Crystal forms and preparation methods of methylpyrazole-substituted pyridineimidazole compounds

Abstract

A crystalline form of a methylpyrazole-substituted pyridine-imidazolium compound (II) and its preparation method.

Description

[0001] This application claims the following priority:

[0002] CN202110106007.1, application date: January 26, 2021. Technical Field

[0003] This invention relates to a crystalline form of a methylpyrazole-substituted pyridineimidazole compound and its preparation method. Background Technology

[0004] Fibroblast growth factor receptors (FGFRs) are a class of receptor proteins that specifically bind to fibroblast growth factor (FGF). The FGFR family includes the following types: FGFR1b, FGFR1c, FGFR2b, FGFR2c, FGFR3b, FGFR3c, and FGFR4. FGFRs are bioactive substances with functions such as transducing biological signals, regulating cell growth, and participating in tissue repair. Clinically, high expression, mutations, or fusions of FGFRs have been found to induce tumor development and progression, for example, in diseases such as liver cancer, bladder cancer, lung cancer, and breast cancer. The binding of FGFRs to their ligand FGF leads to the autophosphorylation of multiple intracellular tyrosine residues, resulting in downstream signal transduction, including MEK / MAPK, PLCy / PKC, PI3K / AKT, and STATS. Therefore, FGFRs are considered important anti-tumor targets.

[0005] The VEGFR family includes three specific tyrosine kinase receptors: VEGFR-1, VEGFR-2 (KDR), and VEGFR-3. VEGFR-2 is a crucial regulator of VEGF signaling, inducing endothelial cell proliferation, increasing vascular permeability, and promoting angiogenesis. Furthermore, VEGFR-2 has a greater affinity for VEGF than VEGFR-1. Studies have shown that endothelial cells express only VEGFR-2, and activation of VEGFR-2 efficiently stimulates angiogenesis. Therefore, VEGFR-2 is a primary target for anti-angiogenic drug development.

[0006] The VEGFR and FGFR pathways work together to activate and generate endothelial cells in angiogenesis. Sometimes, VEGF requires the presence of FGF to exert its pro-angiogenic effect. The synergistic effect of the FGFR and VEGFR pathways can also inhibit tumor immune escape and improve tumor suppression. Summary of the Invention

[0007] This invention provides a compound represented by formula (II),

[0008]

[0009] This invention provides crystal form A of the compound shown in formula (II), characterized by its X-ray powder diffraction pattern exhibiting characteristic diffraction peaks at the following 2θ angles: 7.65±0.20°, 17.70±0.20°, 24.02±0.20°.

[0010]

[0011] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned A-type crystal has characteristic diffraction peaks at the following 2θ angles: 7.65±0.20°, 16.84±0.20°, 17.70±0.20°, 20.10±0.20°, 20.91±0.20°, 24.02±0.20°.

[0012] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned A-type crystal has characteristic diffraction peaks at the following 2θ angles: 7.65±0.20°, 16.84±0.20°, 17.70±0.20°, 20.10±0.20°, 20.91±0.20°, 24.02±0.20°, 24.98±0.20°, 26.60±0.20°.

[0013] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned A-type crystal has characteristic diffraction peaks at the following 2θ angles: 7.65±0.20°, 17.70±0.20°, and / or 24.02±0.20°, and / or 16.84±0.20°, and / or 20.10±0.20°, and / or 20.91±0.20°, and / or 24.98±0.20°, and / or 26.60±0.20°, and / or 12.71±0.20°, and / or 28.08±0.20°.

[0014] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned A-type crystal has characteristic diffraction peaks at the following 2θ angles: 7.649°, 12.713°, 16.841°, 17.695°, 20.100°, 20.912°, 24.018°, 24.976°, 26.599°, and 28.076°.

[0015] In some embodiments of the present invention, the XRPD pattern of the above-mentioned crystal form A is as follows: Figure 1 As shown.

[0016] In some embodiments of the present invention, the XRPD spectra analysis data of the above-mentioned A-type crystal form are shown in Table 1:

[0017] Table 1. XRPD analysis data for crystal form A of compound (II)

[0018]

[0019] In some embodiments of the present invention, the above-mentioned crystal form A has a peak value of an endothermic peak at 283.9±3.0℃ in its differential scanning calorimetry curve.

[0020] In some embodiments of the present invention, the DSC spectrum of the above-mentioned crystal form A is as follows: Figure 2 As shown.

[0021] In some embodiments of the present invention, the above-mentioned crystal form A exhibits a weight loss of 0.955% at 200.0±3.0℃ according to thermogravimetric analysis.

[0022] In some embodiments of the present invention, the TGA spectrum of the above-mentioned crystal form A is as follows: Figure 3 As shown.

[0023] This invention provides crystal form B of the compound shown in formula (II), characterized by its X-ray powder diffraction pattern exhibiting characteristic diffraction peaks at the following 2θ angles: 6.75±0.20°, 9.94±0.20°, 23.94±0.20°.

[0024]

[0025] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 6.75±0.20°, 9.94±0.20°, 11.70±0.20°, 17.52±0.20°, 20.36±0.20°, and 23.94±0.20°.

[0026] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 6.75±0.20°, 9.94±0.20°, 11.70±0.20°, 14.38±0.20°, 17.52±0.20°, 18.95±0.20°, 20.36±0.20°, 23.94±0.20°.

[0027] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 6.75°, 9.94°, 11.70°, 13.62°, 14.38°, 15.47°, 17.52°, 18.95°, 20.36°, 23.94°, 25.34°, 25.46°, 26.93°, and 28.79°.

[0028] In some embodiments of the present invention, the XRPD pattern of the above-mentioned B crystal form is as follows: Figure 4 As shown.

[0029] In some embodiments of the present invention, the XRPD spectra analysis data of the above-mentioned B crystal form are shown in Table 2:

[0030] Table 2 shows the XRPD analysis data for the crystal form of compound B of formula (II).

[0031]

[0032] In some embodiments of the present invention, the differential scanning calorimetry curves of the above-mentioned B crystal form have an endothermic peak starting point at 57.40±3.0℃ and 296.86±3.0℃, respectively.

[0033] In some embodiments of the present invention, the DSC spectrum of the above-mentioned B crystal form is as follows: Figure 5 As shown.

[0034] In some embodiments of the present invention, the above-mentioned B crystal form exhibits a weight loss of 10.53% at 150.0 ± 3.0 °C according to thermogravimetric analysis.

[0035] In some embodiments of the present invention, the TGA spectrum of the above-mentioned B crystal form is as follows: Figure 6 As shown.

[0036] This invention provides the C-crystal form of the compound shown in formula (II), characterized by its X-ray powder diffraction pattern exhibiting characteristic diffraction peaks at the following 2θ angles: 10.74±0.20°, 13.64±0.20°, 21.14±0.20°.

[0037]

[0038] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned C-type crystal has characteristic diffraction peaks at the following 2θ angles: 10.74±0.20°, 13.64±0.20°, 19.62±0.20°, 21.14±0.20°, 25.45±0.20°, and 25.96±0.20°.

[0039] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned C-type crystal has characteristic diffraction peaks at the following 2θ angles: 8.70±0.20°, 10.74±0.20°, 13.64±0.20°, 16.63±0.20°, 19.62±0.20°, 21.14±0.20°, 25.45±0.20°, 27.47±0.20°.

[0040] In some embodiments of the present invention, the above-mentioned C crystal form has X-ray powder diffraction patterns with characteristic diffraction peaks at the following 2θ angles: 5.44°, 8.70°, 10.74°, 13.64°, 15.85°, 16.63°, 17.44°, 19.62°, 21.14°, 21.61°, 24.26°, 25.45°, 25.96°, 27.47°, and 29.07°.

[0041] In some embodiments of the present invention, the XRPD pattern of the above-mentioned C crystal form is as follows: Figure 7 As shown.

[0042] In some embodiments of the present invention, the XRPD spectra analysis data of the above-mentioned C-type crystal are shown in Table 3:

[0043] Table 3 shows the XRPD analysis data for crystal form C of compound (II).

[0044]

[0045] In some embodiments of the present invention, the differential scanning calorimetry curves of the above-mentioned C crystal form have an endothermic peak starting point at 37.60±3.0℃ and 299.00±3.0℃, respectively.

[0046] In some embodiments of the present invention, the DSC spectrum of the above-mentioned C crystal form is as follows: Figure 8 As shown.

[0047] In some embodiments of the present invention, the above-mentioned C crystal form exhibits a weight loss of 7.91% at 150.0 ± 3.0 °C according to thermogravimetric analysis.

[0048] In some embodiments of the present invention, the TGA spectrum of the above-mentioned C crystal form is as follows: Figure 9 As shown.

[0049] This invention provides the D-crystal form of the compound shown in formula (II), characterized by its X-ray powder diffraction pattern exhibiting characteristic diffraction peaks at the following 2θ angles: 10.78±0.20°, 13.64±0.20°, 16.66±0.20°.

[0050]

[0051] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned D crystal form has characteristic diffraction peaks at the following 2θ angles: 10.78±0.20°, 13.64±0.20°, 16.66±0.20°, 19.63±0.20°, 21.13±0.20°, and 25.40±0.20°.

[0052] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned D-type crystal has characteristic diffraction peaks at the following 2θ angles: 5.51±0.20°, 8.73±0.20°, 10.78±0.20°, 13.64±0.20°, 16.66±0.20°, 19.63±0.20°, 21.13±0.20°, 25.40±0.20°.

[0053] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned D-type crystal has characteristic diffraction peaks at the following 2θ angles: 5.51°, 8.10°, 8.73°, 10.78°, 12.64°, 13.64°, 14.47°, 14.92°, 15.80°, 16.66°, 17.47°, 19.03°, 19.63°, 21 .13°, 21.69°, 22.02°, 22.20°, 23.84°, 24.31°, 25.40°, 25.93°, 26.28°, 26.84°, 27.41°, 27.93°, 29.10°, 30.01°, 30.78°, 32.16°, 32.78°, 33.57°, 38.41°.

[0054] In some embodiments of the present invention, the XRPD pattern of the above-mentioned D crystal form is as follows: Figure 10 As shown.

[0055] In some embodiments of the present invention, the XRPD spectra analysis data of the above-mentioned D crystal form are shown in Table 4:

[0056] Table 4 shows the XRPD analysis data for crystal form D of compound (II).

[0057]

[0058]

[0059] In some embodiments of the present invention, the differential scanning calorimetry curves of the above-mentioned D crystal form have an endothermic peak starting point at 27.1±3.0℃ and 298.8±3.0℃, respectively.

[0060] In some embodiments of the present invention, the D-type crystal structure described above has the following DSC spectrum: Figure 11 As shown.

