Salts of arylaminoquinazoline-containing compounds and methods of making and using the same

Abstract

The present application relates to the salt of the compound shown in formula 1 and the preparation method and application. The salt of the compound shown in formula 1 is all solid, good in character, and the solubility in water is obviously improved compared with the compound shown in formula 1, is suitable to be developed into various dosage forms, preferably the salt type and crystal form have the characteristics of low moisture absorption and good stability, and has better drug property compared with the compound shown in formula 1 or other salts.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to salts of compounds containing aromatic aminoquinazoline, their preparation methods, and uses. Background Technology

[0002] Protein tyrosine kinases (PTKs) are a crucial member of the protein kinase family. PTKs transfer the γ-phosphate group from adenosine triphosphate (ATP) to the tyrosine residue of the substrate protein, facilitating intercellular communication through phosphorylation of the phenolic hydroxyl group. They play a vital role in cell development, regulation, and the differentiation, migration, and apoptosis of tumor cells. Uncontrolled PTK regulation can disrupt the proper activation of downstream signaling pathways, leading to dysregulation of cell proliferation and causing various diseases. For example, excessive tyrosine kinase activity can lead to receptor phosphorylation, activating downstream signaling pathways, resulting in excessive cell transformation, proliferation, inhibition of apoptosis, and promotion of cell survival, ultimately leading to malignant tumors. Therefore, developing inhibitors of tyrosine kinases to inhibit their overexpression and restore physiological balance has become a research hotspot in the field of molecularly targeted antitumor therapy, showing great promise.

[0003] Epidermal growth factor receptor (EGFR), fibroblast growth factor receptors (FGFRs), platelet-derived growth factor receptor (PDGFR), and RET proteins encoded by proto-oncogenes involved in rearranged transfection (RET) are important members of PTKs and are important targets for tumor therapy.

[0004] EGFR is a cell growth factor that binds to receptor tyrosine kinases, including EGFR (ErbB-1), human epidermal growth factor receptor type 2 (HER2) (ErbB-2), human epidermal growth factor receptor type 3 (HER3) (ErbB-3), and human epidermal growth factor receptor type 4 (HER4) (ErbB-4). Among these, EGFR and HER2 are the EGFR family members most closely related to tumors. Studies have shown that EGFR is overexpressed, mutated, or fused in various tumors such as lung cancer, gastric cancer, epidermoid carcinoma, renal cell carcinoma, and ovarian cancer.

[0005] FGFRs mainly include four subtypes: FGFR1, FGFR2, FGFR3, and FGFR4. These subtypes are overexpressed or overactivated through gene amplification, mutation, fusion, or ligand induction, playing a crucial role in tumor cell proliferation, invasion, migration, and tumor angiogenesis. Studies have found that FGFRs are overexpressed or overactivated in various tumors, such as non-small cell lung cancer, gastric cancer, colorectal cancer, esophageal cancer, liver cancer, and biliary tract cancers (e.g., intrahepatic cholangiocarcinoma).

[0006] Normal physiological functions of RET include kidney development, nervous system development, maintenance and renewal of sperm stem cells, differentiation of myeloid mononuclear cells, and formation of lymphoid tissue. It is expressed in cells such as human enteric ganglion cells, neuroblastoma, pheochromocytoma, medullary thyroid carcinoma, thyroid C cells, and melanoma. In recent years, in-depth research on RET has revealed that overactivation of RET in tumors significantly promotes the proliferation, survival, invasion, metastasis, and inflammation of various tumors. RET is overexpressed in thyroid cancer (e.g., medullary thyroid carcinoma, papillary thyroid carcinoma), lung cancer (e.g., non-small cell lung cancer), colorectal cancer, pancreatic cancer, and melanoma.

[0007] Compound 1, chemically named 4-(4-bromo-2-fluoroaniline)-6-methoxy-7-[(4-N,N-dimethylamino)butoxy]quinazoline, is a multi-target inhibitor with inhibitory activities on RET, VEGFR (vascular endothelial growth factor receptor), FGFR, EGFR, and FLT (FMS-like tyrosine kinase).

[0008]

[0009] WO2016023330A1 describes compounds containing aromatic aminoquinazolines as tyrosine kinase inhibitors, including compound 1 and its analogues, preparation methods, and pharmaceutical uses. Invention Details

[0011] In a first aspect, this application provides salts of the compounds shown in Formula 1.

[0012]

[0013] The salt is selected from fumarate, trifluoroacetate, hydrobromide, citrate, phosphate, methanesulfonate, benzenesulfonate, ethanesulfonate, succinate, or benzoate. Preferably, it is fumarate, trifluoroacetate, hydrobromide, citrate, phosphate, methanesulfonate, benzenesulfonate, ethanesulfonate, or succinate. More preferably, it is trifluoroacetate, hydrobromide, citrate, phosphate, methanesulfonate, benzenesulfonate, ethanesulfonate, or succinate. Even more preferably, it is methanesulfonate, ethanesulfonate, or succinate.

[0014] In some embodiments of this application, the salt is in solid form; preferably in crystalline form.

[0015] Secondly, this application provides the compound shown in Formula 2.

[0016]

[0017] HA is selected from fumaric acid, trifluoroacetic acid, hydrobromic acid, citric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, succinic acid, malic acid, or benzoic acid.

[0018] n is 0.5, 1, 1.5 or 2; preferably, n is 1 or 2.

[0019] In some embodiments of this application, the HA is selected from fumaric acid, trifluoroacetic acid, hydrobromic acid, citric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, or succinic acid; preferably, the HA is selected from trifluoroacetic acid, hydrobromic acid, citric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, or succinic acid; more preferably, the HA is selected from methanesulfonic acid, ethanesulfonic acid, or succinic acid.

[0020] In some embodiments of this application, the compound represented by Formula 2, wherein HA is fumaric acid and n is 1 or 2; preferably, n is 1.

[0021] In some embodiments of this application, the compound represented by Formula 2, wherein HA is trifluoroacetic acid and n is 1 or 2; preferably, n is 2.

[0022] In some embodiments of this application, the compound represented by Formula 2, wherein HA is hydrobromic acid and n is 1 or 2; preferably, n is 2.

[0023] In some embodiments of this application, the compound represented by Formula 2 is wherein HA is citric acid and n is 1 or 2; preferably, n is 1.

[0024] In some embodiments of this application, the compound represented by Formula 2 is wherein HA is phosphoric acid and n is 1 or 2; preferably, n is 2.

[0025] In some embodiments of this application, the compound represented by Formula 2, wherein HA is methanesulfonic acid and n is 1 or 2; preferably, n is 2.

[0026] In some embodiments of this application, the compound represented by Formula 2 is wherein HA is benzenesulfonic acid and n is 1 or 2; preferably, n is 2.

[0027] In some embodiments of this application, the compound represented by Formula 2, wherein HA is ethanesulfonic acid and n is 1 or 2; preferably, n is 2.

[0028] In some embodiments of this application, the compound represented by Formula 2 is wherein HA is succinic acid and n is 1 or 2; preferably, n is 1.

[0029] In some embodiments of this application, the compound represented by Formula 2 is wherein HA is benzoic acid and n is 1 or 2; preferably, n is 1.

[0030] In some embodiments of this application, the compound represented by Formula 2 is in solid form. Preferably, it is in crystalline form.

[0031] In some embodiments of this application, the compound shown in Formula 2 is a compound shown in Formula 3:

[0032]

[0033] In some embodiments of this application, the compound represented by Formula 3 is in solid form, preferably in crystalline form.

[0034] In some embodiments of this application, the crystalline form of the compound represented by Formula 3, which is crystal form I, has characteristic diffraction peaks (±0.2°) in the following positions when the powder X-ray diffraction pattern is expressed in 2θ angles (°) using Cu-Kα radiation: 4.9, 7.7, 13.4, 16.8, 25.0.

[0035] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 4.4, 4.9, 7.7, 13.4, 16.8, 20.7, 25.0;

[0036] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 4.4, 4.9, 7.7, 13.4, 16.8, 20.7, 23.2, 25.0;

[0037] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 4.4, 4.9, 7.7, 11.5, 13.4, 14.2, 16.8, 20.7, 23.2, 25.0;

[0038] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 4.4, 4.9, 7.7, 11.5, 13.4, 14.2, 15.6, 16.8, 20.7, 23.2, 25.0, 32.1;

[0039] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 4.4, 4.9, 7.7, 11.5, 13.4, 14.2, 15.6, 16.8, 19.7, 20.7, 23.2, 25.0, 29.0, and 32.1.

[0040] In some embodiments of this application, the crystalline form of the compound represented by Formula 3, which is crystal form I, has a powder X-ray diffraction pattern expressed in 2θ angles (°) using Cu-Kα radiation with diffraction peaks (±0.2°) at the following positions: 4.4, 4.9, 7.7, 10.6, 11.5, 13.4, 14.2, 14.7, 15.6, 16.8, 17.6, 18.5, 19.1, 19.7, 20.7, 21.7, 23.2, 25.0, 25.4, 26.5, 28.0, 29.0, 32.1.

[0041] In some embodiments of this application, the crystalline form of the compound represented by Formula 3, which is crystal form I, exhibits substantially the following properties when subjected to Cu-Kα irradiation: Figure 1 The X-ray powder diffraction pattern shown is shown.

[0042] In some embodiments of this application, the compound shown in Formula 2 is a compound shown in Formula 4:

[0043]

[0044] In some embodiments of this application, the compound represented by Formula 4 is in solid form.

[0045] In some embodiments of this application, the compound represented by Formula 4 is in solid form, which is amorphous.

[0046] Alternatively, using Cu-Kα radiation, it has essentially the same effect as... Figure 2 The X-ray powder diffraction pattern shown is shown.

[0047] In some embodiments of this application, the compound shown in Formula 2 is a compound shown in Formula 5:

[0048]

[0049] In some embodiments of this application, the compound represented by Formula 5 is in solid form, preferably in crystalline form.

[0050] In some embodiments of this application, the crystalline form of the compound shown in Formula 5, which is crystal form I, has characteristic diffraction peaks (±0.2°) in the following positions when the powder X-ray diffraction pattern is expressed in 2θ angles (°) using Cu-Kα radiation: 12.2, 18.6, 24.8, 25.8.

[0051] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 12.2, 18.6, 19.0, 19.9, 24.8, 25.8;

[0052] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 12.2, 18.6, 19.0, 19.9, 21.9, 24.2, 24.8, 25.8;

[0053] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 12.2, 18.6, 19.0, 19.9, 21.9, 24.2, 24.8, 25.8, 29.3;

[0054] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 12.2, 17.7, 18.6, 19.0, 19.9, 21.9, 24.2, 24.8, 25.8, 29.3, 34.6;

[0055] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 12.2, 16.3, 17.7, 18.6, 19.0, 19.9, 21.9, 24.2, 24.8, 25.8, 29.3, 34.6.

