Crystalline form of 1-oxo-1,2-dihydrophthalazine compound, and preparation method and use

Abstract

The present disclosure relates to a crystalline form of a 1-oxo-1,2-dihydrophthalazine compound, and a preparation method and a use. Specifically, the present disclosure provides polymorph A, polymorph B, polymorph C, polymorph D, polymorph E, polymorph F, polymorph G, polymorph H, polymorph I, polymorph J, polymorph K, and polymorph L of (M)-(2aS,8aR)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxane-4-carbonitrile, which have good stability and can be better used for clinical treatment.

Description

Crystallographic form, preparation method and uses of a 1-oxo-1,2-dihydrophthalazine compound Technical Field

[0001] This disclosure belongs to the field of pharmaceutical technology and relates to the crystalline form, preparation method and use of a 1-oxo-1,2-dihydrophthalazine compound. Background Technology

[0002] Protein methylarginine transferase 5 (PRMT5), an important type II arginine methyltransferase, regulates various physiological functions in mammalian cells by symmetrically dimethylating arginine residues on histones and non-histone proteins. These functions include genomic epigenetic modification, regulation of RNA splicing, DNA repair, regulation of Treg cell gene expression, and antigen presentation methylation. Studies have shown that PRMT5 overexpression plays a crucial role in proliferative diseases, metabolic diseases, hematological diseases, and various cancers.

[0003] PCT / CN2024 / 110882 provides a PRMT5 inhibitor with the chemical name (M)-(2aS,8aR)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutan[e][1,4]dioxane-4-carboxynitrile, having the structure shown in Formula 1.

[0004] 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. Summary of the Invention

[0005] This disclosure provides a novel crystal form of the compound shown in Formula 1, which exhibits good stability and can be better applied in clinical practice.

[0006] The X-ray powder diffraction pattern of the compound of Formula 1 A provided in this disclosure, expressed as a diffraction angle 2θ, has a characteristic peak at 8.535.

[0007] The crystal form A of the compound of Formula 1 provided in this disclosure has a characteristic peak at 5.138, 7.557, 8.535 and 13.340 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0008] In some embodiments, the crystal form A of the compound shown in Formula 1 has characteristic peaks at 5.138, 7.557, 8.535, 13.340 and 23.961 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0009] In some embodiments, the X-ray powder diffraction pattern of crystal form A of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, is shown in Figure 2.

[0010] This disclosure also provides a method for preparing crystal form A of compound of formula 1, the method comprising: adding compound of formula 1 to solvent I and stirring, wherein solvent I is selected from n-heptane and cyclohexane.

[0011] The crystal form B of the compound of Formula 1 provided in this disclosure has characteristic peaks at 5.313, 8.860 and 9.660 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0012] The crystal form B of the compound of Formula 1 provided in this disclosure has a characteristic peak at 5.313, 8.860, 9.660 and 13.691 in its X-ray powder diffraction pattern expressed as a diffraction angle of 2θ.

[0013] 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 3.

[0014] This disclosure also provides a method for preparing crystal form B of compound of formula 1, the method comprising any of the following methods:

[0015] Method 1: Add the compound of formula 1 to water and stir;

[0016] Method 2: Dissolve the compound of Formula 1 in solvent II, add water, and stir. Solvent II is selected from acetone, tetrahydrofuran, or acetonitrile / methanol (v:v = 1:1).

[0017] The X-ray powder diffraction pattern of the compound of Formula 1 shown in this disclosure, expressed as a diffraction angle 2θ, has characteristic peaks at 4.823, 5.489, 6.786, 8.784, 11.167 and 14.041.

[0018] The X-ray powder diffraction pattern of the compound of Formula 1 shown in this disclosure, expressed as a diffraction angle 2θ, has characteristic peaks at 4.823, 5.489, 6.786, 8.784, 11.167, 13.095, 14.041, 15.023 and 16.039.

[0019] The X-ray powder diffraction pattern of the compound of Formula 1, crystal form C, as expressed in diffraction angle 2θ, has characteristic peaks at 4.823, 5.489, 6.786, 8.784, 11.167, 13.095, 14.041, 15.023, 16.039, 20.596, 22.419, and 27.256.

[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, has the characteristic peak positions shown in Table 5.

[0021] 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 4.

[0022] This disclosure also provides a method for preparing crystal form C of compound of formula 1, said method comprising any of the following methods:

[0023] Method 1: Add the compound of Formula 1 to solvent III and stir. Solvent III is selected from methanol, 10% water / methanol or 50% water / methanol.

[0024] Method 2: Dissolve the compound of Formula 1 in acetonitrile / methanol (v:v = 1:1), add isopropyl ether, and stir.

[0025] The crystal form D of the compound of Formula 1 provided in this disclosure has a characteristic peak at 13.120, 15.412, 15.898, 19.512 and 21.383 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0026] The crystal form D of the compound of Formula 1 provided in this disclosure has characteristic peaks at 13.120, 15.412, 15.898, 19.512, 20.083, 21.383, 22.705, 23.154 and 27.360 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0027] The X-ray powder diffraction pattern of the compound of Formula 1, crystal form D, expressed as a diffraction angle 2θ, has characteristic peaks at 12.710, 13.120, 15.412, 15.898, 16.395, 17.452, 17.756, 19.512, 20.083, 21.383, 22.705, 23.154, and 27.360.

[0028] The X-ray powder diffraction pattern of the compound of Formula 1, crystal form D, as expressed in diffraction angle 2θ, has characteristic peaks at 12.710, 13.120, 15.412, 15.898, 16.395, 17.452, 17.756, 19.512, 19.875, 20.083, 21.383, 22.705, 23.154, and 27.360.

[0029] The X-ray powder diffraction pattern of the compound of Formula 1, crystal form D, expressed as a diffraction angle 2θ, has characteristic peaks at 11.575, 12.710, 13.120, 15.412, 15.898, 16.395, 17.452, 17.756, 18.803, 19.219, 19.512, 19.875, 20.083, 21.383, 22.705, 23.154, 25.827, and 27.360.

[0030] 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, has the characteristic peak positions shown in Table 7.

[0031] 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 5.

[0032] This disclosure also provides a method for preparing crystal form D of compound of formula 1, the method comprising any of the following methods:

[0033] Method 1: Add the compound of Formula 1 to solvent IV and stir. Solvent IV is selected from ethyl acetate, ethanol, isopropanol, n-propanol, acetonitrile, isopropyl acetate, methyl tert-butyl ether, tetrahydrofuran, methyl isobutyl ketone, 10% water / isopropanol, ethyl acetate / n-heptane (v / v = 1:1), tetrahydrofuran / ethanol (v / v = 2:1), and 1,4-dioxane;

[0034] Method 2: Dissolve the compound of formula 1 in DMSO and volatilize it at room temperature;

[0035] Method 3: Dissolve the compound of Formula 1 in tetrahydrofuran, add solvent V, and stir. The solvent V is selected from methyl tert-butyl ether and n-heptane.

[0036] Method 4: Dissolve the compound of Formula 1 in dichloromethane, add solvent VI, and stir. Solvent VI is selected from methyl tert-butyl ether, isopropyl ether, and n-heptane.

[0037] Method 5: Dissolve the compound of Formula 1 in 10% water / isopropanol, add methyl tert-butyl ether, and stir.

[0038] The crystal form E of the compound of Formula 1 provided in this disclosure has characteristic peaks at 9.283, 9.714 and 9.986 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0039] The crystal form E of the compound of Formula 1 provided in this disclosure has characteristic peaks at 9.283, 9.714, 9.986 and 18.643 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0040] The crystal form E of the compound of Formula 1 provided in this disclosure has a characteristic peak at 9.283, 9.714, 9.986, 13.025, 15.654, 18.643, 19.443 and 24.171 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0041] 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, has the characteristic peak positions shown in Table 10.

[0042] 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 6.

[0043] This disclosure also provides a method for preparing crystal form E of compound of formula 1, said method comprising any of the following methods:

[0044] Method 1: Add the compound of formula 1 to 80% water / methanol and stir;

[0045] Method 2: Dissolve the compound of Formula 1 in 10% water / isopropanol, add water, and stir.

[0046] The X-ray powder diffraction pattern of the compound of Formula 1, F, provided in this disclosure, expressed in terms of diffraction angle 2θ, has characteristic peaks at 9.556, 10.944, and 11.307.

[0047] The X-ray powder diffraction pattern of the compound of Formula 1, F, provided in this disclosure, expressed in terms of diffraction angle 2θ, has characteristic peaks at 9.556, 10.944, 11.307, 15.208, and 24.601.

[0048] The crystal form F of the compound of Formula 1 provided in this disclosure has a characteristic peak at 9.556, 10.944, 11.307, 15.208, 19.299, 22.209 and 24.601 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0049] 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, has the characteristic peak positions shown in Table 11.

[0050] 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 7.

[0051] This disclosure also provides a method for preparing crystal form F of compound of formula 1, the method comprising: dissolving compound of formula 1 in 10% water / isopropanol (v / v), adding n-heptane, and stirring.

[0052] The crystal form G of the compound of Formula 1 provided in this disclosure has characteristic peaks at 9.603, 10.931, 11.300, 17.134 and 24.633 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0053] The crystal form G of the compound of Formula 1 provided in this disclosure has characteristic peaks at 9.603, 10.931, 11.300, 13.297, 15.441, 17.134, 21.897 and 24.633 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0054] The crystal form G of the compound of Formula 1 provided in this disclosure has a characteristic peak at 9.603, 10.931, 11.300, 13.297, 14.370, 15.441, 17.134, 21.897, 23.868, 24.633 and 27.129 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0055] 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 diffraction angle 2θ, has the characteristic peak positions shown in Table 12.

[0056] 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 8.

[0057] This disclosure also provides a method for preparing crystal form G of compound of formula 1, the method comprising: dispersing crystal form C of compound of formula 1 in purified water and stirring.

[0058] The X-ray powder diffraction pattern of the compound of Formula 1 H disclosed herein, expressed as a diffraction angle 2θ, has a characteristic peak at 7.5°±0.2°.