[0061] In some embodiments of the present invention, the above-mentioned D crystal form exhibits a weight loss of 3.15% at 150.0 ± 3.0 °C according to thermogravimetric analysis.

[0062] In some embodiments of the present invention, the TGA spectrum of the above-mentioned D crystal form is as follows: Figure 12 As shown.

[0063] This invention provides a compound represented by formula (III),

[0064]

[0065] This invention provides the E crystal form of the compound shown in formula (III), characterized by its X-ray powder diffraction pattern exhibiting characteristic diffraction peaks at the following 2θ angles: 9.56±0.20°, 19.10±0.20°, 27.12±0.20°.

[0066]

[0067] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned E-type crystal has characteristic diffraction peaks at the following 2θ angles: 9.56±0.20°, 10.82±0.20°, 16.94±0.20°, 19.10±0.20°, 27.12±0.20°, and 28.76±0.20°.

[0068] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned E-type crystal has characteristic diffraction peaks at the following 2θ angles: 9.56±0.20°, 10.82±0.20°, 16.94±0.20°, 17.57±0.20°, 19.10±0.20°, 25.00±0.20°, 27.12±0.20°, 28.76±0.20°.

[0069] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned E-type crystal has characteristic diffraction peaks at the following 2θ angles: 7.01°, 9.56°, 10.82°, 13.51°, 13.97°, 16.94°, 17.57°, 19.10°, 21.26°, 23.73°, 24.47°, 25.00°, 26.04°, 26.62°, 27.12°, 28.33°, 28.76°, 29.22°, 30.59°, 31.56°, 32.72°, 35.31°, 36.10°, 37.25°, and 38.64°.

[0070] In some embodiments of the present invention, the XRPD pattern of the above-mentioned E crystal form is as follows: Figure 13 As shown.

[0071] In some embodiments of the present invention, the XRPD spectra analysis data of the above-mentioned E-type are shown in Table 5:

[0072] Table 5. XRPD analysis data for crystal form E of compound (III)

[0073]

[0074] In some embodiments of the present invention, the above-mentioned E crystal form has a differential scanning calorimetry curve with an endothermic peak starting at 303.8±3.0℃.

[0075] In some embodiments of the present invention, the DSC spectrum of the above-mentioned E crystal form is as follows: Figure 14 As shown.

[0076] In some embodiments of the present invention, the above-mentioned E crystal form exhibits a weight loss of 2.27% at 200.0±3.0℃ according to thermogravimetric analysis.

[0077] In some embodiments of the present invention, the TGA spectrum of the above-mentioned E crystal form is as follows: Figure 15 As shown.

[0078] This invention provides the F-crystal form of the compound shown in formula (III), characterized by its X-ray powder diffraction pattern exhibiting characteristic diffraction peaks at the following 2θ angles: 8.08±0.20°, 19.09±0.20°, 26.87±0.20°.

[0079]

[0080] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned F crystal form has characteristic diffraction peaks at the following 2θ angles: 8.08±0.20°, 9.51±0.20°, 12.40±0.20°, 19.09±0.20°, 24.91±0.20°, 26.87±0.20°.

[0081] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned F crystal form has characteristic diffraction peaks at the following 2θ angles: 8.08±0.20°, 9.51±0.20°, 12.40±0.20°, 16.80±0.20°, 17.70±0.20°, 19.09±0.20°, 24.91±0.20°, 26.87±0.20°.

[0082] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned F crystal form has characteristic diffraction peaks at the following 2θ angles: 8.08°, 9.51°, 12.40°, 13.34°, 14.53°, 16.80°, 17.70°, 19.09°, 20.34°, 22.34°, 24.91°, 26.87°, and 28.87°.

[0083] In some embodiments of the present invention, the XRPD pattern of the above-mentioned F crystal form is as follows: Figure 16 As shown.

[0084] In some embodiments of the present invention, the XRPD spectra analysis data of the above-mentioned F crystal form are shown in Table 6:

[0085] Table 6 shows the XRPD analysis data for crystal form F of compound (III).

[0086]

[0087] This invention provides the G-crystal form of the compound shown in formula (III), characterized by its X-ray powder diffraction pattern exhibiting characteristic diffraction peaks at the following 2θ angles: 8.79±0.20°, 17.53±0.20°, 26.33±0.20°.

[0088]

[0089] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned G crystal form has characteristic diffraction peaks at the following 2θ angles: 8.79±0.20°, 12.34±0.20°, 17.53±0.20°, 19.10±0.20°, 25.16±0.20°, 26.33±0.20°.

[0090] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned G crystal form has characteristic diffraction peaks at the following 2θ angles: 8.79±0.20°, 12.34±0.20°, 17.53±0.20°, 19.10±0.20°, 19.65±0.20°, 21.45±0.20°, 25.16±0.20°, 26.33±0.20°.

[0091] In some embodiments of the present invention, the above-mentioned G crystal form has X-ray powder diffraction patterns with characteristic diffraction peaks at the following 2θ angles: 8.79°, 12.34°, 13.92°, 15.13°, 15.76°, 17.08°, 17.53°, 19.10°, 19.65°, 20.61°, 21.45°, 21.90°, 23.38°, 25.16°, 26.33°, 26.70°, 29.18°, 35.42°, and 37.62°.

[0092] In some embodiments of the present invention, the XRPD pattern of the above-mentioned G crystal form is as follows: Figure 17 As shown.

[0093] In some embodiments of the present invention, the XRPD spectra analysis data of the above-mentioned G crystal form are shown in Table 7:

[0094] Table 7 shows the XRPD analysis data for the G crystal form of compound (III).

[0095]

[0096] This invention provides a compound represented by formula (IV),

[0097]

[0098] This invention provides the H crystal form of the compound shown in formula (IV), characterized by its X-ray powder diffraction pattern exhibiting characteristic diffraction peaks at the following 2θ angles: 6.65±0.20°, 17.80±0.20°, 18.92±0.20°.

[0099]

[0100] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned H-type crystal has characteristic diffraction peaks at the following 2θ angles: 6.65±0.20°, 13.42±0.20°, 17.80±0.20°, 18.92±0.20°, 21.99±0.20°, 24.42±0.20°.

[0101] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned H-type crystal has characteristic diffraction peaks at the following 2θ angles: 6.65±0.20°, 13.42±0.20°, 17.80±0.20°, 18.92±0.20°, 20.05±0.20°, 21.99±0.20°, 24.42±0.20°, 26.30±0.20°.

[0102] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned H-type crystal has characteristic diffraction peaks at the following 2θ angles: 6.65°, 13.42°, 17.80°, 18.45°, 18.92°, 20.05°, 21.99°, 24.42°, 26.30°, and 27.00°.

[0103] In some embodiments of the present invention, the XRPD pattern of the above-mentioned H crystal form is as follows: Figure 18 As shown.

[0104] In some embodiments of the present invention, the XRPD spectra analysis data of the above-mentioned H crystal form are shown in Table 8:

[0105] Table 8 shows the XRPD analysis data for the H crystal form of compound (IV).

[0106]

[0107] In some embodiments of the present invention, the differential scanning calorimetry curves of the above-mentioned H crystal form have an endothermic peak starting point at 275.73±3.0℃ and 310.54±3.0℃, respectively.

[0108] In some embodiments of the present invention, the DSC spectrum of the above-mentioned H crystal form is as follows: Figure 19 As shown.

[0109] In some embodiments of the present invention, the above-mentioned H crystal form exhibits a weight loss of 8.58% at 200.0±3.0℃ and a further weight loss of 2.45% at 260.0±3.0℃.

[0110] In some embodiments of the present invention, the TGA spectrum of the above-mentioned H crystal form is as follows: Figure 20 As shown.

[0111] This invention provides crystal form I of the compound shown in formula (IV), characterized by its X-ray powder diffraction pattern exhibiting characteristic diffraction peaks at the following 2θ angles: 5.33±0.20°, 13.74±0.20°, 20.66±0.20°.

[0112]

[0113] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned I crystal form has characteristic diffraction peaks at the following 2θ angles: 5.33±0.20°, 9.02±0.20°, 13.74±0.20°, 18.16±0.20°, 20.66±0.20°, 21.91±0.20°.

[0114] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned I crystal form has characteristic diffraction peaks at the following 2θ angles: 5.33±0.20°, 9.02±0.20°, 11.77±0.20°, 13.74±0.20°, 17.51±0.20°, 18.16±0.20°, 20.66±0.20°, 21.91±0.20°.

[0115] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned I crystal form has characteristic diffraction peaks at the following 2θ angles: 5.33°, 9.02°, 10.62°, 11.77°, 13.74°, 15.99°, 17.51°, 18.16°, 19.63°, 20.66°, 21.24°, 21.91°, 23.15°, 24.94°, and 26.89°.

[0116] In some embodiments of the present invention, the XRPD pattern of the above-mentioned I crystal form is as follows: Figure 21 As shown.

[0117] In some embodiments of the present invention, the XRPD spectra analysis data of the above-mentioned I crystal form are shown in Table 9:

[0118] Table 9 shows the XRPD analysis data for crystal form I of compound (IV).

[0119]

[0120] This invention provides the J-crystal form of the compound shown in formula (IV), characterized by its X-ray powder diffraction pattern exhibiting characteristic diffraction peaks at the following 2θ angles: 5.24±0.20°, 18.48±0.20°, 20.79±0.20°.

[0121]

[0122] In some embodiments of the present invention, the X-ray powder diffraction pattern of the J-type crystal has characteristic diffraction peaks at the following 2θ angles: 5.24±0.20°, 18.48±0.20°, 19.77±0.20°, 20.79±0.20°, 22.67±0.20°, and 23.24±0.20°.

[0123] In some embodiments of the present invention, the X-ray powder diffraction pattern of the J-type crystal has characteristic diffraction peaks at the following 2θ angles: 5.24±0.20°, 18.48±0.20°, 19.77±0.20°, 20.79±0.20°, 22.67±0.20°, 23.24±0.20°, 24.20±0.20°, 26.28±0.20°.

[0124] In some embodiments of the present invention, the J crystal form described above has X-ray powder diffraction patterns with characteristic diffraction peaks at the following 2θ angles: 5.24°, 12.55°, 13.78°, 14.86°, 16.30°, 17.19°, 18.48°, 19.77°, 20.79°, 22.67°, 23.24°, 24.20°, and 26.28°.

[0125] In some embodiments of the present invention, the XRPD pattern of the J crystal form described above is as follows: Figure 22 As shown.

[0126] In some embodiments of the present invention, the XRPD spectra analysis data of the J-type crystal are shown in Table 10:

[0127] Table 10 shows the XRPD analysis data for crystal form J of compound (IV).