[0056] In some embodiments of this application, the crystalline form of the compound represented by Formula 5, which is crystal form I, has a powder X-ray diffraction pattern expressed in 2θ angles (°) using Cu-Kα radiation, with diffraction peaks (±0.2°) at the following positions: 8.0, 10.1, 12.2, 16.0, 16.3, 16.5, 17.7, 18.6, 19.0, 19.9, 21.9, 22.7, 24.2, 24.8, 25.8, 26.8, 27.3, 28.3, 28.7, 29.3, 30.5, 32.4, 33.8, 34.6, 36.0, 37.6.

[0057] In some embodiments of this application, the crystalline form of the compound shown in Formula 5, which is crystal form I, exhibits substantially the following properties when subjected to Cu-Kα irradiation: Figure 3 The X-ray powder diffraction pattern shown is shown.

[0058] In some embodiments of this application, the compound shown in Formula 2 is a compound shown in Formula 6:

[0059]

[0060] In some embodiments of this application, the compound represented by Formula 6 is in solid form, preferably in crystalline form.

[0061] In some embodiments of this application, the crystalline form of the compound represented by Formula 6, which is crystal form I, has characteristic diffraction peaks (±0.2°) in the following positions when the powder X-ray diffraction pattern is expressed in 2θ angles (°) using Cu-Kα radiation: 12.7, 16.2, 17.0, 24.6.

[0062] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 8.7, 12.7, 16.2, 17.0, 21.3, 21.7, 24.6;

[0063] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 5.4, 8.7, 11.8, 12.7, 16.2, 17.0, 21.3, 21.7, 24.6;

[0064] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 5.4, 8.7, 11.8, 12.7, 14.1, 16.2, 17.0, 21.3, 21.7, 23.1, 24.6;

[0065] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 5.4, 8.2, 8.7, 11.8, 12.7, 14.1, 16.2, 17.0, 21.3, 21.7, 23.1, 24.6, 25.8;

[0066] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 5.4, 8.2, 8.7, 11.8, 12.7, 14.1, 15.3, 16.2, 17.0, 20.2, 21.3, 21.7, 23.1, 24.6, 25.8;

[0067] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 5.4, 6.8, 8.2, 8.7, 11.8, 12.7, 14.1, 15.3, 16.2, 17.0, 18.5, 20.2, 21.3, 21.7, 23.1, 24.6, 25.8;

[0068] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 5.4, 6.8, 8.2, 8.7, 11.8, 12.7, 14.1, 15.3, 16.2, 17.0, 18.5, 20.2, 21.3, 21.7, 22.4, 23.1, 24.6, 25.8, 26.4.

[0069] In some embodiments of this application, the crystalline form of the compound represented by Formula 6, which is crystal form I, has diffraction peaks (±0.2°) at the following positions in the powder X-ray diffraction pattern expressed in 2θ angles (°) using Cu-Kα radiation: 5.4, 6.8, 8.2, 8.7, 10.8, 11.8, 12.7, 14.1, 15.3, 16.2, 17.0, 18.5, 20.2, 21.3, 21.7, 22.4, 23.1, 24.1, 24.6, 25.8, 26.4, 27.2, 28.3, 28.7, 29.5, 31.9, and 36.0.

[0070] In some embodiments of this application, the crystalline form of the compound shown in Formula 6, which is crystal form I, exhibits substantially the following properties when subjected to Cu-Kα irradiation: Figure 4 The X-ray powder diffraction pattern shown is shown.

[0071] In some embodiments of this application, the compound shown in Formula 2 is a compound shown in Formula 7:

[0072]

[0073] In some embodiments of this application, the compound represented by Formula 7 is in solid form, preferably in crystalline form.

[0074] In some embodiments of this application, the crystalline form of the compound represented by Formula 7, which is crystal form I, has characteristic diffraction peaks (±0.2°) in the following positions when the powder X-ray diffraction pattern is expressed in 2θ angles (°) using Cu-Kα radiation: 8.1, 17.1, 18.1, 25.3.

[0075] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 8.1, 17.1, 18.1, 22.2, 24.6, 25.3;

[0076] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 5.4, 8.1, 9.7, 17.1, 18.1, 22.2, 24.6, 25.3;

[0077] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 5.4, 8.1, 9.7, 15.9, 17.1, 18.1, 20.3, 22.2, 24.6, 25.3;

[0078] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 5.4, 8.1, 9.7, 13.5, 15.9, 17.1, 18.1, 19.0, 20.3, 22.2, 24.6, 25.3.

[0079] In some embodiments of this application, the crystalline form of the compound represented by Formula 7, which is crystal form I, has a powder X-ray diffraction pattern expressed in 2θ angles (°) using Cu-Kα radiation, with diffraction peaks (±0.2°) at the following positions: 5.4, 8.1, 9.0, 9.7, 13.5, 14.2, 15.9, 16.5, 17.1, 18.1, 19.0, 20.3, 22.2, 24.0, 24.6, 25.3, 25.8, 26.8, 27.4, 32.9.

[0080] In some embodiments of this application, the crystalline form of the compound represented by Formula 7, which is crystal form I, exhibits substantially the following properties when subjected to Cu-Kα irradiation: Figure 5 The X-ray powder diffraction pattern shown is shown.

[0081] In some embodiments of this application, the compound shown in Formula 2 is a compound shown in Formula 8:

[0082]

[0083] In some embodiments of this application, the compound represented by Formula 8 is in solid form, preferably in crystalline form.

[0084] In some embodiments of this application, the crystalline form of the compound represented by Formula 8, which is crystal form I, has characteristic diffraction peaks (±0.2°) in the following positions when the powder X-ray diffraction pattern is expressed in 2θ angles (°) using Cu-Kα radiation: 3.6, 11.9, 22.4, 25.7, 27.0.

[0085] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 3.6, 6.6, 11.9, 19.7, 22.4, 25.7, 27.0;

[0086] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 3.6, 6.6, 11.9, 16.4, 19.3, 19.7, 22.4, 25.7, 27.0;

[0087] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 3.6, 6.6, 11.9, 16.4, 17.2, 19.3, 19.7, 22.4, 23.6, 25.7, 27.0;

[0088] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 3.6, 6.6, 11.9, 16.4, 17.2, 19.3, 19.7, 22.4, 23.6, 24.8, 25.7, 27.0.

[0089] In some embodiments of this application, the crystalline form of the compound represented by Formula 8, which is crystal form I, has a powder X-ray diffraction pattern expressed in 2θ angles (°) using Cu-Kα radiation, with diffraction peaks (±0.2°) at the following positions: 3.6, 6.6, 11.9, 12.3, 13.6, 14.0, 15.8, 16.4, 17.2, 18.5, 19.3, 19.7, 20.6, 21.8, 22.4, 23.6, 24.8, 25.7, 27.0.

[0090] In some embodiments of this application, the crystalline form of the compound represented by Formula 8, which is crystal form I, exhibits substantially the following properties when subjected to Cu-Kα irradiation: Figure 6 The X-ray powder diffraction pattern shown is shown.

[0091] In some embodiments of this application, the compound shown in Formula 2 is a compound shown in Formula 9:

[0092]

[0093] In some embodiments of this application, the compound represented by Formula 9 is in solid form, preferably in crystalline form.

[0094] In some embodiments of this application, the crystalline form of the compound represented by Formula 9, which is crystal form I, has characteristic diffraction peaks (±0.2°) at the following positions in the powder X-ray diffraction pattern expressed in 2θ angles (°) using Cu-Kα radiation: 5.7, 16.0, 23.7, 25.0, 25.6.

[0095] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 4.7, 5.7, 16.0, 18.4, 23.7, 25.0, 25.6;

[0096] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 4.7, 5.7, 16.0, 17.4, 18.4, 23.7, 24.3, 25.0, 25.6;

[0097] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 4.7, 5.7, 9.8, 16.0, 17.4, 18.4, 23.7, 24.3, 25.0, 25.6, 26.4;

[0098] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 4.7, 5.7, 9.8, 12.9, 15.2, 16.0, 17.4, 18.4, 23.7, 24.3, 25.0, 25.6, 26.4;

[0099] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 4.7, 5.7, 9.8, 12.9, 13.9, 15.2, 16.0, 17.4, 18.4, 20.8, 23.7, 24.3, 25.0, 25.6, 26.4;

[0100] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 4.7, 5.7, 9.8, 12.9, 13.9, 15.2, 16.0, 16.8, 17.4, 18.4, 19.7, 20.8, 23.7, 24.3, 25.0, 25.6, 26.4;

[0101] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 4.7, 5.7, 9.8, 10.7, 12.9, 13.9, 15.2, 16.0, 16.8, 17.4, 18.4, 19.7, 20.8, 22.8, 23.7, 24.3, 25.0, 25.6, 26.4.

[0102] In some embodiments of this application, the crystalline form of the compound represented by Formula 9, which is crystal form I, has a powder X-ray diffraction pattern expressed in 2θ angles (°) using Cu-Kα radiation with diffraction peaks (±0.2°) at the following positions: 4.7, 5.7, 9.8, 10.7, 12.9, 13.9, 15.2, 16.0, 16.8, 17.4, 18.4, 19.7, 20.8, 21.4, 22.8, 23.7, 24.3, 25.0, 25.6, 26.4, 28.2, 29.4, and 30.7.

[0103] In some embodiments of this application, the crystalline form of the compound represented by Formula 9, which is crystal form I, exhibits substantially the following properties when subjected to Cu-Kα irradiation: Figure 7 The X-ray powder diffraction pattern shown is shown.

[0104] In some embodiments of this application, the compound shown in Formula 2 is a compound shown in Formula 10:

[0105]

[0106] In some embodiments of this application, the compound represented by Formula 10 is in solid form, preferably in crystalline form.

[0107] In some embodiments of this application, the crystalline form of the compound represented by Formula 10, which is crystal form I, has characteristic diffraction peaks (±0.2°) in the following positions when the powder X-ray diffraction pattern is expressed in 2θ angles (°) using Cu-Kα radiation: 4.4, 5.5, 14.6, 15.7, 25.4.

[0108] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 4.4, 5.5, 14.6, 15.7, 18.2, 23.9, 25.4;

[0109] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 4.4, 5.5, 9.3, 14.6, 15.7, 18.2, 22.4, 23.9, 25.4;

[0110] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 4.4, 5.5, 9.3, 13.1, 14.6, 15.7, 18.2, 22.4, 23.9, 25.4, 26.0;

[0111] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 4.4, 5.5, 9.3, 10.7, 13.1, 13.5, 14.6, 15.7, 18.2, 18.5, 22.4, 23.9, 25.4, 26.0.

[0112] In some embodiments of this application, the crystalline form of the compound represented by Formula 10, which is crystal form I, has diffraction peaks (±0.2°) at the following positions in the powder X-ray diffraction pattern expressed in 2θ angles (°) using Cu-Kα radiation: 4.4, 5.5, 9.3, 10.7, 13.1, 13.5, 14.6, 15.7, 16.3, 16.6, 17.4, 18.2, 18.5, 19.9, 20.8, 21.8, 22.4, 22.7, 23.5, 23.9, 25.4, 26.0, 26.2.

[0113] In some embodiments of this application, the crystalline form of the compound represented by Formula 10, which is crystal form I, exhibits substantially the following properties when subjected to Cu-Kα irradiation: Figure 8 The X-ray powder diffraction pattern shown is shown.