[0059] The crystal form H of the compound of Formula 1 provided in this disclosure has a characteristic peak in the X-ray powder diffraction pattern expressed as a diffraction angle 2θ at at least one location (e.g., location 1, 2, 3, or 4) selected from 7.5°±0.2°, 15.0°±0.2°, 16.5°±0.2°, and 24.2°±0.2°.

[0060] The crystal form H of the compound shown in Formula 1 provided in this disclosure has characteristic peaks at 7.5°±0.2°, 15.0°±0.2°, 16.5°±0.2°, and 24.2°±0.2° in X-ray powder diffraction pattern expressed as diffraction angle 2θ.

[0061] The crystal form H of the compound of Formula 1 provided in this disclosure has a characteristic peak in the X-ray powder diffraction pattern expressed as a diffraction angle 2θ at at least one location selected from 7.5°±0.2°, 9.8°±0.2°, 11.6°±0.2°, 12.4°±0.2°, 15.0°±0.2°, 16.5°±0.2°, and 24.2°±0.2° (e.g., at locations 1, 2, 3, 4, 5, 6, and 7).

[0062] The X-ray powder diffraction pattern of the compound of Formula 1 H disclosed herein, expressed as a diffraction angle 2θ, has characteristic peaks at 7.5°±0.2°, 9.8°±0.2°, 11.6°±0.2°, 12.4°±0.2°, 15.0°±0.2°, 16.5°±0.2°, and 24.2°±0.2°.

[0063] 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 9.

[0064] This disclosure also provides a method for preparing crystal form H of compound of formula 1, the method comprising: adding crystal forms D and G of compound of formula 1 to an acetonitrile / water mixed solvent and stirring.

[0065] The crystal form I of the compound of Formula 1 provided in this disclosure has an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, which has a characteristic peak at at least one location (e.g., location 1, 2, or 3) selected from 5.3°±0.2°, 21.2±0.2°, and 24.4±0.2°.

[0066] The X-ray powder diffraction pattern of the compound of Formula 1 provided in this disclosure, expressed as a diffraction angle 2θ, has characteristic peaks at 5.3°±0.2°, 21.2±0.2°, and 24.4±0.2°.

[0067] The crystal form I of the compound of Formula 1 provided in this disclosure has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, which has a characteristic peak at at least one of the following angles (e.g., 1, 2, 3, 4, 5, 6): 5°±0.2°, 14.5±0.2°, 21.2±0.2°, 22.2±0.2°, 24.4±0.2°, 29.2±0.2°.

[0068] The X-ray powder diffraction pattern of the compound of Formula 1 provided in this disclosure, expressed in terms of diffraction angle 2θ, has characteristic peaks at 5.3°±0.2°, 14.5±0.2°, 21.2±0.2°, 22.2±0.2°, 24.4±0.2°, and 29.2±0.2°.

[0069] The crystal form I of the compound of Formula 1 provided in this disclosure has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, which has a characteristic peak at at least one of the following angles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11): 5.3°±0.2°, 10.5±0.2°, 14.5±0.2°, 15.8±0.2°, 21.2±0.2°, 22.0±0.2°, 22.2±0.2°, 23.4±0.2°, 23.8±0.2°, 24.4±0.2°, and 29.2±0.2°.

[0070] The X-ray powder diffraction pattern of the compound of Formula 1 shown in this disclosure, expressed as a diffraction angle 2θ, has characteristic peaks at 5.3°±0.2°, 10.5±0.2°, 14.5±0.2°, 15.8±0.2°, 21.2±0.2°, 22.0±0.2°, 22.2±0.2°, 23.4±0.2°, 23.8±0.2°, 24.4±0.2°, and 29.2±0.2°.

[0071] 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 10.

[0072] This disclosure also provides a method for preparing crystal form I of compound formula 1, the method comprising: adding crystal form G of compound formula 1 to a mixed solvent of ethyl acetate / ethanol or a mixed solvent of tetrahydrofuran / ethanol, and stirring.

[0073] This disclosure provides a crystal form J of the aforementioned compound of formula 1, whose X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has a characteristic peak at at least one location (e.g., location 1, 2, 3, 4, or 5) selected from 15.2°±0.2°, 15.7°±0.2°, 19.4°±0.2°, 19.9°±0.2°, and 27.2°±0.2°.

[0074] This disclosure provides a crystal form J of the aforementioned compound of formula 1, and an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, which has characteristic peaks at 15.2°±0.2°, 15.7°±0.2°, 19.4°±0.2°, 19.9°±0.2°, and 27.2°±0.2°.

[0075] This disclosure provides a crystal form J of the aforementioned compound of formula 1, whose X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has a characteristic peak at at least one of the following angles (e.g., 1, 2, 3, 4, 5, 6, 7, 8): 12.9°±0.2°, 15.2°±0.2°, 15.7±0.2°, 16.2°±0.2°, 19.4°±0.2°, 19.9°±0.2°, 21.2°±0.2°, and 27.2°±0.2°.

[0076] This disclosure provides a crystal form J of the aforementioned compound of formula 1, and an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, which has characteristic peaks at 12.9°±0.2°, 15.2°±0.2°, 15.7±0.2°, 16.2°±0.2°, 19.4°±0.2°, 19.9°±0.2°, 21.2°±0.2°, and 27.2°±0.2°.

[0077] This disclosure provides a crystal form J of the aforementioned compound of formula 1, whose X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has a characteristic peak at at least one of the following angles (e.g., 12, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13): 12.9°±0.2°, 15.2°±0.2°, 15.7°±0.2°, 16.2°±0.2°, 17.3°±0.2°, 17.5°±0.2°, 18.7°±0.2°, 19.4°±0.2°, 19.9°±0.2°, 21.2°±0.2°, 22.6°±0.2°, 23.0°±0.2°, 27.2°±0.2°.

[0078] This disclosure provides a crystal form J of the aforementioned compound of formula 1, and an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, which has characteristic peaks at 12.9°±0.2°, 15.2°±0.2°, 15.7°±0.2°, 16.2°±0.2°, 17.3°±0.2°, 17.5°±0.2°, 18.7°±0.2°, 19.4°±0.2°, 19.9°±0.2°, 21.2°±0.2°, 22.6°±0.2°, 23.0°±0.2°, and 27.2°±0.2°.

[0079] This disclosure provides an X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, for crystal form J of the aforementioned compound of formula 1, selected from 11.4°±0.2°, 12.5°±0.2°, 12.9°±0.2°, 15.2°±0.2°, 15.7°±0.2°, 16.2°±0.2°, 17.3°±0.2°, 17.5°±0.2°, and 18.7°. At least one of the following (e.g., positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16) at ±0.2°, 19.4°±0.2°, 19.9°±0.2°, 21.2°±0.2°, 22.6°±0.2°, 23.0°±0.2°, 25.7°±0.2°, or 27.2°±0.2°) has a characteristic peak.

[0080] This disclosure provides a crystal form J of the aforementioned compound of formula 1, and its X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 11.4°±0.2°, 12.5°±0.2°, 12.9°±0.2°, 15.2°±0.2°, 15.7°±0.2°, 16.2°±0.2°, 17.3°±0.2°, 17.5°±0.2°, 18.7°±0.2°, 19.4°±0.2°, 19.9°±0.2°, 21.2°±0.2°, 22.6°±0.2°, 23.0°±0.2°, 25.7°±0.2°, and 27.2°±0.2°.

[0081] 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 11.

[0082] This disclosure also provides a method for preparing crystal form J of compound formula 1, the method comprising any of the following methods:

[0083] Method 1: Dissolve the compound of formula 1 in ethanol and evaporate the solvent.

[0084] Method 2: Dissolve the crystal form G of compound 1 in 1,4-dioxane or a water / ethanol mixture, and evaporate the solvent.

[0085] This disclosure provides a crystal form K of the aforementioned compound of formula 1, whose X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has a characteristic peak at at least one location (e.g., location 1 or 2) selected from 24.4°±0.2° and 32.7°±0.2°.

[0086] This disclosure provides a crystal form K of the aforementioned compound of formula 1, whose X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 24.4°±0.2° and 32.7°±0.2°.

[0087] This disclosure provides a crystal form K of the aforementioned compound of formula 1, whose X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has a characteristic peak at at least one location (e.g., location 1, 2, 3, or 4) selected from 5.1°±0.2°, 5.3°±0.2°, 24.4°±0.2°, and 32.7°±0.2°.

[0088] This disclosure provides a crystal form K of the aforementioned compound of formula 1, and its X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 5.1°±0.2°, 5.3°±0.2°, 24.4°±0.2°, and 32.7°±0.2°.

[0089] This disclosure provides a crystal form K of the aforementioned compound of formula 1, whose X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has a characteristic peak at at least one of the following angles (e.g., 1, 2, 3, 4, 5, 6, 7, 8): 5.1°±0.2°, 5.3°±0.2°, 14.4°±0.2°, 16.0°±0.2°, 21.1°±0.2°, 22.2°±0.2°, 24.4°±0.2°, and 32.7°±0.2°.

[0090] This disclosure provides a crystal form K of the aforementioned compound of formula 1, and its X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 5.1°±0.2°, 5.3°±0.2°, 14.4°±0.2°, 16.0°±0.2°, 21.1°±0.2°, 22.2°±0.2°, 24.4°±0.2°, and 32.7°±0.2°.

[0091] This disclosure provides a crystal form K of the aforementioned compound of formula 1, whose X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has a characteristic peak at at least one of the following angles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12): 5.1°±0.2°, 5.3°±0.2°, 11.2°±0.2°, 14.4°±0.2°, 16.0°±0.2°, 19.9°±0.2°, 21.1°±0.2°, 22.2°±0.2°, 22.9°±0.2°, 24.4°±0.2°, 29.3°±0.2°, and 32.7°±0.2°.

[0092] This disclosure provides a crystal form K of the aforementioned compound of formula 1, and its X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 5.1°±0.2°, 5.3°±0.2°, 11.2°±0.2°, 14.4°±0.2°, 16.0°±0.2°, 19.9°±0.2°, 21.1°±0.2°, 22.2°±0.2°, 22.9°±0.2°, 24.4°±0.2°, 29.3°±0.2°, and 32.7°±0.2°.

