A crystalline form of a dihydrofuro[3,4-f]quinazoline compound, methods of preparation and uses

Abstract

The present disclosure relates to a crystalline form of a dihydrofuro[3,4-f]quinazoline compound and a preparation method thereof. Specifically, the present disclosure provides Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J and Form K of 2-amino-4-((S)-5-chloro-3-(((R)-2-(difluoromethylidene)tetrahydro-1H-pyrrozine-7a(5H)-yl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, which has good stability and can be better used for clinical treatment.

Description

Technical Field

[0001] This disclosure belongs to the field of pharmaceutical technology and relates to the crystalline form, preparation method and use of a dihydrofurano[3,4-f]quinazoline compound. Background Technology

[0002] The KRAS protein encoded by the KARS gene is a small GTPase belonging to the RAS superprotein family. KRAS is one of the most common oncogenes in solid tumors, with mutations found in approximately 19% of tumors, including ~90% of pancreatic cancers, ~50% of colon cancers, and ~30% of lung adenocarcinomas. It also occurs in a certain proportion of other cancer types such as cholangiocarcinoma, cervical cancer, bladder cancer, liver cancer, and breast cancer.

[0003] PCT / CN2025 / 087757 provides a KRAS inhibitor with the chemical name 2-amino-4-((S)-5-chloro-3-(((R)-2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7,9-dihydrofurano[3,4-f]quinazolin-6-yl)-7-fluorobenzo[b]thiophene-3-carboxynitrile, having the structure shown in Formula 1.

[0004] .

[0005] 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

[0006] 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.

[0007] .

[0008] The crystal form A of the compound of Formula 1 provided in this disclosure has a characteristic peak at 6.129, 13.379, 16.716 and 18.448 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0009] The crystal form A of the compound of Formula 1 provided in this disclosure has a characteristic peak at 6.129, 6.826, 12.111, 13.379, 16.716, 17.842, 18.448, 21.781 and 24.169 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0010] The crystal form A of the compound of Formula 1 disclosed herein, as expressed in X-ray powder diffraction patterns at diffraction angles 2θ, exhibits characteristic peaks at 6.129, 6.826, 12.111, 13.379, 14.091, 16.716, 17.842, 18.448, 21.216, 21.781, 22.773, and 24.169.

[0011] In some embodiments, the X-ray powder diffraction pattern of the compound of Formula 1, represented by the diffraction angle 2θ, has the characteristic peak positions shown in Table 3.

[0012] 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 as follows: Figure 2 As shown.

[0013] This disclosure also provides a method for preparing crystal form A of compound of formula 1, the method comprising any of the following methods:

[0014] Method 1: Dissolve the compound of formula 1 in ethanol, add n-heptane, and stir;

[0015] Method 2: Add the compound of Formula 1 to solvent I and stir; wherein solvent I is selected from ethanol / n-heptane mixed solvent and ethyl acetate / n-heptane mixed solvent; in some embodiments, the ethanol / n-heptane mixed solvent is ethanol / n-heptane (1:9, v / v) mixed solvent; in some embodiments, the ethyl acetate / n-heptane mixed solvent is ethyl acetate / n-heptane (1:9, v / v) mixed solvent;

[0016] Method 3: Dissolve the compound of formula 1 in acetone, add n-heptane, and stir;

[0017] Method 4: Dissolve the compound of formula 1 in ethyl acetate, add n-heptane, and stir;

[0018] Method 5: Dissolve the compound of formula 1 in ethyl acetate, add isopropyl ether, and stir;

[0019] Method 6: Dissolve the compound of Formula 1 in solvent II and stir, wherein solvent II is selected from acetonitrile, ethyl acetate and isopropyl acetate;

[0020] Method 7: Add the compound of Formula 1 to solvent III and stir, wherein solvent III is selected from acetone / cyclohexane mixed solvent and ethyl acetate / cyclohexane mixed solvent; in some embodiments, the acetone / cyclohexane mixed solvent is an acetone / cyclohexane (1:4, v / v) mixed solvent; in some embodiments, the ethyl acetate / cyclohexane mixed solvent is an ethyl acetate / cyclohexane (1:4, v / v) mixed solvent.

[0021] The crystal form B of the compound of Formula 1 provided in this disclosure has a characteristic peak at 6.251, 6.938, 12.837, 15.263, 20.037 and 21.802 in its X-ray powder diffraction pattern expressed as a diffraction angle of 2θ.

[0022] The crystal form B of the compound of Formula 1 provided in this disclosure has characteristic peaks at 6.251, 6.938, 12.837, 13.616, 14.320, 15.263, 20.037, 20.715, 21.802 and 22.981 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0023] The X-ray powder diffraction pattern of crystal form B of the compound of Formula 1 provided in this disclosure, expressed as a diffraction angle 2θ, has characteristic peaks at 6.251, 6.938, 9.408, 12.837, 13.616, 14.320, 15.263, 17.418, 20.037, 20.715, 21.802, 22.981, 23.224, 24.505, 26.576, and 27.460.

[0024] 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, has the characteristic peak positions shown in Table 8.

[0025] 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 as follows: Figure 3 As shown.

[0026] This disclosure also provides a method for preparing crystal form B of compound of formula 1, the method comprising any of the following methods:

[0027] Method 1: Dissolve the compound of formula 1 in butyl formate and stir;

[0028] Method 2: Add the compound of Formula 1 to a butyl formate / cyclohexane mixed solvent and stir; in some embodiments, the butyl formate / cyclohexane mixed solvent is a butyl formate / cyclohexane (1:9, v / v) mixed solvent.

[0029] 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 6.624, 16.960, 18.249 and 25.485.

[0030] The crystal form C of the compound shown in Formula 1 provided in this disclosure has a characteristic peak at 6.624, 16.426, 16.960, 18.249, 19.717, 20.253, 23.223 and 25.485 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0031] The X-ray powder diffraction pattern of the compound of Formula 1, crystal form C, expressed as a diffraction angle 2θ, has characteristic peaks at 6.624, 13.493, 15.345, 16.426, 16.960, 18.249, 19.717, 20.253, 22.259, 23.223, 25.485, and 32.844.

[0032] 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 9.

[0033] In some embodiments, the X-ray powder diffraction pattern of crystal form C of the compound shown in Formula 1, expressed as a diffraction angle 2θ, is as follows: Figure 4 As shown.