[0114] In some embodiments of this application, the compound shown in Formula 2 is a compound shown in Formula 11:

[0115]

[0116] In some embodiments of this application, the compound represented by Formula 11 is in solid form, preferably in crystalline form.

[0117] In some embodiments of this application, the crystalline form of the compound represented by Formula 11, which is crystal form I, has characteristic diffraction peaks (±0.2°) in the following positions when the powder X-ray diffraction pattern is expressed in 2θ angles (°) using Cu-Kα radiation: 6.3, 7.8, 18.9, 22.5.

[0118] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 6.3, 7.8, 13.7, 16.0, 18.9, 22.5;

[0119] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 6.3, 7.8, 13.7, 16.0, 18.9, 20.4, 22.0, 22.5;

[0120] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 6.3, 7.8, 13.7, 15.2, 16.0, 18.9, 20.4, 22.0, 22.5, 24.3;

[0121] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 6.3, 7.8, 9.8, 13.7, 15.2, 16.0, 18.9, 20.4, 22.0, 22.5, 24.3, 27.6;

[0122] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 6.3, 7.8, 9.8, 12.0, 13.7, 15.2, 16.0, 18.9, 20.4, 22.0, 22.5, 22.9, 24.3, 27.6.

[0123] In some embodiments of this application, the crystalline form of the compound represented by Formula 11, which is crystal form I, has a powder X-ray diffraction pattern expressed in 2θ angles (°) using Cu-Kα radiation, with diffraction peaks (±0.2°) at the following positions: 6.3, 7.8, 9.8, 11.2, 12.0, 13.7, 15.2, 16.0, 17.0, 18.9, 20.4, 22.0, 22.5, 22.9, 24.1, 24.3, 24.8, 26.3, 27.6, 29.3, 29.8.

[0124] In some embodiments of this application, the crystalline form of the compound represented by Formula 11, which is crystal form I, exhibits substantially the following properties when subjected to Cu-Kα irradiation: Figure 9 The X-ray powder diffraction pattern shown is shown.

[0125] In some embodiments of this application, the compound shown in Formula 2 is a compound shown in Formula 13:

[0126]

[0127] In some embodiments of this application, the compound represented by Formula 13 is in solid form, preferably in crystalline form.

[0128] In some embodiments of this application, the crystalline form of the compound represented by Formula 13, which is crystal form I, has characteristic diffraction peaks (±0.2°) in the following positions when the powder X-ray diffraction pattern is expressed in 2θ angles (°) using Cu-Kα radiation: 3.8, 9.3, 20.7, 22.7, 24.4.

[0129] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 3.8, 9.3, 19.1, 20.7, 22.7, 24.4, 27.2;

[0130] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 3.8, 9.3, 11.5, 19.1, 20.7, 22.2, 22.7, 24.4, 27.2;

[0131] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 3.8, 9.3, 11.5, 15.8, 17.2, 19.1, 20.7, 22.2, 22.7, 24.4, 27.2;

[0132] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 3.8, 9.3, 11.5, 13.4, 14.4, 15.8, 17.2, 19.1, 20.7, 22.2, 22.7, 24.4, 27.2;

[0133] Alternatively, using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles (°), shows characteristic diffraction peaks (±0.2°) at the following positions: 3.8, 9.3, 11.5, 13.4, 14.4, 15.8, 17.2, 19.1, 20.7, 21.1, 22.2, 22.7, 23.1, 24.4, 27.2.

[0134] In some embodiments of this application, the crystalline form of the compound represented by Formula 13, which is crystal form I, has diffraction peaks (±0.2°) in the following positions when irradiated with Cu-Kα and expressed in 2θ angles (°): 3.8, 9.3, 11.5, 13.4, 14.1, 14.4, 15.3, 15.8, 17.2, 18.7, 19.1, 19.5, 20.2, 20.7, 21.1, 21.4, 22.2, 22.7, 23.1, 24.4, 24.9, 25.8, 26.2, 26.8, 27.2, 27.7, 28.0, 29.2, 29.6.

[0135] In some embodiments of this application, the crystalline form of the compound represented by Formula 13, which is crystal form I, exhibits substantially the following properties when subjected to Cu-Kα irradiation: Figure 10 The X-ray powder diffraction pattern shown is shown.

[0136] Thirdly, this application provides a crystalline composition comprising a salt of a compound of Formula 1 or a compound of Formula 2 in solid form.

[0137] In some embodiments of this application, the solid form of the salt of the compound shown in Formula 1 or the solid form of the compound shown in Formula 2 is crystal form I of the compound shown in Formula 3. Preferably, crystal form I accounts for 40%, 50%, 60%, 70%, 80%, 90%, or 95% or more of the weight of the crystalline composition.

[0138] In some embodiments of this application, the solid form of the salt of the compound shown in Formula 1 or the solid form of the compound shown in Formula 2 is the amorphous form of the compound shown in Formula 4. Preferably, the amorphous form accounts for 5% or more, 10% or more, 15% or more, 20% or more, 30% or more, 40% or more, 50% or more, 70% or more, or 80% or more by weight of the crystalline composition.

[0139] In some embodiments of this application, the solid form of the salt of the compound shown in Formula 1 or the solid form of the compound shown in Formula 2 is crystal form I of the compound shown in Formula 5. Preferably, crystal form I accounts for 40%, 50%, 60%, 70%, 80%, 90%, or 95% or more of the weight of the crystalline composition.

[0140] In some embodiments of this application, the solid form of the salt of the compound shown in Formula 1 or the solid form of the compound shown in Formula 2 is crystal form I of the compound shown in Formula 6. Preferably, crystal form I accounts for more than 40%, 50%, 60%, 70%, 80%, 90%, or 95% of the weight of the crystalline composition.

[0141] In some embodiments of this application, the solid form of the salt of the compound shown in Formula 1 or the solid form of the compound shown in Formula 2 is crystal form I of the compound shown in Formula 7. Preferably, crystal form I accounts for 40%, 50%, 60%, 70%, 80%, 90%, or 95% or more of the weight of the crystalline composition.

[0142] In some embodiments of this application, the solid form of the salt of the compound shown in Formula 1 or the solid form of the compound shown in Formula 2 is crystal form I of the compound shown in Formula 8. Preferably, crystal form I accounts for 40%, 50%, 60%, 70%, 80%, 90%, or 95% or more of the weight of the crystalline composition.

[0143] In some embodiments of this application, the solid form of the salt of the compound shown in Formula 1 or the solid form of the compound shown in Formula 2 is crystal form I of the compound shown in Formula 9. Preferably, crystal form I accounts for 40%, 50%, 60%, 70%, 80%, 90%, or 95% or more of the weight of the crystalline composition.

[0144] In some embodiments of this application, the solid form of the salt of the compound shown in Formula 1 or the solid form of the compound shown in Formula 2 is crystal form I of the compound shown in Formula 10. Preferably, crystal form I accounts for more than 40%, 50%, 60%, 70%, 80%, 90%, or 95% of the weight of the crystalline composition.

[0145] In some embodiments of this application, the solid form of the salt of the compound shown in Formula 1 or the solid form of the compound shown in Formula 2 is crystal form I of the compound shown in Formula 11. Preferably, crystal form I accounts for 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or 95% or more by weight of the crystalline composition.

[0146] In some embodiments of this application, the solid form of the salt of the compound shown in Formula 1 or the solid form of the compound shown in Formula 2 is crystal form I of the compound shown in Formula 13. Preferably, crystal form I accounts for 40%, 50%, 60%, 70%, 80%, 90%, or 95% or more of the weight of the crystalline composition.

[0147] Fourthly, this application provides a pharmaceutical composition comprising a salt of the compound shown in Formula 1, a compound shown in Formula 2, a compound shown in Formula 3, a compound shown in Formula 4, a compound shown in Formula 5, a compound shown in Formula 6, a compound shown in Formula 7, a compound shown in Formula 8, a compound shown in Formula 9, a compound shown in Formula 10, a compound shown in Formula 11 or a compound shown in Formula 13, or the aforementioned crystalline composition.

[0148] In some embodiments of this application, the pharmaceutical composition comprises a salt of the compound shown in Formula 1, a compound shown in Formula 2, a compound shown in Formula 3, a compound shown in Formula 4, a compound shown in Formula 5, a compound shown in Formula 6, a compound shown in Formula 7, a compound shown in Formula 8, a compound shown in Formula 9, a compound shown in Formula 10, a compound shown in Formula 11 or a compound shown in Formula 13, or the aforementioned crystalline composition, and contains one or more pharmaceutically acceptable excipients.

[0149] In some embodiments of this application, the term "pharmaceuticalally acceptable excipient," also known as "excipient," "adjuvant," or "additional agent," refers to the collective term for all additional materials used in formulating prescriptions and manufacturing pharmaceuticals, excluding the active ingredient. These are generally pharmaceutically acceptable inert ingredients that have undergone reasonable safety assessments. Examples of excipients, without limitation, include fillers (or diluents), disintegrants, lubricating excipients (lubricants, flow aids, anti-adhesion agents), binders, stabilizers, flavoring agents, thickeners, dispersants, colorants, antibacterial agents, antioxidants, pH adjusters, surfactants, fragrances, and coating materials (including plasticizers, opacifiers, pigments, etc.). For example, excipients can enhance the operational characteristics of pharmaceutical formulations, such as by increasing flowability and / or adhesion to ensure the formulation meets process requirements. Furthermore, the "excipient" should possess good compatibility with the active ingredient, meaning that the excipient itself or its impurities will not chemically react with the structural groups in the active ingredient or cause degradation of the active ingredient, resulting in a decrease in the content of the active ingredient.

[0150] In some embodiments of this application, the term "filler" or "diluent" refers to an excipient used to increase the weight and volume of the pharmaceutical composition to facilitate shaping and dispensing. The filler described in this application may be a single filler or a mixture of two or more fillers. In some embodiments of this application, the filler includes starch and its derivatives, microcrystalline cellulose, dextrin, sugar alcohols, and inorganic calcium salts; preferably, the filler is selected from one or more of starch, pregelatinized starch, dextrin, powdered sugar, magnesium hydroxide, lactose, mannitol, xylitol, or microcrystalline cellulose.

[0151] In some embodiments of this application, the term "disintegrant" refers to an excipient used to promote the disintegration of the pharmaceutical composition in the gastrointestinal tract and increase the dissolution rate of the active ingredient. In some embodiments of this application, the pharmaceutical composition does not contain a disintegrant. In some embodiments of this application, the pharmaceutical composition contains a disintegrant, and the disintegrant is selected from one or more of the following: dry starch, sodium carboxymethyl cellulose, microcrystalline cellulose, powdered cellulose, methyl cellulose, potassium plutonium, sodium alginate, sodium starch glycolate, polyvinylpyrrolidone, maltodextrin, magnesium aluminum silicate, corn starch, pregelatinized starch, crospovidone, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, effervescent disintegrant, sodium carboxymethyl starch, and crospovidone carboxymethyl cellulose.