[0093] 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 12.

[0094] This disclosure also provides a method for preparing crystal form K of compound formula 1, the method comprising: adding crystal form G of compound formula 1 to 2-butanone or 1,4-dioxane and stirring.

[0095] This disclosure provides a crystal form L of the aforementioned compound of formula 1, whose X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has a characteristic peak at at least one location (e.g., location 1, 2, 3, 4, or 5) selected from 7.2°±0.2°, 14.9°±0.2°, 15.1°±0.2°, 23.8°±0.2°, and 24.0°±0.2°.

[0096] This disclosure provides a crystal form L of the aforementioned compound of formula 1, and an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, which has characteristic peaks at 7.2°±0.2°, 14.9°±0.2°, 15.1°±0.2°, 23.8°±0.2°, and 24.0°±0.2°.

[0097] This disclosure provides a crystal form L of the aforementioned compound of formula 1, whose X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has a characteristic peak at at least one of the following angles (e.g., 1, 2, 3, 4, 5, 6, 7, 8): 6.5°±0.2°, 7.2°±0.2°, 14.9°±0.2°, 15.1°±0.2°, 16.4°±0.2°, 23.8°±0.2°, 24.0°±0.2°, and 26.3°±0.2°.

[0098] This disclosure provides a crystal form L of the aforementioned compound of formula 1, and an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, which has characteristic peaks at 6.5°±0.2°, 7.2°±0.2°, 14.9°±0.2°, 15.1°±0.2°, 16.4°±0.2°, 23.8°±0.2°, 24.0°±0.2°, and 26.3°±0.2°.

[0099] This disclosure provides a crystal form L of the aforementioned compound of formula 1, whose X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has a characteristic peak at at least one of the following angles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11): 5.8°±0.2°, 6.5°±0.2°, 7.2°±0.2°, 12.4°±0.2°, 14.9°±0.2°, 15.1°±0.2°, 16.4°±0.2°, 18.1°±0.2°, 23.8°±0.2°, 24.0°±0.2°, 26.3°±0.2°.

[0100] This disclosure provides a crystal form L of the aforementioned compound of formula 1, and an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, which has characteristic peaks at 5.8°±0.2°, 6.5°±0.2°, 7.2°±0.2°, 12.4°±0.2°, 14.9°±0.2°, 15.1°±0.2°, 16.4°±0.2°, 18.1°±0.2°, 23.8°±0.2°, 24.0°±0.2°, and 26.3°±0.2°.

[0101] 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.

[0102] This disclosure also provides a method for preparing crystal form L of compound of formula 1, the method comprising: adding compound of formula 1 to a mixed solvent of acetonitrile / methanol and stirring.

[0103] This disclosure also relates to the following specific implementation plans:

[0104] 1. A crystal form of a compound of formula 1, characterized in that its X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has a characteristic peak at 8.535°, for example, characteristic peaks at 5.138°, 7.557°, 8.535°, and 13.340°, and characteristic peaks at 5.138°, 7.557°, 8.535°, 13.340°, and 23.961°.

[0105] 2. The crystal form as described in Scheme 1, characterized in that the X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 2.

[0106] 3. The method for preparing the crystal form as described in embodiment 1 or 2, the method comprising: adding the compound of formula 1 to solvent I and stirring, wherein solvent I is selected from n-heptane and cyclohexane.

[0107] 4. A crystal form of a compound of Formula 1, characterized in that the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 5.313, 8.860 and 9.660, for example, characteristic peaks at 5.313, 8.860, 9.660 and 13.691.

[0108] 5. The crystal form as described in embodiment 4, characterized in that the X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 3.

[0109] 6. The method for preparing the crystal form as described in embodiment 4 or 5, wherein the method comprises any of the following methods:

[0110] Method 1: Add the compound of formula 1 to water and stir;

[0111] Method 2: Dissolve the compound of Formula 1 in solvent II, add water, and stir. Solvent II is selected from acetone, tetrahydrofuran, or acetonitrile / methanol (v:v = 1:1).

[0112] 7. A crystal form of a compound of Formula 1, characterized in that the X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 4.823, 5.489, 6.786, 8.784, 11.167, and 14.041, for example, characteristic peaks at 4.823, 5.489, 6.786, 8.784, 11.167, 13.095, 14.041, 15.023, and 16.039, for example, characteristic peaks at 4.823, 5.489, 6.786, 8.784, 11.167, 13.095, 14.041, 15.023, 16.039, 20.596, 22.419, and 27.256.

[0113] 8. The crystal form as described in embodiment 7, characterized in that the X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 4.

[0114] 9. The method for preparing the crystal form as described in embodiment 7 or 8, wherein the method comprises any of the following methods:

[0115] Method 1: Add the compound of Formula 1 to solvent III and stir. Solvent III is selected from methanol, 10% water / methanol or 50% water / methanol.

[0116] Method 2: Dissolve the compound of Formula 1 in acetonitrile / methanol (v:v = 1:1), add isopropyl ether, and stir.

[0117] 10. A crystal form of a compound of Formula 1, characterized in that the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 13.120, 15.412, 15.898, 19.512 and 21.383, for example, characteristic peaks at 13.120, 15.412, 15.898, 19.512, 20.083, 21.383, 22.705, 23.154 and 27.360, for example, characteristic peaks at 12.710, 13.120, 15.412, 15.898, 16.395, 17.452, 17.756, 19.512, 20.083, 21.383, 22.705, 23.154 and 27.360.

[0118] 11. The crystal form as described in embodiment 10, characterized in that the X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 5.

[0119] 12. A method for preparing the crystal form as described in embodiment 10 or 11, the method comprising:

[0120] Method 1: Add the compound of Formula 1 to solvent IV and stir. Solvent IV is selected from ethyl acetate, ethanol, isopropanol, n-propanol, acetonitrile, isopropyl acetate, methyl tert-butyl ether, tetrahydrofuran, methyl isobutyl ketone, 10% water / isopropanol, ethyl acetate / n-heptane (v / v = 1:1), tetrahydrofuran / ethanol (v / v = 2:1), and 1,4-dioxane;

[0121] Method 2: Dissolve the compound of formula 1 in DMSO and volatilize it at room temperature;

[0122] Method 3: Dissolve the compound of Formula 1 in tetrahydrofuran, add solvent V, and stir. The solvent V is selected from methyl tert-butyl ether and n-heptane.

[0123] Method 4: Dissolve the compound of Formula 1 in dichloromethane, add solvent VI, and stir. Solvent VI is selected from methyl tert-butyl ether, isopropyl ether, and n-heptane.

[0124] Method 5: Dissolve the compound of Formula 1 in 10% water / isopropanol, add methyl tert-butyl ether, and stir.

[0125] 13. A crystal form of the compound shown in Formula 1, characterized in that the X-ray powder diffraction pattern, expressed in terms of diffraction angle 2θ, has characteristic peaks at 9.283, 9.714, and 9.986, for example, at 9.283, 9.714, 9.986, and 18.643, for example, at 9.283, 9.714, 9.986, 13.025, 15.654, 18.643, 19.443, and 24.171.

[0126] 14. The crystal form as described in embodiment 13, characterized in that the X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 6.

[0127] 15. A method for preparing the crystal form as described in embodiment 13 or 14, wherein the method comprises any of the following methods:

[0128] Method 1: Add the compound of formula 1 to 80% water / methanol and stir;

[0129] Method 2: Dissolve the compound of Formula 1 in 10% water / isopropanol, add water, and stir.

[0130] 16. A crystal form 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 9.556, 10.944, and 11.307, for example, at 9.556, 10.944, 11.307, 15.208, and 24.601, for example, at 9.556, 10.944, 11.307, 15.208, 19.299, 22.209, and 24.601.

[0131] 17. The crystal form as described in embodiment 16, characterized in that the X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 7.

[0132] 18. A method for preparing the crystal form as described in embodiment 16 or 17, the method comprising: dissolving the compound of formula 1 in 10% water / isopropanol (v / v), adding n-heptane, and stirring.

[0133] 19. A crystal form 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 9.603, 10.931, 11.300, 17.134, and 24.633, for example, at 9.603, 10.931, 11.300, 13.297, 15.441, 17.134, 21.897, and 24.633, for example, at 9.603, 10.931, 11.300, 13.297, 14.370, 15.441, 17.134, 21.897, 23.868, 24.633, and 27.129.

[0134] 20. The crystal form as described in embodiment 19, characterized in that the X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 8.

[0135] 21. A method for preparing the crystal form as described in embodiment 19 or 20, the method comprising: dispersing the crystal form of the compound of formula 1 as described in embodiment 7 or 8 in purified water and stirring.

[0136] 22. As described in any one of the embodiments 1-2, 4-5, 7-8, 10-11, 13-14, 16-17, 19-20, the 2θ angle error range is ±0.20.

[0137] 23. A pharmaceutical composition comprising the crystal form described in any one of embodiments 1-2, 4-5, 7-8, 10-11, 13-14, 16-17, 19-20 and optionally a pharmaceutically acceptable excipient.

[0138] 24. A method for preparing a pharmaceutical composition, comprising the step of mixing the crystal form described in any one of embodiments 1-2, 4-5, 7-8, 10-11, 13-14, 16-17, 19-20 with a pharmaceutically acceptable excipient.

[0139] 25. Use of the crystal form described in any one of embodiments 1-2, 4-5, 7-8, 10-11, 13-14, 16-17, 19-20, or the pharmaceutical composition described in embodiment 23, in the preparation of a medicament for the prevention and / or treatment of cancer.

[0140] In some embodiments, the acetonitrile / water mixed solvent is 88% acetonitrile / water;

[0141] In some embodiments, the ethyl acetate / ethanol mixed solvent is ethyl acetate / ethanol (v:v = 1:1);

[0142] In some embodiments, the tetrahydrofuran / ethanol mixed solvent is tetrahydrofuran / ethanol (v / v = 2:1);

[0143] In some embodiments, the water / ethanol mixed solvent is 7% water / ethanol;

[0144] In some embodiments, the acetonitrile / methanol mixed solvent is acetonitrile / methanol (v:v = 1:1).