[0034] This disclosure also provides a method for preparing crystal form C of compound of formula 1, said method comprising any of the following methods:

[0035] Method 1: Add the compound of Formula 1 to solvent IV and stir. Solvent IV is selected from a mixture of 1,4-dioxane / n-heptane, ethyl acetate / cyclohexane, acetone / n-heptane, tetrahydrofuran / n-heptane, and isopropanol / cyclohexane. In some embodiments, the 1,4-dioxane and n-heptane mixture is a 1,4-dioxane / n-heptane (1:8, v / v) mixture. In some embodiments, the ethyl acetate / cyclohexane mixture is an ethyl acetate / cyclohexane (1:4, v / v) mixture. In some embodiments, the acetone / n-heptane mixture is an acetone / n-heptane (1:9, v / v) mixture. In some embodiments, the tetrahydrofuran / n-heptane mixture is a tetrahydrofuran / n-heptane (1:9, v / v) mixture. In some embodiments, the isopropanol / cyclohexane mixture is an isopropanol / cyclohexane (1:9, v / v) mixture.

[0036] Method 2: Dissolve the compound of formula 1 in isopropanol, add cyclohexane, and stir;

[0037] Method 3: Dissolve the compound of formula 1 in tetrahydrofuran, add n-heptane, and stir;

[0038] Method 4: Dissolve the compound of Formula 1 in toluene and stir.

[0039] The crystal form D of the compound of Formula 1 provided in this disclosure has a characteristic peak at 5.617, 9.126, 13.745, 14.709, 15.983 and 18.320 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0040] 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 5.617, 9.126, 12.850, 13.745, 14.709, 15.983, 18.320, 18.773, 18.980, 23.112, and 26.177.

[0041] 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 5.617, 7.533, 9.126, 10.852, 12.850, 13.398, 13.745, 14.709, 15.983, 18.320, 18.773, 18.980, 23.112, 25.867, and 26.177.

[0042] 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 diffraction angle 2θ, has the characteristic peak positions shown in Table 11.

[0043] 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 as follows: Figure 5 As shown.

[0044] This disclosure also provides a method for preparing crystal form D of compound of formula 1, the method comprising: adding compound of formula 1 to isopropyl ether and stirring.

[0045] The crystal form E of the compound of Formula 1 provided in this disclosure has a characteristic peak at 6.244, 12.862, 13.767, 14.683, 18.824, 22.176 and 25.620 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0046] The X-ray powder diffraction pattern of the compound of Formula 1, E, provided in this disclosure, expressed in terms of diffraction angle 2θ, has characteristic peaks at 6.244, 11.762, 12.349, 12.862, 13.767, 14.683, 18.000, 18.824, 22.176, 24.626, and 25.620.

[0047] The X-ray powder diffraction pattern of the compound of Formula 1, crystal form E, expressed as a diffraction angle 2θ, has characteristic peaks at 5.919, 6.244, 8.062, 11.762, 12.349, 12.862, 13.767, 14.683, 16.413, 17.026, 18.000, 18.824, 21.369, 22.176, 24.626, and 25.620.

[0048] 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 12.

[0049] 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 as follows: Figure 6 As shown.

[0050] This disclosure also provides a method for preparing crystal form E of compound of formula 1, the method comprising: adding compound of formula 1 to a methyl isobutyl ketone / cyclohexane mixed solvent; in some embodiments, the methyl isobutyl ketone / cyclohexane mixed solvent is a methyl isobutyl ketone / cyclohexane (1:9, v / v) mixed solvent.

[0051] 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 6.312, 13.588, 16.371, 16.961, and 24.571.

[0052] 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 6.312, 12.385, 13.588, 16.371, 16.961, 18.501, 24.571, 25.792, and 26.337.

[0053] 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 6.312, 12.385, 13.588, 16.371, 16.961, 18.501, 22.249, 23.169, 24.571, 25.792, and 26.337.

[0054] 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 13.

[0055] 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 as follows: Figure 7 As shown.

[0056] This disclosure also provides a method for preparing crystal form F of compound formula 1, the method comprising any of the following methods:

[0057] Method 1: Add the compound of Formula 1 to solvent VI and stir. Solvent VI is selected from ethyl acetate / n-hexane mixed solvent and acetone / cyclohexane mixed solvent. In some embodiments, the ethyl acetate / n-hexane mixed solvent is an ethyl acetate / n-hexane (1:8, v / v) mixed solvent. In some embodiments, the acetone / cyclohexane mixed solvent is an acetone / cyclohexane (1:4, v / v) mixed solvent.

[0058] Method 2: Place the compound of Formula 1 in an ethyl acetate environment.

[0059] The crystal form G of the compound of Formula 1 provided in this disclosure has characteristic peaks at 5.694, 16.740, 18.815, 22.149 and 26.004 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0060] The crystal form G of the compound of Formula 1 provided in this disclosure has characteristic peaks at 5.694, 13.992, 16.286, 16.740, 18.815, 19.032, 22.149, 24.381, 25.719 and 26.004 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0061] The crystal form G of the compound of Formula 1 provided in this disclosure has a characteristic X-ray powder diffraction pattern expressed as a diffraction angle 2θ at 5.694, 13.992, 16.286, 16.740, 17.453, 17.782, 18.815, 19.032, 22.149, 24.381, 25.061, 25.719, 26.004, and 27.034.

[0062] 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, has the characteristic peak positions shown in Table 14.

[0063] In some embodiments, the X-ray powder diffraction pattern of the crystal form G of the compound shown in Formula 1, expressed as a diffraction angle 2θ, is as follows: Figure 8 As shown.

[0064] This disclosure also provides a method for preparing crystal form G of compound of formula 1, the method comprising: dissolving compound of formula 1 in tetrahydrofuran, adding water, and stirring.

[0065] The crystal form H of the compound of Formula 1 provided in this disclosure has a characteristic peak at 7.012, 14.277, 15.237, 19.912, 23.139 and 26.334 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0066] The X-ray powder diffraction pattern of the compound of formula 1, H, provided in this disclosure, expressed as a diffraction angle 2θ, has characteristic peaks at 6.297, 7.012, 13.738, 14.277, 15.237, 19.912, 21.678, 23.139, 25.609, 26.334, and 27.128.

[0067] The X-ray powder diffraction pattern of the compound of formula 1, H, provided in this disclosure, expressed as a diffraction angle 2θ, has characteristic peaks at 6.297, 7.012, 12.798, 13.738, 14.277, 15.237, 17.661, 19.912, 21.678, 22.281, 23.139, 24.403, 25.609, 26.334, and 27.128.

[0068] The X-ray powder diffraction pattern of the compound of formula 1, H, provided in this disclosure, expressed as a diffraction angle 2θ, has characteristic peaks at 6.297, 7.012, 9.490, 12.798, 13.180, 13.738, 14.277, 14.552, 15.237, 17.386, 17.661, 18.782, 19.912, 21.678, 22.281, 23.139, 24.403, 25.609, 26.334, 27.128, and 29.104.

[0069] In some embodiments, the X-ray powder diffraction pattern of the compound of Formula 1, represented by the diffraction angle 2θ, has the characteristic peak positions shown in Table 15.