[0152] In some embodiments of this application, the term "lubricating excipient" is a broad term referring to a lubricant used to reduce friction between particles and between particles and die orifices in a pharmaceutical composition, thereby improving force transmission and distribution. Lubricating excipients are further classified into lubricants, flow aids, and anti-adhesion agents based on their functions of reducing friction, increasing particle flowability, and preventing adhesion between die orifices and pharmaceutical particles. The lubricant includes one or more of stearic acid, magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitate stearate, sodium benzoate, sodium lauryl sulfate, talc, silica, zinc stearate, sodium stearoyl fumarate, magnesium stearoyl fumarate, magnesium lauryl sulfate, hydrogenated vegetable oil, sodium lauryl sulfate, magnesium lauryl sulfate, or polyethylene glycol. The flow aid is selected from one or more of colloidal silica or aluminum hydroxide.

[0153] In some embodiments of this application, the term "adhesive" or "adhesive agent" refers to a viscous excipient that enables non-sticky or low-sticky materials or excipients to aggregate and bind into granules or be compressed into molds. It can be a solid powder or a viscous liquid. In some embodiments of this application, the adhesive is selected from one or more of starch paste, copovidone, cellulose derivatives, powdered sugar, syrup, polyvinylpyrrolidone, adhesive, polyethylene glycol 4000, and dextrin; the cellulose derivative includes methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethylcellulose, or sodium carboxymethyl cellulose; the dextrin includes maltodextrin; and the adhesive includes gum arabic paste, gelatin paste, etc.

[0154] In some embodiments of this application, the "coating material," "coating powder," "coating agent," or "coating premix" is a mixture of various pharmaceutical excipients, whose main functions are coloring, masking odor, light protection, extending shelf life, and improving appearance. The "film-coated tablet" or "film-coated tablet" described in this application refers to a tablet with a film coating on the tablet core (which is prepared by compression of the pharmaceutical composition of this application). The film coating can be prepared using coating materials and methods commonly used in the art. For example, film coating materials typically contain one or more of the following: film-forming agents (or polymeric materials), plasticizers, pore-forming agents, colorants, light-blocking agents, and certain solid materials; furthermore, the coating material can be dissolved in a solvent to form a coating solution. The polymer material can be selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethylcellulose, acrylic resin, ethylcellulose, cellulose acetate, cellulose acetate phthalate, polyvinyl alcohol phthalate, cellulose acetate triterpenoid, hydroxypropyl methylcellulose phthalate, and polyvinyl alcohol; the plasticizer can be selected from glycerol, propylene glycol, polyethylene glycol, glycerol monoacetate, glycerol triacetate, dibutyl sebacate, dibutyl phthalate, diethyl phthalate, castor oil, silicone oil, corn oil, liquid paraffin, etc.; the pore-forming agent (also known as the release rate regulator) can be selected from sucrose, sodium chloride, surfactant, etc.; the solid material can be selected from talc, magnesium stearate, colloidal silica, etc.; the light-blocking agent includes titanium dioxide; and conventional colorants in the art can also be used as appropriate, such as the colorant selected from one or more of amaranth, carmine, tartrazine, soluble indigo, orange G, eosin, fuchsin, methylene blue, Sudan yellow, or mercurochrome. Alternatively, commercially available premixed coating powder can be used as the coating material, for example... Series of coating powders, Series of coating powders, Series of coating powders, Series of coating powders, A series of coating powders, etc. The coating material can be a gastrointestinal or enteric coating material. The film coating weight gain accounts for 1-5% of the tablet core weight, preferably 1.5-4%, more preferably 1.5%-3%. The coating solvent is selected from water and ethanol, preferably water, which can be removed during drying and does not remain in the final product.

[0155] In some embodiments of this application, the pharmaceutical composition is formulated as an oral dosage form; preferably, the oral dosage form is an oral solid dosage form; more preferably, the oral solid dosage form is selected from capsules, tablets, powders, and granules; further preferably, capsules and tablets; even more preferably, tablets; even more preferably, the tablet is a coated tablet; even more preferably, the tablet is a film-coated tablet.

[0156] In some embodiments of this application, each dosage unit of the oral formulation or oral solid dosage form may contain 1-500 mg of the active ingredient, or 10-450 mg, or 25-400 mg, or 50-350 mg, or 100-300 mg, or 150-200 mg, or 25-200 mg; for example, a single-dose form of the drug may contain 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 50 mg, 60 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, etc. of the active ingredient; wherein the active ingredient is calculated as a compound represented by Formula 2. Preferably, the dosage is calculated as a compound represented by Formula 2 in anhydrous form.

[0157] In some embodiments of this application, the oral formulation or oral solid dosage form contains a therapeutically effective amount of the compound shown in Formula 2, with the following dosage: 25 mg-900 mg per dose; preferably, 200 mg-800 mg per dose; more preferably, 300 mg-700 mg per dose; more preferably, 300 mg-600 mg per dose; more preferably, 400 mg-600 mg per dose; more preferably, 450 mg-600 mg per dose; exemplary dosages include 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, or 900 mg per dose. The dosage is calculated based on the compound shown in Formula 2. Preferably, the dosage is calculated based on the compound shown in Formula 2 in its anhydrous form.

[0158] Fifthly, this application provides the use of the salts of the aforementioned compounds of Formula 1, the compounds of Formula 2, Formula 3, Formula 4, Formula 5, Formula 6, Formula 7, Formula 8, Formula 9, Formula 10, Formula 11 or Formula 13, the aforementioned crystalline compositions or the aforementioned pharmaceutical compositions for the preparation of a medicament as a receptor tyrosine kinase inhibitor.

[0159] In some embodiments of this application, the receptor tyrosine kinase is one or more of VEGFR, FLT, FGFR, RET, EGFR, and their mutants.

[0160] In a sixth aspect, this application also provides the use of salts of the compound shown in Formula 1 above, compounds shown in Formula 2, Formula 3, Formula 4, Formula 5, Formula 6, Formula 7, Formula 8, Formula 9, Formula 10, Formula 11 or Formula 13, the aforementioned crystalline compositions or the aforementioned pharmaceutical compositions in the treatment of receptor tyrosine kinase-related diseases.

[0161] In a seventh aspect, this application also provides a method for treating receptor tyrosine kinase-related diseases, comprising administering to a subject a therapeutically effective amount of a salt of the compound shown in Formula 1, the compound shown in Formula 2, the crystalline composition, or the pharmaceutical composition described above.

[0162] Eighthly, this application also provides salts of the aforementioned compounds of Formula 1, Formula 2, Formula 3, Formula 4, Formula 5, Formula 6, Formula 7, Formula 8, Formula 9, Formula 10, Formula 11 or Formula 13, the aforementioned crystalline compositions or the aforementioned pharmaceutical compositions for treating receptor tyrosine kinase-related diseases.

[0163] In some embodiments of this application, the receptor tyrosine kinase-related diseases described in the above aspects (fourth to eighth aspects) are diseases caused by one or more of VEGFR, FLT, FGFR, RET, EGFR, and their mutants. In some embodiments of this application, the disease is a proliferative disease. In some embodiments of this application, the disease involves dysregulation of the expression, level, or activity of one or more of VEGFR, FLT, FGFR, RET, and EGFR proteins. In some embodiments of this application, the proliferative disease is a tumor or cancer. In some embodiments of this application, the tumor includes thyroid cancer, biliary tract cancer, epidermoid carcinoma, melanoma, colorectal cancer, gastric cancer, esophageal cancer, pancreatic cancer, renal cancer, liver cancer, lung cancer, or ovarian cancer. In some embodiments of this application, the thyroid cancer is medullary thyroid carcinoma, the lung cancer is non-small cell lung cancer, and the biliary tract cancer is intrahepatic cholangiocarcinoma. In some embodiments of this application, the non-small cell lung cancer is RET fusion-type non-small cell lung cancer.

[0164] In a ninth aspect, this application also provides the use of the salts of the aforementioned compounds of Formula 1, the compounds of Formula 2, Formula 3, Formula 4, Formula 5, Formula 6, Formula 7, Formula 8, Formula 9, Formula 10, Formula 11 or Formula 13, the aforementioned crystalline compositions or the aforementioned pharmaceutical compositions in the preparation of antitumor drugs.

[0165] In a tenth aspect, this application also provides the use of salts of the aforementioned compounds of Formula 1, compounds of Formula 2, compounds of Formula 3, compounds of Formula 4, compounds of Formula 5, compounds of Formula 6, compounds of Formula 7, compounds of Formula 8, compounds of Formula 9, compounds of Formula 10, compounds of Formula 11 or compounds of Formula 13, the aforementioned crystalline compositions or the aforementioned pharmaceutical compositions in the treatment of tumors.

[0166] Eleventhly, this application also provides a method for treating tumor diseases, comprising administering to a subject a therapeutically effective amount of a salt of the aforementioned compound of Formula 1, the compound of Formula 2, the compound of Formula 3, the compound of Formula 4, the compound of Formula 5, the compound of Formula 6, the compound of Formula 7, the compound of Formula 8, the compound of Formula 9, the compound of Formula 10, the compound of Formula 11 or the compound of Formula 13, the aforementioned crystalline composition or the aforementioned pharmaceutical composition.

[0167] In a twelfth aspect, this application also provides salts of the aforementioned compounds of Formula 1, Formula 2, Formula 3, Formula 4, Formula 5, Formula 6, Formula 7, Formula 8, Formula 9, Formula 10, Formula 11, or Formula 13, as well as the aforementioned crystalline compositions or pharmaceutical compositions for treating tumor diseases.

[0168] In some embodiments of this application, the tumors or tumor diseases described in the above aspects (fifth to twelfth aspects) include thyroid cancer, biliary tract cancer, epidermoid carcinoma, melanoma, colorectal cancer, gastric cancer, esophageal cancer, pancreatic cancer, renal cancer, liver cancer, lung cancer, or ovarian cancer. In some embodiments of this application, the thyroid cancer is medullary thyroid carcinoma, the lung cancer is non-small cell lung cancer, and the biliary tract cancer is intrahepatic bile duct cancer. In some embodiments of this application, the non-small cell lung cancer is RET fusion-type non-small cell lung cancer. In some embodiments of this application, the tumor or tumor disease is a tumor or tumor disease caused by one or more of VEGFR, FLT, FGFR, RET, EGFR, and their mutants. In some embodiments of this application, the tumor or tumor disease involves dysregulation of the expression, level, or activity of one or more of VEGFR, FLT, FGFR, RET, and EGFR proteins.

[0169] The aforementioned “subjects” include all members of the animal kingdom, including but not limited to mammals (e.g., mice, rats, cats, monkeys, dogs, pigs, etc.) and humans.

[0170] In a thirteenth aspect, this application provides a method for preparing the compound shown in Formula 2, comprising reacting the compound shown in Formula 1 with an acid (HA) in a suitable solvent to separate and obtain the compound shown in Formula 2:

[0171]

[0172] in,

[0173] HA is an acid;

[0174] n is 0.5, 1, 1.5 or 2.

[0175] In some embodiments of this application, the HA is selected from fumaric acid, trifluoroacetic acid, hydrobromic acid, citric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, succinic acid, or benzoic acid.

[0176] In some embodiments of this application, the molar ratio of the aromatic aminoquinazoline compound represented by Formula 1 to the acid is 1:1 to 2.5, preferably 1:1 to 2.3, preferably 1:1 to 2.2, and more preferably 1:1 to 2.

