Acid addition salts and crystalline forms of fibroblast activation protein targeting agents and uses thereof

Abstract

This invention discloses a pharmaceutically acceptable acid addition salt of the compound represented by formula (I) and its crystal form. The inventors of this invention have developed a drug (the compound represented by formula (I)) for treating diseases related to FAP expression. To find a solid form with better drug-like properties, they obtained various acid addition salts of the compound represented by formula (I) and their crystal forms. The acid addition salts and their crystal forms prepared according to this invention exhibit significantly improved purity, significantly improved stability, and physical properties more conducive to formulation.

Description

Technical Field

[0001] This invention relates to the field of pharmaceuticals, specifically to an acid addition salt and crystal form of a protein that targets fibroblast activation, and its uses. Background Technology

[0002] Fibroblast activating protein (FAP, also known as fibroblast activating protein α, FAPα) is highly overexpressed in cancer-associated fibroblasts (CAFs) in solid tumors, but is generally not expressed in normal tissues and benign tumors. Tumor stromal CAFs can promote the growth and invasion of tumor cells and have become important targets for tumor intervention. Overexpression of the tumor biomarker FAP is a significant characteristic of CAFs, and FAP is a potential target for CAF targeting in tumor diagnosis and treatment.

[0003] FAP is a type II transmembrane serine protease found on tumor fibroblasts. It exists on the cell surface as a homodimer and belongs to the proline oligopeptidase family. Its enzymatic activity plays a crucial role in tumor growth and tissue remodeling. Surface-specific FAP on tumor cells (CFS) can promote tumor progression by enhancing tumor cell-directed invasion along fibroblasts through matrix remodeling, participating in VEGF / AKT / ERK signaling pathways, and participating in tumor angiogenesis to form a tumor biobarrier and inhibit effector T cell function. The inducible high expression of FAP in the tumor stroma also depends on malignant transformation of the tumor tissue. High FAP expression is positively correlated with poor tumor prognosis.

[0004] Small-molecule FAP selective (targeted) inhibitors, after structural modification and optimized screening, have significant advantages and development value for cancer diagnosis and treatment. However, different salts and solid forms of the active pharmaceutical ingredient may have different properties (e.g., dissolution rate, stability, shelf life, exposure, bioavailability, or prolonged half-life). Therefore, it is necessary to further develop pharmaceutically acceptable salts or crystal forms targeting fibroblast activation proteins to facilitate further drug development. Summary of the Invention

[0005] This invention aims to at least partially address one of the technical problems existing in the prior art. One object of this invention is to propose an acid addition salt and crystal form targeting fibroblast activation proteins.

[0006] The following description only outlines some aspects of the invention and is not intended to limit it. These aspects and other parts are described in more detail below. All references in this specification are incorporated herein by reference in their entirety. In the event of any discrepancy between the disclosure in this specification and the cited references, the disclosure in this specification shall prevail.

[0007] The inventors of this invention previously screened drugs targeting fibroblast activation proteins, obtaining the compound shown in formula (I). However, this compound often exists in an oily amorphous form, which is not conducive to accurate sampling, results in poor product stability, and also leads to a decrease in purity and an increase in impurities over long-term storage. Therefore, this invention screens the compound for its crystal form to identify the optimal crystal form, which exhibits better stability and higher purity compared to the compound shown in formula (I).

[0008] This invention provides an acid addition salt and crystal form targeting fibroblast activation protein, which can be used to diagnose and / or treat and / or prevent diseases expressing fibroblast activation protein, such as sarcoma, osteosarcoma and other sarcoma-like malignant tumors, pancreatic cancer, ovarian cancer, melanoma, esophageal cancer, breast cancer, bile duct cancer, lung cancer, liver cancer, colorectal cancer, head and neck cancer, neuroendocrine tumors, etc.

[0009] In a first aspect, the present invention provides a pharmaceutically acceptable acid addition salt of a compound of formula (I).

[0010]

[0011] The inventors of this invention have developed a drug (the compound shown in formula (I)) for treating diseases caused by FAP expression. In order to find a solid form with better drug-like properties, the inventors have conducted a large number of experimental studies to obtain various acid addition salts of the compound shown in formula (I) and the crystal forms of its salts.

[0012] According to embodiments of the present invention, the acid addition salt includes inorganic acid salts or organic acid salts.

[0013] According to embodiments of the present invention, the inorganic acid salt includes phosphate, sulfate or hydrobromide.

[0014] According to embodiments of the present invention, the organic acid salt includes p-toluenesulfonate.

[0015] According to embodiments of the present invention, the acid addition salt includes phosphates, sulfates, hydrobromic acid salts, or p-toluenesulfonates of compounds represented by formula (I).