[0128]

[0129] This invention provides the K-crystal form of the compound shown in formula (IV), characterized by its X-ray powder diffraction pattern exhibiting characteristic diffraction peaks at the following 2θ angles: 17.97±0.20°, 20.47±0.20°, 25.16±0.20°.

[0130]

[0131] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned K crystal form has characteristic diffraction peaks at the following 2θ angles: 6.79±0.20°, 17.97±0.20°, 20.47±0.20°, 23.46±0.20°, 23.87±0.20°, and 25.16±0.20°.

[0132] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned K crystal form has characteristic diffraction peaks at the following 2θ angles: 6.79±0.20°, 17.97±0.20°, 18.74±0.20°, 19.47±0.20°, 20.47±0.20°, 23.46±0.20°, 23.87±0.20°, 25.16±0.20°.

[0133] In some embodiments of the present invention, the above-mentioned K crystal form has X-ray powder diffraction patterns with characteristic diffraction peaks at the following 2θ angles: 6.79°, 7.87°, 8.65°, 11.69°, 16.47°, 17.97°, 18.28°, 18.74°, 19.47°, 20.47°, 20.76°, 21.73°, 22.33°, 23.46°, 23.87°, 25.16°, 25.94°, 26.30°, 27.06°, 28.07°, 29.34°, 30.18°, 31.69°, 33.26°, and 34.45°.

[0134] In some embodiments of the present invention, the XRPD pattern of the above-mentioned K crystal form is as follows: Figure 23 As shown.

[0135] In some embodiments of the present invention, the XRPD spectra analysis data of the above-mentioned K crystal form are shown in Table 11:

[0136] Table 11 XRPD analysis data for crystal form K of compound (IV)

[0137]

[0138]

[0139] This invention provides a compound of formula (V).

[0140]

[0141] This invention provides the L-crystal form of the compound shown in formula (V), characterized by its X-ray powder diffraction pattern exhibiting characteristic diffraction peaks at the following 2θ angles: 5.85±0.20°, 16.75±0.20°, 20.67±0.20°.

[0142]

[0143] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned L-type crystal has characteristic diffraction peaks at the following 2θ angles: 5.85±0.20°, 11.57±0.20°, 16.75±0.20°, 20.67±0.20°, 22.50±0.20°, and 25.29±0.20°.

[0144] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned L-type crystal has characteristic diffraction peaks at the following 2θ angles: 5.85±0.20°, 11.57±0.20°, 16.75±0.20°, 18.10±0.20°, 20.67±0.20°, 22.50±0.20°, 23.34±0.20°, 25.29±0.20°.

[0145] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned L-type crystal has characteristic diffraction peaks at the following 2θ angles: 5.85°, 8.36°, 11.57°, 16.75°, 18.10°, 20.67°, 22.50°, 23.34°, 25.29°, 27.93°, and 31.76°.

[0146] In some embodiments of the present invention, the XRPD pattern of the above-mentioned L-crystal form is as follows: Figure 24 As shown.

[0147] In some embodiments of the present invention, the XRPD spectra analysis data of the L-type crystal are shown in Table 12:

[0148] Table 12 XRPD analysis data for the L crystal form of compound (V)

[0149]

[0150] This invention provides the M-type crystal form of the compound shown in formula (V), characterized by its X-ray powder diffraction pattern exhibiting characteristic diffraction peaks at the following 2θ angles: 5.72±0.20°, 16.77±0.20°, 17.51±0.20°.

[0151]

[0152] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned M-type crystal has characteristic diffraction peaks at the following 2θ angles: 5.72±0.20°, 11.52±0.20°, 16.77±0.20°, 17.51±0.20°, 18.10±0.20°, and 20.05±0.20°.

[0153] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned M-type crystal has characteristic diffraction peaks at the following 2θ angles: 5.72±0.20°, 11.52±0.20°, 16.77±0.20°, 17.51±0.20°, 18.10±0.20°, 20.05±0.20°, 22.48±0.20°, 25.30±0.20°.

[0154] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned M-type crystal has characteristic diffraction peaks at the following 2θ angles: 5.42°, 5.72°, 11.52°, 13.57°, 14.92°, 16.77°, 17.51°, 18.10°, 20.05°, 22.48°, 23.35°, 23.91°, 25.30°, 27.10°, 27.94°, 30.00°, and 31.77°.

[0155] In some embodiments of the present invention, the XRPD pattern of the above-mentioned M crystal form is as follows: Figure 25 As shown.

[0156] In some embodiments of the present invention, the XRPD spectra analysis data of the above-mentioned M crystal form are shown in Table 13:

[0157] Table 13 XRPD analysis data for crystal form M of compound (V)

[0158]

[0159]

[0160] This invention provides the N-crystal form of the compound shown in formula (V), characterized by its X-ray powder diffraction pattern exhibiting characteristic diffraction peaks at the following 2θ angles: 4.55±0.20°, 16.76±0.20°, and 18.30±0.20°.

[0161]

[0162] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned N-type crystal has characteristic diffraction peaks at the following 2θ angles: 4.55±0.20°, 16.14±0.20°, 16.76±0.20°, 17.20±0.20°, 18.30±0.20°, and 20.22±0.20°.

[0163] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned N-type crystal has characteristic diffraction peaks at the following 2θ angles: 4.55±0.20°, 16.14±0.20°, 16.76±0.20°, 17.20±0.20°, 18.30±0.20°, 20.22±0.20°, 22.63±0.20°, and 24.50±0.20°.

[0164] In some embodiments of the present invention, the above-mentioned N crystal form has X-ray powder diffraction patterns with characteristic diffraction peaks at the following 2θ angles: 4.55°, 16.14°, 16.76°, 17.20°, 18.30°, 20.22°, 22.63°, 24.50°, 26.73°, and 31.76°.

[0165] In some embodiments of the present invention, the XRPD pattern of the above-mentioned N crystal form is as follows: Figure 26 As shown.

[0166] In some embodiments of the present invention, the XRPD spectra analysis data of the above-mentioned N-type crystal form are shown in Table 14:

[0167] Table 14 XRPD analysis data for the N crystal form of compound (V)

[0168]

[0169] This invention provides the compound shown in formula (VI),

[0170]

[0171] This invention provides the O-crystal form of the compound shown in formula (VI), characterized by its X-ray powder diffraction pattern exhibiting characteristic diffraction peaks at the following 2θ angles: 4.57±0.20°, 5.79±0.20°, 18.06±0.20°.

[0172]

[0173] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned O-type crystal has characteristic diffraction peaks at the following 2θ angles: 4.57±0.20°, 5.79±0.20°, 16.38±0.20°, 18.06±0.20°, 19.32±0.20°, and 20.13±0.20°.

[0174] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned O-type crystal has characteristic diffraction peaks at the following 2θ angles: 4.57±0.20°, 5.79±0.20°, 9.09±0.20°, 14.52±0.20°, 16.38±0.20°, 18.06±0.20°, 19.32±0.20°, and 20.13±0.20°.

[0175] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned O-type crystal has characteristic diffraction peaks at the following 2θ angles: 4.57°, 5.79°, 6.45°, 9.09°, 10.09°, 12.20°, 13.04°, 14.52°, 16.38°, 18.06°, 18.33°, 19.32°, 20.13°, 22.42°, 22.74°, 23.32°, 23.90°, 27.37°, and 29.29°.

[0176] In some embodiments of the present invention, the XRPD pattern of the above-mentioned O crystal form is as follows: Figure 27 As shown.

[0177] In some embodiments of the present invention, the XRPD spectra analysis data of the above-mentioned O-type crystal form are shown in Table 15:

[0178] Table 15 XRPD analysis data for the O crystal form of compound (VI)

[0179]

[0180]

[0181] This invention provides the P-crystal form of the compound shown in formula (VI), characterized by its X-ray powder diffraction pattern exhibiting characteristic diffraction peaks at the following 2θ angles: 9.96±0.20°, 17.02±0.20°, 21.78±0.20°.

[0182]

[0183] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned P-type crystal has characteristic diffraction peaks at the following 2θ angles: 9.96±0.20°, 17.02±0.20°, 21.31±0.20°, 21.78±0.20°, 24.71±0.20°, 25.52±0.20°.

[0184] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned P-type crystal has characteristic diffraction peaks at the following 2θ angles: 9.96±0.20°, 16.23±0.20°, 17.02±0.20°, 17.81±0.20°, 21.31±0.20°, 21.78±0.20°, 24.71±0.20°, 25.52±0.20°.

[0185] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned P-type crystal has characteristic diffraction peaks at the following 2θ angles: 6.87°, 8.26°, 9.96°, 13.64°, 15.18°, 16.23°, 17.02°, 17.81°, 18.62°, 21.31°, 21.78°, 24.71°, 25.52°, 29.14°, and 31.47°.

[0186] In some embodiments of the present invention, the XRPD pattern of the above-mentioned P crystal form is as follows: Figure 28 As shown.

[0187] In some embodiments of the present invention, the XRPD spectra analysis data of the above-mentioned P-type crystal are shown in Table 16:

[0188] Table 16 XRPD analysis data for the P crystal form of compound (VI)

[0189]

[0190]

[0191] This invention provides a compound represented by formula (VII).

[0192]

[0193] This invention provides the Q crystal form of the compound shown in formula (VII), characterized by its X-ray powder diffraction pattern exhibiting characteristic diffraction peaks at the following 2θ angles: 7.90±0.20°, 16.76±0.20°, 25.94±0.20°.

[0194]

[0195] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned Q crystal form has characteristic diffraction peaks at the following 2θ angles: 7.90±0.20°, 16.76±0.20°, 17.19±0.20°, 20.09±0.20°, 23.82±0.20°, 25.94±0.20°.

[0196] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned Q crystal form has characteristic diffraction peaks at the following 2θ angles: 7.90±0.20°, 11.53±0.20°, 16.76±0.20°, 17.19±0.20°, 20.09±0.20°, 20.94±0.20°, 23.82±0.20°, 25.94±0.20°.

[0197] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned Q crystal form has characteristic diffraction peaks at the following 2θ angles: 7.90°, 8.53°, 9.90°, 11.53°, 12.98°, 15.12°, 16.76°, 17.19°, 19.68°, 20.09°, 20.94°, 22.50°, 22.86°, 23.82°, 25.32°, 25.94°, 27.16°, 27.83°, 29.17°, 30.11°, 31.83°, and 33.48°.

[0198] In some embodiments of the present invention, the XRPD pattern of the above-mentioned Q crystal form is as follows: Figure 29 As shown.