[0177] In some embodiments of this application, the reaction temperature is 10-90°C, preferably 40-70°C.

[0178] In some embodiments of this application, the reaction solvent is selected from one or a combination of two of alcohols, ketones, nitriles or heterocyclic alkanes; preferably, it is selected from one or a combination of two of ethyl acetate, methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, DMF, NMP, isopropanol, n-propanol, DMA, dioxane; more preferably, it is selected from one or a combination of two of ethyl acetate, methanol, ethanol, acetone or acetonitrile.

[0179] In some embodiments of this application, the reaction solvent is a combination of methanol and ethyl acetate. In some embodiments of this application, the reaction solvent is methanol. In some embodiments of this application, the reaction solvent is ethanol. In some embodiments of this application, the reaction solvent is a combination of methanol and acetonitrile. In some embodiments of this application, the reaction solvent is a combination of methanol and acetone. In some embodiments of this application, the reaction solvent is a combination of ethanol and acetonitrile.

[0180] In some embodiments of this application, when the above-mentioned reaction solvents are a combination of two, they can be added separately, that is, solvent 1 is added first, followed by solvent 2. Preferably, solvent 1 is selected from one or more of methanol, ethanol, or isopropanol, and solvent 2 is selected from one or more of ethyl acetate, acetonitrile, or acetone.

[0181] In some embodiments of this application, the compound of Formula 2 is isolated in solid form; preferably, the compound of Formula 2 is isolated in crystalline form.

[0182] In some embodiments of this application, after the reaction is completed, the temperature is lowered to crystallization temperature of -5 to 35°C, preferably 0 to 25°C, more preferably room temperature, and the mixture is stirred to crystallize for 0.5 to 24 hours. The solid is then separated, dried, and the compound shown in Formula 2 is obtained. Preferably, the salt is collected at room temperature, and the crystallization time is 0.5 to 5 hours; more preferably 1 to 3 hours; and even more preferably 2 to 3 hours.

[0183] In some embodiments of this application, the separation step includes using suitable methods such as vacuum filtration, filtration, centrifugation, etc., to separate the salt of the compound represented by Formula 2 from the crystallization liquid.

[0184] In some embodiments of this application, the drying method may employ any suitable known method, including low-temperature drying, room-temperature drying, or oven drying. Specific drying conditions include, for example, using a vacuum drying oven, with a temperature preferably 30–65°C, more preferably 40–55°C; and a drying time preferably 1–50 h, more preferably 1–16 h, and even more preferably 3–6 h. Regardless of the drying method used, it is preferable that the solvent residue in the resulting product meets the quality standards.

[0185] The compound shown in Formula 1 can be prepared by referring to the methods disclosed in the prior art, such as the method described in WO2016023330A1, the contents of which are incorporated herein by reference.

[0186] Definitions and Explanations

[0187] 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.

[0188] Within the scope of this application, various options for any feature can be combined with various options for other features to form many different embodiments. This application is intended to include all possible embodiments composed of various options for all technical features.

[0189] The term "crystalline form" as used in this application refers to the compound of Formula 2 in a crystalline form, including the anhydrous and solvent-free form, hydrate form, and solvate form of the compound of Formula 2.

[0190] The term "solvent" or "solvent compound" refers to an association formed by solvent molecules in stoichiometric or non-stoichiometric proportions with the compound shown in Formula 2 of this application, including associations containing both water molecules and one or more other solvent molecules, and associations containing only one or more other solvent molecules.

[0191] The term "hydrate" refers to an associative compound formed by stoichiometric or non-stoichiometric water molecules and the compound shown in Formula 2 of this application.

[0192] The term "anhydrous and solvent-free form" refers to a form that does not contain water or solvent molecules, or where water or solvent molecules coexist with the compound shown in Formula 2 in a manner not bound by intermolecular forces, such as through adsorption.

[0193] Unless otherwise specified, “2θ”, “2θ angle” or “2θ angle” in this application refers to the diffraction angle, in degrees or degrees. The error range of 2θ can be ±0.5, ±0.4, ±0.3, ±0.2 or ±0.1°.

[0194] Unless otherwise specified, the "heating temperature", "cooling temperature" or "crystallization temperature" mentioned in this application are in °C or degrees Celsius, and the error range can be ±10, ±5, ±4, ±3, ±2 or ±1 °C.

[0195] The term "basically as shown" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% of the peaks in the X-ray powder diffraction pattern are displayed in its pattern. Furthermore, as the content of a certain crystal form in the product gradually decreases, some diffraction peaks attributable to that crystal form in its powder X-ray diffraction pattern may decrease due to factors such as the instrument's detection sensitivity.

[0196] The term "characteristic diffraction peak" refers to a diffraction peak in an X-ray powder diffraction pattern that can be used to represent the crystal form. It is related to the peak position, peak shape and relative peak intensity of the diffraction peak. For example, a small-angle peak, a sharp peak shape and a relative peak intensity of at least 3%, or at least 5%, or at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 75%.

[0197] The term "crystalline composition" refers to a solid form that contains one or more of the solid, crystalline, or specific crystal forms of the compounds mentioned in this application (salts of compounds shown in Formula 1, compounds shown in Formula 2, or compounds shown in Formulas 3 to 13, etc.). For example, in one embodiment of this application, it contains crystal form I of the compound shown in Formula 3 mentioned in this application. Furthermore, in addition to crystal form I, the crystalline composition of the compound shown in Formula 3 may optionally contain other crystalline forms, other crystal forms, or other amorphous forms of the compound shown in Formula 3, or impurities other than these substances. Those skilled in the art will understand that the sum of the contents of all components in the crystalline composition should be 100%.

[0198] The term "room temperature" refers to room temperature in the conventional sense of the art, generally 10 to 30°C, preferably 25°C ± 5°C.

[0199] The term "cell proliferation disorder" refers to a condition in which the cell population grows at a rate lower or higher than the expected rate under given physiological conditions.

[0200] The term "tumor" includes benign tumors, malignant tumors, and borderline tumors, with malignant tumors collectively referred to as cancer.

[0201] The term "treatment" generally refers to achieving the desired pharmacological and / or physiological effects, including partially or completely stabilizing or curing a disease and / or effects resulting from the disease. As used herein, "treatment" encompasses any treatment of a subject's disease, including: (a) suppressing the symptoms of the disease, i.e., preventing its progression; or (b) alleviating the symptoms of the disease, i.e., causing the disease or symptoms to regress. The terms "effective amount" or "therapeutic effective amount" mean (i) the amount of the compound of this application used to treat a specific disease, or (ii) to reduce, improve, or eliminate one or more symptoms of a specific disease. The term "therapeutic effective amount" means the amount of the compound administered to a subject for the treatment of a disease that is sufficient to achieve the treatment of that disease. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and this disclosure.

[0202] The compounds in this application can be prepared by a variety of 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 examples in this application.

[0203] The chemical reactions in the specific embodiments of this application are carried out in a suitable solvent, which must be suitable for the chemical changes and the reagents or materials required in this application. In order to obtain the compounds of this application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction process based on existing embodiments.

[0204] The present application will be described in detail below through embodiments, which are not intended to limit the present application in any way.

[0205] All solvents used in this application are commercially available and can be used without further purification.

[0206] Beneficial effects

[0207] This application provides compounds of Formula 2 and their solid, crystalline, or specific crystalline or amorphous forms, which have one or more of the following characteristics:

[0208] Beneficial effects:

[0209] The compound shown in Formula 2 has good solid properties;

[0210] The resulting crystalline form of the compound shown in Formula 2 is in a good crystalline state;

[0211] Compared with free base, the specific crystal form or amorphous form of the compound shown in Formula 2 has significantly improved solubility in water and is non-hygroscopic or slightly hygroscopic, making it suitable for storage as a raw material.

[0212] It possesses good physical and chemical stability;

[0213] Different drug formulations can be developed according to clinical needs. Attached Figure Description

[0214] Figure 1 XRPD spectrum of crystal form I of the fumarate of compound 1 obtained in Example 1.

[0215] Figure 2 Amorphous XRPD spectrum of trifluoroacetate of compound 1 obtained in Example 2.

[0216] Figure 3 XRPD spectrum of crystal form I of hydrobromide of compound 1 obtained in Example 3.

[0217] Figure 4 XRPD spectrum of crystal form I of citrate of compound 1 obtained in Example 4.

[0218] Figure 5 XRPD spectrum of phosphate form I of compound 1 obtained in Example 5.

[0219] Figure 6 XRPD spectrum of crystal form I of the methanesulfonate of compound 1 obtained in Example 6.

[0220] Figure 7 XRPD spectrum of crystal form I of benzenesulfonate of compound 1 obtained in Example 7.

[0221] Figure 8 XRPD spectrum of ethanesulfonate of compound 1 obtained in Example 8, crystal form I.

[0222] Figure 9 XRPD spectrum of crystal form I of succinate of compound 1 obtained in Example 9.

[0223] Figure 10 XRPD spectrum of benzoate I of compound 1 obtained in Example 10. Detailed Implementation

[0224] The technical solutions of this application will be further described in detail below with reference to specific embodiments. The following embodiments are merely illustrative and explanatory of this application and should not be construed as limiting the scope of protection of this application. All technologies implemented based on the above content of this application are covered within the scope of protection intended by this application.

[0225] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0226] In the following embodiments, the analysis and detection conditions are as follows:

[0227] 1. Content

[0228] Detection instrument: Agilent 1260 (LC1260-3-DAD) high performance liquid chromatograph

[0229] Column: C18 4.6*250mm, 5μm

[0230] Test conditions: wavelength 252nm; column temperature 45℃;

[0231] 2. Solubility (water and pH 2.0 buffer solution)

[0232] Testing instrument: Agilent 1260 high performance liquid chromatograph

[0233] Detection media: purified water, pH 2.0 phosphate-disodium hydrogen phosphate buffer

[0234] Preparation of reference solution: Take an appropriate amount of compound 1 reference standard, accurately weigh it, add solvent to completely dissolve it, and dilute it to prepare a 100 μg / mL solution. Accurately measure 10 μL and use HPLC to determine the content of compound 1 in the reference solution.

[0235] 3. X-ray Powder Diffraction (XRPD)

[0236] Testing instrument: Bruker D2 PHASER powder X-ray diffractometer

[0237] Test conditions:

[0238] X-ray tube type: Cu target, ceramic X-ray tube;

[0239] X-ray wavelength: CuKα, 1.5406;

[0240] Voltage and current: 30kV, 10mA;

[0241] Scanning range: 3–40°2θ;

[0242] Total scan time: 40 min;

[0243] Scanning speed: 0.5 seconds / step;

[0244] Sample dosage: 3 mg (Examples 1-11)

[0245] Data acquisition software: Diffrac Plus XRD Commander

[0246] Analysis software: MDI Jade 6.0

[0247] 4. Proton NMR spectrum

[0248] Instrument Model: Bruker Advance 600 Nuclear Magnetic Resonance Spectrometer

[0249] Measurement conditions: The test was conducted at room temperature (~25℃) using DMSO-d6 as the solvent.