[0016] According to an embodiment of the present invention, the acid addition salt includes at least one of the following crystal forms of the compound represented by formula (I): p-toluenesulfonate crystal form A, p-toluenesulfonate crystal form B, phosphate crystal form A, phosphate crystal form B, phosphate crystal form C, sulfate crystal form A, sulfate crystal form B, hydrobromide crystal form A, p-toluenesulfonate crystal form A, and p-toluenesulfonate crystal form B.

[0017] In an optional embodiment of the present invention, the hydrochloride salt has the crystal form of p-toluenesulfonate crystal form A and / or p-toluenesulfonate crystal form B of the compound represented by formula (I). In an optional embodiment of the present invention, the sulfate salt has the crystal form of sulfate crystal form A and / or sulfate crystal form B of the compound represented by formula (I). In an optional embodiment of the present invention, the phosphate salt has the crystal form of phosphate crystal form A, phosphate crystal form B, and / or phosphate crystal form C of the compound represented by formula (I).

[0018] The “2θ or 2θ angle” mentioned in this disclosure refers to the diffraction angle, where θ is the Bragg angle, and the unit is ° or degree; the error range of 2θ for each characteristic peak is ±0.20 (including the case where the number has more than two decimal places after rounding).

[0019] According to embodiments of the present invention, those skilled in the art will understand that when the compound of formula (I) forms a salt with an acid, the molar ratio of the compound of formula (I) to the acid can be 5:1 to 1:5, for example, 3:1, 2:1, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.5, 1:2, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3, or any range of two ratios therebetween.

[0020] According to an embodiment of the present invention, the acid addition salt is p-toluenesulfonate crystal form A of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 5.76±0.2°, 11.61±0.2°, and 11.98±0.2°.

[0021] According to an embodiment of the present invention, the acid addition salt is p-toluenesulfonate crystal form A of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 5.76±0.2°, 11.61±0.2°, 11.98±0.2°, 17.34±0.2°, 20.71±0.2°, 21.23±0.2°, 26.32±0.2°.

[0022] According to an embodiment of the present invention, the acid addition salt is p-toluenesulfonate crystal form A of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 5.76±0.2°, 8.17±0.2°, 11.61±0.2°, 11.98±0.2°, 17.34±0.2°, 20.30±0.2°, 20.71±0.2°, 21.23±0.2°, 24.87±0.2°, 26.32±0.2°.

[0023] According to an embodiment of the present invention, the acid addition salt is p-toluenesulfonate crystal form A of the compound shown in formula (I), which has a weight loss of 11.4 ± 0.1% at 150 °C.

[0024] According to an embodiment of the present invention, the acid addition salt is p-toluenesulfonate crystal form A, whose DSC diagram contains one or more endothermic signals at 102.1℃±3℃ and 138.0℃±3℃.

[0025] According to an embodiment of the present invention, the acid addition salt is p-toluenesulfonate crystal form A of the compound represented by formula (I), which has substantially the following characteristics: Figure 2-1 The X-ray powder diffraction pattern shown.

[0026] According to an embodiment of the present invention, the acid addition salt is p-toluenesulfonate crystal form A of the compound represented by formula (I), wherein p-toluenesulfonate crystal form A has an XRPD analysis data table as shown in Table 1 (see Example 1 for details).

[0027] In some embodiments, the acid addition salt of the present invention is p-toluenesulfonate crystal form A of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to p-toluenesulfonic acid in p-toluenesulfonate crystal form A is 1:(0.33-3).

[0028] In some embodiments, the acid addition salt of the present invention is p-toluenesulfonate crystal form A of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to p-toluenesulfonic acid in p-toluenesulfonate crystal form A is 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:2.5, or 1:3. In some embodiments, the acid addition salt of the present invention is p-toluenesulfonate crystal form A of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to p-toluenesulfonic acid in p-toluenesulfonate crystal form A is 1:1.

[0029] According to an embodiment of the present invention, the acid addition salt is p-toluenesulfonate crystal form A of the compound represented by formula (I), which has substantially the following characteristics: Figure 2-2 The TGA and DSC diagrams are shown below.

[0030] According to an embodiment of the present invention, the acid addition salt is p-toluenesulfonate crystal form B of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 6.71±0.2°, 13.48±0.2°, and 20.26±0.2°.

[0031] According to an embodiment of the present invention, the acid addition salt is p-toluenesulfonate crystal form B of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 6.71±0.2°, 8.60±0.2°, 11.65±0.2°, 13.48±0.2°, 20.26±0.2°, 23.04±0.2°, 24.38±0.2°.

[0032] According to an embodiment of the present invention, the acid addition salt is p-toluenesulfonate crystal form B of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 6.71±0.2°, 8.60±0.2°, 11.65±0.2°, 13.48±0.2°, 17.67±0.2°, 20.26±0.2°, 20.92±0.2°, 21.99±0.2°, 23.04±0.2°, 24.38±0.2°.

[0033] According to an embodiment of the present invention, the acid addition salt is p-toluenesulfonate crystal form B of the compound shown in formula (I), which has a weight loss of 7.9 ± 0.1% at 160 °C.