[0070] 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 as follows: Figure 9 As shown.

[0071] This disclosure also provides a method for preparing crystal form H of compound of formula 1, the method comprising: placing compound of formula 1 in a butyl formate environment.

[0072] 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 6.284, 6.761, 8.763 and 16.027.

[0073] The X-ray powder diffraction pattern of the compound of Formula 1 shown in this disclosure, expressed in terms of diffraction angle 2θ, has characteristic peaks at 6.284, 6.761, 8.763, 15.112, 16.027, 17.692 and 19.866.

[0074] The X-ray powder diffraction pattern of the compound of Formula 1 shown in this disclosure, expressed in terms of diffraction angle 2θ, has characteristic peaks at 6.284, 6.761, 7.562, 8.763, 15.112, 16.027, 17.692, 19.866, 22.597, and 25.453.

[0075] 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, has the characteristic peak positions shown in Table 16.

[0076] 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 as follows: Figure 10 As shown.

[0077] This disclosure also provides a method for preparing compound I of crystal form I, the method comprising: adding compound I to isopropanol and stirring.

[0078] The crystal form J of the compound of Formula 1 provided in this disclosure has a characteristic peak at 13.843, 14.825, 18.018, 19.802, 22.176 and 24.691 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0079] The X-ray powder diffraction pattern of the compound of formula 1 J provided in this disclosure, expressed as a diffraction angle 2θ, has characteristic peaks at 8.188, 13.193, 13.843, 14.825, 18.018, 18.862, 19.325, 19.802, 20.689, 22.176, 24.312, and 24.691.

[0080] The X-ray powder diffraction pattern of the compound of formula 1 J provided in this disclosure, expressed as a diffraction angle 2θ, has characteristic peaks at 7.495, 8.188, 9.973, 13.193, 13.843, 14.825, 18.018, 18.862, 19.325, 19.802, 20.689, 20.976, 22.176, 24.312, 24.691, 27.427, and 29.838.

[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 diffraction angle 2θ, has the characteristic peak positions shown in Table 17.

[0082] 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 as follows: Figure 11 As shown. This disclosure also provides a method for preparing crystal form J of compound of formula 1, the method comprising: adding the compound of formula 1 to an isopropanol / n-heptane mixed solvent and stirring; in some embodiments, the isopropanol / n-heptane mixed solvent is an isopropanol / n-heptane (1:8, v / v) mixed solvent.

[0083] The crystal form K of the compound of Formula 1 provided in this disclosure has characteristic peaks at 5.477, 16.195 and 16.901 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0084] The crystal form K of the compound of Formula 1 provided in this disclosure has characteristic peaks at 5.477, 13.418, 16.195, 16.901 and 19.171 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0085] The crystal form K of the compound of Formula 1 provided in this disclosure has characteristic peaks at 5.477, 12.345, 13.418, 14.549, 16.195, 16.901, 19.171 and 23.156 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0086] 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, has the characteristic peak positions shown in Table 18.

[0087] In some embodiments, the crystal form K of the compound shown in Formula 1, expressed as an X-ray powder diffraction pattern in terms of the diffraction angle 2θ, is as follows: Figure 12 As shown.

[0088] This disclosure also provides a method for preparing crystal form K of compound of formula 1, the method comprising: adding the compound of formula 1 to an isopropanol / isopropyl ether mixed solvent and stirring; in some embodiments, the isopropanol / isopropyl ether mixed solvent is an isopropanol / isopropyl ether (1:8, v / v) mixed solvent.

[0089] In some embodiments of this disclosure, the "stirring" is stirring at room temperature; in some embodiments, the "stirring" is stirring at 40°C first, then cooling to 5°C and stirring again; in some embodiments, the "stirring" is stirring at 50°C.

[0090] In some embodiments of this disclosure, the “room temperature” is 15 to 35°C.

[0091] In some embodiments, the preparation method described in this disclosure further includes any one of the steps of crystallization, centrifugation (filtration), washing, or drying.

[0092] 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.

[0093] 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 and crystal form K, and a pharmaceutical excipient optionally selected from pharmaceutically acceptable excipients.

[0094] 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, and K, and optionally a pharmaceutically acceptable excipient.

[0095] 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 and crystal form K with a pharmaceutically acceptable excipient.

[0096] 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, and K, or the use of the aforementioned compositions in the preparation of medicaments for the prevention and / or treatment of cancer.

[0097] In some embodiments, the cancers described in this disclosure are selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small bowel cancer, gastrointestinal stromal tumor, urothelial carcinoma, urethral cancer, bladder cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma, and glioblastoma; in some embodiments, the cancers are selected from pancreatic cancer, colorectal cancer, and non-small cell lung cancer.

[0098] In some embodiments, the colorectal cancer described in this disclosure is colon cancer or rectal cancer.

[0099] In some embodiments, the brain cancer described in this disclosure is selected from glioblastoma multiforme or neuroblastoma; the soft tissue cancer is selected from fibrosarcoma, gastrointestinal sarcoma, rhabdomyosarcoma, leiomyosarcoma, dedifferentiated liposarcoma, pleomorphic liposarcoma, malignant fibrous histiocytoma, round cell sarcoma, and synovial sarcoma; the lymphoma is selected from Hodgkin's disease and non-Hodgkin's lymphoma (e.g., mantle cell lymphoma, diffuse large B-cell lymphoma, follicular center lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma, and peripheral T-cell lymphoma); in some embodiments, the liver cancer is hepatocellular carcinoma; lung cancer (also known as bronchogenic carcinoma) The cancer cells are selected from non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), and squamous cell carcinoma; the renal cell carcinoma is selected from renal cell carcinoma, clear cell renal cell carcinoma, and renal eosinophilic tumor; the leukemia is selected from chronic lymphocytic leukemia (CLL), chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myeloid leukemia (CML), and acute myeloid leukemia (AML); the skin cancer is selected from malignant melanoma, squamous cell carcinoma, basal cell carcinoma, and angiosarcoma; in some embodiments, the myeloma is multiple myeloma.

[0100] 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.

[0101] The numerical values ​​in this disclosure, such as those relating to the content of certain substances, are calculated based on measurements and are inevitably subject to a certain degree of error. Generally, ±10% is within the reasonable error range. The error may vary to a certain 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%, and in some embodiments, ±5%.

[0102] 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.

[0103] The drying temperature described in this disclosure is generally 25℃-100℃, and in some embodiments it is 40℃-70℃. Drying can be carried out under normal pressure or reduced pressure.

[0104] 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, and in some embodiments, it is from -10°C to 60°C. Stirring may also be performed during the crystallization process.

[0105] 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.