[0250] 5. Hygroscopicity

[0251] Test steps: (1) Take a dry, stoppered glass weighing bottle (outer diameter 50 mm, height 15 mm), place it in a suitable 25℃±1℃ constant temperature desiccator (with ammonium chloride saturated solution at the bottom) one day before the test, and accurately weigh it (m1). (2) Take an appropriate amount of the test sample, spread it evenly in the weighing bottle, the thickness of the test sample is generally about 1 mm, and accurately weigh it (m2). (3) Leave the weighing bottle open and place it under the constant temperature and humidity conditions mentioned above for 24 hours. (4) Close the weighing bottle lid and accurately weigh it (m3).

[0252]

[0253] Preparation Example 1: Preparation of Compound 1

[0254]

[0255] The compound of Formula 1, a light brown solid, was prepared by referring to the method described in Example 22 of Patent Document WO2016023330A1.

[0256] 1 H-NMR (600MHz, DMSO-d6) δ: 9.53 (s, 1H), 8.36 (s, 1H), 7.80 (s, 1H), 7.66 (dd, J = 10.2Hz, J = 2.4Hz, 1H), 7.54 (t, J = 8.4Hz, 1H), 7.47 (dd, J = 8. 4Hz, J=2.4Hz,1H),7.19(s,1H),4.15(t,J=6.6Hz,2H),3.95(s,3H),2.29-2.26(m,2H),2.14(s,6H),1.82-1.79(m,2H),1.59-1.57(m,2H).

[0257] Preparation Example 2: Preparation of the dihydrochloride of Compound 1

[0258]

[0259] 10 g (21.58 mmol) of compound 1 obtained in Preparation Example 1 was weighed into a flask, methanol solvent (110 mL) was added, the temperature was raised to 55 ± 5 °C, and the mixture was stirred until dissolved. Hydrochloric acid (3.7 mL, 44.4 mmol) was added dropwise, and the mixture was stirred for 20 minutes. 200 mL of ethyl acetate was slowly added, the temperature was lowered to 5 ± 5 °C, and the mixture was stirred for 2 ± 1 h. The mixture was filtered, and the filter cake was washed with ethyl acetate (20 mL) to give 11 g of white dihydrochloride of compound 1, with a yield of 94.8%.

[0260] 1 H-NMR (600MHz, DMSO-d6) δ: 15.41 (s, 1H), 11.78 (s, 1H), 10.44 (s, 1H), 8.80 (s, 1H), 8.42 (s, 1H), 7.78 (dd, J=9.6Hz, J=2.4Hz, 1 H),7.58-7.52(m,2H),7.47(s,1H),4.24(t,J=6Hz,2H),4.03(s,3H),3.15-3.14(m,2H),2.76-2.75(m,6H),1.90-1.88(m,4H).

[0261] By determining the chloride ion content using ion chromatography and calculating the stoichiometric ratio of the hydrochloride (see table below), it can be deduced that the base / acid ratio of the hydrochloride is 1:2.

[0262] Preparation Example 2 1:2 13.24％ 13.10％

[0263] The obtained hydrochloride sample was subjected to X-ray powder diffraction, which showed good crystallinity. It was named crystal form I of the dihydrochloride, and its XRPD pattern has the diffraction peak data listed in the table below. DSC-TGA analysis of the sample revealed two endothermic peaks: Endothermic peak 1: an endothermic peak initiation point at 219.1℃, reaching a peak value near 231.0℃; Endothermic peak 2: an endothermic peak initiation point at 235.1℃, reaching a peak value near 284.2℃, and decomposing at around 205℃. PLM analysis showed that its crystalline particles have a regular morphology.

[0264] 8.117 4.2 20.302 15.4 28.628 9.0 9.436 2.6 21.722 3.7 29.887 8.4 9.893 10.6 22.250 4.7 30.861 6.3 10.240 4.3 22.960 5.7 31.617 1.8 12.414 16.5 24.569 29.7 32.310 7.5 15.579 3.8 24.977 14.8 33.988 3.1 16.111 5.4 25.404 2.8 34.988 0.9 16.775 4.3 26.022 10.7 36.121 0.9 17.553 2.4 26.121 5.2 36.464 4.7 18.304 1.8 26.929 1.5 37.732 3.9 18.823 100 27.697 4.2 19.250 8.7 28.325 5.4

[0265] Example 1: Preparation of fumarate of compound 1

[0266]

[0267] Compound 1 (3 g, 6.5 mmol) obtained in Preparation Example 1 and fumaric acid (0.75 g, 6.5 mmol) were weighed into a flask, methanol (10 mL) was added, the mixture was stirred and heated to 60 ± 5 °C, and stirred for 10 minutes. Acetonitrile (30 mL) was then added, and the mixture was stirred for 5 minutes after the addition was complete. The mixture was then cooled to room temperature and reacted for 1 hour. The mixture was filtered, and the filter cake was washed with acetonitrile (20 mL) to obtain a white powdery solid (2.36 g), with a yield of 62.9%.

[0268] Nuclear magnetic resonance hydrogen spectroscopy confirmed that it had formed a salt with an acid-base ratio of 1:1.

[0269] The obtained fumarate sample was subjected to X-ray powder diffraction, which showed good crystallinity. It was named fumarate I of compound 1, and its XRPD characterization spectrum is shown below. Figure 1 As shown, the main diffraction peak data are shown in Table 1.

[0270] Table 1. XRPD diffraction peak data of crystal form I of the fumarate obtained in Example 1.

[0271] 4.448 67.0 15.578 16.1 23.179 46.6 4.931 100.0 16.826 81.5 24.951 66.6 7.688 89.6 17.605 9.4 25.388 31.7 10.597 9.7 18.495 9.0 26.479 23.9 11.512 20.6 19.073 20.8 27.964 9.3 13.364 59.4 19.720 23.9 29.046 19.2 14.213 32.1 20.736 47.0 32.145 19.4 14.737 10.4 21.687 12.9

[0272] Example 2: Preparation of trifluoroacetate of compound 1

[0273]

[0274] Compound 1 (5 g, 10.8 mmol) obtained in Preparation Example 1 was weighed into a reaction flask, methanol (10 mL) was added, and the mixture was stirred and heated to 55 ± 5 °C. After dissolving, trifluoroacetic acid (1.8 mL, 24 mmol) was added, and the mixture was stirred for another 10 minutes. Then acetone (30 mL) was added, and the mixture was cooled to room temperature and stirred for 2 hours. The mixture was then filtered, and the filter cake was washed with acetone (30 mL) to obtain a white powdery solid (7.2 g), with a yield of 96.5%.

[0275] Nuclear magnetic resonance hydrogen spectroscopy confirmed that it had formed a salt with an acid-base ratio of 2:1.

[0276] The obtained trifluoroacetate sample was subjected to X-ray powder diffraction. The resulting solid was amorphous, and its XRPD characterization spectrum is shown below. Figure 2 As shown.

[0277] Example 3: Preparation of hydrobromide of compound 1

[0278]

[0279] Compound 1 (5 g, 10.8 mmol) obtained in Preparation Example 1 was weighed into a reaction flask, methanol (10 mL) was added, and the mixture was stirred and heated to 55 ± 5 °C. After dissolving, 40% hydrobromic acid (3.4 mL, 23.8 mmol) was added, and the mixture was stirred for 10 minutes. Then ethyl acetate (30 mL) was added, and the mixture was cooled to room temperature and stirred for 2 hours. The mixture was then filtered, and the filter cake was washed with ethyl acetate (30 mL) to obtain a white powdery solid (6.36 g), with a yield of 94.2%.

[0280] Nuclear magnetic resonance hydrogen spectroscopy confirmed that it had formed a salt with an acid-base ratio of 2:1.

[0281] The obtained hydrobromide sample was subjected to X-ray powder diffraction. The obtained hydrobromide exhibited good crystallinity and was named as crystal form I of the hydrobromide of compound 1. Its XRPD characterization spectrum is shown below. Figure 3 As shown in Table 2, the main diffraction peak data are as follows.

[0282] Table 2. XRPD diffraction peak data of crystal form I of hydrobromide obtained in Example 3.

[0283] 7.977 6.6 19.877 58.7 28.730 11.9 10.112 7.0 21.885 37.0 29.392 9.5 12.236 77.5 22.685 7.7 30.516 14.6 16.045 13.0 24.285 20.2 32.399 21.7 16.342 23.0 24.824 82.2 33.843 12.8 16.468 8.8 25.769 100.0 34.602 18.1 17.747 29.0 26.764 12.2 36.038 10.8 18.6 73.2 27.285 19.7 37.638 12.1 19.024 54.3 28.288 14.3

[0284] Example 4: Preparation of citrate of compound 1

[0285]

[0286] Compound 1 (5 g, 10.8 mmol) obtained in Preparation Example 1 and citric acid monohydrate (2.72 g, 13.0 mmol) were weighed into a reaction flask, methanol (10 mL) was added, and the mixture was stirred and heated to 55 ± 5 °C. After dissolving, the mixture was stirred for another 10 minutes, then ethyl acetate (30 mL) and methanol (120 mL) were added. The mixture was cooled to room temperature and stirred for another 2 hours. The mixture was then filtered, and the filter cake was washed with ethyl acetate (30 mL) to obtain a white powdery solid (6.8 g), with a yield of 93.5%.

[0287] Nuclear magnetic resonance hydrogen spectroscopy confirmed that it had formed a salt with an acid-base ratio of 1:1.

[0288] The obtained citrate sample was subjected to X-ray powder diffraction, which showed good crystallinity. It was named crystal form I of citrate of compound 1, and its XRPD characterization spectrum is shown below. Figure 4 As shown in Table 3, the main diffraction peak data are as follows.

[0289] Table 3. XRPD diffraction peak data of citrate crystal form I obtained in Example 4.

[0290] 5.384 34.5 17.009 67.6 25.819 36.5 6.820 19.3 18.513 24.8 26.365 25.8 8.247 42.2 20.184 21.4 27.230 21.3 8.710 42.8 20.208 21.3 28.254 13.5 10.815 10.0 21.280 51.3 28.685 17.9 11.822 38.8 21.680 68.9 29.518 19.5 12.694 60.3 22.373 10.9 31.922 16.1 14.123 23.5 23.144 40.0 36.022 16.9 15.279 25.1 24.101 27.2 16.245 69.7 24.642 100.0

[0291] Example 5: Preparation of phosphate of compound 1

[0292]

[0293] Compound 1 (5 g, 10.8 mmol) obtained in Preparation Example 1 was weighed into a reaction flask, methanol (10 mL) was added, and the mixture was stirred and heated to 55 ± 5 °C. After dissolving, 85% phosphoric acid (1.5 mL, 25.86 mmol) was added, and the mixture was stirred for 10 minutes. Then ethyl acetate (30 mL) was added, and the mixture was cooled to room temperature and stirred for 2 hours. The mixture was then filtered, and the filter cake was washed with ethyl acetate (30 mL) to obtain a white powdery solid (7.05 g), with a yield of 99.1%.

[0294] Nuclear magnetic resonance hydrogen spectroscopy confirmed that it had formed a salt with an acid-base ratio of 2:1.