[0034] According to an embodiment of the present invention, the acid addition salt is p-toluenesulfonate crystal form B, whose DSC diagram contains one or more endothermic signals at 89.3℃±3℃ and 130.4℃±3℃.

[0035] According to an embodiment of the present invention, the acid addition salt is p-toluenesulfonate crystal form B of the compound represented by formula (I), which has substantially the following characteristics: Figure 3-1 The X-ray powder diffraction pattern shown.

[0036] According to an embodiment of the present invention, the acid addition salt is p-toluenesulfonate crystal form B of the compound represented by formula (I), wherein p-toluenesulfonate crystal form B has an XRPD analysis data table substantially as shown in Table 2 (see Example 1 for details).

[0037] In some embodiments, the acid addition salt of the present invention is p-toluenesulfonate crystal form B of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to p-toluenesulfonic acid in p-toluenesulfonate crystal form B is 1:(0.33-3).

[0038] In some embodiments, the acid addition salt of the present invention is p-toluenesulfonate crystal form B of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to p-toluenesulfonic acid in p-toluenesulfonate crystal form B is 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:2.5, or 1:3. In some embodiments, the acid addition salt of the present invention is p-toluenesulfonate crystal form B of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to p-toluenesulfonic acid in p-toluenesulfonate crystal form B is 1:1.

[0039] According to an embodiment of the present invention, the acid addition salt is p-toluenesulfonate crystal form B of the compound represented by formula (I), which has substantially the following characteristics: Figure 3-2 The TGA and DSC diagrams are shown below.

[0040] According to an embodiment of the present invention, the acid addition salt is the phosphate crystal form A of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 3.33±0.2°, 3.97±0.2°, and 6.19±0.2°.

[0041] According to an embodiment of the present invention, the acid addition salt is the phosphate crystal form A of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 3.33±0.2°, 3.97±0.2°, 5.18±0.2°, 6.19±0.2°, 9.16±0.2°, 18.59±0.2°, and 23.52±0.2°.

[0042] According to an embodiment of the present invention, the acid addition salt is the phosphate crystal form A of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 3.33±0.2°, 3.97±0.2°, 5.18±0.2°, 6.19±0.2°, 9.16±0.2°, 11.92±0.2°, 12.87±0.2°, 15.67±0.2°, 18.59±0.2°, 23.52±0.2°.

[0043] According to an embodiment of the present invention, the acid addition salt is the phosphate crystal form A of the compound shown in formula (I), which has a weight loss of 13.5 ± 0.1% at 180 °C.

[0044] According to an embodiment of the present invention, the acid addition salt is phosphate crystal form A, and its DSC diagram includes one or more endothermic signals among 70.6℃±3℃, 126.8℃±3℃, 191.4℃±3℃, 208.2℃±3℃ and 229.2℃±3℃.

[0045] According to an embodiment of the present invention, the acid addition salt is a phosphate crystal form A of the compound represented by formula (I), which has substantially the following characteristics: Figure 4-1 The X-ray powder diffraction pattern shown.

[0046] According to an embodiment of the present invention, the acid addition salt is a phosphate crystal form A of the compound represented by formula (I), wherein the phosphate crystal form A has an XRPD analysis data table as shown in Table 3 (see Example 1 for details).

[0047] According to an embodiment of the present invention, the acid addition salt is a phosphate crystal form A of the compound represented by formula (I), which has substantially the following characteristics: Figure 4-2 The TGA and DSC diagrams are shown below.

[0048] According to an embodiment of the present invention, the acid addition salt is the phosphate crystal form B of the compound shown in formula (I), which has a weight loss of 3.3 ± 0.1% at 120 °C.

[0049] According to an embodiment of the present invention, the acid addition salt is phosphate crystal form B, and its DSC diagram contains one or more endothermic signals at 56.2℃±3℃ and 151.9℃±3℃.

[0050] According to an embodiment of the present invention, the acid addition salt is a phosphate crystal form B of the compound represented by formula (I), which has substantially the following characteristics: Figure 5-1 The X-ray powder diffraction pattern shown.

[0051] In some embodiments, the acid addition salt of the present invention is the phosphate crystal form B of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to phosphoric acid in the phosphate crystal form B is 1:(0.33-3).

[0052] In some embodiments, the acid addition salt of the present invention is the phosphate crystal form B of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to phosphoric acid in phosphate crystal form B is 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:2.5, or 1:3. In some embodiments, the acid addition salt of the present invention is the phosphate crystal form B of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to phosphoric acid in phosphate crystal form B is 1:1.

[0053] According to an embodiment of the present invention, the acid addition salt is a phosphate crystal form B of the compound represented by formula (I), which has substantially the following characteristics: Figure 5-2 The TGA and DSC diagrams are shown below.

[0054] According to an embodiment of the present invention, the acid addition salt is the phosphate crystal form C of the compound shown in formula (I), which has a weight loss of 9.0 ± 0.1% at 150 °C.