[0145] In some embodiments, the volume ratio of each component in a mixed solvent, expressed as a percentage, such as X%A / B, refers to the percentage of solvent A in the A / B mixed solvent system by a unit volume; for example, 88% acetonitrile / water means that acetonitrile accounts for 88% of the unit volume in the acetonitrile / water mixed solvent system. In some embodiments, the present disclosure uses a volume ratio (v:v) to express the proportion of each component in a mixed solvent, such as ethyl acetate / ethanol (v:v = 1:1), which means that the volume ratio of ethyl acetate to ethanol in the ethyl acetate / ethanol mixed solvent system is 1:1.

[0146] In some embodiments, the preparation method described in this disclosure further includes any one of the steps of crystallization, centrifugation (filtration), washing, or drying.

[0147] The crystallization methods disclosed herein include, but are not limited to, stirred crystallization, static crystallization, volatilization crystallization, room temperature crystallization, and cooling crystallization. In some embodiments, the crystallization is stirred crystallization. In some embodiments, the crystallization is static crystallization.

[0148] This disclosure also provides a pharmaceutical composition comprising the aforementioned compound of Formula 1 in 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 and crystal form L, and a pharmaceutical excipient optionally selected from pharmaceutically acceptable excipients.

[0149] This disclosure also provides a pharmaceutical composition prepared from the aforementioned compounds of Formula 1 in crystal forms A, B, C, D, E, F, G, H, I, J, K, and L, and optionally a pharmaceutically acceptable excipient.

[0150] This disclosure also provides a method for preparing a pharmaceutical composition, comprising the step of mixing the aforementioned compounds of Formula 1 in 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 and crystal form L with a pharmaceutically acceptable excipient.

[0151] This disclosure also provides the use of the aforementioned compounds of Formula 1 in crystal forms A, B, C, D, E, F, G, H, I, J, K, and L, or the use of the aforementioned compositions in the preparation of medicaments for the prevention and / or treatment of cancer.

[0152] The uses described in this disclosure, wherein the cancers are selected from lung cancer (such as non-small cell lung cancer), kidney cancer, liver cancer (such as hepatocellular carcinoma), head and neck cancer, esophageal cancer (also called esophageal cancer), lymphoma (such as diffuse large B-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, mantle cell lymphoma, T-cell or B-cell-derived lymphoid malignancies, follicular lymphoma), glioblastoma, glioblastoma, colorectal cancer (such as colon cancer and rectal cancer), malignant peripheral nerve sheath tumor (MP). NST, also known as malignant peripheral nerve sheath tumor, melanoma, gastric cancer, pancreatic cancer, bile duct cancer, bladder cancer, breast cancer, ovarian cancer, vaginal cancer, cervical cancer, endometrial cancer, prostate cancer, testicular cancer, seminoma, myeloma (such as multiple myeloma), leukemia (such as acute leukemia, chronic leukemia, myeloid leukemia, myelofibrosis, erythroleukemia), acoustic neuroma, basal cell carcinoma, brain cancer, bronchial cancer, sarcoma (such as chondrosarcoma, soft tissue sarcoma, fibrosarcoma, smooth muscle cell carcinoma). Sarcoma, liposarcoma, lymphangiosarcoma, myxosarcoma, osteoblastic sarcoma, rhabdomyosarcoma, Ewing's sarcoma), choriocarcinoma, craniopharyngioma, cystadenocarcinoma, hemangioendothelioma, ependymoma, epithelial carcinoma, glioma, astrocytoma, hemangioblastoma, medulloblastoma, meningioma, mesothelioma, neuroblastoma, bone cancer, nasopharyngeal carcinoma, oral cancer, laryngeal cancer, thyroid cancer, retinoblastoma, skin cancer, squamous cell carcinoma (such as head and neck squamous cell carcinoma), synovoma, sweat gland carcinoma, and myelocystitis. Abnormal syndrome; in some embodiments, the cancer is selected from ovarian cancer, lymphoma, pancreatic cancer, bladder cancer, gastric cancer, colorectal cancer, bile duct cancer, mesothelioma, malignant peripheral nerve sheath tumor (MPNST), glioblastoma and lung cancer; in some embodiments, the cancer is selected from lung cancer, mesothelioma, malignant peripheral nerve sheath tumor (MPNST) and pancreatic cancer; in some embodiments, the cancer is selected from liver cancer, breast cancer, skin cancer, bladder cancer, pancreatic cancer and head and neck cancer.

[0153] In some implementations, the cancers described in this disclosure are MTAP-related cancers.

[0154] In some implementations, the lung cancer described in this disclosure is non-small cell lung cancer.

[0155] 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.

[0156] 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%.

[0157] 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.

[0158] The drying temperature described in this disclosure is generally 25℃-100℃, preferably 40℃-70℃, and can be dried under normal pressure or reduced pressure.

[0159] 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.

[0160] 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.

[0161] 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 2020 edition of the Chinese Pharmacopoeia,

[0162] Deliquescence: Absorbs sufficient moisture to form a liquid;

[0163] Extremely hygroscopic: the weight gain due to hygroscopic absorption is not less than 15%;

[0164] It has hygroscopic properties: the weight gain due to hygroscopic absorption is less than 15% but not less than 2%;

[0165] Slightly hygroscopic: the weight gain due to moisture absorption is less than 2% but not less than 0.2%;

[0166] It has little or no hygroscopicity: the weight gain due to moisture absorption is less than 0.2%.

[0167] 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. Attached Figure Description

[0168] Figure 1 shows the amorphous XRPD spectrum of compound 1.

[0169] Figure 2 shows the XRPD spectrum of crystal form A of compound of formula 1.

[0170] Figure 3 shows the XRPD spectrum of crystal form B of compound 1.

[0171] Figure 4 shows the XRPD spectrum of crystal form C of compound 1.

[0172] Figure 5 shows the XRPD spectrum of crystal form D of compound of formula 1.

[0173] Figure 6 shows the XRPD spectrum of crystal form E of compound 1.

[0174] Figure 7 shows the XRPD spectrum of crystal form F of compound 1.

[0175] Figure 8 shows the XRPD spectrum of compound G of Formula 1.

[0176] Figure 9 shows the XRPD spectrum of crystal form H of compound 1.

[0177] Figure 10 shows the XRPD spectrum of crystal form I of compound 1.

[0178] Figure 11 shows the XRPD spectrum of crystal form J of compound 1.

[0179] Figure 12 shows the XRPD spectrum of crystal form K of compound 1.

[0180] Figure 13 shows the XRPD spectrum of crystal form L of compound 1.

[0181] Figure 14 shows the efficacy data of compound of formula 1 against Lu99 xenografts in NUNU nude mice.

[0182] Figure 15 shows the effect of compound 1 on the body weight of NUNU nude mice. Detailed Implementation

[0183] 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.

[0184] Test conditions of the instruments used in the experiment:

[0185] 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 ohms. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0186] MS measurements were performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS LC-MS system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a waters ACQuity UPLC-QD / SQD system (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector), or a THERMO Ultimate 3000-Q Exactive system (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0187] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 HPLC system.

[0188] High performance liquid chromatography (HPLC) was performed using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatographs.

[0189] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0190] XRPD (X-ray Powder Diffraction) was used for analysis: measurements were performed using a BRUKER D8 X-ray diffractometer. Specific data collected included: Cu anode (40 kV, 40 mA), Cu-Kα1 rays. Kα2 rays Kβ rays Scanning mode: θ / 2θ, scanning range (2θ range): 3°~45°.

[0191] 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 25-350℃), and the nitrogen purging rate was 50mL / min.

[0192] 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 25-350℃). The nitrogen purging rate was 50mL / min.

[0193] 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 size 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 criteria are dm / dt not greater than 0.002% and Tmax not greater than 360 min.

[0194] 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.

[0195] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0196] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0197] 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. 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.

[0198] Example 1: Preparation of Compound 1

[0199] (M)-(2aS,8aR)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutan[e][1,4]dioxane-4-carboxylonitrile 1 (Refer to the preparation method of compound 2-p1 in patent application PCT / CN2024 / 110882)

[0200] first step

[0201] 2-(2-bromo-4,6-difluorophenoxy)cyclobut-1-one 1c

[0202] 2-Bromo-4,6-difluorophenol 1b (473 g, 2.04 mol, Jiangsu Aikon) was dissolved in N,N-dimethylformamide (3000 mL), and sodium carbonate (997.14 g, 9.41 mol) and 2-bromocyclobutanone 1a (410.08 g, 2.34 mol, prepared by the method disclosed in Intermediate I-07A on page 53 of patent application "WO2018013770") were added. The mixture was stirred at 80 °C for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with 4000 mL of ethyl acetate. The filtrate was collected, and 4000 mL of water was added to separate the organic phase. The aqueous phase was extracted once with 500 mL of ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 1c (260 g, yield: 46%).

[0203] MS m / z(ESI):276.9[M+1].

[0204] Step 2

[0205] 2-(2-bromo-4,6-difluorophenoxy)cyclobut-1-ol 1d

[0206] Compound 1c (240 g, 822.92 mmol) was dissolved in tetrahydrofuran (1500 mL), cooled to -70 °C, and a 1 M solution of tri-sec-butylborohydride in tetrahydrofuran (905 mL) was added dropwise. The mixture was stirred for 1 hour while maintaining the temperature. The solution was then quenched with 500 mL of water, followed by the addition of 500 mL of 1% sodium hydroxide solution. The mixture was extracted with ethyl acetate (500 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure to obtain the crude title compound 1d (272 g). The product was used directly in the next reaction without purification. MS m / z (ESI): 278.9 [M+1].

[0207] Step 3

[0208] 4-Bromo-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutan[e][1,4]dioxanecyclo1e

[0209] Compound 1d (272 g, 779.71 mmol) was dissolved in dimethyl sulfoxide (2700 mL), and cesium carbonate (762.13 g, 2.34 mol) was added. The mixture was heated to 120 °C and stirred for 1 hour. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (500 mL × 2). The organic phases were combined, washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 1e (201 g, yield: 69.7%).

[0210] MS m / z(ESI):258.9[M+1].