[0295] The obtained phosphate sample was subjected to X-ray powder diffraction. The obtained phosphate exhibited good crystallinity and was named as crystal form I of phosphate of compound 1. Its XRPD characterization spectrum is shown below. Figure 5 As shown, the main diffraction peak data are shown in Table 4.

[0296] Table 4. XRPD diffraction peak data of phosphate crystal form I obtained in Example 5

[0297] 5.409 19.3 16.468 17.5 24.628 56.9 8.120 77.2 17.086 70.7 25.304 83.9 8.976 10.6 18.146 100.0 25.771 34.3 9.739 22.4 18.979 21.8 26.778 28.3 13.545 14.6 20.282 20.8 27.404 16.9 14.243 9.7 22.244 49.7 32.937 9.4 15.892 21.7 23.989 34.6

[0298] Example 6: Preparation of methanesulfonate of compound 1

[0299]

[0300] Compound 1 (5 g, 10.8 mmol) obtained in Preparation Example 1 was weighed into a reaction flask, methanol (10 mL) was added, and the mixture was stirred and heated to 60 ± 5 °C. After dissolving, methanesulfonic acid (1.55 mL, 23.8 mmol) was added to the reactor, followed by ethyl acetate (30 mL). The mixture was cooled to room temperature, concentrated under reduced pressure, and acetone (20 mL) was added. The mixture was stirred to induce crystallization, filtered, and the filter cake was washed with acetone (20 mL) to obtain a white powdery solid (6.8 g), with a yield of 96.1%.

[0301] Nuclear magnetic resonance hydrogen spectroscopy confirmed that it had formed a salt with an acid-base ratio of 2:1.

[0302] The obtained methanesulfonate sample was subjected to X-ray powder diffraction. The obtained methanesulfonate exhibited good crystallinity and was named as crystal form I of the methanesulfonate of compound 1. Its XRPD characterization spectrum is shown below. Figure 6 As shown, the main diffraction peak data are shown in Table 5.

[0303] Table 5. XRPD diffraction peak data of crystal form I of the methanesulfonate obtained in Example 6.

[0304] 3.608 78.6 16.390 40.0 21.800 17.8 6.569 49.0 17.246 35.2 22.365 61.3 11.920 44.3 18.493 18.1 23.612 27.5 12.294 22.5 19.266 65.2 24.773 34.9 13.601 14.1 19.692 77.8 25.669 100.0 13.961 10.2 20.598 12.8 26.959 95.3 15.757 14.6

[0305] Example 7: Preparation of benzenesulfonate of compound 1

[0306]

[0307] Compound 1 (5 g, 10.8 mmol) obtained in Preparation Example 1 and benzenesulfonic acid 1,5-hydrate (4.4 g, 23.7 mmol) were weighed into a reaction flask, methanol (10 mL) was added, and the mixture was stirred and heated to 55 ± 5 °C. After dissolving, the mixture was stirred for another 10 minutes, acetone (30 mL) was added, the mixture was cooled to room temperature, isopropyl ether (30 mL) was added, and the mixture was stirred for another 2 hours. The mixture was then filtered, and the filter cake was washed with a small amount of isopropyl ether to obtain a white powdery solid (1.77 g), with a yield of 26.4%.

[0308] Nuclear magnetic resonance hydrogen spectroscopy confirmed that it had formed a salt with an acid-base ratio of 2:1.

[0309] The obtained benzenesulfonate sample was subjected to X-ray powder diffraction. The obtained benzenesulfonate exhibited good crystallinity and was named as crystal form I of benzenesulfonate of compound 1. Its XRPD characterization spectrum is shown below. Figure 7 As shown, the main diffraction peak data are shown in Table 6.

[0310] Table 6. XRPD diffraction peak data of crystal form I of the benzenesulfonate obtained in Example 7.

[0311] 4.668 61.7 16.812 18.9 24.305 39.3 5.668 100.0 17.435 51.0 25.006 74.1 9.773 30.1 18.406 67.2 25.639 64.7 10.747 22.5 19.706 23.9 26.408 32.6 12.899 29.4 20.789 17.0 28.201 17.7 13.896 28.2 21.433 15.7 29.363 12.6 15.189 34.9 22.769 21.9 30.652 11.5 16.028 63.7 23.728 66.4

[0312] Example 8: Preparation of ethanesulfonate of compound 1

[0313]

[0314] Compound 1 (4 g, 8.63 mmol) obtained in Preparation Example 1 and ethanesulfonic acid (2.1 g, 19.07 mmol) were weighed into a reaction flask, methanol (10 mL) was added, and the mixture was stirred and heated to 55 ± 5 °C. After dissolving, the mixture was stirred for another 10 minutes, acetone (30 mL) was added, the mixture was cooled to room temperature, acetone (30 mL) was added, and the mixture was stirred for another 2 hours. The mixture was then filtered, and the filter cake was washed with acetone (30 mL) to obtain a white powdery solid (5.8 g), with a yield of 98.3%.

[0315] Nuclear magnetic resonance hydrogen spectroscopy confirmed that it had formed a salt with an acid-base ratio of 2:1.

[0316] The obtained ethanesulfonate sample was subjected to X-ray powder diffraction. The obtained ethanesulfonate exhibited good crystallinity and was named as crystal form I of ethanesulfonate of compound 1. Its XRPD characterization spectrum is shown below. Figure 8 As shown, the main diffraction peak data are shown in Table 7.

[0317] Table 7. XRPD diffraction peak data of crystal form I of the ethanesulfonate obtained in Example 8.

[0318]

[0319]

[0320] Example 9: Preparation of succinate of compound 1

[0321]

[0322] Compound 1 (4 g, 8.63 mmol) obtained in Preparation Example 1 and succinic acid (1.2 g, 10.16 mmol) were weighed into a reaction flask, methanol (10 mL) was added, and the mixture was stirred and heated to 55 ± 5 °C. After dissolving, the mixture was stirred for another 10 minutes, then ethyl acetate (30 mL) was added. The mixture was cooled to room temperature and stirred for another 2 hours. The mixture was then filtered, and the filter cake was washed with ethyl acetate (30 mL) to obtain a white powdery solid (4.9 g), with a yield of 97.6%.

[0323] Nuclear magnetic resonance hydrogen spectroscopy confirmed that it had formed a salt with an acid-base ratio of 1:1.

[0324] The obtained succinate sample was subjected to X-ray powder diffraction. The obtained succinate exhibited good crystallinity and was named as crystal form I of succinate of compound 1. Its XRPD characterization spectrum is shown below. Figure 9 As shown, the main diffraction peak data are shown in Table 8.

[0325] Table 8. XRPD diffraction peak data of crystal form I of the succinate obtained in Example 9.

[0326] 6.347 78.6 17.029 11.8 24.796 14.0 7.791 63.7 18.938 100.0 26.265 13.1 9.782 27.0 20.434 37.1 27.565 17.4 11.213 14.2 22.012 52.3 29.338 16.6 11.971 20.8 22.465 80.3 29.828 16.0 13.711 50.6 22.924 21.8 15.180 31.9 24.118 15.0 16.041 46.1 24.296 37.7

[0327] Example 10: Preparation of benzoate of compound 1

[0328]

[0329] Compound 1 (4 g, 8.63 mmol) obtained in Preparation Example 1 and benzoic acid (2.2 g, 18.02 mmol) were weighed into a reaction flask, methanol (8 mL) was added, and the mixture was stirred and heated to 55 ± 5 °C. After dissolving, the mixture was stirred for another 10 minutes, then ethyl acetate (24 mL) was added. The mixture was cooled to room temperature, and then ethyl acetate (24 mL) was added. The mixture was stirred for another 2 hours, filtered, and the filter cake was washed with a small amount of ethyl acetate and dried at low temperature to obtain a white powdery solid (3.34 g), with a yield of 66.1%.

[0330] Nuclear magnetic resonance hydrogen spectroscopy confirmed that it had formed a salt with an acid-base ratio of 1:1.

[0331] The obtained benzoate sample was subjected to X-ray powder diffraction. The obtained benzoate showed good crystallinity and was named as crystal form I of benzoate of compound 1. Its XRPD characterization spectrum is shown below. Figure 10 As shown, the main diffraction peak data are shown in Table 9.

[0332] Table 9. XRPD diffraction peak data of benzoate crystal form I obtained in Example 10

[0333] 3.847 33.9 19.102 39.2 24.885 9.6 9.341 73.3 19.498 10.5 25.790 16.1 11.478 27.1 20.207 8.6 26.162 13.0 13.350 20.4 20.737 100.0 26.841 10.4 14.055 11.1 21.058 19.1 27.154 38.6 14.428 24.5 21.359 9.8 27.659 9.7 15.259 8.3 22.172 28.8 27.973 13.4 15.759 24.1 22.748 49.9 28.069 9.0 17.219 29.0 23.100 19.1 29.226 13.1 18.711 8.1 24.404 42.9 29.596 16.5

[0334] Example 11: Preparation of oxalate of compound 1

[0335]

[0336] Take 5 g (10.8 mmol) of the sample from Preparation Example 1 into a reaction flask and prepare the oxalate as shown in Formula 14 according to the reaction conditions in the table below. The operation procedure is the same as in Example 1, and the results are shown in Table 10. The formation of the salt was confirmed by 1H NMR spectroscopy, and the acid-base ratio was 1:1.

[0337] Table 10 Salt formation reaction conditions and results

[0338]

[0339] Comparative Examples 1-4: Preparation of monohydrochloride, mandelate, tartrate and malate salts of compound 1

[0340] Three portions of the sample from Preparation Example 1 (5 g, 10.8 mmol) were placed in reaction flasks. The compounds shown in Formula 2-1 (the monohydrochloride salt of compound 1), Formula 2-2 (the mandelic acid salt of compound 1), and Formula 2-3 (the tartrate salt of compound 1) were prepared according to the reaction conditions in Table 11-1. The procedure was the same as in Example 3, and the results are shown in Table 11-1. Hydrogen NMR spectroscopy confirmed the formation of salts.

[0341] The sample from Preparation Example 1 was placed in a reaction flask, and the compound shown in Formula 2-4 (malate of Compound 1) was prepared according to the reaction conditions in Table 11-2 below. The procedure was the same as in Example 3, and the results are shown in Table 11-2. Hydrogen NMR spectroscopy confirmed that salt formation had occurred.

[0342]

[0343] Table 11-1 Salt formation reaction conditions and results

[0344]

[0345] Note: ① Method for confirming the base / acid ratio in Comparative Example 1: determination of chloride ion content; ② Method for confirming the base / acid ratio in Comparative Examples 2-3: 1H NMR spectroscopy and determination of free base content.

[0346] When a free base is used to react with mandelic acid, no solid is precipitated in the system.

[0347] Table 11-2 Salt formation reaction conditions and results

[0348]

[0349] Note: The base / acid ratio of Comparative Examples 4-1 and 4-2 was confirmed by: 1H NMR spectroscopy and determination of free base content.