[0106] 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,

[0107] Deliquescence: Absorbs sufficient moisture to form a liquid;

[0108] Extremely hygroscopic: hygroscopic weight gain is no less than 15%;

[0109] It has hygroscopic properties: the weight gain due to hygroscopic absorption is less than 15% but not less than 2%;

[0110] Slightly hygroscopic: weight gain due to moisture absorption is less than 2% but not less than 0.2%;

[0111] It has little or no hygroscopicity: the weight gain due to moisture absorption is less than 0.2%.

[0112] 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

[0113] Figure 1 The image shows the amorphous XRPD spectrum of compound 1.

[0114] Figure 2 The image shows the XRPD spectrum of crystal form A of compound of formula 1.

[0115] Figure 3 The image shows the XRPD spectrum of crystal form B of compound 1.

[0116] Figure 4 The image shows the XRPD spectrum of crystal form C of compound 1.

[0117] Figure 5 The image shows the XRPD spectrum of crystal form D of compound of formula 1.

[0118] Figure 6 The image shows the XRPD spectrum of crystal form E of compound 1.

[0119] Figure 7 The image shows the XRPD spectrum of crystal form F of compound 1.

[0120] Figure 8 The image shows the XRPD spectrum of compound G, which is the crystal form of Formula 1.

[0121] Figure 9 The image shows the XRPD spectrum of compound H, which is the crystal form of Formula 1.

[0122] Figure 10 The image shows the XRPD spectrum of crystal form I of compound 1.

[0123] Figure 11 The image shows the XRPD spectrum of crystal form J of compound 1.

[0124] Figure 12 The image shows the XRPD spectrum of crystal form K of compound formula 1. Detailed Implementation

[0125] 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.

[0126] Test conditions of the instruments used in the experiment:

[0127] 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.

[0128] MS measurements were performed using the following instruments: Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS LC-MS system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), Waters ACQuity UPLC-QD / SQD system (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), and THERMO Ultimate 3000-Q Exactive system (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0129] 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.

[0130] High performance liquid chromatography (HPLC) was performed using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatographs.

[0131] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0132] XRPD (X-ray Powder Diffraction) was used for measurement. Measurements were performed using a BRUKER D8 X-ray diffractometer. Specific data collected included: Cu anode (40 kV, 40 mA), Cu-Kα1 rays (λ = 1.54060 Å), Kα2 rays (λ = 1.54439 Å), and Kβ rays (λ = 1.39222 Å). The scanning mode was θ / 2θ, and the scanning range (2θ range) was 3°–45°.

[0133] DSC stands for Differential Scanning Calorimetry: Measurements were performed using a METTLER TOLEDO DSC 3+ differential scanning calorimeter with a heating rate of 10℃ / min. The specific temperature range was referenced from the corresponding spectra (mostly 25-300℃), and the nitrogen purging rate was 50 mL / min.

[0134] TGA is thermogravimetric analysis: the test was performed using a METTLER TOLEDO TGA 2 thermogravimetric analyzer, with a heating rate of 10℃ / min, and the specific temperature range was referenced from the corresponding spectrum (mostly 30-400℃). The nitrogen purging rate was 50 mL / min.

[0135] DVS stands for Dynamic Moisture Adsorption: The detection was performed using SMS DVS Advantage at 25℃, with humidity changes of 50%-95%-0%-95%-50% in 10% increments (the final step is 5%) (the specific humidity range is subject to the corresponding spectrum; the methods listed here are the most commonly used). The judgment criteria are dm / dt not greater than 0.002% / min and Tmax not greater than 360min.

[0136] The known starting materials disclosed herein can be synthesized using or according to 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.

[0137] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0138] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0139] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system used for column chromatography to purify the compounds, and the developing solvent system for TLC included: A: n-hexane / ethyl acetate system, B: dichloromethane / methanol system. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0140] Example 1: Preparation of Compound 1

[0141] 2-Amino-4-((S)-5-chloro-3-(((R)-2-(difluoromethylidene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7,9-dihydrofurano[3,4-f]quinazolin-6-yl)-7-fluorobenzo[b]thiophene-3-carboxylonitrile 1 (synthesized according to the preparation method of Example 1 in PCT / CN2025 / 087757)

[0142]

[0143] first step

[0144] 2-(difluoromethylidene)-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid ethyl ester 1b

[0145] Ethyl 2,5-dioxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate 1a (18.08 g, 85.60 mmol, Jiangsu Aikang) and (triphenylphosphonium)difluoroacetic acid inner salt (67.1 g, 188.3 mmol, Jiangsu Aikang) were dissolved in N,N-dimethylformamide (350 mL). The reaction mixture was stirred at 85°C for 17 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give title compound 1b (4.83 g, yield: 23%).

[0146] MS m / z (ESI): 246.1 [M+1].

[0147] Step 2

[0148] (2-(difluoromethyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol1c

[0149] (R)-(2-(difluoromethyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol1c-1

[0150] (S)-(2-(difluoromethyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol1c-2

[0151] Compound 1b (4.83 g, 19.7 mmol) was dissolved in tetrahydrofuran (250 mL), and a 1 M diisobutylaluminum hydride tetrahydrofuran solution (98.5 mL) was added under ice bath conditions. After stirring for 5 hours to allow the temperature to recover naturally, sodium sulfate decahydrate was added and stirred for 0.5 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound 1c (2.1 g).

[0152] MS m / z (ESI): 190.1 [M+1].

[0153] The isomer mixture 1c (1 g) was resolved by a chiral column (Shimadzu LC-20AP, column: DAICELCHIRALPAK IG, 20 × 250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.1% 7M NH3 in MeOH solution), gradient ratio: A:B: 80:20, flow rate: 20 mL / min) to give title compounds 1c-1 (450 mg, yield: 45%) and 1c-2 (450 mg, yield: 45%).

[0154] Chiral HPLC analysis of compound 1c-1: retention time 3.220 min, purity: 99% (column: Agilent 1260 DAD, column: CHIRALPAK IG 150*4.6mm, 5um; mobile phase A: ethanol (0.1% diethylamine, mobile phase B: n-hexane), gradient ratio: A:B: 20:80, flow rate: 1 mL / min).

[0155] Chiral HPLC analysis of compound 1c-2: retention time 4.330 min, purity: 99% (column: Agilent 1260 DAD, column: CHIRALPAK IG 150*4.6mm, 5um; mobile phase A: ethanol (0.1% diethylamine, mobile phase B: n-hexane), gradient ratio: A:B: 20:80, flow rate: 1 mL / min).