[0211] Step 4

[0212] 6-Fluoro-1,2,2a,8a-Tetrahydrobenzo[b]cyclobutan[e][1,4]dioxane-4-carboxynitrile 1f

[0213] Compound 1e (5.45 g, 21 mmol) was dissolved in N,N-dimethylacetamide (50 mL), and zinc cyanide (4.94 g, 42 mmol), zinc powder (1.44 g, 22.1 mmol), and tetrakis(triphenylphosphine)palladium (1.2 g, 1.05 mmol) were added. The mixture was purged with nitrogen and heated to 100 °C for 16 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and filtered. The filtrate was washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 1f (3.52 g, yield: 81.5%).

[0214] MS m / z(ESI):206.2[M+1].

[0215] Step 5

[0216] 6-Fluoro-5-iodo-1,2,2a,8a-tetrahydrobenzo[b]cyclobutan[e][1,4]dioxane-4-carboxynitrile 1g

[0217] Compound 1f (2.32 g, 11.3 mmol) was dissolved in tetrahydrofuran (80 mL), cooled to -78 °C, and 6.3 mL of a 2 M diisopropylaminolithium tetrahydrofuran solution was added dropwise. After stirring for 30 minutes, 10 mL of a tetrahydrofuran solution of iodine (3.0 g, 11.8 mmol) was added, and the reaction was stirred for 30 minutes. The reaction was quenched by adding saturated sodium sulfite solution and sodium bicarbonate aqueous solution. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give compound 1 g (1.5 g, yield: 40%).

[0218] Step 6

[0219] 6-Fluoro-5-(1-(methyl-d3)-1H-pyrazol-5-yl)-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxane-4-carboxynitrile 1i

[0220] 1-(methyl-d3)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1H-pyrazole 1h (3g, 14.2mmol, according to the Example on page 178 of the specification in patent application "WO2019079469"). 25) prepared by the disclosed method) and 1 g (2.4 g, 7.25 mmol) of compound were dissolved in water (8 mL) and 1,4-dioxane (40 mL), and sodium carbonate (1.6 g, 15.1 mmol) and 1,1'-bis(di-tert-butylphosphine)ferrocene dipalladium chloride (470 mg, 718.9 μmol) were added. The mixture was purged with nitrogen and heated to 85 °C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1i (2 g, yield: 99%).

[0221] MS m / z(ESI):289.0[M+1].

[0222] Step 7

[0223] 5-(4-bromo-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxane-4-carboxynitrile 1j

[0224] Compound 1i (1.9 g, 6.6 mmol) was dissolved in acetonitrile (40 mL), and N-bromosuccinimide (1.3 g, 7.25 mmol) was added. The mixture was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 1j (2.1 g, yield: 86.7%).

[0225] MS m / z(ESI): 367.2 [M+1].

[0226] Step 8

[0227] 5-(4-(4-((1,3-dioxoisoindoline-2-yl)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxanecyclo-4-carboxynitrile 1l

[0228] Under a nitrogen atmosphere, compound 1j (1.5 g, 4.08 mmol), compound 1k (1.8 g, 4.17 mmol, prepared by the method disclosed in the literature "Journal of Medicinal Chemistry, 2022, vol. 65, #3, p. 1749-1766"), 1,1'-bis(di-tert-butylphosphine)ferrocene dipalladium chloride (2.7 g, 4 mmol) and sodium bicarbonate (686 mg, 8.17 mmol) were dissolved in 1,4-dioxane (20 mL) and water (4 mL). The mixture was stirred at 80 °C for 4 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give title compound 1l (760 mg, yield: 31.4%).

[0229] MS m / z(ESI): 592.2 [M+1].

[0230] Steps 9 and 10

[0231] 5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxane-4-carboxynitrile 1m

[0232] (M)-(2aS,8aR)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxane-4-carboxylonitrile

[0233] (M)-(2aR,8aS)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxane-4-carboxylon 2

[0234] (P)-(2aS,8aR)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxane-4-carboxylonitrile3

[0235] (P)-(2aR,8aS)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxane-4-carboxylonitrile

[0236] Compound 1L (760 mg, 1.28 mmol) was dissolved in ethanol (15 mL), and hydrazine hydrate (605 mg, 10.2 mmol, 85% purity) was added. The mixture was stirred at 80 °C for 2 hours. The reaction solution was concentrated under reduced pressure. Dichloromethane / methanol (V:V = 5:1) was added to the residue, and the mixture was stirred for 10 minutes and then filtered. The filtrate was concentrated under reduced pressure to obtain crude compound 1M (590 mg). The crude compound 1M was purified by preparative high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs, Prep 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-42%, flow rate: 30 mL / min) to obtain two fractions: fraction A (short retention time, 130 mg, yield: 22%) and fraction B (long retention time, 130 mg, yield: 22%).

[0237] Component A (130 mg) was resolved by a chiral column (Gilson-281, column: CHIRALPAK IE, 20*250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.5% 7M ammonia methanol solution), gradient ratio: A:B = 50:50, flow rate: 15 mL / min) to give compound 4 (30 mg, 23%) and compound 1 (30 mg, 23%).

[0238] The single configuration 4 compound (shorter retention time in component A) (30 mg, 23%).

[0239] Chiral HPLC analysis: retention time 13.617 min, purity: 99% (column: CHIRALPAK IG 150*4.6mm, 5μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), gradient ratio: A:B 50:50, flow rate: 1.0 mL / min).

[0240] MS m / z(ESI):462.1[M+1].

[0241] 1 H NMR (500MHz, CD3OD): δ8.30(d,1H),8.15(s,1H),7.77(d,1H),7.70(dd,1H),7.33(d,1H),4.11-4.00(m,2H),3.34-3.32(m,2H),2.37-2.17(m,4H).

[0242] Compound with single configuration 1 (longer retention time in component A): (30 mg, 23%).

[0243] Chiral HPLC analysis: retention time 18.128 min, purity: 98% (column: CHIRALPAK IE 150*4.6mm, 5μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), gradient ratio: A:B 50:50, flow rate: 1.0 mL / min).

[0244] X-ray powder diffraction analysis showed that the compound of formula 1 was amorphous, and the XRPD spectrum is shown in Figure 1.

[0245] MS m / z(ESI):462.1[M+1].

[0246] 1 H NMR (500MHz, DMSO-d6): δ12.44(s,1H),8.25(s,1H),8.19-8.17(m,1H),7.76-7.74(m,1H),7.71-7.7 0(m,1H),7.60-7.58(m,1H),4.97-4.90(m,2H),3.80-3.73(m,2H),2.26-2.13(m,4H),1.91(brs,2H).

[0247] Component B (130 mg) was resolved by a chiral column (Gilson-281, column: CHIRALPAK IE, 20*250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.5% 7M ammonia methanol solution), gradient ratio: A:B = 50:50, flow rate: 15 mL / min) to give compound 3 (30 mg, 23%) and compound 2 (47 mg, 36.1%).

[0248] Compound with single configuration 3 (shorter retention time in component B): (30 mg, 23%).

[0249] Chiral HPLC analysis: retention time 13.073 min, purity: 99% (column: CHIRALPAK IE 150*4.6mm, 5μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), gradient ratio: A:B 50:50, flow rate: 1.0 mL / min).

[0250] MS m / z(ESI):462.1[M+1].

[0251] 1 H NMR (500MHz, DMSO-d6): δ12.42(s,1H),8.24(s,1H),8.15-8.14(m,1H),7.74-7.73(m,1H),7.68-7.6 6(m,1H),7.59-7.57(m,1H),4.96-4.89(m,2H),3.81-3.74(m,2H),2.26-2.11(m,4H),1.82(brs,2H).

[0252] Compound with single configuration 2 (longer retention time in component B): (47 mg, 36.1%).

[0253] Chiral HPLC analysis: retention time 23.504 min, purity: 99% (column: CHIRALPAK IE 150*4.6mm, 5μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), gradient ratio: A:B 50:50, flow rate: 1.0 mL / min).

[0254] MS m / z(ESI):462.1[M+1].

[0255] 11H NMR (500 MHz, CD3OD): δ 8.27 (d, 1H), 8.15 (s, 1H), 7.73 (d, 1H), 7.68 (dd, 1H), 7.33 (d, 1H), 4.07 - 3.97 (m, 2H), 3.38 - 3.34 (m, 2H), 2.35 - 2.21 (m, 4H).

[0256] Test Example 1 HCT116 and HCT116 MTAP- / - Cell Proliferation Experiment

[0257] I. Experimental Materials and Instruments

[0258] 1. HCT116 cell line (Nanjing Kebai, CBP60028)

[0259] 2. HCT116 MTAP- / - cell line (Nanjing Kebai, CBP75002)

[0260] 3. DMSO (Sigma, D2650) <000054​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​

[0271] 14. Biosafety Cabinet (Thermo, 1300AII)

[0272] 15. Cell counter (Countstar, IC1000)

[0273] 16. Incubator (Thermo, I160)

[0274] 17. Centrifuge (Beckman Coulter, Allegra X-12 centrifuge)

[0275] 18. PHERAstar FS Microplate Reader (BMG Labtech)

[0276] II. Experimental Procedure

[0277] 1. Cell plating (Day 0)

[0278] a) Observe the cell state under a microscope to ensure that the cell confluence is ~90%.

[0279] b) Discard the cell supernatant, rinse once with PBS, and discard the PBS. Add an appropriate amount of trypsin to digest the cells, and incubate at 37°C for 3 minutes.

[0280] c) Terminize digestion with an equal volume of McCoy's 5A medium containing 10% FBS, and collect the cell suspension. Centrifuge at 300g for 3 minutes. Resuspend the cells in an appropriate amount of fresh culture medium.

[0281] d) Take the resuspended cell suspension and count the cells.

[0282] e) Dilute the cell suspension to 1e4 / mL with McCoy's 5A medium containing 10% FBS, 50 μL / well. For HCT116, use 500 cells / well; for HCT116 MTAP- / -, use 500 cells / well.

[0283] f) Incubate the cell plate overnight in an incubator at 37°C with 5% carbon dioxide.