[0199] In some embodiments of the present invention, the XRPD spectra analysis data of the above-mentioned Q crystal form are shown in Table 17:

[0200] Table 17 XRPD analysis data for the Q crystal form of compound (VII)

[0201]

[0202]

[0203] This invention provides a compound represented by formula (VIII),

[0204]

[0205] This invention provides the R crystal form of the compound shown in formula (VIII), characterized by its X-ray powder diffraction pattern exhibiting characteristic diffraction peaks at the following 2θ angles: 3.18±0.20°, 6.43±0.20°, 16.67±0.20°.

[0206]

[0207] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned R crystal form has characteristic diffraction peaks at the following 2θ angles: 3.18±0.20°, 6.43±0.20°, 16.67±0.20°, 18.20±0.20°, 18.63±0.20°, and 19.53±0.20°.

[0208] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned R crystal form has characteristic diffraction peaks at the following 2θ angles: 3.18±0.20°, 6.43±0.20°, 16.67±0.20°, 18.20±0.20°, 18.63±0.20°, 19.53±0.20°, 20.02±0.20°, 27.78±0.20°.

[0209] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned R crystal form has characteristic diffraction peaks at the following 2θ angles: 3.18°, 6.43°, 11.35°, 13.24°, 16.67°, 18.20°, 18.63°, 19.53°, 20.02°, 21.59°, 23.44°, 27.78°.

[0210] In some embodiments of the present invention, the XRPD pattern of the aforementioned R crystal form is as follows: Figure 30 As shown.

[0211] In some embodiments of the present invention, the XRPD spectra analysis data of the above-mentioned R crystal form are shown in Table 18:

[0212] Table 18 XRPD analysis data for crystal form R of compound (VIII)

[0213]

[0214] This invention provides a compound represented by formula (X).

[0215]

[0216] This invention provides the S-crystal form of the compound shown in formula (X), characterized by its X-ray powder diffraction pattern exhibiting characteristic diffraction peaks at the following 2θ angles: 4.74±0.20°, 17.04±0.20°, 24.77±0.20°.

[0217]

[0218] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned S-crystal form has characteristic diffraction peaks at the following 2θ angles: 4.74±0.20°, 11.97±0.20°, 17.04±0.20°, 20.65±0.20°, 24.77±0.20°, and 31.75±0.20°.

[0219] In some embodiments of the present invention, the XRPD pattern of the above-mentioned S-crystal form is as follows: Figure 31 As shown.

[0220] In some embodiments of the present invention, the XRPD spectra analysis data of the above-mentioned S-crystal form are shown in Table 19:

[0221] Table 19 XRPD analysis data for the S crystal form of compound (X)

[0222]

[0223] This invention provides a T-crystal form of the compound shown in formula (I), characterized by its X-ray powder diffraction pattern exhibiting characteristic diffraction peaks at the following 2θ angles: 8.37±0.20°, 11.54±0.20°, 16.76±0.20°.

[0224]

[0225] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned T-type crystal has characteristic diffraction peaks at the following 2θ angles: 8.37±0.20°, 11.54±0.20°, 16.76±0.20°, 22.49±0.20°, 23.36±0.20°, and 25.26±0.20°.

[0226] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned T-type crystal has characteristic diffraction peaks at the following 2θ angles: 8.37±0.20°, 11.54±0.20°, 16.76±0.20°, 19.53±0.20°, 22.49±0.20°, 23.36±0.20°, 25.26±0.20°, 27.12±0.20°.

[0227] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned T-type crystal has characteristic diffraction peaks at the following 2θ angles: 8.37°, 9.98°, 11.54°, 13.44°, 15.08°, 16.76°, 18.70°, 19.53°, 20.03°, 21.14°, 22.49°, 23.36°, 25.26°, 27.12°, 27.92°, and 31.77°.

[0228] In some embodiments of the present invention, the XRPD pattern of the above-mentioned T crystal form is as follows: Figure 32 As shown.

[0229] In some embodiments of the present invention, the XRPD spectra analysis data of the above-mentioned T-type crystal form are shown in Table 20:

[0230] Table 20 shows the XRPD analytical data for crystal form T of compound (I).

[0231]

[0232]

[0233] In some embodiments of the present invention, the above-mentioned T-crystal form has a peak value of an endothermic peak at 282.6±3.0℃ in its differential scanning calorimetry curve.

[0234] In some embodiments of the present invention, the DSC spectrum of the above-mentioned T crystal form is as follows: Figure 33 As shown.

[0235] In some embodiments of the present invention, the above-mentioned T-type crystal has a thermogravimetric analysis curve showing a weight loss of 1.56% at 250.0±3.0℃.

[0236] In some embodiments of the present invention, the T-type crystal structure described above has the following TGA spectrum: Figure 34 As shown.

[0237] The present invention also provides the use of the above-mentioned compounds or the above-mentioned crystal forms A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S and T in the preparation of medicaments for treating diseases related to FGFR / VEGFR dual kinase inhibitors.

[0238] In some embodiments of the present invention, the above-described application is characterized in that the FGFR / VEGFR dual kinase inhibitor-related drugs are drugs used to treat solid tumors.

[0239] Definitions and Explanations

[0240] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular phrase or term should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient.

[0241] The intermediate compounds of the present invention can be prepared by various synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0242] The chemical reactions in the specific embodiments of this invention are carried out in a suitable solvent, which must be suitable for the chemical changes of this invention and the reagents and materials required therefor. To obtain the compounds of this invention, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction flow based on existing embodiments.

[0243] The structures of the compounds of this invention can be confirmed by conventional methods well known to those skilled in the art. If this invention relates to the absolute configuration of a compound, that absolute configuration can be confirmed by conventional techniques in the art. For example, single-crystal X-ray diffraction (SXRD) is used, where the cultured single crystal is used to collect diffraction intensity data using a Bruker D8 venture diffractometer with CuKα radiation as the light source. The scanning method is as follows: After scanning and collecting relevant data, the crystal structure can be further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0244] Unless otherwise stated, the DSC patterns used in this article are downward endothermic.

[0245] The present invention will be described in detail below through embodiments, which are not intended to limit the present invention in any way.

[0246] All solvents used in this invention are commercially available and can be used without further purification.

[0247] The solvents used in this invention are commercially available. The following abbreviations are used in this invention: DCM represents dichloromethane; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOH represents ethanol; MeOH represents methanol; TFA represents trifluoroacetic acid; ATP represents adenosine triphosphate; HEPES represents 4-hydroxyethylpiperazine ethanesulfonic acid; MgCl2 represents magnesium dichloride; Pd(PPh3)2Cl2 represents bis(triphenylphosphine)palladium dichloride.

[0248] Technical effect

[0249] The compounds of this invention exhibit good crystal stability and are easy to formulate into drugs; the crystal form of this invention also possesses excellent DNA-PK kinase inhibitory activity. X-ray powder diffractometer (XRPD) analysis of this invention is also performed.

[0250] Instrument Model: PANalytical X'Pert 3 X-ray Diffractometer

[0251] Test method: Approximately 10 mg of sample was used for XRPD detection.

[0252] The detailed XRPD parameters are as follows:

[0253] X-ray source: Cu,kα ( Kα2 / Kα1 intensity ratio: 0.5

[0254] Phototube voltage: 45kV, Phototube current: 40mA

[0255] Diverging slit: Fixed 1 / 8deg

[0256] First Solar Slit: 0.04 rad, Second Solar Slit: 0.04 rad

[0257] Receiving slit: None; Anti-scattering slit: 7.5mm

[0258] Measurement time: 5 min

[0259] Scanning angle range: 3-40 degrees

[0260] Step width angle: 0.0263deg

[0261] Step length: 46.665 seconds

[0262] Sample tray rotation speed: 15 rpm

[0263] This invention relates to Differential Scanning Calorimeter (DSC).

[0264] Instrument Model: TA Discovery DSC 2500 Differential Scanning Calorimeter

[0265] Test method: Take a sample (about 1-5 mg) and place it in a DSC aluminum dish for testing. Under 50 mL / min N2 conditions, heat the sample from 25 °C (room temperature) to before sample decomposition at a heating rate of 10 °C / min.

[0266] This invention utilizes a thermogravimetric analyzer (TGA).

[0267] Instrument Model: TA Discovery TGA 5500 Thermogravimetric Analyzer

[0268] Test method: Take a sample (about 1-5 mg) and place it in a TGA aluminum dish for testing. Under N2 conditions of 10 mL / min, heat the sample from room temperature to 350℃ at a heating rate of 10℃ / min.

[0269] This invention presents a method for dynamic vapor adsorption analysis (DVS).

[0270] Instrument Model: SMS Intrinsic Dynamic Steam Adsorption Analyzer

[0271] Test conditions: Take a sample (10-30 mg) and place it in the DVS sample tray for testing.

[0272] The detailed DVS parameters are as follows:

[0273] Temperature: 25℃

[0274] Equilibrium: dm / dt = 0.002% / min (shortest: 10min, longest: 180min)

[0275] RH range: 0%RH-95%RH-0%RH; RH gradient: 10% (90%RH-0%RH-90%RH)

[0276] 5%(95%RH-90%RH and 90%RH-95%RH)

[0277] Hygroscopicity evaluation is classified as follows:

[0278] Hygroscopic classification ΔW% deliquescence Absorbs sufficient water to form a liquid Highly hygroscopic ΔW% ≥ 15% Hygroscopic 15% > ΔW% ≥ 2% Slightly hygroscopic 2% > ΔW% ≥ 0.2% None or almost none of the hygroscopic properties ΔW%<0.2%

[0279] Note: ΔW% represents the moisture gain of the test sample at 25±1℃ and 80±2%RH. Attached Figure Description

[0280] Figure 1 The XRPD spectrum of Cu-Kα radiation for crystal form A of compound (II) is shown.

[0281] Figure 2 The DSC spectrum of compound A of formula (II) is shown.

[0282] Figure 3 The TGA spectrum of compound A of formula (II) is shown.

[0283] Figure 4 The XRPD spectrum of Cu-Kα radiation for the B crystal form of compound (II) is shown.

[0284] Figure 5 The DSC spectrum of compound B of formula (II) is shown.

[0285] Figure 6 The TGA spectrum of compound B of formula (II) is shown.

[0286] Figure 7 The XRPD spectrum of Cu-Kα radiation for the C crystal form of compound (II) is shown.

[0287] Figure 8 The DSC spectrum of the C crystal form of compound (II) is shown.

[0288] Figure 9 The TGA spectrum of compound C of formula (II) is shown.

[0289] Figure 10 The XRPD spectrum of Cu-Kα radiation for the D crystal form of compound (II) is shown.

[0290] Figure 11 The DSC spectrum of compound D of formula (II) is shown.

[0291] Figure 12 The TGA spectrum of compound D of formula (II) is shown.