[0156] Step 3

[0157] 6-Bromo-5-chloro-3-(ethylsulfonyl)-7,9-dihydrofurano[3,4-f]quinazolin 1e

[0158] 6-Bromo-3-(ethylthio)-5-chloro-7,9-dihydrofurano[3,4-f]quinazoline 1d (1.94 g, 5.61 mmol, prepared by the method disclosed in preparation 300 on page 192 of patent application "WO2023183585A1") was dissolved in dichloromethane (50 mL), and m-chloroperoxybenzoic acid (3.42 g, 16.8 mmol, 85% purity) was added. The mixture was stirred for 2 hours, and saturated sodium bicarbonate solution was added to the reaction solution. The mixture was extracted with dichloromethane (30 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried with ethyl acetate, filtered, and the filter cake was dried to obtain the crude title compound 1e (1.76 g), which was used directly in the next reaction without purification.

[0159] MS m / z (ESI): 376.9 [M+1].

[0160] Step 4

[0161] (R)-6-bromo-5-chloro-3-((2-(difluoromethylidene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7,9-dihydrofurano[3,4-f]quinazolino1f

[0162] Compound 1c-1 (142 mg, 750 μmol) was dissolved in tetrahydrofuran (10 mL). A 2 M tetrahydrofuran solution of sodium bis(trimethylsilyl)amino (374 μL) was added under ice bath conditions. After stirring for 30 minutes while maintaining the temperature, a tetrahydrofuran solution of compound 1e (225 mg, 596 μmol) (5 mL) was added under ice bath conditions. The reaction was heated to 50 °C and reacted for 1 hour. After cooling to room temperature, the reaction mixture was quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 1f (176 mg, yield: 62.4%).

[0163] MS m / z (ESI): 472.2 [M+1].

[0164] Step 5

[0165] (4-(5-chloro-3-(((R)-2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7,9-dihydrofurano[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorobenzo[b]thiophene-2-yl)tert-butyl carbamate 1g

[0166] Compound 1f (176 mg, 372 μmol) and (3-cyano-4-(5,5-dimethyl-1,3,2-dioxoborhexane-2-yl)-7-fluorobenzo[b]thiophene-2-yl)carbamate tert-butyl ester (300 mg, 742 μmol) were dissolved in 1,4-dioxane (10 mL), cesium carbonate (303 mg, 0.93 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (55 mg, 75 μmol) were added. The reaction was carried out at 100 °C for 2 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane. Water was added, and the aqueous phase was extracted with dichloromethane (15 mL × 2). 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 the title compound 1g (211 mg, yield: 82.8%).

[0167] MS m / z (ESI): 684.5 [M+1].

[0168] Step 6

[0169] 2-Amino-4-(5-chloro-3-(((R)-2-(difluoromethylidene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7,9-dihydrofurano[3,4-f]quinazolino-6-yl)-7-fluorobenzo[b]thiophene-3-carboxynitrile1h

[0170] 2-Amino-4-((S)-5-chloro-3-(((R)-2-(difluoromethylidene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7,9-dihydrofurano[3,4-f]quinazolino-6-yl)-7-fluorobenzo[b]thiophene-3-carboxylonitrile

[0171] 1 g (211 mg, 308 μmol) of the compound was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane. The pH was adjusted to >7 with saturated sodium bicarbonate. The aqueous phase was extracted with dichloromethane (10 mL × 2). The organic phases were combined and dried with anhydrous sodium sulfate. After filtering to remove the desiccant, the mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30 × 150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 32%-45%, flow rate: 30 mL / min) to give the title compound 1h (95 mg, yield: 52.7%).

[0172] The isomer mixture (90 mg) was resolved at 1 h using a chiral column (Gilson-281, column: CHIRALPAK IG, 20 × 250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.1% 7M ammonia-methanol solution), gradient ratio: A:B: 70:30, flow rate: 20 mL / min). The compound with the shorter retention time, i.e., compound 1 (30 mg, yield: 33.3%), was collected. X-ray powder diffraction analysis showed it to be amorphous, and the XRPD pattern is shown below. Figure 1 As shown.

[0173] MS m / z (ESI): 584.2 [M+1].

[0174] 1 H NMR (500 MHz, DMSO-d6): δ 9.49 (s, 1H), 8.10-8.08 (m, 2H), 7.26-7.24 (m, 1H), 7.17-7.13 (m, 1H), 5.56-5.55 (m, 2H), 4.90-4.87 (m, 1H), 4.74-4.71 (m, 1H), 4.38-4.36 (m, 1H), 4.24-4.22 (m, 1H), 3.71-3.68 (m, 1H), 3.32-3.31 (m, 1H), 3.04-3.00 (m, 1H), 2.72-2.69 (m, 1H), 2.59-2.55 (m, 1H), 2.48-2.45 (m, 1H), 2.06-2.00 (m, 1H), 1.92-1.78 (m, 3H).

[0175] Comparison Example

[0176]

[0177] Using steps four through six of the synthetic route in Example 1, the starting compound 1c-1 in step four was replaced with ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a-yl)methanol to obtain control compound 3 (300 mg, yield: 22.2%).

[0178] MS m / z (ESI): 554.5 [M+1].

[0179] 1H NMR (500 MHz, CD3OD): δ 9.37 (s, 1H), 7.22 (dd, 1H), 7.06 (t, 1H), 5.62 (q, 2H), 5.44 – 5.20 (m, 1H), 4.98 (dt, 1H), 4.85 – 4.77 (m, 1H), 4.49(d, 1H), 4.40 (d, 1H), 3.28 – 3.15 (m, 2H), 3.09 – 3.01 (m, 1H), 2.56 – 2.35(m, 1H), 2.35 – 2.16 (m, 3H), 2.14 – 1.88 (m, 3H).

[0180] Test Example 1: 3D Cell Proliferation Inhibition Experiment

[0181] This experiment used the cell evaluation compounds listed in the table below to assess their inhibitory effect on the proliferation of KRAS-mutant or KRAS-amplified cells.

[0182]

[0183] On the first day of the experiment, well-grown cells with 70%-80% confluence were digested, resuspended in culture medium, and the cell density was adjusted to the desired level. 90 µL of cell suspension was added to each well of a U-shaped, low-adsorption 96-well plate (Corning, 7007), with cell density as shown in the table above. The cell plate was centrifuged at 2500 rpm for 5 minutes and then incubated for 24 hours. On the second day, the 20 mM test compound dissolved in DMSO was diluted with DMSO to an initial concentration of 2 or 0.2 mM, and then serially diluted 5-fold for a total of 9 concentration points. The control wells contained DMSO. The serially diluted compounds were then further diluted 20-fold with culture medium. 10 μL of the culture medium-diluted test compound was added to each well of the cell plate. The final concentration of the compound was determined by the 9 concentration points obtained from 5-fold serial dilutions starting at 10 or 1 μM. Cell wells containing 0.5% DMSO were set as solvent control wells, and wells containing only culture medium and 0.5% DMSO were set as blank control wells. After centrifuging the cell culture plate at 2000 rpm for 3 minutes, it was incubated in an incubator for 5 days. On the seventh day, the 96-well cell culture plate was removed, and 50 μL of CellTiter-Glo® 3D Cell ViabilityAssay (Promega, G9683) was added to each well. After shaking at room temperature for 25 minutes, the mixture was thoroughly mixed by pipetting and aspiration, and 100 μL was transferred from each well to a white, opaque OptiPlate. TMIn a 96-well plate (PerkinElmer, 6005290), a multifunctional microplate reader (PerkinElmer, EnVision2105) was used to read the luminescence signal value.