[0284] 2. Administer medication. (Day 1)

[0285] a) Quantitatively dilute each compound to 9 concentration points using DMSO (starting concentration 10000 μM, 3-fold dilution; adjustments can be made for different compounds based on their different maximum concentrations at IC50). For example, in a 96-well round-bottom plate, serially dilute 5 μL of the compound to 10 μL of DMSO.

[0286] b) Dilute each compound at each concentration point by 250 times into the corresponding volume of McCoy's 5A medium.

[0287] c) Add 50 μL of the diluted compound solution to each well of cell supernatant in each cell plate.

[0288] d) Place the cell plate after drug administration in an incubator at 37°C with 5% carbon dioxide.

[0289] 3. Re-digest the plaster and add medication (Day 5)

[0290] a) Five days after drug administration, discard the drug-containing culture medium, then add 100 μL / well of PBS to rinse once, and immediately remove the PBS.

[0291] b) Add 25 μL of trypsin to digest the cells, incubate at 37°C for 3 minutes, and then add McCoy's 5A medium containing 10% FBS at 175 μL / well to terminate the digestion.

[0292] c) Mix the cells by pipetting with a pipette and re-plate them at a ratio of 1:20, i.e., aspirate 10 μL of cell suspension into a new 96-well plate (pre-fill the new plate with 40 μL of McCoy's 5A medium containing 10% FBS).

[0293] d) Prepare and add the compound according to steps a) to c) in section 2, 50 μL per well.

[0294] e) Place the cell plate after drug administration in an incubator at 37°C with 5% carbon dioxide for incubation.

[0295] 4. CTG test (day 10)

[0296] a) Before use, allow the CellTiter-Glo buffer and lyophilized CellTiter-Glo substrate to equilibrate to room temperature, mix them thoroughly to prepare 100 mL of CellTiter-Glo reagent (or take the mixed CellTiter-Glo reagent out of -20℃ and equilibrate to room temperature).

[0297] b) Remove the plate to be tested from the incubator, equilibrate to room temperature, and add 50 μL of CellTiter-Glo reagent to each well.

[0298] c) Shake and mix for 2 minutes to allow the cells to fully lyse.

[0299] d) After the signal stabilizes at room temperature for 28 minutes, it is detected on a Pherastar FS.

[0300] Comparative Example 1 (refer to WO2022192745A1, Examples 16-90), the structure is as follows:

[0301] Table 1 IC of the compounds of the present disclosure against the growth inhibition of HCT116 MTAP- / - cells 50 value

[0302] Conclusion: The compound of formula 1 has a good selective inhibitory effect on the growth of HCT116 MTAP- / - cells. Compared with Comparative Example 1, the compound of formula 1 has a better inhibitory effect on the growth of HCT116 MTAP- / - cells.

[0303] Test Example 2 Pharmacodynamic experiment

[0304] 1. Experimental purpose

[0305] To evaluate the growth inhibitory effect of the compound of formula 1 on the subcutaneous xenograft tumors of human giant cell lung cancer cell line Lu99 in female NUNU nude mice.

[0306] 2. Experimental drugs

[0307] The compound of formula 1.

[0308] A solution of 20% PEG400 + 70% (10% TPGS) + 5% DMSO + 5% (1% HPMCK100LV) is used.

[0309] 3. Experimental methods and materials

[0310] 3.1 Experimental animals and feeding conditions

[0311] Experimental animals: NUNU nude mice, female, purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd. (License number: SCXK(Zhe)2024-0001, Animal certificate number: 20240524Abzz0619000789), with a body weight of about 20 - 24 g when purchased.

[0312] Feeding conditions: Raised at 5 animals per cage, with a 12 / 12 hour light / dark cycle adjustment, a constant temperature of 23 ± 1 °C, a humidity of 50 to 60%, and free access to food and water.

[0313] 3.2 Animal grouping

[0314] After the NUNU nude mice were adaptively raised, the grouping and dosing regimens were as follows:

[0315] Table 1-1. Grouping and dosing regimens of animals in in vivo pharmacodynamic experiments Note: qd means administered once a day; i.g. means administered by gavage.

[0316] 3.3 Experimental methods:

[0317] 0.1 ml (5×10 5Lu99 cells (1:1 volume ratio with 50% Matrigel) were subcutaneously inoculated into the right upper limb of each mouse, resulting in an average tumor volume of 75 mm². 3 The mice were randomly divided into four groups of 12 mice each, based on tumor volume and body weight, as shown in Table 4. The day of grouping was designated D0, and administration began once or twice daily via gavage for 21 days. Day 21 after administration was designated D21 (Table 1-2). Tumor volume was measured twice weekly using calipers, and body weight was measured twice weekly, with data recorded.

[0318] 3.4 Data Statistics

[0319] All data were plotted and statistically analyzed using Excel and GraphPad Prism 10 software.

[0320] The formula for calculating tumor volume (V) is: V = 1 / 2 × a × b 2 Where a and b represent length and width, respectively.

[0321] The relative tumor proliferation rate T / C (%) = (T-T0) / (C-C0) × 100 (%), where T and C are the tumor volumes of the treatment group and the control group at the end of the experiment; T0 and C0 are the tumor volumes at the beginning of the experiment.

[0322] Tumor inhibition rate TGI (%) = 100 - T / C (%).

[0323] 4. Results

[0324] The efficacy data of compound 1 against Lu99 xenografts in NUNU nude mice are shown in Tables 1-2 and Figure 14.

[0325] The effect of compound 1 on the body weight of NUNU nude mice is shown in Figure 15.

[0326] Table 1-2. Efficacy of Compound 1 against Lu99 xenografts in NUNU nude mice. Note: qd means once a day; d means day; ig means gavage; SEM means standard error.

[0327] 5. Conclusion

[0328] Compound of Formula 1, administered once daily for 21 days, showed a tumor inhibition rate of 72% in the low-dose group (50 mpk / qd), 90% in the medium-dose group (100 mpk / qd), and 95% in the high-dose group (200 mpk / qd). The administration had no effect on the body weight of the mice.

[0329] Test Example 3: Pharmacokinetic Evaluation

[0330] I. Nu / Nu Mouse Experiment

[0331] 1. Abstract

[0332] Nu / Nu mice were used as test animals. The plasma concentration of compound 1 was determined at different time points after gavage (ig) administration to Nu / Nu mice using LC / MS / MS. The pharmacokinetic behavior of compound 1 in Nu / Nu mice was studied and its pharmacokinetic characteristics were evaluated.

[0333] 2. Test Plan

[0334] 2.1 Test Drugs

[0335] Compound of Formula 1 and Comparative Example 1.

[0336] 2.2 Experimental Animals

[0337] Eighteen female Nu / Nu mice were provided by Vital River Laboratory Animal Technology Co., Ltd., and divided into two groups on average.

[0338] 2.3 Drug Preparation

[0339] Weigh out a certain amount of the test compound and add 5% DMSO + 20% PEG400 + 70% (10% TPGS) + 5% (1% HMPC K100LV) to prepare a 10 mg / mL colorless and clear solution.

[0340] 2.4. Administration

[0341] The dosage is 100 mg / kg, and the administration volume is 10 mL / kg.

[0342] 3. Operation

[0343] Mice were not fasted. After gavage administration, and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration, 0.1 mL of blood was collected from the orbital cavity and placed in EDTA-K2 anticoagulant tubes. Plasma was separated by centrifugation at 10,000 rpm for 1 minute (4°C) and stored at -20°C for analysis within 1 hour. The entire process, from blood collection to centrifugation, was performed under ice bath conditions.

[0344] To determine the content of the target compounds in the plasma of Nu / Nu mice after administration of different compounds: 20 μL of plasma samples from Nu / Nu mice at various time points after administration were taken, and 200 μL of acetonitrile and 25 μL of verapamil (100 ng / mL) were added. The mixture was vortexed for 5 minutes and centrifuged at 4000 rpm for 15 minutes. 90 μL of water and 90 μL of supernatant were vortexed for 5 minutes, and 2 μL of the supernatant (compound of Formula 1) and 0.5 μL of the supernatant (Comparative Example 1) were injected for LC / MS / MS analysis.

[0345] 4. Pharmacokinetic Parameter Results

[0346] Table 1-3 Pharmacokinetic parameters of the compounds disclosed herein in Nu / Nu mice

[0347] Conclusion: Compared with Comparative Example 1, Compound 1 exhibits higher blood concentrations, higher exposure, and lower clearance in Nu / Nu mice, demonstrating pharmacokinetic advantages.

[0348] Example 2: Preparation of crystal form A

[0349] Add 5 mg of compound 1 to 0.5 mL of n-heptane, stir to induce crystallization, centrifuge, collect the solid and dry it under vacuum to obtain the product.

[0350] X-ray powder diffraction analysis identified the product as crystal form A. The XRPD spectrum is shown in Figure 2, and the positions of its characteristic peaks are listed in Table 2. The DSC spectrum shows endothermic peaks at 53.31, 136.96, 218.78, and 239.78 °C. The TGA spectrum shows a weight loss of 0.57% between 30 °C and 91 °C.

[0351] Table 2

[0352] Example 3: Preparation of crystal form A

[0353] 5 mg of compound 1 was added to 0.5 mL of cyclohexane, stirred to induce crystallization, 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 A.

[0354] Example 4: Preparation of Crystal Form B

[0355] Add 5 mg of compound 1 to 0.5 mL of water, stir to induce crystallization, centrifuge, collect the solid and dry it under vacuum to obtain the product.

[0356] X-ray powder diffraction analysis identified the product as crystal form B. The XRPD spectrum is shown in Figure 3, and the positions of its characteristic peaks are listed in Table 3. The DSC spectrum shows endothermic peaks at 56.66, 135.32, 157.82, 240.15, and 270.15 °C. The TGA spectrum shows a weight loss of 0.86% between 30 °C and 119 °C.

[0357] Table 3

[0358] Example 5: Preparation of crystal form B

[0359] 5 mg of compound of formula 1 was dissolved in 0.05 mL of acetone, followed by the addition of 0.2 mL of water. The mixture was stirred to induce crystallization, centrifuged, and the solid was collected and dried under vacuum at 40 °C to obtain the product. X-ray powder diffraction analysis showed that the product was crystal form B.

