain the product. X-ray powder diffraction analysis identified the product as 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 of Form K

[0239] Example 31 Preparation of Form L

[0240] The compound represented by 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 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 Study on the stability of influencing factors

[0243] The D, E, and H crystal forms were exposed and laid flat, and the stability of the samples was investigated under light (4500 Lux), high temperature (40°C, 60°C), and high humidity (RH 75%, RH 92.5%) conditions, respectively. The sampling period was 1 month.

[0244] Table 27 Factors affecting stability of Form D

[0245] Conclusion: Form D has good physical and chemical stability when placed under light (4500 Lux), high temperature (40°C, 60°C), and high humidity (RH 75%, RH 92.5%) conditions for 30 days.

[0246] Table 28 Factors affecting the stability of Form E

[0247] Conclusion: Form E has good physical and chemical stability when placed under light (4500 Lux), high temperature (40°C, 60°C), and high humidity (RH 75%, RH 92.5%) conditions for 30 days.

[0248] Table 29 Factors affecting the stability of Form H

[0249] Conclusion: Form H has good physical and chemical stability when placed under light (4500 Lux), high temperature (40°C, 60°C), and high humidity (RH 75%, RH 92.5%) conditions for 30 days.

[0250] Example 33 Long-term / accelerated stability

[0251] The stability of Forms D, E, and H was investigated by placing them under 25°C / 60% RH and 40°C / 75% RH conditions respectively:

[0252] Table 30 Long-term / accelerated stability of Form D

[0253] Conclusion: Form D has good physical and chemical stability under long-term / accelerated conditions.

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

[0255] Conclusion: Form E has good physical and chemical stability under long-term / accelerated conditions.

[0256] Table 32 Long-term / accelerated stability of Form H

[0257] Conclusion: Form H has good physical and chemical stability under long-term accelerated conditions.

Claims

1. A crystalline form E of the compound represented by formula 1, characterized in that: The X-ray powder diffraction pattern represented by the diffraction angle 2θ has 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, more preferably at 10.080, There are characteristic peaks 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.

2. The crystalline form E according to claim 1, characterized in that The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG5 .

3. A method for preparing the crystalline form E according to claim 1 or 2, comprising: Method 1: adding the compound represented by formula 1 into solvent I and stirring, wherein the 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: dissolving the compound shown in formula 1 in solvent II, adding solvent III, and stirring; when the solvent II is selected from n-propanol, the added solvent III is selected from one of ethyl acetate, acetonitrile, methyl tert-butyl ether, and methyl isobutyl ketone; when the II is selected from propylene glycol methyl ether or tetrahydrofuran, the added solvent III is selected from one of ethyl acetate, acetonitrile, methyl tert-butyl ether, methyl isobutyl ketone, and n-heptane; when the II is selected from dichloromethane, the added solvent III is selected from one of isopropyl ether, methyl isobutyl ketone, and n-heptane.

4. A crystalline form D of the compound represented by formula 1, characterized in that: The X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 6.989, 10.610, 13.927, 14.544, 18.332, 18.930 and 23.940, preferably at 6.989, 7.512, 10.223, 10.610, 11.281, 13.927, 14.544, 14.805, 16.535, 18. The invention discloses a novel nanostructured carbonyl compound having a plurality of nanostructured carbonyl compounds and a plurality of nanostructured carbonyl compounds, and the nanostructured carbonyl compounds have characteristic peaks at 332, 18.930 and 23.940, and more preferably have 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.

5. The crystal form D according to claim 1, characterized in that The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG4 .

6. A method for preparing the crystalline form D according to claim 4 or 5, comprising: Method 1: adding the compound represented by formula 1 into a solvent V and stirring, wherein the solvent V is selected from one or more of water, isopropyl acetate, toluene, and ethyl acetate / n-heptane = 1:1 (v / v); Method 2: dissolving the compound represented by Formula 1 in a solvent VI and stirring, wherein the 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: dissolving the compound represented by formula 1 in solvent VII, adding solvent VIII, and stirring; when the VII is selected from one of n-propanol, propylene glycol methyl ether, and tetrahydrofuran, the added solvent VIII is water; when the VII is selected from dichloromethane, the added solvent VIII is selected from one of ethyl acetate and methyl tert-butyl ether; Method 4: dissolving the compound represented by formula 1 in a solvent IX, volatilizing and crystallizing; the solvent IX is selected from one or more of propylene glycol methyl ether and N,N-dimethylformamide.

7. A crystalline form H of the compound represented by formula 1, characterized in that: The X-ray powder diffraction pattern, represented by 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, 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.

8. The crystal form H according to claim 1, characterized in that: The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG8 .

9. A method for preparing the crystalline form H according to claim 7 or 8, comprising: Method 1: Dissolve the compound of formula 1 in water / ethanol = 0.7:9.3 (v / v), isopropanol or 2-butanone and stir; Method 2: Dissolve the compound represented by formula 1 in dichloromethane, add acetonitrile and stir.

10. According to the crystal form according to any one of claims 1-2, 4-5, 7-8, the 2θ angle error range is ±0.

20.

11. A pharmaceutical composition comprising the crystal form according to any one of claims 1-2, 4-5, 7-8 and optionally selected from pharmaceutically acceptable excipients.

12. A method for preparing a pharmaceutical composition, comprising the step of mixing the crystal form according to any one of claims 1-2, 4-5, 7-8 and a pharmaceutically acceptable excipient.

13. 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 drug for treating and / or preventing cancer or tumor.

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