[0184] The inhibition rate was calculated using the following formula: Inhibition rate = (Luminescence value 溶媒对照孔 - Luminescence value 受试化合物 ) / (Luminescence value 溶媒对照孔 - Luminescence value 空白对照孔 ) × 100%. The IC of the inhibitory activity of the compounds was calculated using GraphPad Prism software 50 value, and the results are shown in the following table.

[0185] Table 1. 3D cell proliferation inhibitory activity data (unit: nM)

[0186]

[0187] Conclusion: The compounds of the present disclosure have a good inhibitory effect on the 3D proliferation of the aforementioned cells.

[0188] Test Example 2. Pharmacokinetic Evaluation

[0189] 1. Summary

[0190] Using SD rats as test animals, the LC-MS / MS method was applied to determine the drug concentration in plasma at different time points after intragastric (i.g.) administration of the compound of Formula 1 to rats, to study the in vivo pharmacokinetic behavior of the compounds of the present disclosure in rats and evaluate their pharmacokinetic characteristics.

[0191] 2. Test Protocol

[0192] 2.1 Test Drugs

[0193] The compound of Formula 1 and Compound 3.

[0194] 2.2 Test Animals

[0195] 6 female rats, provided by Beijing Vital River Laboratory Animal Technology Co., Ltd., with production license SCXK (Zhejiang) 2024-0001.

[0196] 2.3 Drug Formulation

[0197] Compound of Formula 1: A certain amount of each test compound was weighed, and 5% DMSO + 10% HS15 + 17% (w / v) SBE-β-CD was added to prepare colorless clear solutions of 2.0 mg / mL and 6.0 mg / mL, respectively.

[0198] Compound 3: Weigh a certain amount of the test compound, add 5% DMSO + 10% HS15 + 17% (w / v) SBE-β-CD, and prepare a 2.0 mg / mL yellow suspension.

[0199] 2.4. Administration

[0200] Compound of Formula 1: Dosage: 20.0 mg / kg and 60 mg / kg, both administered in 10 mL / kg volume.

[0201] Compound 3: Dosage dose 20.0 mg / kg, administration volume 10 mL / kg.

[0202] 3. Operation

[0203] Blood samples of 0.2 mL were collected from the orbital cavity before 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. The samples were placed in EDTA-K2 anticoagulant tubes and centrifuged at 10,000 rpm for 2 minutes (4°C). Plasma was separated within 1 hour and stored at -20°C or -80°C for later analysis. The entire process, from blood collection to centrifugation, was performed under ice bath conditions.

[0204] The concentration of the target compound in rat plasma after administration of different compounds was determined: For compounds of formula 1 (20 mg / kg / 60 mg / kg), 25 μL / 20 μL of rat plasma samples were taken at each time point after administration, and 200 μL / 250 μL of internal standard acetonitrile solution were added. The mixture was vortexed and centrifuged at 4000 rpm for 15 minutes. The supernatant was then analyzed by LC-MS / MS.

[0205] Compound 3: Take 20 μL of rat plasma samples at each time point after drug administration, add 250 μL of internal standard acetonitrile solution, vortex mix, and centrifuge at 4000 rpm for 15 minutes. Take the supernatant for LC-MS / MS analysis.

[0206] 4. Pharmacokinetic Parameter Results

[0207] Table 2. Pharmacokinetic parameters of the compounds disclosed herein in rats.

[0208]

[0209] Conclusion: The compound disclosed herein exhibits high blood concentrations and high exposure levels in rats, demonstrating pharmacokinetic advantages.

[0210] Example 2. Preparation of crystal form A

[0211] 10 mg of compound 1 was dissolved in 0.1 mL of ethanol at room temperature, 0.5 mL of n-heptane was added, the mixture was stirred to induce crystallization, centrifuged, and dried under vacuum to obtain the solid product.

[0212] X-ray powder diffraction analysis identified the product as crystal form A, and the XRPD spectrum is shown below. Figure 2 The positions of its characteristic peaks are shown in Table 3. The DSC spectrum shows that the endothermic peak has a peak value of 154.00℃. The TGA spectrum shows that the weight loss is approximately 1.23% between 97℃ and 217℃.

[0213] Table 3

[0214]

[0215] Example 3. Preparation of crystal form A

[0216] 10 mg of compound 1 of formula 1 was added to 1 mL of solvent from Table 4, stirred at room temperature for 3 days, centrifuged, and dried under vacuum to obtain a solid product. X-ray powder diffraction analysis showed that the product was crystal form A.

[0217] Table 4

[0218]

[0219] Example 4. Preparation of crystal form A

[0220] 10 mg of compound 1 was dissolved in 0.1 mL of solvent 1 (Table 5), and 0.5 mL of solvent 2 (Table 5) was added. The mixture was stirred at room temperature to induce crystallization, centrifuged, and dried under vacuum to obtain a solid product. X-ray powder diffraction analysis showed that the product was crystal form A.

[0221] Table 5

[0222]

[0223] Example 5. Preparation of crystal form A

[0224] Five mg of compound 1 was dissolved in 0.05 mL of solvent from Table 6 at room temperature. The mixture was stirred to induce crystallization, centrifuged, and dried under vacuum to obtain a solid product. X-ray powder diffraction analysis confirmed that the product was crystal form A.

[0225] Table 6

[0226]

[0227] Example 6. Preparation of crystal form A

[0228] Add 5 mg of compound 1 to 1 mL of solvent from Table 7, stir at 40 °C for 1 h, cool to 5 °C, stir to induce crystallization, centrifuge, and dry the solid under vacuum to obtain the solid product. X-ray powder diffraction analysis showed that the product is crystal form A.

[0229] Table 7

[0230]

[0231] Example 7. Preparation of crystal form B

[0232] 5 mg of compound of formula 1 was dissolved in 0.05 mL of butyl formate, stirred at 40 °C for 1 h, cooled to 5 °C, stirred to precipitate crystals, centrifuged, and dried under vacuum to obtain the solid product.

[0233] X-ray powder diffraction analysis identified the product as crystal form B. The XRPD spectrum is shown below. Figure 3 The positions of its characteristic peaks are shown in Table 8. The DSC spectrum shows that the endothermic peak has a peak value of 146.82℃. The TGA spectrum shows that the weight loss is 4.29% from 72℃ to 125℃.