[0360] Example 6: Preparation of Crystal Form B

[0361] 5 mg of compound of formula 1 was dissolved in 0.05 mL of the solvent in Table 4, 0.2 mL of water was added, the mixture was stirred to induce crystallization, centrifuged, and the solid was collected and dried under vacuum at 40 °C to obtain the product. X-ray powder diffraction analysis showed that the product was crystal form B.

[0362] Table 4

[0363] Example 7: Preparation of Crystal Form C

[0364] Add 5 mg of compound 1 to 0.5 mL of methanol, stir to induce crystallization, centrifuge, collect the solid and dry it under vacuum to obtain the product.

[0365] X-ray powder diffraction analysis identified the product as crystal form C. The XRPD spectrum is shown in Figure 4, and the positions of its characteristic peaks are listed in Table 5. The DSC spectrum shows endothermic peaks at 51.50, 143.49, and 185.82 °C. The TGA spectrum shows a weight loss of 1.11% between 30 °C and 120 °C.

[0366] Table 5

[0367] Example 8: Preparation of Crystal Form C

[0368] Add 5 mg of compound 1 to 0.5 mL of the solvent in Table 6, stir to induce crystallization, centrifuge, collect the solid and dry under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product is crystalline form C.

[0369] Table 6

[0370] Example 9: Preparation of Crystal Form C

[0371] 5 mg of compound 1 was dissolved in 0.1 mL of acetonitrile / methanol (v:v = 1:1), followed by the addition of 0.4 mL of isopropyl ether. The mixture was stirred to induce crystallization, centrifuged, and the solid was collected and dried under vacuum at 40 °C to obtain the product. X-ray powder diffraction analysis confirmed that the product was crystalline form C.

[0372] Example 10: Preparation of crystal form D

[0373] 100 mg of compound 1 was added to 1 mL of ethyl acetate, stirred to induce crystallization, centrifuged, and the solid was collected and dried under vacuum to obtain the product.

[0374] X-ray powder diffraction analysis identified the product as crystal form D. The XRPD spectrum is shown in Figure 5, and the positions of its characteristic peaks are listed in Table 7. The DSC spectrum shows endothermic peaks at 240.45 and 244.66 °C. The TGA spectrum shows no significant weight loss.

[0375] DVS testing showed that under normal storage conditions (i.e., 25°C, 60% RH), the sample's moisture absorption weight gain was approximately 0.34%; under accelerated testing conditions (i.e., 70% RH), the moisture absorption weight gain was approximately 0.47%; and under extreme conditions (90% RH), the moisture absorption weight gain was approximately 1.18%. Furthermore, retesting of the crystal form after DVS testing showed no change in crystal form.

[0376] Table 7

[0377] Example 11: Preparation of crystal form D

[0378] 5 mg of compound of formula 1 was added to 0.5 mL of DMSO, dissolved, and slowly evaporated at room temperature to obtain the product. X-ray powder diffraction analysis showed that the product was crystal form D.

[0379] Example 12: Preparation of crystal form D

[0380] 5 mg of compound 1 was dissolved in 0.1 mL of tetrahydrofuran, followed by the addition of 0.3 mL of methyl tert-butyl ether. The mixture was stirred to induce crystallization, centrifuged, and the solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis revealed that the product was crystal form D.

[0381] Example 13: Preparation of crystal form D

[0382] 5 mg of compound 1 was dissolved in 0.1 mL of tetrahydrofuran, followed by the addition of 0.3 mL of n-heptane. The mixture was stirred to induce crystallization, centrifuged, and the solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis revealed that the product was crystal form D.

[0383] Example 14: Preparation of crystal form D

[0384] 5 mg of compound 1 was dissolved in 0.15 mL of dichloromethane, followed by the addition of 0.3 mL of methyl tert-butyl ether. The mixture was stirred to induce crystallization, centrifuged, and the solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis revealed that the product was crystal form D.

[0385] Example 15: Preparation of crystal form D

[0386] 5 mg of compound 1 was dissolved in 0.15 mL of dichloromethane, followed by the addition of 0.3 mL of the solvent from Table 8. The mixture was stirred to induce crystallization, centrifuged, and the solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis confirmed that the product was crystal form D.

[0387] Table 8

[0388] Example 16: Preparation of crystal form D

[0389] 5 mg of compound 1 was dissolved in 0.25 mL of 10% water / isopropanol, followed by the addition of 1 mL of methyl tert-butyl ether. The mixture was stirred to induce crystallization, 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.

[0390] Example 17: Preparation of Crystal Form D

[0391] Add 5 mg of compound 1 to 0.5 mL of ethanol, stir to induce crystallization, centrifuge, collect the solid and dry under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product is crystal form D.

[0392] Example 18: Preparation of crystal form D

[0393] Add 5 mg of compound 1 to 0.5 mL of the solvent in Table 9, stir to induce crystallization, centrifuge, collect the solid and dry it under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product is crystal form D.

[0394] Table 9

[0395] Example 19: Preparation of Crystal Form D

[0396] Compound of Formula 1 (1.0 g, 2.17 mmol) was added to 20 mL of ethyl acetate and stirred at room temperature for 10 minutes until most of it dissolved. The temperature was then raised to 50 °C and stirred for 2 hours. After cooling to room temperature, the mixture was stirred for 16 hours. The mixture was filtered, and the filter cake was collected and dried under vacuum to obtain the product (810 mg). X-ray powder diffraction analysis showed that the crystal form was D.

[0397] Example 20: Preparation of Crystal Form D

[0398] Compound 1 (1.0 g, 2.17 mmol) was added to 20 mL of isopropanol and stirred at room temperature for 10 minutes until most of it dissolved. The temperature was then raised to 50 °C and stirred for 2 hours. After cooling to room temperature, the mixture was stirred for 16 hours. The mixture was filtered, and the filter cake was collected and dried under vacuum to obtain the product (915 mg). X-ray powder diffraction analysis showed that the crystal form was D.

[0399] Example 21: Preparation of crystal form E

[0400] Add 5 mg of compound 1 to 0.5 mL of 80% water / methanol, stir to induce crystallization, centrifuge, collect the solid and dry it under vacuum to obtain the product.

[0401] X-ray powder diffraction analysis identified the product as crystal form E. The XRPD spectrum is shown in Figure 6, and the positions of its characteristic peaks are listed in Table 10. The DSC spectrum shows endothermic peaks at 56.15, 161.46, 198.48, and 240.47 °C. The TGA spectrum shows a weight loss of 1.61% between 32 °C and 120 °C.

[0402] Table 10

[0403] Example 22: Preparation of crystal form E

[0404] 5 mg of compound of formula 1 was dissolved in 0.25 mL of 10% water / isopropanol, 1 mL of water was added, the mixture was stirred to induce crystallization, 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.

[0405] Example 23: Preparation of crystal form F

[0406] 5 mg of compound 1 was dissolved in 0.25 mL of 10% water / isopropanol, 0.7 mL of n-heptane was added, the mixture was stirred to induce crystallization, centrifuged, and the solid was collected and dried under vacuum to obtain the product.

[0407] X-ray powder diffraction analysis identified the product as crystal form F. The XRPD spectrum is shown in Figure 7, and the positions of its characteristic peaks are listed in Table 11. The DSC spectrum shows endothermic peaks at 88.16, 160.97, and 190.80 °C. The TGA spectrum shows a weight loss of 1.30% between 31 °C and 120 °C.

[0408] Table 11

[0409] Example 24: Preparation of crystal form G

[0410] The crystal form C of compound 1 (0.5 g) was dispersed in 10 mL of purified water, stirred for 72 hours, filtered and the filter cake was collected, and dried under vacuum at 45 °C for 3 hours to obtain a solid product (0.46 g).

[0411] X-ray powder diffraction analysis identified the product as crystal form G, with characteristic peak positions shown in Table 12 and the X-ray powder diffraction pattern shown in Figure 8. The DSC spectrum showed an endothermic peak at 160.38℃. The TGA spectrum showed a weight loss of 3.25% from 40℃ to 130℃ and a weight loss of 0.15% from 130℃ to 180℃.

[0412] Table 12

[0413] Example 25: Preparation of Amorphous Forms

[0414] 5 mg of compound 1 was dissolved in 0.05 mL of acetone and allowed to slowly evaporate at room temperature to obtain the product.

[0415] X-ray powder diffraction analysis revealed that the product was amorphous.

[0416] Example 26: Preparation of Amorphous Forms

[0417] 5 mg of compound 1 was added to 0.05 mL of the solvent listed in Table 13, dissolved, and slowly evaporated at room temperature to obtain the product.

[0418] X-ray powder diffraction analysis revealed that the product was amorphous.

[0419] Table 13

[0420] Example 27: Preparation of Amorphous Forms

[0421] 5 mg of compound 1 was dissolved in 0.05 mL of acetone, followed by the addition of 0.5 mL of n-heptane. The mixture was stirred to induce crystallization, centrifuged, and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was amorphous.

[0422] Example 28: Preparation of Amorphous Forms

[0423] 5 mg of compound 1 was dissolved in 0.05 mL of methanol / acetonitrile (v / v = 1:1), followed by the addition of 0.5 mL of n-heptane. The mixture was stirred to induce crystallization, centrifuged, and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was amorphous.

[0424] Example 29: Preparation of Amorphous Forms

[0425] 5 mg of compound 1 was dissolved in 0.05 mL of acetone, followed by the addition of 0.5 mL of methyl tert-butyl ether. The mixture was stirred to induce crystallization, centrifuged, and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was amorphous.

[0426] Example 30: Preparation of Amorphous Forms

[0427] 5 mg of compound 1 was dissolved in 0.05 mL of methanol / acetonitrile (v / v = 1:1), followed by the addition of 0.5 mL of methyl tert-butyl ether. The mixture was stirred to induce crystallization, centrifuged, and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was amorphous.

[0428] Example 31: Preparation of Amorphous Form

[0429] Compound of Formula 1 (39.7 mg) was added to isopropanol (40 mL), stirred until insoluble, and then water (360 mL) was added. The mixture was stirred at room temperature for 3 hours, filtered, and the filter cake was collected and dried under vacuum to obtain the product (24.47 mg).