[0292] Figure 13 XRPD spectrum of Cu-Kα radiation for E crystal form of compound (III);

[0293] Figure 14 The DSC spectrum of compound E of formula (III) is shown.

[0294] Figure 15 The TGA spectrum of compound E of formula (III) is shown.

[0295] Figure 16 XRPD spectrum of Cu-Kα radiation for the F crystal form of compound (III);

[0296] Figure 17 XRPD spectrum of Cu-Kα radiation for G crystal form of compound (III);

[0297] Figure 18 XRPD spectrum of Cu-Kα radiation for H crystal form of compound (IV);

[0298] Figure 19 The DSC spectrum of compound H of formula (IV) is shown.

[0299] Figure 20 The TGA spectrum of compound H of formula (IV) is shown.

[0300] Figure 21 XRPD spectrum of Cu-Kα radiation for crystal form I of compound (IV);

[0301] Figure 22 XRPD spectrum of Cu-Kα radiation for J crystal form of compound (IV);

[0302] Figure 23 XRPD spectrum of Cu-Kα radiation for K crystal form of compound (IV);

[0303] Figure 24 XRPD spectrum of Cu-Kα radiation for the L crystal form of compound (V);

[0304] Figure 25 XRPD spectrum of Cu-Kα radiation for the M crystal form of compound (V);

[0305] Figure 26 The XRPD spectrum of Cu-Kα radiation for the N-crystal form of compound (V);

[0306] Figure 27 XRPD spectrum of Cu-Kα radiation for O crystal form of compound (VI);

[0307] Figure 28 XRPD spectrum of Cu-Kα radiation for the P-crystal form of compound (VI);

[0308] Figure 29 The XRPD spectrum of Cu-Kα radiation for the Q crystal form of compound (VII);

[0309] Figure 30 XRPD spectrum of Cu-Kα radiation for the R crystal form of compound (VIII);

[0310] Figure 31 The XRPD spectrum of Cu-Kα radiation for the S-crystal form of compound (X);

[0311] Figure 32 The XRPD spectrum of Cu-Kα radiation for the T-crystal form of compound (I) is shown.

[0312] Figure 33 The DSC spectrum of compound T of formula (I) is shown.

[0313] Figure 34 The TGA spectrum of compound T of formula (I) is shown.

[0314] Figure 35 The image shows the DVS spectrum of compound A of formula (II). Detailed Implementation

[0315] To better understand the content of this invention, further explanation will be provided below with reference to specific embodiments. However, the specific implementation methods are not intended to limit the content of this invention.

[0316] Example 1: Preparation of crystal form A of compound (II)

[0317]

[0318] Add 15 L of dioxane and 5 L of water to a 50 L reactor at 10–30 °C. While stirring, add compound 1 (1500 g) and compound 2 (1335 g) to the reactor all at once. Add 1930 g of potassium carbonate to the reactor all at once while stirring. Purge with nitrogen for 10 minutes, then add 100 g of Pd(dppf)Cl2 to the reactor all at once. Heat the reaction mixture to an internal temperature of 88–90 °C and continue stirring for 16 hours. Take 10 L of the reaction solution and add it to the 50 L reactor. Add 30 L of water while stirring and stir at room temperature for 15 minutes. Repeat the above steps for the remaining 10 L. Filter under reduced pressure to obtain a filter cake. Place the filter cake in a 50 °C oven and dry for 48 hours. Add 1000g of metal scavenger, 1000g of activated carbon, and 1000g of magnesium sulfate to a 50L reactor. Stir at 60°C for 18 hours. After the reaction solution cools to room temperature, filter through diatomaceous earth and collect the filtrate. Concentrate the filtrate to obtain a crude product. Filter the reaction solution under reduced pressure while hot. Wash the filter cake with anhydrous dioxane (4L*2) to obtain the filtrate. Dry the filtrate under reduced pressure at 40-50°C to obtain the residue. Transfer the concentrated crude product to a 50L reactor, add 15L of n-heptane and 1.5L of dichloromethane, and stir at 25-35°C for 16 hours. Filter the suspension in the reactor through a benchtop filter. Wash the filter cake with n-heptane (2L*2), collect the solid, and dry the solid under reduced pressure at 40-50°C to obtain compound 3.

[0319]

[0320] 15 L of N,N-dimethylformamide was added to a 50 L reaction flask at 10–30 °C. Compound 3 (1.5 kg) and Compound 4 (619.5 g) were added to the flask simultaneously with stirring. Potassium carbonate (1.81 kg) and Xphos (415.5 g) were then added to the reaction vessel simultaneously with stirring. The mixture was purged with nitrogen for 10 minutes. Pd2(dba)3 (399 g) was then added to the reaction vessel simultaneously. The reaction was heated to an internal temperature of 90–95 °C (external temperature 100 °C) and stirred for 8 hours. HPLC monitoring was performed until Compound 3 was ≤1%. 1 kg of diatomaceous earth was added to a benchtop filtration funnel, and the mixture was filtered under reduced pressure using a benchtop filtration system. DMF (1 L * 2) was added for washing, and the filtrate was collected. The filtrate was concentrated under reduced pressure using an oil pump to approximately 1 / 3 of the reaction volume. The above concentrated solution was added to a 50L reactor, followed by 3V of water. The pH was adjusted to 11-12 with 4M sodium hydroxide aqueous solution. The mixture was filtered under reduced pressure. The filtrate was extracted with ethyl acetate (15L*2) to remove some impurities. The aqueous phase was then adjusted to pH 5-6 with 3M hydrochloric acid aqueous solution. A large amount of yellow solid particles precipitated out. The solid was then filtered through a benchtop vacuum filter funnel, and the filter cake was dried in a 50°C vacuum drying oven to obtain compound 5.

[0321]

[0322] At 20–30°C, 11.5 L of ethylene glycol dimethyl ether and 3.8 L of water were added to a 50 L reactor. While stirring, compound 5 (1150 g) and compound 6 (676.15 g) were added to the reaction flask all at once. While stirring, potassium carbonate (1183.60 g) was added to the reaction flask all at once. The mixture was purged with nitrogen for 10 minutes. Then, Pd(dppf)Cl2 (208.87 g) was added to the reaction flask all at once. The reaction was heated to an internal temperature of 77–80°C and stirred for 16 hours. HPLC was used to monitor the reaction until compound 5 was ≤1%. The mixture was filtered under reduced pressure using a benchtop vacuum funnel, and then washed with 1 L of ethylene glycol dimethyl ether. The filtrate was collected. The filtrate was concentrated by a pressure pump to about 1 / 3 of the reaction volume. The concentrated solution was added to a 50L reactor, followed by 3V water. The pH was adjusted to 13 with 4M sodium hydroxide aqueous solution and then to 6 with 3M hydrochloric acid aqueous solution. A large amount of brownish-yellow solid particles precipitated out. The mixture was then filtered through a desktop vacuum filter funnel, and the filter cake was collected. The filter cake was dried in a 50°C oven to obtain the crude product.

[0323] Add 10.0 L of DCM to a 50 L reactor at 20–30 °C. While stirring, add the crude product (1000 g), DPPE (37.94 g), and propylenediamine (81.11 mL) to the reactor all at once. Heat the reaction to an internal temperature of 40 °C and continue stirring for 16 hours. Filter under reduced pressure, add 500 mL of DCM to wash, and collect the filter cake. Repeat the above operation 3 times. Add 3.0 L of THF to a 50 L reaction flask at 10–30 °C. Add the filter cake to the reaction vessel while stirring. Heat the reaction to an internal temperature of 60 °C and continue stirring for 16 hours. Filter under reduced pressure, then add 500 mL of THF for washing and collect the filter cake. Dry the filter cake under vacuum at 40–50 °C. Add 5.0 L of DMF and 5.0 L of dioxane to a 50 L reaction vessel at 10–30 °C. Add the crude product to the reaction vessel while stirring. Heat the reaction to an internal temperature of 50 °C and continue stirring for 16 hours. Filter under reduced pressure, then add 500 mL of dioxane for washing and collect the filter cake. Dry the filter cake under vacuum at 40–50 °C. Add 10.0 L of THF to a 50 L reaction vessel at 10–30 °C. Add the filter cake to the reaction flask while stirring. Heat the reaction to an internal temperature of 60 °C and continue stirring for 16 hours. Filter under reduced pressure, then add 500 mL of THF for washing and collect the filter cake. The filter cake was vacuum dried at 40–50°C to obtain the crude product. 20.0 L of water was added to a 50 L reactor at 10–30°C, and the filter cake was added to the reactor with stirring. The pH was adjusted to 5–6, and the reactor was heated to 40°C with continued stirring for 16 hours. The mixture was then filtered under reduced pressure, washed with 2 L of water, and the filter cake was collected. The filter cake was vacuum dried at 40–50°C to obtain compound (I). XRPD characterization of compound (I) showed it to be of the T-crystal form. The XRPD spectrum is shown below. Figure 32 As shown, the DSC spectrum is as follows Figure 33 As shown, the TGA spectrum is as follows Figure 34 As shown.

[0324]

[0325] Compound (I) (740 g) was added to DMSO (7.4 L). Methanesulfonic acid (155.41 g, 1.62 mol, 115.12 mL, 1.05 eq) was added to the reaction solution at 20–30 °C and stirred for 4 hours. Then, 37 L of ethyl acetate was added to the reaction solution, and the reaction was continued with stirring for 16 hours. A large amount of solid precipitated. The mixture was filtered, and the filter cake was washed with ethyl acetate (2 L * 2). The filter cake was then evaporated under reduced pressure at 40–50 °C to obtain compound (II) in crystal form A. The XRPD spectrum of crystal form A is shown below. Figure 1 As shown, the DSC spectrum is as follows Figure 2 As shown, the TGA spectrum is as follows Figure 3 As shown.

[0326] 1¹H NMR (400MHz, DMSO-d⁶) δ 8.83 (d, J = 4.0Hz, 1H), 8.60 (s, 1H), 8.46 (s, 1H), 8.27 (s, 1H), 8.10–8.04 (m, 2H), 7.76 (s, 1H), 7.72 (d, J = 4.0Hz, 1H), 7.50–7.32 (m, 2H), 7.24 (s, 1H), 3.93 (s, 3H), 3.47 (s, 3H), 2.30 (s, 3H). Example 2:

[0327] Preparation of crystal form B of compound (II)

[0328] Weigh 20 mg of compound (I) and methanesulfonic acid (1 eq) and add them separately to an HPLC vial. Add 0.5 mL of acetone and stir at room temperature for 4 days. Centrifuge and transfer the solid to 50 °C for vacuum drying for half an hour to obtain compound (II) B crystal form.