[0234] Table 8

[0235]

[0236] Continued from Table 8

[0237]

[0238] Example 8. Preparation of crystal form B

[0239] 10 mg of compound 1 was added to 1 mL of butyl formate / cyclohexane (1:9, v / v), stirred at room temperature for 3 days, centrifuged, and dried under vacuum to obtain a solid product. X-ray powder diffraction analysis showed that the product was crystal form B.

[0240] Example 9. Preparation of Crystal Form C

[0241] 40 mg of the crude compound 1 was added to 0.4 mL of a 1,4-dioxane / n-heptane (1:8, v / v) mixed solvent, stirred at room temperature for 4 days, filtered, and the filter cake was collected and dried under vacuum to obtain the solid product.

[0242] X-ray powder diffraction analysis determined this crystal form to be crystal form C. The X-ray powder diffraction pattern is shown below. Figure 4 As shown in Table 9, the positions of its characteristic peaks are as follows.

[0243] Table 9

[0244]

[0245] Example 10. Preparation of Crystal Form C

[0246] 10 mg of compound 1 was dissolved in 0.1 mL of isopropanol, 0.5 mL of cyclohexane was added, the mixture was stirred at room temperature to crystallize, centrifuged, and dried under vacuum to obtain the solid product.

[0247] X-ray powder diffraction analysis revealed that the product is crystalline form C.

[0248] Example 11. Preparation of Crystal Form C

[0249] 10 mg of compound of formula 1 was dissolved in 0.1 mL of tetrahydrofuran, and 0.5 mL of n-heptane was added. The mixture was stirred at room temperature to induce crystallization, centrifuged, and dried under vacuum to obtain a solid product. X-ray powder diffraction analysis showed that the product was crystalline form C.

[0250] Example 12. Preparation of Crystal Form C

[0251] 5 mg of compound 1 was dissolved in 0.05 mL of toluene at room temperature, stirred at 40 °C for 1 h, cooled to 5 °C, stirred to induce crystallization, centrifuged, and dried under vacuum to obtain a solid product. X-ray powder diffraction analysis showed that the product was crystalline form C.

[0252] Example 13. Preparation of Crystal Form C

[0253] 10 mg of compound 1 was added to 0.2 mL of ethyl acetate / cyclohexane (1:4, v / v), stirred at 50 °C for 3 days, centrifuged, and dried under vacuum to obtain a solid product. X-ray powder diffraction analysis showed that the product was crystalline form C.

[0254] Example 14. Preparation of Crystal Form C

[0255] 10 mg of compound 1 was added to 1 mL of Table 10 solvent, stirred at room temperature for 3 days, centrifuged, and dried under vacuum to obtain a solid product. X-ray powder diffraction analysis showed that the product was crystalline form C.

[0256] Table 10

[0257]

[0258] Example 15. Preparation of crystal form D

[0259] Add 5 mg of compound 1 to 1 mL of isopropyl ether, stir at room temperature for 5 days, centrifuge, and dry the solid under vacuum to obtain the solid product.

[0260] X-ray powder diffraction analysis determined the product to be crystal form D. The XRPD spectrum is shown below. Figure 5 The positions of its characteristic peaks are shown in Table 11. The DSC spectrum shows that the endothermic peak has a peak value of 158.21℃.

[0261] Table 11

[0262]

[0263] Example 16. Preparation of crystal form D

[0264] Add 40 mg of the crude compound 1 to 0.4 mL of isopropyl ether, stir at room temperature for 4 days, filter, collect the filter cake and dry it under vacuum to obtain the solid product.

[0265] X-ray powder diffraction analysis revealed that the crystal form is crystal form D.

[0266] Example 17. Preparation of crystal form E

[0267] 10 mg of compound 1 was added to 1 mL of methyl isobutyl ketone / cyclohexane (1:9, v / v), stirred at room temperature for 3 days, centrifuged, and dried under vacuum to obtain the solid product.

[0268] X-ray powder diffraction analysis determined the product to be crystal form E. The XRPD spectrum is shown below. Figure 6 The positions of its characteristic peaks are shown in Table 12. The DSC spectrum shows that the endothermic peaks are at 108.18℃ and 157.85℃. The TGA spectrum shows that the weight loss is approximately 1.96% between 30℃ and 156℃.

[0269] Table 12

[0270]

[0271] Example 18. Preparation of crystal form F

[0272] 40 mg of the crude compound 1 was added to 0.4 mL of ethyl acetate / n-hexane (1:8, v / v) mixed solvent, stirred at room temperature for 4 days, filtered, and the filter cake was collected and dried under vacuum to obtain the solid product.

[0273] X-ray powder diffraction analysis revealed that the crystal form is F. The X-ray powder diffraction pattern is shown below. Figure 7 As shown, the positions of its characteristic peaks are shown in Table 13.

[0274] Table 13

[0275]

[0276] Example 19. Preparation of crystal form F

[0277] 10 mg of compound 1 was added to 0.2 mL of acetone / cyclohexane (1:4, v / v), stirred at 50 °C for 3 days, centrifuged, and dried under vacuum to obtain the solid product.

[0278] X-ray powder diffraction analysis revealed that the product is crystal form F.

[0279] Example 20. Preparation of crystal form F

[0280] 10 mg of compound 1 was placed in an ethyl acetate environment for gas-solid diffusion for 7 days to obtain a solid product. X-ray powder diffraction analysis showed that the product was of crystal form F.

[0281] Example 21. Preparation of crystal form G

[0282] 10 mg of compound of formula 1 was dissolved in 0.1 mL of tetrahydrofuran, 0.5 mL of water was added, the mixture was stirred at room temperature to induce crystallization, centrifuged, and dried under vacuum to obtain the solid product.

[0283] X-ray powder diffraction analysis determined the product to be crystal form G. The XRPD spectrum is shown below. Figure 8 The positions of its characteristic peaks are shown in Table 14. The DSC spectrum shows endothermic peaks at 124.85℃ and 154.52℃. The TGA spectrum shows a weight loss of 6.19% between 30℃ and 163℃.

[0284] Table 14

[0285]

[0286] Implementation 22. Preparation of Crystal Form H

[0287] 10 mg of compound 1 was placed in a butyl formate environment for gas-solid diffusion for 7 days to obtain a solid product.

[0288] X-ray powder diffraction analysis determined the product to be crystal form H. The XRPD spectrum is shown below. Figure 9 The positions of its characteristic peaks are shown in Table 15. The DSC spectrum shows that the endothermic peak has a peak value of 137.53℃. The TGA spectrum shows that the weight loss is approximately 1.72% from 30℃ to 97℃ and approximately 8.18% from 97℃ to 170℃. Table 15

[0289]

[0290] Continued from Table 15

[0291]

[0292] Example 23. Preparation of Crystal Form I

[0293] 100 mg of the crude compound 1 was added to 1 mL of isopropanol, stirred at room temperature for 4 days, filtered, and the filter cake was collected and dried under vacuum to obtain the solid product.