[0430] X-ray powder diffraction analysis showed that it was amorphous.

[0431] Example 32: Preparation of crystal form H

[0432] Weigh approximately 4 mg each of crystal form D and crystal form G of the compound shown in Formula 1, add 0.1 mL of 88% acetonitrile / water, and stir at room temperature for 7 days to obtain a solid product.

[0433] X-ray powder diffraction analysis determined the product to be crystal form H. The XRPD spectrum is shown in Figure 9, and the positions of its characteristic peaks are shown in Table 14.

[0434] Table 14

[0435] Example 33: Preparation of Crystal Form I

[0436] Weigh approximately 10 mg of the crystal form G of the compound shown in Formula 1, add 0.2 mL of ethyl acetate / ethanol (v:v = 1:1), stir at room temperature for 3 days to obtain a solid product.

[0437] X-ray powder diffraction analysis determined the product to be crystal form I. The XRPD spectrum is shown in Figure 10, and the positions of its characteristic peaks are listed in Table 15.

[0438] As shown in Table 15.

[0439] Example 34: Preparation of Crystal Form I

[0440] Approximately 10 mg of the crystalline form G of the compound shown in Formula 1 was weighed and added to 0.2 mL of tetrahydrofuran / ethanol (v / v = 2:1). The mixture was stirred at room temperature for 3 days to obtain a solid product. X-ray powder diffraction analysis confirmed that the product was crystalline form I.

[0441] Example 35: Preparation of crystal form J

[0442] Weigh about 10 mg of the compound shown in Formula 1, add 1.0 mL of ethanol, stir at room temperature, filter to obtain a clear liquid, evaporate at room temperature to obtain a solid product.

[0443] X-ray powder diffraction analysis determined the product to be crystal form J. The XRPD spectrum is shown in Figure 11, and the positions of its characteristic peaks are shown in Table 16.

[0444] Table 16

[0445] Example 36: Preparation of crystal form J

[0446] Weigh approximately 10 mg of the crystalline form G of the compound shown in Formula 1, add 1.0 mL of the solvent shown in Table 17, stir at room temperature, filter to obtain a clear liquid, evaporate at room temperature to obtain a solid product. X-ray powder diffraction analysis showed that the product is crystalline form J.

[0447] Table 17

[0448] Example 37: Preparation of crystal form K

[0449] Weigh approximately 10 mg of the crystal form G of the compound shown in Formula 1, add 0.2 mL of 2-butanone, and stir at room temperature to obtain a solid product.

[0450] X-ray powder diffraction analysis determined the product to be crystal form K. The XRPD spectrum is shown in Figure 12, and the positions of its characteristic peaks are shown in Table 18.

[0451] Table 18

[0452] Example 38: Preparation of crystal form K

[0453] Approximately 10 mg of the crystalline form G of the compound shown in Formula 1 was weighed and added to 0.2 mL of 1,4-dioxane. The mixture was stirred at room temperature to obtain a solid product. X-ray powder diffraction analysis confirmed that the product was crystalline form K.

[0454] Example 39: Preparation of crystal form L

[0455] Weigh about 5 mg of the compound shown in Formula 1, add 0.1 mL of acetonitrile / methanol (v:v = 1:1), and evaporate at room temperature to obtain a solid.

[0456] X-ray powder diffraction analysis determined the product to be crystal form L. The XRPD spectrum is shown in Figure 13, and the positions of its characteristic peaks are shown in Table 19.

[0457] Table 19

[0458] Example 40: Stability Study of Influencing Factors

[0459] Crystal form D was laid flat with its opening exposed, and the stability of the sample 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.

[0460] Table 20 Factors affecting the stability of crystal form D

[0461] Conclusion: Crystal form D exhibits decreased purity under high temperature and light conditions, but demonstrates good physicochemical stability under high humidity conditions.

[0462] Example 41: Long-term / accelerated stability

[0463] The stability of crystal form D was investigated under conditions of 25℃ / 60%RH and 40℃ / 75%RH.

[0464] Table 21 Long-term / accelerated stability of crystal form D

[0465] Conclusion: The chemical purity of crystal form D decreases under accelerated conditions, but its physicochemical stability is good under long-term conditions.

Claims

1. A crystal form A of a compound of formula 1, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has a characteristic peak at 8.535°, preferably at 5.138°, 7.557°, 8.535°, and 13.340°, and more preferably at 5.138°, 7.557°, 8.535°, 13.340°, and 23.961°.

2. The crystal form A 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 2.

3. A method for preparing crystal form A as described in claim 1 or 2, the method comprising: The compound of Formula 1 was added to solvent I and stirred. Solvent I was selected from n-heptane and cyclohexane.

4. A crystal form B of a compound of formula 1, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 5.313, 8.860, and 9.660, preferably at 5.313, 8.860, 9.660, and 13.

691.

5. The crystal form B according to claim 4, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 3.

6. A method for preparing crystal form B as described in claim 4 or 5, the method comprising any of the following methods: Method 1: Add the compound of formula 1 to water and stir; Method 2: Dissolve the compound of Formula 1 in solvent II, add water, and stir. Solvent II is selected from acetone, tetrahydrofuran, or acetonitrile / methanol (v:v = 1:1).

7. A crystal form C of a compound of formula 1, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 4.823, 5.489, 6.786, 8.784, 11.167, and 14.041, preferably at 4.823, 5.489, 6.786, 8.784, 11.167, 13.095, 14.041, 15.023, and 16.039, and more preferably at 4.823, 5.489, 6.786, 8.784, 11.167, 13.095, 14.041, 15.023, 16.039, 20.596, 22.419, and 27.

256.

8. The crystal form C according to claim 7, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 4.

9. A method for preparing crystal form C as described in claim 7 or 8, the method comprising any of the following methods: Method 1: Add the compound of Formula 1 to solvent III and stir. Solvent III is selected from methanol, 10% water / methanol or 50% water / methanol. Method 2: Dissolve the compound of Formula 1 in acetonitrile / methanol (v:v = 1:1), add isopropyl ether, and stir.

10. A crystal form D of a compound of formula 1, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 13.120, 15.412, 15.898, 19.512, and 21.383, preferably at 13.120, 15.412, 15.898, 19.512, 20.083, 21.383, 22.705, 23.154, and 27.360, and more preferably at 12.710, 13.120, 15.412, 15.898, 16.395, 17.452, 17.756, 19.512, 20.083, 21.383, 22.705, 23.154, and 27.

360.

11. The crystal form D according to claim 10, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 5.

12. A method for preparing crystal form D as described in claim 10 or 11, the method comprising: Method 1: Add the compound of Formula 1 to solvent IV and stir. Solvent IV is selected from ethyl acetate, ethanol, isopropanol, n-propanol, acetonitrile, isopropyl acetate, methyl tert-butyl ether, tetrahydrofuran, methyl isobutyl ketone, 10% water / isopropanol, ethyl acetate / n-heptane (v / v = 1:1), tetrahydrofuran / ethanol (v / v = 2:1), and 1,4-dioxane; Method 2: Dissolve the compound of Formula 1 in DMSO and volatilize it at room temperature; Method 3: Dissolve the compound of Formula 1 in tetrahydrofuran, add solvent V, and stir. The solvent V is selected from methyl tert-butyl ether and n-heptane. Method 4: Dissolve the compound of Formula 1 in dichloromethane, add solvent VI, and stir. Solvent VI is selected from methyl tert-butyl ether, isopropyl ether, and n-heptane. Method 5: Dissolve the compound of Formula 1 in 10% water / isopropanol, add methyl tert-butyl ether, and stir.

13. 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, has characteristic peaks at 9.283, 9.714, and 9.986, preferably at 9.283, 9.714, 9.986, and 18.643, and more preferably at 9.283, 9.714, 9.986, 13.025, 15.654, 18.643, 19.443, and 24.

171.

14. The crystal form E according to claim 13, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 6.

15. A method for preparing crystal form E as described in claim 13 or 14, the method comprising any of the following methods: Method 1: Add the compound of formula 1 to 80% water / methanol and stir; Method 2: Dissolve the compound of Formula 1 in 10% water / isopropanol, add water, and stir.

16. A crystal form F 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 9.556, 10.944, and 11.307, preferably at 9.556, 10.944, 11.307, 15.208, and 24.601, and more preferably at 9.556, 10.944, 11.307, 15.208, 19.299, 22.209, and 24.

601.

17. The crystal form F according to claim 16, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 7.

18. A method for preparing crystal form F as described in claim 16 or 17, the method comprising: The compound of Formula 1 was dissolved in 10% water / isopropanol (v / v), then n-heptane was added and stirred.

19. A crystal form G 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 9.603, 10.931, 11.300, 17.134, and 24.633, preferably at 9.603, 10.931, 11.300, 13.297, 15.441, 17.134, 21.897, and 24.633, and more preferably at 9.603, 10.931, 11.300, 13.297, 14.370, 15.441, 17.134, 21.897, 23.868, 24.633, and 27.

129.

20. The crystal form G according to claim 19, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 8.

21. A method for preparing crystal form G as described in claim 19 or 20, the method comprising: The crystal form C of compound 1 was dispersed in purified water and stirred.

22. The crystal form according to any one of claims 1-2, 4-5, 7-8, 10-11, 13-14, 16-17, 19-20, wherein the 2θ angle error range is ±0.

20.

23. A pharmaceutical composition comprising the crystal form as described in any one of claims 1-2, 4-5, 7-8, 10-11, 13-14, 16-17, 19-20 and optionally a pharmaceutically acceptable excipient.

24. A method for preparing a pharmaceutical composition, comprising the following steps: The step of mixing the crystal form and pharmaceutically acceptable excipient as described in any one of claims 1-2, 4-5, 7-8, 10-11, 13-14, 16-17, 19-20.

25. Use of the crystal form according to any one of claims 1-2, 4-5, 7-8, 10-11, 13-14, 16-17, 19-20, or the pharmaceutical composition according to claim 23, in the preparation of a medicament for the prevention and / or treatment of cancer.

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