[0329] Preparation of the C crystal form of compound (II)

[0330] Weigh 20 mg of compound (I) and methanesulfonic acid (1 eq) and add them separately to an HPLC vial. Add 0.5 mL of LEtOH / H2O (19:1, v / v), stir at room temperature for 4 days, centrifuge, and transfer the solid to 50 °C for vacuum drying for half an hour to obtain the C crystal form of compound (II).

[0331] Preparation of crystal form D of compound (II)

[0332] 75 g of compound (I) was added to 750 mL of DMSO. Methanesulfonic acid (15 g, 1 eq) was added to the reaction solution at 20-30 °C. The reaction solution dissolved completely, and the mixture was stirred for 4 hours. Then, 1.5 L of ethyl acetate was added to the reaction solution, and the mixture was stirred for 20 hours. A solid precipitated out. The solid was filtered, and the filter cake was washed with ethyl acetate (50 mL x 2). The mixture was concentrated to dryness to obtain a crude product (approximately 45 g). The crude product was added to 450 mL of ethanol, and the mixture was stirred at 20-30 °C for 24 hours. The mixture was filtered, and the filter cake was washed with ethanol (10 mL x 2). The filter cake was then evaporated to dryness under reduced pressure at 40-50 °C to obtain the D crystal form of compound (II).

[0333] 1H NMR (400MHz, DMSO-d6) δ11.07(brs,1H),8.86(d,J=4.0Hz,1H),8.63(s,1H),8.56(s,1H),8.26(s,1H),8.15(s,1 H),8.08-8.06(m,1H),7.79-7.77(m,2H),7.48-7.30(m,2H),7.27(s,1H),3.93(s,3H),3.47(s,3H),2.41(s,3H).

[0334] Preparation of crystal form E of compound (III)

[0335] Weigh 100 mg of compound (I) and add it to DMSO (1 mL). Add hydrochloric acid (20.51 mg, 208.12 μmol, 17.34 μL, 37% purity) to the reaction solution at 20-30 °C and stir for 24 hours at 20-30 °C. Filter the solution and wash the filter cake with ethyl acetate (1 mL * 2). Dry the filter cake under reduced pressure at 40-50 °C to obtain compound (III) in crystal form E.

[0336] 1 H NMR(400MHz,DMSO-d6)δ11.04(brs,1H),8.85(d,J=4.0Hz,1H),8.63(s,1H),8.49(s,1H),8.29(s,1 H),8.08-8.06(m,2H),7.77-7.72(m,2H),7.49-7.34(m,2H),7.26(s,1H),3.94(s,3H),3.46(s,3H).

[0337] Preparation of crystal form F of compound (III)

[0338] Weigh 20 mg of compound (I) and hydrochloric acid (1 eq) and add them separately to an HPLC vial. Add 0.5 mL of EtOH / H2O (19:1, v / v), stir at room temperature for 4 days, centrifuge, and transfer the solid to 50 °C for vacuum drying for half an hour to obtain the F crystal form of compound (III).

[0339] Preparation of the G crystal form of compound (III)

[0340] Weigh 100 mg of compound (I) and add it to DMSO (1 mL). Add hydrochloric acid (20.51 mg, 208.12 μmol, 17.34 μL, 37% purity) to the reaction solution at 20-30 °C and stir for 24 hours at 20-30 °C. Filter the solution and wash the filter cake with ethyl acetate (1 mL * 2). Dry the filter cake under reduced pressure at 40-50 °C to obtain compound (III) in crystal form G.

[0341] Preparation of the H crystal form of compound (IV)

[0342] Weigh 20 mg of compound (I) and sulfuric acid (1 eq) and add them separately to an HPLC vial. Add 0.5 mL of ethanol, stir at room temperature for 4 days, centrifuge, and transfer the solid to 50 °C for vacuum drying for half an hour to obtain the H crystal form of compound (IV).

[0343] Preparation of crystal form I of compound (IV)

[0344] Weigh 20 mg of compound (I) and sulfuric acid (1 eq) and add them separately to an HPLC vial. Add 0.5 mL of EtOH / H2O (19:1, v / v), stir at room temperature for 4 days, centrifuge, and transfer the solid to 50 °C for vacuum drying for half an hour to obtain the crystal form of compound (IV).

[0345] Preparation of crystal form J of compound (IV)

[0346] Weigh 20 mg of compound (I) and sulfuric acid (1 eq) and add them separately to an HPLC vial. Add 0.5 mL of tetrahydrofuran and stir at room temperature for 4 days. Centrifuge and transfer the solid to 50 °C for vacuum drying for half an hour to obtain compound (IV) J crystal form.

[0347] Preparation of the K crystal form of compound (IV)

[0348] Weigh 100 mg of compound (I) and add it to DMSO (1 mL). Add sulfuric acid (20.41 mg, 208.12 μmol, 11.09 μL, 1 eq) to the reaction solution at 20–30 °C. Stir the reaction solution at 20–30 °C for 20 hours. Add 2 mL of ethyl acetate to the reaction solution and continue stirring for 20 hours. Filter the solution and wash the filter cake with ethyl acetate (1 mL * 2). Dry the filter cake under reduced pressure at 40–50 °C to obtain compound (IV) K crystal form.

[0349] 1 H NMR (400MHz, DMSO-d6) δ11.05(brs,1H),8.85(d,J=4.0Hz,1H),8.63(s,1H),8.53(s,1H),8.30(s,1 H),8.09-8.06(m,2H),7.77-7.75(m,2H),7.49-7.33(m,2H),7.24(s,1H),3.94(s,3H),3.46(s,3H).

[0350] Preparation of the L-crystal form of compound (V)

[0351] Weigh 20 mg of compound (I) and phosphoric acid (1 eq) and add them separately to an HPLC vial. Add 0.5 mL of ethanol, stir at room temperature for 4 days, centrifuge, and transfer the solid to 50 °C for vacuum drying for half an hour to obtain compound (V) in L crystal form.

[0352] 1 H NMR (400MHz, DMSO-d6) δ8.84(d,J=4.0Hz,1H),8.63(s,1H),8.47(s,1H),8.28(s,1H),8.09-8.02(m,2H),7.77-7. 70(m,2H),7.50-7.45(m,3H),7.36(t,J=4.0Hz,1H),7.24(s,1H),7.11(d,J=4.0Hz,2H),3.94(s,3H),2.29(s,3H).

[0353] Preparation of crystal form M of compound (V)

[0354] Weigh 20 mg of compound (I) and phosphoric acid (1 eq) and add them separately to an HPLC vial. Add 0.5 mL of EtOH / H2O (19:1, v / v), stir at room temperature for 4 days, centrifuge, and transfer the solid to 50 °C for vacuum drying for half an hour to obtain compound (V) M crystal form.

[0355] Preparation of the N-crystal form of compound (V)

[0356] Weigh 20 mg of compound (I) and phosphoric acid (1 eq) and add them separately to an HPLC vial. Add 0.5 mL of tetrahydrofuran and stir at room temperature for 4 days. Centrifuge and transfer the solid to 50 °C for vacuum drying for half an hour to obtain compound (V) N crystal form.

[0357] Preparation of O crystal form of compound (VI)

[0358] Weigh 20 mg of compound (I) and p-toluenesulfonic acid (1 eq) and add them separately to an HPLC vial. Add 0.5 mL of acetone and stir at room temperature for 4 days. Centrifuge and transfer the solid to 50 °C for vacuum drying for half an hour to obtain compound (VI) O crystal form.

[0359] Preparation of the P-type crystal form of compound (VI)

[0360] Weigh 20 mg of compound (I) and p-toluenesulfonic acid (1 eq) and add them separately to an HPLC vial. Add 0.5 mL of tetrahydrofuran and stir at room temperature for 4 days. Centrifuge and transfer the solid to 50 °C for vacuum drying for half an hour to obtain compound (VI) in crystal form P.

[0361] Preparation of the Q crystal form of compound (VII)

[0362] Weigh 20 mg of compound (I) and oxalic acid (1 eq) and add them separately to an HPLC vial. Add 0.5 mL of EtOH / H2O (19:1, v / v), stir at room temperature for 4 days, centrifuge, and transfer the solid to 50 °C for vacuum drying for half an hour to obtain compound (VII) in crystal form Q.

[0363] Preparation of R crystal form of compound (VIII)

[0364] Weigh 20 mg of compound (I) and maleic acid (1 eq) and add them separately to an HPLC vial. Add 0.5 mL of acetone and stir at room temperature for 4 days. Centrifuge and transfer the solid to 50 °C for vacuum drying for half an hour to obtain compound (VIII) R crystal form.

[0365] 1 H NMR(400MHz, DMSO-d6)δ8.73(d,J=4.0Hz,1H),8.47(s,1H),8.21(s,2H),8.09-8.03(m,2H),7. 99(s,1H),7.75(s,1H),7.49-7.30(m,3H),7.23(s,1H),6.22(s,2H),3.92(s,3H),3.46(s,3H).

[0366] Preparation of the S-crystal form of compound (X)

[0367] Weigh 20 mg of compound (I) and tartaric acid (1 eq) and add them separately to an HPLC vial. Add 0.5 mL of acetone and stir at room temperature for 4 days. Centrifuge and transfer the solid to 50 °C for vacuum drying for half an hour to obtain the S crystal form of compound (X).

[0368] 1 H NMR(400MHz,DMSO-d6)δ8.68(d,J=4.0Hz,1H),8.47(s,1H),8.13(s,1H),8.09-8.02(m,2 H),7.95(s,1H),7.77(s,1H),7.49-7.33(m,3H),7.24(s,1H),4.32(s,3H),3.94(s,3H).

[0369] Experimental Example 3: Study on the hygroscopicity of crystal form A of compound (II)

[0370] Experimental materials:

[0371] SMS Intrinsic Dynamic Vapor Adsorption Unit

[0372] Experimental methods:

[0373] Take 10-30 mg of compound A of formula (II) and place it in the DVS sample tray for testing.

[0374] Experimental results:

[0375] The DVS spectrum of compound A of formula (II) is as follows: Figure 35 As shown, △W = 1.708%.

[0376] Experimental conclusion:

[0377] Compound A of formula (II) has a hygroscopic weight gain of 1.708% at 25°C and 80% RH, indicating that it is hygroscopic.

[0378] Experimental Example 4: Stability data of crystal form A of compound (II)

[0379] For high temperature, high humidity and light conditions tests, the sample is placed in an open, clean weighing bottle and spread into a thin layer of ≤5mm. Three parallel samples (1.1g / sample) are weighed at each time point under each condition. The prepared samples are placed under each condition and samples are taken for analysis after the time point is reached.