[0055] According to an embodiment of the present invention, the acid addition salt is phosphate crystal form C, and its DSC diagram contains one or more endothermic signals at 59.8℃±3℃ and 182.6℃±3℃.

[0056] According to an embodiment of the present invention, the acid addition salt is the phosphate crystal form C of the compound represented by formula (I), which has substantially the following characteristics: Figure 6-1 The X-ray powder diffraction pattern shown.

[0057] In some embodiments, the acid addition salt of the present invention is the phosphate crystal form C of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to phosphoric acid in the phosphate crystal form C is 1:(0.33-3).

[0058] In some embodiments, the acid addition salt of the present invention is the phosphate crystal form C of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to phosphoric acid in phosphate crystal form C is 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, or 1:3. In some embodiments, the acid addition salt of the present invention is the phosphate crystal form C of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to phosphoric acid in phosphate crystal form C is 1:2.7.

[0059] According to an embodiment of the present invention, the acid addition salt is the phosphate crystal form C of the compound represented by formula (I), which has substantially the following characteristics: Figure 6-2 The TGA and DSC diagrams are shown below.

[0060] According to an embodiment of the present invention, the acid addition salt is the sulfate crystal form A of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 9.30±0.2°, 10.75±0.2°, and 20.78±0.2°.

[0061] According to an embodiment of the present invention, the acid addition salt is the sulfate crystal form A of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 8.15±0.2°, 9.30±0.2°, 10.75±0.2°, 13.20±0.2°, 13.61±0.2°, 14.74±0.2°, and 20.78±0.2°.

[0062] According to an embodiment of the present invention, the acid addition salt is the sulfate crystal form A of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 8.15±0.2°, 9.30±0.2°, 10.75±0.2°, 11.69±0.2°, 13.20±0.2°, 13.61±0.2°, 14.74±0.2°, 20.78±0.2°, 29.20±0.2°, 29.76±0.2°.

[0063] According to an embodiment of the present invention, the acid addition salt is the sulfate crystal form A of the compound shown in formula (I), which has a weight loss of 7.7 ± 0.1% at 120 °C.

[0064] According to an embodiment of the present invention, the acid addition salt is sulfate crystal form A, and its DSC diagram contains one or more endothermic signals at 68.2℃±3℃ and 207.3℃±3℃.

[0065] According to an embodiment of the present invention, the acid addition salt is a sulfate crystal form A of the compound represented by formula (I), which has substantially the following characteristics: Figure 7-1 The X-ray powder diffraction pattern shown.

[0066] According to an embodiment of the present invention, the acid addition salt is the sulfate crystal form A of the compound represented by formula (I), wherein the sulfate crystal form A has an XRPD analysis data table as shown in Table 4 (see Example 1 for details).

[0067] In some embodiments, the acid addition salt of the present invention is the sulfate crystal form A of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to sulfuric acid in sulfate crystal form A is 1:(0.33-3).

[0068] In some embodiments, the acid addition salt of the present invention is the sulfate crystal form A of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to sulfuric acid in sulfate crystal form A is 3:1, 2:1, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.5, 1:2, 1:2.5, or 1:3. In some embodiments, the acid addition salt of the present invention is the sulfate crystal form A of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to sulfuric acid in sulfate crystal form A is 1:0.7.

[0069] According to an embodiment of the present invention, the acid addition salt is a sulfate crystal form A of the compound represented by formula (I), which has substantially the following characteristics: Figure 7-2 The TGA and DSC diagrams are shown below.

[0070] According to an embodiment of the present invention, the acid addition salt is the sulfate crystal form B of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 11.48±0.2°, 17.48±0.2°, and 20.58±0.2°.

[0071] According to an embodiment of the present invention, the acid addition salt is the sulfate crystal form B of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 11.48±0.2°, 15.75±0.2°, 16.68±0.2°, 17.48±0.2°, 20.58±0.2°, 24.57±0.2°, 28.96±0.2°.

[0072] According to an embodiment of the present invention, the acid addition salt is the sulfate crystal form B of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 7.11±0.2°, 7.74±0.2°, 11.48±0.2°, 13.20±0.2°, 15.75±0.2°, 16.68±0.2°, 17.48±0.2°, 20.58±0.2°, 24.57±0.2°, 28.96±0.2°.

[0073] According to an embodiment of the present invention, the acid addition salt is the sulfate crystal form B of the compound shown in formula (I), which has a weight loss of 6.1 ± 0.1% at 120 °C.

[0074] According to an embodiment of the present invention, the acid addition salt is sulfate crystal form B, and its DSC diagram contains one or more endothermic signals at 76.5℃±3℃ and 142.2℃±3℃.

[0075] According to an embodiment of the present invention, the acid addition salt is a sulfate crystal form B of the compound represented by formula (I), which has substantially the following characteristics: Figure 8-1 The X-ray powder diffraction pattern shown.