[0294] X-ray powder diffraction analysis determined this crystal form to be crystal form I. The X-ray powder diffraction pattern is shown below. Figure 10 As shown in Table 16, the positions of its characteristic peaks are as follows.

[0295] Table 16

[0296]

[0297] Example 24. Preparation of crystal form J

[0298] 100 mg of the crude compound 1 was added to 3 mL of a mixed solvent of isopropanol / n-heptane (1:8, v / v), stirred at room temperature for 4 days, filtered, and the filter cake was collected and dried under vacuum to obtain the solid product.

[0299] X-ray powder diffraction analysis revealed that the crystal form is J. The X-ray powder diffraction pattern is shown below. Figure 11 As shown in Table 17, the positions of its characteristic peaks are as follows.

[0300] Table 17

[0301]

[0302] Continued from Table 17

[0303]

[0304] Example 25. Preparation of crystal form K

[0305] 40 mg of the crude compound 1 was added to 0.4 mL of a mixed solvent of isopropanol / isopropyl ether (1:8, v / v), stirred at room temperature for 4 days, filtered, and the filter cake was collected and dried under vacuum to obtain the solid product.

[0306] X-ray powder diffraction analysis determined the product to be crystal form K. The X-ray powder diffraction pattern is shown below. Figure 12 As shown, the positions of its characteristic peaks are shown in Table 18.

[0307] Table 18

[0308]

[0309] Example 26. Preparation of amorphous materials

[0310] 10 mg of compound 1 was dissolved in 0.05 mL of 10% water-methanol (v / v), stirred at 40 °C for 1 h, and then stirred at 5 °C to precipitate. The precipitate was centrifuged and dried under vacuum to obtain a solid product. X-ray powder diffraction analysis showed that the product was amorphous.

[0311] Example 27. Preparation of amorphous materials

[0312] 10 mg of compound 1 was dissolved in 0.1 mL of solvent 1 (Table 19), and 0.5 mL of solvent 2 (Table 19) was added. The mixture was stirred at room temperature to precipitate, centrifuged, and dried under vacuum to obtain a solid product. X-ray powder diffraction analysis showed that the product was amorphous.

[0313] Table 19

[0314]

[0315] Example 28. Preparation of amorphous materials

[0316] 5 mg of compound 1 was dissolved in 0.05 mL of solvent 1 in Table 20, and then added to 0.6 mL of solvent 2 in Table 20. The mixture was stirred at room temperature to precipitate, centrifuged, and dried under vacuum to obtain a solid product. X-ray powder diffraction analysis showed that the product was amorphous.

[0317] Table 20

[0318]

[0319] Example 29. Preparation of amorphous materials

[0320] 5 mg of compound 1 was dissolved in the solvent in Table 21 and allowed to evaporate and solidify at room temperature to obtain a solid product. X-ray powder diffraction analysis showed that the product was amorphous.

[0321] Table 21

[0322]

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, shows characteristic peaks at 6.129, 13.379, 16.716, and 18.448, preferably at 6.129, 6.826, 12.111, 13.379, 16.716, 17.842, 18.448, 21.781, and 24.169, and more preferably at 6.129, 6.826, 12.111, 13.379, 14.091, 16.716, 17.842, 18.448, 21.216, 21.781, 22.773, and 24.

169. 。 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 any of the following methods: Method 1: Dissolve the compound of formula 1 in ethanol, add n-heptane, and stir; Method 2: Add the compound of Formula 1 to solvent I and stir; solvent I is selected from a mixture of ethanol / n-heptane and a mixture of ethyl acetate / n-heptane. Method 3: Dissolve the compound of formula 1 in acetone, add n-heptane, and stir; Method 4: Dissolve the compound of formula 1 in ethyl acetate, add n-heptane, and stir; Method 5: Dissolve the compound of formula 1 in ethyl acetate, add isopropyl ether, and stir; Method 6: Dissolve the compound of Formula 1 in solvent II and stir, wherein solvent II is selected from acetonitrile, ethyl acetate and isopropyl acetate; Method 7: Add the compound of Formula 1 to solvent III and stir. Solvent III is selected from acetone / cyclohexane mixed solvent and ethyl acetate / cyclohexane mixed solvent.

4. 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 6.624, 16.960, 18.249, and 25.485, preferably at 6.624, 16.426, 16.960, 18.249, 19.717, 20.253, 23.223, and 25.485, and even more preferably at 6.624, 13.493, 15.345, 16.426, 16.960, 18.249, 19.717, 20.253, 22.259, 23.223, 25.485, and 32.

844.

5. The crystal form C 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 4.

6. A method for preparing crystal form C as described in claim 4 or 5, the method comprising any of the following methods: Method 1: Add the compound of Formula 1 to solvent IV and stir. Solvent IV is selected from 1,4-dioxane / n-heptane mixed solvent, ethyl acetate / cyclohexane, acetone / n-heptane mixed solvent, tetrahydrofuran / n-heptane mixed solvent and isopropanol / cyclohexane mixed solvent. Method 2: Dissolve the compound of formula 1 in isopropanol, add cyclohexane, and stir; Method 3: Dissolve the compound of formula 1 in tetrahydrofuran, add n-heptane, and stir; Method 4: Dissolve the compound of Formula 1 in toluene and stir.

7. A crystal form F 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 6.312, 13.588, 16.371, 16.961, and 24.571, preferably at 6.312, 12.385, 13.588, 16.371, 16.961, 18.501, 24.571, 25.792, and 26.337, and more preferably at 6.312, 12.385, 13.588, 16.371, 16.961, 18.501, 22.249, 23.169, 24.571, 25.792, and 26.

337.

8. The crystal form F 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 7.

9. A method for preparing crystal form F 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 VI and stir. Solvent VI is selected from a mixture of ethyl acetate / n-hexane and a mixture of acetone / cyclohexane. Method 2: Place the compound of Formula 1 in an ethyl acetate environment.

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

20.

11. A pharmaceutical composition comprising the crystal form as described in any one of claims 1-2, 4-5, 7-8 and optionally a pharmaceutically acceptable excipient.

12. A method for preparing a pharmaceutical composition, comprising the following steps: The step of mixing the crystal form as described in any one of claims 1-2, 4-5, 7-8 with a pharmaceutically acceptable excipient.

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

14. The use according to claim 13, wherein the cancer is selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, laryngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small bowel cancer, gastrointestinal stromal tumor, urothelial carcinoma, urethral cancer, bladder cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma, and glioblastoma; preferably, the cancer is selected from pancreatic cancer, colorectal cancer, and non-small cell lung cancer.

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