[0380] For accelerated and long-term stability tests, the samples were placed in double-layered pharmaceutical low-density polyethylene (PDPE) bags, each layer of which was sealed with a buckle. The double-layered PDPE bags were then placed in aluminum foil bags and heat-sealed. Six parallel aliquots (1.1 g / aliquot) were weighed at each time point under each condition. The prepared samples were placed under each condition, and samples were taken for analysis after each time point was reached.

[0381] The physical properties of compound A (II) were investigated under the following conditions, and samples were taken at different time points. The content and total impurities were analyzed by HPLC. The study conditions and detection items are shown in Table 21 below.

[0382] Table 21 Stability test of compound A (II)

[0383]

[0384]

[0385] Experimental conclusion: Compound A of formula (II) has good crystal stability.

[0386] Biological test data:

[0387] Experimental Example 1: Study on the inhibitory effect of compound A of formula (II) on cell proliferation

[0388] Experimental objective:

[0389] The compounds of this invention can target and inhibit the FGFR and VEGFR pathways, thereby inhibiting tumor cell growth by suppressing the VEGF / VEGFR and FGF / FGFR signaling pathways. In this experiment, human non-small cell lung cancer cells NCI-H1581 (highly expressing FGFR1), gastric cancer cells SNU-16 (highly expressing FGFR2), and human bladder cancer cells RT112 / 84 (highly expressing FGFR3) were selected. This experiment investigated the inhibitory effect of the compounds on cell proliferation by detecting their effects on in vitro cell viability in tumor cell lines NCI-H1581, SNU-16, and RT-112 / 84.

[0390] Experimental methods and procedures:

[0391] Cell culture

[0392] The tumor cell lines were cultured in an incubator at 37°C and 5% CO2 according to the culture conditions shown in Table 22. Cells were passaged periodically, and cells in the logarithmic growth phase were used for plating.

[0393] Table 22 Cell lines and culture methods

[0394]

[0395] Cell plating

[0396] (1) Use trypan blue to stain cells and count live cells.

[0397] (2) Adjust the cell concentration to a suitable level.

[0398] cell lines Density (per pore) NCI-H1581 4000 SNU-16 7000 RT-112 / 84 8000

[0399] (3) Add 90 μL of cell suspension to each well of the culture plate, and add cell-free culture medium to the blank control well.

[0400] (4) Incubate the culture plate overnight in an incubator at 37°C, 5% CO2 and 100% relative humidity.

[0401] Preparation of 10X compound working solution; compound treatment of cells.

[0402] (1). Preparation of 10X compound working solution: Add 78 μL of cell culture medium to a 96-well plate with a V-bottom. Add 2 μL of the compound from a 400X compound storage plate to the cell culture medium in the 96-well plate. Add 2 μL of DMSO to the solvent control and blank control. After adding the compound or DMSO, mix thoroughly by pipetting.

[0403] (2) Drug addition: Add 10 μL of the 10X compound working solution to the cell culture plate. Add 10 μL of DMSO-cell culture medium mixture to the solvent control and blank control. The final concentration of DMSO is 0.25%.

[0404] (3) The 96-well cell plate was placed back into the incubator and cultured for 3 days before being tested.

[0405] CellTiter-Glo luminescence assay for cell viability

[0406] The following steps were performed in accordance with the instructions for the Promega CellTiter-Glo luminescence assay kit (Promega-G7573).

[0407] (1). Melt the CellTiter-Glo buffer and let it come to room temperature.

[0408] (2). Place the CellTiter-Glo substrate at room temperature.

[0409] (3) Add CellTiter-Glo buffer to a bottle of CellTiter-Glo substrate to dissolve the substrate, thereby preparing CellTiter-Glo working solution.

[0410] (4) Slow vortexing to ensure complete dissolution.

[0411] (5) Remove the cell culture plate and let it stand for 30 minutes to allow it to equilibrate to room temperature.

[0412] (6) Add 50 μL of CellTiter-Glo working solution (equivalent to half the volume of cell culture medium in each well) to each well. Wrap the cell plate with aluminum foil to protect it from light.

[0413] (7) Shake the culture plate on a track shaker for 2 minutes to induce cell lysis.

[0414] (8) The culture plate was placed at room temperature for 10 minutes to stabilize the luminescence signal.

[0415] (9) Detect the light emission signal on the 2104EnVision reader.

[0416] Data Analysis:

[0417] The inhibition rate (IR) of the detected compound is calculated using the following formula: IR (%) = (1 – (RLU compound – RLU blank control) / (RLU solvent control – RLU blank control)) * 100%. The inhibition rates of different compound concentrations are calculated in Excel, and then inhibition curves are plotted and relevant parameters, including minimum inhibition rate, maximum inhibition rate, and IC50, are calculated using GraphPad Prism software. 50 The following formula calculates IC. 50 .

[0418] Y = minimum inhibition rate + (maximum inhibition rate - minimum inhibition rate) / (1 + 10^(LogIC)) 50 -X)*HillSlope))

[0419] X: log(concentration)

[0420] Y: Reaction value, negatively correlated with X.

[0421] HillSlope: Slope Factor

[0422] Experimental results: see Table 23.

[0423] Table 23 Study on the cell proliferation inhibition effect of compound A (II)

[0424] Tumor cell lines NCI-H1581 SNU-16 RT-112 / 84 <![CDATA[IC 50 (nM)]]> Formula (II) Compound A Crystal Form 116.7 44.5 166.8

[0425] Experimental conclusion: Compound A of formula (II) showed certain anti-cell proliferation activity against three tumor cell lines with high FGFR expression. Experimental example 2: In vitro activity of compound A of formula (II) in BaF3 cell line.

[0426] Experimental objective:

[0427] In this experiment, VEGFR-expressing engineered cells (Ba / F3-TEL-FLT1 (VEGFR1), Ba / F3-TEL-FLT4 (VEGFR3), Ba / F3-TEL-VEGFR2) were selected to evaluate the in vitro proliferation inhibitory effect of compound A of formula (II) on BaF3 cell lines.

[0428] Experimental methods and procedures:

[0429] Preparation of 1000× solution of compound A (II)

[0430] A 10 mM stock solution of compound A (Formula II) was prepared by dissolving it in DMSO. Nine concentration gradients (10.0000 mM, 2.5000 mM, 0.6250 mM, 0.1563 mM, 0.0391 mM, 0.0098 mM, 0.0024 mM, 0.0006 mM, and 0.0002 mM) were prepared by diluting the solution four times and stored in 96-well blister packs (Beaver, Suzhou). An equal volume of DMSO solvent was used as a negative control.

[0431] 1. Take the logarithmic growth phase cell suspension and seed it into a 96-well white cell culture plate (Corning 3917, NY, USA), with a volume of 95 μl per well (2000 cells / well).

[0432] 2. Add the diluted culture medium-compound mixture to each well, with a volume of 5 μl. The final concentration of DMSO in Ba / F3-TEL-FLT1 (VEGFR1), Ba / F3-TEL-FLT4 (VEGFR3), and Ba / F3-TEL-VEGFR2 cells is 0.1%.

[0433] Table 24 Cells and Culture Conditions

[0434] cell culture medium Cultivation conditions Ba / F3-TEL-FLT1(VEGFR1) RPMI 1640+10%FBS+1%PS+IL-3 Cultured at 37℃ with 5% CO2 Ba / F3-TEL-FLT4(VEGFR3) RPMI 1640 + 10% FBS + 1% PS <![CDATA[Cultured at 37°C and 5% CO2]]> Ba / F3-TEL-VEGFR2 RPMI 1640 + 10% FBS + 1% PS <![CDATA[Cultured at 37°C and 5% CO2]]>

[0435] 3. Incubate at 37℃ and 5% CO2 for 72 hours.

[0436] 4. The proliferation inhibition activity and data analysis of compounds obtained by the CellTiter-Glo method are the same as in Experiment 1.

[0437] Experimental results: see Table 25.

[0438] Table 25 shows the in vitro activity of compound A (II) in BaF3 cell lines.

[0439]

[0440] Experimental conclusion: In VEGFR-expressing engineered cells (Ba / F3-TEL-FLT1 (VEGFR1), Ba / F3-TEL-FLT4 (VEGFR3), Ba / F3-TEL-VEGFR2), the crystal form of compound (II) A showed certain anti-cell proliferation activity, among which Ba / F3-TEL-VEGFR2 showed stronger anti-proliferation activity.

[0441] Experimental Example 3: Pharmacokinetic Evaluation of Compound A (II)

[0442] Experimental Objective: To evaluate the oral absorption of compound (II) crystal form A in SD rats via single intravenous bolus injection and gavage. Experimental Materials: SD rats, EDTA-K2

[0443] Experimental procedure:

[0444] Experimental procedure: A clear solution of compound (II) A crystal form with a concentration of 5 mg / mL was prepared by 5% DMSO / 10% Solutol / 85% water as solvent and injected intravenously into male and female SD rats (fasted overnight, 7-11 weeks old) at a dose of 10 mg / kg.

[0445] Compound A of formula (II) was administered by gavage to male and female SD rats (7-11 weeks old, fasted overnight) at doses of 1 mg / mL, 3 mg / mL, and 10 mg / mL in 5% DMSO / 10% Kolliphor HS15 / 85% (0.2% (v / v) Tween 80 aqueous solution). Approximately 0.2 mL of blood was collected from the jugular vein at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, and 24 h post-administration (0.083 h in group IV) and placed in anticoagulant tubes containing EDTA-K2. Plasma was then separated by centrifugation. Blood concentrations were determined by LC-MS / MS using WinNonlin. TM Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software calculates relevant pharmacokinetic parameters using the linear logarithmic trapezoidal method with a non-compartmental model.

[0446] Experimental results:

[0447] Following a single intravenous bolus injection of 1 mg / kg of compound (II) A crystal form into male and female SD rats, the plasma clearance (Cl) was 8.78 and 7.03 mL / min / kg, respectively, and the steady-state apparent volume of distribution (Vd) was [not specified]. ss The concentrations were 0.419 and 0.366 L / kg, respectively, with an elimination half-life (Ti). 1 / 2 The values ​​were 0.675 and 0.765 h, respectively, and the area under the plasma concentration-time curve (AUC) from 0 point to the last quantifiable time point was... 0-last The values ​​of ) are 3980 and 4930 nM·h, respectively.

[0448] Systemic exposure (AUC) in male and female SD rats at the intravenous bolus dose. 0-last There were no significant gender differences between C0 and C2.

[0449] Following a single oral administration of 10, 30, and 100 mg / kg of compound (II) A crystal form to male SD rats, the peak concentration (C0) of compound (II) A crystal form was determined. max The peak times (T) were 3780, 16700, and 19900 nM, respectively, and the peak times (T) were... max The AUC values ​​were observed at 0.500, 1.00, and 0.833 h after drug administration. 0-last The bioavailability of the drug was 7150, 38200, and 113000 nM·h, respectively. The bioavailability of the drug in the 10 mg / kg gavage dose group was 18.0%.