[0076] According to an embodiment of the present invention, the acid addition salt is the sulfate crystal form B of the compound represented by formula (I), wherein the sulfate crystal form B has an XRPD analysis data table as shown in Table 5 (see Example 1 for details).

[0077] In some embodiments, the acid addition salt of the present invention is the sulfate crystal form B of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to sulfuric acid in sulfate crystal form B is 1:(0.33-3).

[0078] In some embodiments, the acid addition salt of the present invention is the sulfate crystal form B of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to sulfuric acid in sulfate crystal form B is 3:1, 2:1, 1:1, 1:1.5, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, or 1:3. In some embodiments, the acid addition salt of the present invention is the sulfate crystal form B of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to sulfuric acid in sulfate crystal form B is 1:2.2.

[0079] According to an embodiment of the present invention, the acid addition salt is a sulfate crystal form B of the compound represented by formula (I), which has substantially the following characteristics: Figure 8-2 The TGA and DSC diagrams are shown below.

[0080] According to an embodiment of the present invention, the acid addition salt is the hydrobromide crystal form A of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 3.89±0.2°, 4.23±0.2°, and 8.16±0.2°.

[0081] According to an embodiment of the present invention, the acid addition salt is the hydrobromide crystal form A of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 3.89±0.2°, 4.23±0.2°, 8.16±0.2°, 16.38±0.2°, 17.88±0.2°, and 24.60±0.2°.

[0082] According to an embodiment of the present invention, the acid addition salt is the hydrobromide crystal form A of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 3.89±0.2°, 4.23±0.2°, 8.16±0.2°, 16.38±0.2°, 17.88±0.2°, 19.66±0.2°, 21.29±0.2°, 24.60±0.2°, 31.79±0.2°.

[0083] According to an embodiment of the present invention, the acid addition salt is the hydrobromide crystal form A of the compound shown in formula (I), which has a weight loss of 9.0 ± 0.1% at 150 °C.

[0084] According to an embodiment of the present invention, the acid addition salt is hydrobromide crystal form A, and its DSC diagram contains an endothermic signal of 66.8℃±3℃.

[0085] According to an embodiment of the present invention, the acid addition salt is the hydrobromide crystal form A of the compound represented by formula (I), which has substantially the following characteristics: Figure 9-1 The X-ray powder diffraction pattern shown.

[0086] According to an embodiment of the present invention, the acid addition salt is the hydrobromide crystal form A of the compound represented by formula (I), wherein the hydrobromide crystal form A has an XRPD analysis data table as shown in Table 6 (see Example 1 for details).

[0087] In some embodiments, the acid addition salt of the present invention is the hydrobromide crystal form A of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to hydrobromic acid in the hydrobromide crystal form A is 1:(0.33-3).

[0088] In some embodiments, the acid addition salt of the present invention is the hydrobromide crystal form A of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to hydrobromic acid in the hydrobromide crystal form A is 3:1, 2:1, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.5, 1:2, 1:2.5, or 1:3. In some embodiments, the acid addition salt of the present invention is the hydrobromide crystal form A of the compound shown in formula (I), wherein the molar ratio of the compound shown in formula (I) to hydrobromic acid in the hydrobromide crystal form A is 1:2.5.

[0089] According to an embodiment of the present invention, the acid addition salt is the hydrobromide crystal form A of the compound represented by formula (I), which has substantially the following characteristics: Figure 9-2 The TGA and DSC diagrams are shown below.

[0090] In a second aspect of the invention, a pharmaceutically acceptable crystal form of the compound shown in formula (I) is provided.

[0091]

[0092] According to an embodiment of the present invention, the crystal form is a free crystal form A, and the X-ray powder diffraction pattern of the free crystal form A has diffraction peaks at the following 2θ angles: 4.67±0.2°, 5.39±0.2°, and 12.10±0.2°.

[0093] According to an embodiment of the present invention, the crystal form is a free crystal form A, and the X-ray powder diffraction pattern of the free crystal form A has diffraction peaks at the following 2θ angles: 4.67±0.2°, 5.39±0.2°, 11.18±0.2°, 12.10±0.2°, 15.56±0.2°, 16.08±0.2°, and 17.32±0.2°.

[0094] According to an embodiment of the present invention, the crystal form is a free crystal form A, and the X-ray powder diffraction pattern of the free crystal form A has diffraction peaks at the following 2θ angles: 4.67±0.2°, 5.39±0.2°, 11.18±0.2°, 12.10±0.2°, 12.87±0.2°, 14.23±0.2°, 15.56±0.2°, 16.08±0.2°, 17.32±0.2°, and 20.80±0.2°.

[0095] According to an embodiment of the present invention, the crystal form is a free crystal form A, which has a weight loss of 0.6 ± 0.1% at 100°C.

[0096] According to an embodiment of the present invention, the crystal form is a free crystal form A, and the free crystal form A contains an endothermic signal of 204.3±3℃.