[0350] Test Example 1: Solubility Test

[0351] The salt samples obtained from Preparation Example 1, Examples 1 to 11, and Comparative Examples 1, 3, and 4-1 were tested for solubility in water. The test results are shown in the table below:

[0352] Table 12 Solubility results of different samples

[0353]

[0354] Results: Compared with Preparation Example 1, the samples from Examples 1 to 11 all showed a significant increase in water solubility (increase factor > 28). Among them, the solubility of trifluoroacetate, methanesulfonate, succinate, and ethanesulfonate samples was significantly higher (increase factor > 1700 compared to Preparation Example 1). The monohydrochloride, tartrate, and malate samples (Comparative Example 4-1) formed a jelly-like or milky state after dissolving in water, and could not be filtered; their solubility was not tested.

[0355] Based on the general requirements for the solubility of active pharmaceutical ingredients (APIs) in drug dosage forms, solid oral dosage forms require a water solubility greater than 0.1 g / L, while solutions such as injections or oral liquids require a solubility greater than 10 g / L. More importantly, the solubility of the drug should meet the clinically required dose concentration. Based on the solubility results in Table 12, Examples 1 to 11 can be considered for preparing solid oral dosage forms, while Examples 2 to 9 can be further considered for preparing solutions such as injections or oral liquids.

[0356] Test Example 2: Hygroscopicity Test

[0357] Weigh appropriate amounts of samples from Examples 1 to 9, Sample 1 of Preparation, and Comparative Examples 1 and 3, and conduct hygroscopicity tests at 25±5℃ and 80%RH. The results are shown in Table 13.

[0358] Table 13 Hygroscopicity results of different samples

[0359]

[0360] Conclusion: The salt samples obtained in Examples 1 to 9 performed well in the hygroscopicity test. With a significant improvement in solubility, they showed almost no hygroscopicity or only slight hygroscopicity, making them more suitable for storage as raw materials.

[0361] Test Example 3: Stability Test

[0362] Take appropriate amounts of the salt samples obtained in Examples 1 to 10, seal them with polyethylene film at 40±2℃ and 75%±5%RH for 5 months, and conduct the experiment. The results are as follows:

[0363] Table 14 Stability results and crystal form detection results of different samples

[0364]

[0365] Note: / indicates not detected.

[0366] Results: After 5 months of storage, all the salt samples listed in the table above remained stable, with no significant decrease in product purity and unchanged crystal form, demonstrating good physical and chemical stability.

[0367] Test Example 4: Drug Efficacy Experiment in a Human Melanoma A375 Nude Mouse Xenograft Model

[0368] A suspension of well-grown human melanoma A375 cells was inoculated subcutaneously into the axillary tissue of null / null female nude mice at a volume of 0.1 mL, containing approximately 1 × 10⁻⁶ tumor cells. 7 When the tumor volume reaches 100mm... 3 In this study, mice with well-developed tumors were selected and divided into five groups based on tumor volume: a blank control group, a vandetanib 12.5 mg / kg group, a vandetanib 25 mg / kg group, a sample from Preparation Example 2 12.5 mg / kg group, and a sample from Preparation Example 2 25 mg / kg group, with six animals in each group. The blank control group was administered distilled water orally, while the other groups were administered the corresponding test drug orally. The dosage was 20 mL / kg, once daily, for up to day 20. After administration, the animals were fed normally, and the antitumor effect of the test drug was dynamically observed by measuring tumor diameter. At the end of the experiment (day 21), the animals were euthanized, the tumors were removed, weighed, and the tumor inhibition rate was calculated.

[0369] Van der Thani:

[0370] Table 15. Preparation of Sample 2 and Effect of Vandetanib on Tumor Weight in Human Melanoma A375 Transplantation Model

[0371]

[0372] Note: **Compared with the blank control group, p<0.01; #Compared with the same dose of vandetanib, p<0.05.

[0373] Results: Compared with the blank control group, the sample of Preparation Example 2 significantly inhibited tumor growth in a dose-dependent manner, and had a better tumor-suppressing effect than the control drug vandetanib. Therefore, the inhibitory effects of the samples in Examples 1 to 11 are similar to those of Preparation Example 2.

[0374] Based on the conversion factor between human and animal body surface area (refer to "Pharmacological Experimental Methodology", chief editor: Xu Shuyun), the effective dose in the mouse model was converted to the equivalent dose for adults. The effective doses of 12.5 mg / kg and 25 mg / kg in the mouse model correspond to equivalent doses of 1.37 mg / kg and 2.74 mg / kg for adults (70 kg), respectively. The single oral dose for adults (70 kg) is 95.9 mg and 191.8 mg. If formulated into small-sized injections or solutions (5 mL), the drug solubility needs to reach 11.51 mg / mL and 23.02 mg / mL or higher, respectively (the absolute bioavailability in dogs and monkeys in animal pharmacokinetics experiments is about 60%, therefore, the oral bioavailability for humans is assumed to be 60% here). By analogy, the requirements for drug solubility are even higher when formulating even smaller-sized (less than 5 mL) liquid preparations. Based on the solubility test results in Table 12, for a 5mL liquid formulation, if the dosage is 1.37mg / kg, Examples 2 to 9 meet the solubility requirements; if the dosage is 2.74mg / kg, Examples 2, 6, and 8 to 9 meet the solubility requirements.

[0375] In summary, through screening and experimentation with the salt forms of Compound 1, the inventors found that the solubility of most salt forms was significantly improved compared to Compound 1. For example, in Examples 1 to 9, the solubility of trifluoroacetate, methanesulfonate, ethanesulfonate, and succinate was significantly improved (by a factor of >1700), meeting the general requirements for the solubility of active pharmaceutical ingredients in solid and liquid dosage forms. Furthermore, the resulting salt crystal forms exhibited good stability. Among these, trifluoroacetate, methanesulfonate, ethanesulfonate, and succinate showed superior performance, meeting the solubility requirements for small-volume liquid dosage forms and exhibiting low hygroscopicity, thus possessing the potential to be developed into drugs of various dosage forms and strengths.

Claims

1. A compound in solid form, wherein, The compound is the compound shown in Formula 4, and the solid form is amorphous. ， The powder X-ray diffraction pattern, expressed in 2θ angle using Cu-Kα radiation, is shown in Figure 2.

2. Compounds in solid form, wherein, The compound is the compound shown in Formula 8. ， The solid form is crystal type I, and the powder X-ray diffraction pattern, expressed in 2θ angles, shows characteristic diffraction peaks at the following positions using Cu-Kα radiation: 3.6±0.2°, 6.6±0.2°, 11.9±0.2°, 19.7±0.2°, 22.4±0.2°, 25.7±0.2°, and 27.0±0.2°.

3. The compound in solid form according to claim 2, wherein, Using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles, shows characteristic diffraction peaks at the following positions: 3.6±0.2°, 6.6±0.2°, 11.9±0.2°, 16.4±0.2°, 19.3±0.2°, 19.7±0.2°, 22.4±0.2°, 25.7±0.2°, and 27.0±0.2°.

4. The compound in solid form according to claim 2, wherein, Using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles, shows characteristic diffraction peaks at the following positions: 3.6±0.2°, 6.6±0.2°, 11.9±0.2°, 16.4±0.2°, 17.2±0.2°, 19.3±0.2°, 19.7±0.2°, 22.4±0.2°, 23.6±0.2°, 25.7±0.2°, and 27.0±0.2°.

5. The compound in solid form according to claim 2, wherein, The powder X-ray diffraction pattern, expressed in 2θ angle, using Cu-Kα radiation is shown in Figure 6.

6. Compounds in solid form, wherein, The compound is the compound shown in Formula 10. ， The solid form is crystal type I, and the powder X-ray diffraction pattern, expressed in 2θ angles using Cu-Kα radiation, has characteristic diffraction peaks at the following positions: 4.4±0.2°, 5.5±0.2°, 14.6±0.2°, 15.7±0.2°, 18.2±0.2°, 23.9±0.2°, and 25.4±0.2°.

7. The compound in solid form according to claim 6, wherein, Using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles, shows characteristic diffraction peaks at the following positions: 4.4±0.2°, 5.5±0.2°, 9.3±0.2°, 14.6±0.2°, 15.7±0.2°, 18.2±0.2°, 22.4±0.2°, 23.9±0.2°, and 25.4±0.2°.

8. The compound in solid form according to claim 6, wherein, Using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles, shows characteristic diffraction peaks at the following positions: 4.4±0.2°, 5.5±0.2°, 9.3±0.2°, 13.1±0.2°, 14.6±0.2°, 15.7±0.2°, 18.2±0.2°, 22.4±0.2°, 23.9±0.2°, 25.4±0.2°, and 26.0±0.2°.

9. The compound in solid form according to claim 6, wherein, Figure 8 shows the powder X-ray diffraction pattern expressed in 2θ angle using Cu-Kα radiation.

10. Compounds in solid form, wherein, The compound is the compound shown in Formula 11. ， The solid form is crystal type I, and the powder X-ray diffraction pattern, expressed in 2θ angles, shows characteristic diffraction peaks at the following positions using Cu-Kα radiation: 6.3±0.2°, 7.8±0.2°, 13.7±0.2°, 16.0±0.2°, 18.9±0.2°, 20.4±0.2°, 22.0±0.2°, and 22.5±0.2°.

11. The compound in solid form according to claim 10, wherein, Using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles, shows characteristic diffraction peaks at the following positions: 6.3±0.2°, 7.8±0.2°, 13.7±0.2°, 15.2±0.2°, 16.0±0.2°, 18.9±0.2°, 20.4±0.2°, 22.0±0.2°, 22.5±0.2°, and 24.3±0.2°.

12. The compound in solid form according to claim 10, wherein, Using Cu-Kα radiation, the powder X-ray diffraction pattern, expressed in 2θ angles, shows characteristic diffraction peaks at the following positions: 6.3±0.2°, 7.8±0.2°, 9.8±0.2°, 13.7±0.2°, 15.2±0.2°, 16.0±0.2°, 18.9±0.2°, 20.4±0.2°, 22.0±0.2°, 22.5±0.2°, 24.3±0.2°, and 27.6±0.2°.

13. The compound in solid form according to claim 10, wherein, Figure 9 shows the powder X-ray diffraction pattern expressed in 2θ angle using Cu-Kα radiation.

14. A pharmaceutical composition comprising the compound in solid form according to any one of claims 1-13.

15. The pharmaceutical composition of claim 14, comprising the compound in solid form as described in any one of claims 1-13, and containing one or more pharmaceutically acceptable excipients.

16. Use of the compound in solid form according to any one of claims 1-13 or the pharmaceutical composition according to claim 14 or 15 in the preparation of a medicament for treating tumors, wherein, The tumors are selected from thyroid cancer, bile duct cancer, epidermoid carcinoma, melanoma, colorectal cancer, gastric cancer, esophageal cancer, pancreatic cancer, kidney cancer, liver cancer, lung cancer, and ovarian cancer.

17. The use according to claim 16, wherein, The thyroid cancer is medullary thyroid carcinoma, the lung cancer is non-small cell lung cancer, and the biliary tract cancer is intrahepatic bile duct carcinoma.

18. The use according to claim 17, wherein, The non-small cell lung cancer mentioned is RET fusion-type non-small cell lung cancer.

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