[0450] Following a single oral administration of 10, 30, and 100 mg / kg of compound (II) A crystal form to female SD rats, the peak concentration (C0) of compound (II) A crystal form was determined. max The peak times (T) were 9170, 24500, and 27400 nM, respectively, and the peak times (T) were... max The AUC values ​​were observed at 0.667, 1.00, and 0.500 h after drug administration, respectively. 0-last The bioavailability of the drug was 24,800, 65,600, and 125,000 nM·h, respectively. The bioavailability of the drug in the 10 mg / kg gavage dose group was 50.3%.

[0451] Systemic exposure (AUC) in male and female SD rats at oral gavage doses of 30 and 100 mg / kg 0-last With C max There were no significant gender differences. Conclusion: Compound A of formula (II) has a low clearance rate and acceptable oral bioavailability in rats, indicating good druggability.

[0452] Experimental Example 4: Pharmacokinetic Study of the Compounds of the Invention in Rats

[0453] Laboratory animals:

[0454] SD rats (overnight fasted, 7-11 weeks old)

[0455] Experimental procedure:

[0456] Experimental procedure: A clear solution of the compound of the present invention or its crystal form at a concentration of 10 mg / mL was administered intravenously to male SD rats (fasted overnight, 7-11 weeks old) using 5% DMSO / 10% Solutol / 85% water as the solvent. The dosage was 100 mg / kg.

[0457] The compound of the present invention or its crystalline form, at a concentration of 10 mg / mL, was administered orally to male SD rats (fasted overnight, 7-11 weeks old) in 5% DMSO / 10% Kolliphor HS15 / 85% (0.2% (v / v) Tween 80 aqueous solution). Approximately 0.2 mL of blood was collected from the jugular vein of all three groups of animals at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, and 24 h post-administration and placed in anticoagulant tubes containing EDTA-K2. Plasma was separated by centrifugation. Blood concentrations were determined by LC-MS / MS using WinNonlin. TM Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software calculates relevant pharmacokinetic parameters using the linear logarithmic trapezoidal method with a non-compartmental model.

[0458] Experimental results:

[0459] Table 26 Pharmacokinetic Test Results

[0460]

[0461] Experimental conclusion: At the same dose, the D crystal form of compound (II) exhibits higher exposure and Cmax than the E crystal form of compound (III) and compound (I).

[0462] Experimental Example 5: Antitumor activity test of compound A of formula (II) in an in vivo animal tumor model

[0463] Experimental objective:

[0464] This study used a Renca subcutaneous xenograft tumor nude mouse model to evaluate the antitumor effect of compound A of formula (II).

[0465] Laboratory animals:

[0466] Female Balb / c mice (6-8 weeks old)

[0467] Experimental methods:

[0468] Cell culture

[0469] Mouse renal cell carcinoma Renca cells (ATCC-CRL-2947) were cultured in vitro in adherent form under the following conditions: RPMI 1640 medium supplemented with 10% fetal bovine serum, 0.1 mM non-essential amino acids, 1 mM sodium pyruvate, 2 mM glutamine, 100 U / mL penicillin, and 100 μg / mL streptomycin, incubated at 37°C in a 5% CO2 incubator. Routine passages were performed twice a week. When cell saturation reached 80%-90% and the desired number was achieved, cells were harvested, counted, and seeded.

[0470] Cell inoculation

[0471] 0.1 mL (1×10 5 (Number) Renca cells were subcutaneously injected into the dorsal side of the right upper limb of each mouse, and the average tumor volume reached approximately 50-80 mm. 3 Dosing will begin in groups at that time.

[0472] Tumor measurements and experimental indicators

[0473] The tumor diameter was measured twice a week using calipers. The formula for calculating tumor volume is: V = 0.5a × b 2 , where a and b represent the long and short diameters of the tumor, respectively.

[0474] The antitumor efficacy of the compound was evaluated using TGI (%) or relative tumor proliferation rate (T / C) (%). Relative tumor proliferation rate (T / C) = T RTV / C RTV ×100% (T) RTV : Mean RTV in the treatment group; C RTV The mean RTV of the negative control group was calculated based on tumor measurements. The relative tumor volume (RTV) was calculated using the formula: RTV = V0 / V0. t / V0, where V0 is the tumor volume measured at the time of group administration (i.e., D0), V t To correspond to the tumor volume at a specific measurement in mice, T RTV With C RTV Take data from the same day.

[0475] TGI (%) reflects the tumor growth inhibition rate. TGI (%) = [(1 - (mean tumor volume at the end of treatment - mean tumor volume at the start of treatment)) / (mean tumor volume at the end of treatment in the solvent control group - mean tumor volume at the start of treatment in the solvent control group)] × 100%.

[0476] Statistical analysis was performed using SPSS software based on the RTV data at the end of the experiment. Comparisons between two groups were analyzed using the T-test; comparisons between three or more groups were analyzed using one-way ANOVA. If the variances were homogeneous (no significant difference in F-values), Tukey's test was used; if the variances were unequal (significant difference in F-values), the Games-Howell test was used. A p-value < 0.05 was considered statistically significant.

[0477] Experimental results:

[0478] The dosage group of compound A crystal form (100 mg / kg) of formula (II) showed a significant inhibitory effect on tumor growth, with a p = 0.031 compared with the solvent control group, indicating a significant difference.

[0479] Table 27 Results of in vivo antitumor activity assay in mice

[0480] Renca xenograft tumor model TGI% (last dose taken on day 19) p-value Formula (II) Compound A Crystal Form 100mg / kg QD 72％ 0.031

[0481] Note: QD: once a day; TGI%: tumor growth inhibition rate. Experimental conclusion: Compound A of formula (II) showed excellent tumor inhibition effect in the Renca xenograft tumor model.

Claims

1. The compound shown in formula (II), 2. The A-crystal form of the compound shown in formula (II), characterized in that, Its X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angles: 7.65±0.20°, 16.84±0.20°, 17.70±0.20°, 20.10±0.20°, 20.91±0.20°, 24.02±0.20°.

3. The A-type crystal according to claim 2, wherein its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.65±0.20°, 16.84±0.20°, 17.70±0.20°, 20.10±0.20°, 20.91±0.20°, 24.02±0.20°, 24.98±0.20°, 26.60±0.20°.

4. The A-type crystal according to claim 3, wherein its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.649°, 12.713°, 16.841°, 17.695°, 20.100°, 20.912°, 24.018°, 24.976°, 26.599°, 28.076°.

5. The XRPD pattern of the A crystal form according to claim 4 is shown in Figure 1.

6. The A-type crystal according to any one of claims 2 to 5, wherein the differential scanning calorimetry curve at 283.9 ± 3.0 °C has a peak value of an endothermic peak.

7. The A-type crystal according to claim 6, its DSC spectrum is shown in Figure 2.

8. The A crystal form according to any one of claims 2 to 5, wherein the thermogravimetric analysis curve shows a weight loss of 0.955% at 200.0 ± 3.0 °C.

9. The TGA spectrum of the A crystal form according to claim 8 is shown in Figure 3.

10. The B-crystal form of the compound shown in formula (II), characterized in that, Its X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angles: 6.75±0.20°, 9.94±0.20°, 11.70±0.20°, 17.52±0.20°, 20.36±0.20°, and 23.94±0.20°.

11. The B-type crystal according to claim 10, wherein its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.75±0.20°, 9.94±0.20°, 11.70±0.20°, 14.38±0.20°, 17.52±0.20°, 18.95±0.20°, 20.36±0.20°, 23.94±0.20°.

12. The B-type crystal according to claim 11, wherein its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.75°, 9.94°, 11.70°, 13.62°, 14.38°, 15.47°, 17.52°, 18.95°, 20.36°, 23.94°, 25.34°, 25.46°, 26.93°, 28.79°.

13. The B crystal form according to claim 12, its XRPD pattern is shown in Figure 4.

14. The B crystal form according to any one of claims 10 to 13, wherein the differential scanning calorimetry curves have an endothermic peak starting point at 57.40±3.0℃ and 296.86±3.0℃ respectively.

15. The B crystal form according to claim 14, its DSC spectrum is shown in Figure 5.

16. The B-type crystal according to any one of claims 10 to 13, wherein the thermogravimetric analysis curve shows a weight loss of 10.53% at 150.0 ± 3.0 °C.

17. The B crystal form according to claim 16, its TGA spectrum is shown in Figure 6.

18. The D-crystal form of the compound shown in formula (II), characterized in that, Its X-ray powder diffraction pattern exhibits characteristic diffraction peaks at the following 2θ angles: 10.78±0.20°, 13.64±0.20°, 16.66±0.20°, 19.63±0.20°, 21.13±0.20°, 25.40±0.20°.

19. The D-type according to claim 18, wherein its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.51±0.20°, 8.73±0.20°, 10.78±0.20°, 13.64±0.20°, 16.66±0.20°, 19.63±0.20°, 21.13±0.20°, 25.40±0.20°.

20. The D-type crystal according to claim 19, wherein its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.51°, 8.10°, 8.73°, 10.78°, 12.64°, 13.64°, 14.47°, 14.92°, 15.80°, 16.66°, 17.47°, 19.03°, 19.63°, 2θ. 1.13°, 21.69°, 22.02°, 22.20°, 23.84°, 24.31°, 25.40°, 25.93°, 26.28°, 26.84°, 27.41°, 27.93°, 29.10°, 30.01°, 30.78°, 32.16°, 32.78°, 33.57°, 38.41°.

21. The D-type crystal according to claim 20, the XRPD pattern of which is shown in Figure 10.

22. The D-type according to any one of claims 18 to 21, wherein the differential scanning calorimetry curves have an endothermic peak starting point at 27.1±3.0℃ and 298.8±3.0℃ respectively.

23. The D-type crystal according to claim 22, its DSC spectrum is shown in Figure 11.

24. The D-type according to any one of claims 18 to 21, wherein the thermogravimetric analysis curve shows a weight loss of 3.15% at 150.0 ± 3.0 °C.

25. The D-type crystal according to claim 24, its TGA spectrum is shown in Figure 12.

26. The use of the compound according to claim 1, or the A crystal form according to any one of claims 2 to 9, or the B crystal form according to any one of claims 10 to 17, or the D crystal form according to any one of claims 18 to 25, in the preparation of a medicament for treating diseases related to FGFR / VEGFR dual kinase inhibitors.

27. The application according to claim 26, characterized in that, The aforementioned FGFR / VEGFR dual kinase inhibitors are drugs used to treat solid tumors.

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