[0097] According to an embodiment of the present invention, the crystal form is a free crystal form A, and the free crystal form A has substantially the following characteristics: Figure 10-1 The X-ray powder diffraction pattern shown.

[0098] According to an embodiment of the present invention, the crystal form is a free crystal form A, which has an XRPD analytical data table as shown in Table 7 (see Example 2 for details).

[0099] According to an embodiment of the present invention, the crystal form is a free crystal form A, and the free crystal form A has substantially the following characteristics: Figure 10-2 The TGA and DSC diagrams are shown below.

[0100] According to an embodiment of the present invention, the crystal form is a free crystal form B, and the X-ray powder diffraction pattern of the free crystal form B has diffraction peaks at the following 2θ angles: 12.47±0.2°, 13.73±0.2°, and 16.84±0.2°.

[0101] According to an embodiment of the present invention, the crystal form is a free crystal form B, and the X-ray powder diffraction pattern of the free crystal form B has diffraction peaks at the following 2θ angles: 9.16±0.2°, 12.47±0.2°, 13.73±0.2°, 16.08±0.2°, 16.47±0.2°, 16.84±0.2°, and 20.61±0.2°.

[0102] According to an embodiment of the present invention, the crystal form is a free crystal form B, and the X-ray powder diffraction pattern of the free crystal form B has diffraction peaks at the following 2θ angles: 4.38±0.2°, 7.59±0.2°, 8.27±0.2°, 9.16±0.2°, 12.47±0.2°, 13.73±0.2°, 16.08±0.2°, 16.47±0.2°, 16.84±0.2°, and 20.61±0.2°.

[0103] According to an embodiment of the present invention, the crystal form is a free crystal form B, and the free crystal form B has substantially the following characteristics: Figure 11 The X-ray powder diffraction pattern shown.

[0104] According to an embodiment of the present invention, the crystal form is a free crystal form B, which has an XRPD analytical data table as shown in Table 8 (see Example 2 for details).

[0105] According to an embodiment of the present invention, the crystal form is a free crystal form C, and the X-ray powder diffraction pattern of the free crystal form C has diffraction peaks at the following 2θ angles: 15.61±0.2°, 22.69±0.2°, and 24.11±0.2°.

[0106] According to an embodiment of the present invention, the crystal form is a free crystal form C, and the X-ray powder diffraction pattern of the free crystal form C has diffraction peaks at the following 2θ angles: 14.82±0.2°, 15.61±0.2°, 18.57±0.2°, 22.69±0.2°, 24.11±0.2°, 24.55±0.2°, and 26.69±0.2°.

[0107] According to an embodiment of the present invention, the crystal form is a free crystal form C, and the X-ray powder diffraction pattern of the free crystal form C has diffraction peaks at the following 2θ angles: 4.98±0.2°, 11.05±0.2°, 14.82±0.2°, 15.61±0.2°, 18.00±0.2°, 18.57±0.2°, 22.69±0.2°, 24.11±0.2°, 24.55±0.2°, 26.69±0.2°.

[0108] According to an embodiment of the present invention, the crystal form is free crystal form C, which has a weight loss of 9.1 ± 0.1% at 150°C.

[0109] According to an embodiment of the present invention, the crystal form is a free crystal form C, and the free crystal form C contains an endothermic signal of 82.2℃±3℃~101.8℃±3℃.

[0110] In an optional embodiment of the present invention, the crystal form is a free crystal form C, which contains an endothermic signal of 25℃±3℃ to 101.8℃±3℃. Exemplarily, the free crystal form C contains an endothermic signal of 25℃ to 101.8℃.

[0111] According to an embodiment of the present invention, the crystal form is a free crystal form C, and the free crystal form C has substantially the following properties: Figure 12-1 The X-ray powder diffraction pattern shown.

[0112] According to an embodiment of the present invention, the crystal form is a free crystal form C, which has an XRPD analytical data table as shown in Table 9 (see Example 2 for details).

[0113] According to an embodiment of the present invention, the crystal form is a free crystal form C, and the free crystal form C has substantially the following properties: Figure 12-2 The TGA and DSC diagrams are shown below.

[0114] According to an embodiment of the present invention, the crystal form is a free crystal form D, and the X-ray powder diffraction pattern of the free crystal form D has diffraction peaks at the following 2θ angles: 4.05±0.2°, 13.85±0.2°, and 15.75±0.2°.

[0115] According to an embodiment of the present invention, the crystal form is a free crystal form D, and the X-ray powder diffraction pattern of the free crystal form D has diffraction peaks at the following 2θ angles: 4.05±0.2°, 5.39±0.2°, 9.49±0.2°, 13.85±0.2°, 15.75±0.2°, 18.49±0.2°, and 18.76±0.2°.

[0116] According to an embodiment of the present invention, the crystal form is a free crystal form D, and the X-ray powder diffraction pattern of the free crystal form D has diffraction peaks at the following 2θ angles: 4.05±0.2°, 5.39±0.2°, 6.93±0.2°, 9.49±0.2°, 10.85±0.2°, 11.18±0.2°, 13.85±0.2°, 15.75±0.2°, 18.49±0.2°, and 18.76±0.2°.

[0117] According to an embodiment of the present invention, the crystal form is a free crystal form D, which has a weight loss of 1.0 ± 0.1% at 100°C.

[0118] According to an embodiment of the present invention, the crystal form is a free crystal form D, and the free crystal form D contains an endothermic signal of 199.7℃±3℃.

[0119] According to an embodiment of the present invention, the crystal form is a free crystal form D, and the free crystal form D has substantially the following characteristics: Figure 13-1 The X-ray powder diffraction pattern shown.

[0120] According to an embodiment of the present invention, the crystal form is a free crystal form D, which has an XRPD analytical data table as shown in Table 10 (see Example 2 for details).

[0121] According to an embodiment of the present invention, the crystal form is a free crystal form D, and the free crystal form D has substantially the following characteristics: Figure 13-2 The TGA and DSC diagrams are shown below.

[0122] According to an embodiment of the present invention, the crystal form is a free crystal form E, and the X-ray powder diffraction pattern of the free crystal form E has diffraction peaks at the following 2θ angles: 4.67±0.2°, 5.33±0.2°, and 15.23±0.2°.

[0123] According to an embodiment of the present invention, the crystal form is a free crystal form E, and the X-ray powder diffraction pattern of the free crystal form E has diffraction peaks at the following 2θ angles: 4.67±0.2°, 5.33±0.2°, 10.11±0.2°, 10.72±0.2°, 13.96±0.2°, 15.23±0.2°, and 22.40±0.2°.

[0124] According to an embodiment of the present invention, the crystal form is a free crystal form E, and the X-ray powder diffraction pattern of the free crystal form E has diffraction peaks at the following 2θ angles: 4.67±0.2°, 5.33±0.2°, 10.11±0.2°, 10.72±0.2°, 12.10±0.2°, 13.96±0.2°, 15.23±0.2°, 15.67±0.2°, 17.09±0.2°, and 22.40±0.2°.

[0125] According to an embodiment of the present invention, the crystal form is a free crystal form E, which has a weight loss of 7.4 ± 0.1% at 150 °C.

[0126] According to an embodiment of the present invention, the crystal form is a free state crystal form E, which includes one or more endothermic signals selected from 108.4℃±3℃ and 205.0℃±3℃.

[0127] According to an embodiment of the present invention, the crystal form is a free crystal form E, and the free crystal form E has substantially the following characteristics: Figure 14-1 The X-ray powder diffraction pattern shown.

[0128] According to an embodiment of the present invention, the crystal form is a free crystal form E, which has an XRPD analytical data table as shown in Table 11 (see Example 2 for details).

[0129] According to an embodiment of the present invention, the crystal form is a free crystal form E, and the free crystal form E has substantially the following characteristics: Figure 14-2 The TGA and DSC diagrams are shown below.

[0130] According to an embodiment of the present invention, the crystal form is a free crystal form F, and the X-ray powder diffraction pattern of the free crystal form F has diffraction peaks at the following 2θ angles: 4.71±0.2°, 8.11±0.2°, and 13.16±0.2°.

[0131] According to an embodiment of the present invention, the crystal form is a free crystal form F, and the X-ray powder diffraction pattern of the free crystal form F has diffraction peaks at the following 2θ angles: 4.71±0.2°, 8.11±0.2°, 9.92±0.2°, 11.55±0.2°, 13.16±0.2°, 15.91±0.2°, 19.70±0.2°, and 31.01±0.2°.

[0132] According to an embodiment of the present invention, the crystal form is a free crystal form F, which has a weight loss of 3.0 ± 0.1% at 120°C.

[0133] According to an embodiment of the present invention, the crystal form is a free crystal form F, which contains one or more endothermic signals at 65.4℃±3℃ and 168.7℃±3℃.

[0134] According to an embodiment of the present invention, the crystal form is a free crystal form F, and the free crystal form F has substantially the following characteristics: Figure 15-1 The X-ray powder diffraction pattern shown.

[0135] According to an embodiment of the present invention, the crystal form is a free crystal form F, which has an XRPD analytical data table as shown in Table 12 (see Example 2 for details).

[0136] According to an embodiment of the present invention, the crystal form is a free crystal form F, and the free crystal form F has substantially the following characteristics: Figure 15-2 The TGA and DSC diagrams are shown below.

[0137] According to an embodiment of the present invention, the crystal form is a free crystal form G, and the X-ray powder diffraction pattern of the free crystal form G has diffraction peaks at the following 2θ angles: 4.22±0.2°, 7.79±0.2°, and 12.14±0.2°.

[0138] According to an embodiment of the present invention, the crystal form is a free crystal form G, and the X-ray powder diffraction pattern of the free crystal form G has diffraction peaks at the following 2θ angles: 4.22±0.2°, 7.79±0.2°, 8.07±0.2°, 8.76±0.2°, 9.41±0.2°, 12.14±0.2°, 13.19±0.2°, and 16.20±0.2°.

[0139] According to an embodiment of the present invention, the crystal form is a free crystal form G, and the X-ray powder diffraction pattern of the free crystal form G has diffraction peaks at the following 2θ angles: 4.22±0.2°, 7.79±0.2°, 8.07±0.2°, 8.76±0.2°, 9.41±0.2°, 10.96±0.2°, 12.14±0.2°, 13.19±0.2°, 16.20±0.2°, and 20.24±0.2°.

[0140] According to an embodiment of the present invention, the crystal form is a free crystal form G, which has a weight loss of 1.1 ± 0.1% at 100°C.

[0141] According to an embodiment of the present invention, the crystal form is a free crystal form G, and the free crystal form G contains an endothermic signal of 196.1℃±3℃.

[0142] According to an embodiment of the present invention, the crystal form is a free crystal form G, and the free crystal form G has substantially the following characteristics: Figure 16-1 The X-ray powder diffraction pattern shown.

[0143] According to an embodiment of the present invention, the crystal form is a free crystal form G, which has an XRPD analytical data table as shown in Table 13 (see Example 2 for details).

[0144] According to an embodiment of the present invention, the crystal form is a free crystal form G, and the free crystal form G has substantially the following characteristics: Figure 16-2 The TGA and DSC diagrams are shown below.

[0145] In a third aspect, the present invention provides a pharmaceutical composition. According to embodiments of the invention, the pharmaceutical composition comprises a pharmaceutically acceptable acid addition salt of a compound of formula (I) as described in the first aspect or a crystal form as described in the second aspect. The pharmaceutical composition of the present invention can treat or prevent diseases related to FAP expression.

[0146] According to embodiments of the present invention, the pharmaceutical composition further comprises pharmaceutically acceptable excipients.

[0147] In some embodiments, the acid addition salt in the pharmaceutical composition of the present invention can be any crystalline form of the salt, specifically any crystal form, amorphous form, or any combination thereof. In some embodiments, the pharmaceutical composition of the present invention comprises any acid addition salt of the compound shown in formula (I), or any crystal form or amorphous form of the present invention, or any combination of the salt, crystal form, and amorphous form.

[0148] In a fourth aspect of the invention, the invention provides for the use of a pharmaceutically acceptable acid addition salt of a compound of formula (I) as described in the first aspect, a crystal form as described in the second aspect, or a pharmaceutical composition as described in the third aspect in the preparation of one or more pharmaceuticals; said pharmaceuticals are used to treat and / or prevent diseases associated with FAP expression.

[0149] According to an embodiment of the present invention, the related diseases caused by FAP expression are selected from tumors and cancers that express FAP.

[0150] According to embodiments of the present invention, the tumor or cancer expressing FAP is selected from at least one of melanoma, esophageal cancer, breast cancer, bile duct cancer, lung cancer, liver cancer, colorectal cancer, fibrosarcoma, osteosarcoma, pancreatic cancer, ovarian cancer, head and neck cancer, and neuroendocrine tumors.

[0151] According to an embodiment of the present invention, the tumor or cancer expressing FAP is selected from at least one of fibrosarcoma, osteosarcoma, pancreatic cancer, and ovarian cancer.

[0152] In a fifth aspect, the present invention provides for the use of a pharmaceutically acceptable acid addition salt of the compound represented by formula (I) of the first aspect, the crystal form of the compound represented by the second aspect, or the pharmaceutical composition of the compound represented by the third aspect in the inhibition of FAP. The pharmaceutically acceptable acid addition salt, crystal form, or pharmaceutical composition of the compound represented by formula (I) of the present invention can be used to inhibit FAP in vivo and in vitro.

[0153] In a sixth aspect of the invention, the invention proposes the use of a pharmaceutically acceptable acid addition salt of a compound of formula (I) as described in the first aspect, a crystal form as described in the second aspect, or a pharmaceutical composition as described in the third aspect in the prevention and / or treatment of diseases associated with FAP expression.

[0154] According to an embodiment of the present invention, the related diseases caused by FAP expression are selected from tumors and cancers that express FAP.

[0155] According to embodiments of the present invention, the tumor or cancer expressing FAP is selected from at least one of melanoma, esophageal cancer, breast cancer, bile duct cancer, lung cancer, liver cancer, colorectal cancer, fibrosarcoma, osteosarcoma, pancreatic cancer, ovarian cancer, head and neck cancer, and neuroendocrine tumors.

[0156] According to an embodiment of the present invention, the tumor or cancer expressing FAP is selected from at least one of fibrosarcoma, osteosarcoma, pancreatic cancer, and ovarian cancer.

[0157] In a seventh aspect of the invention, the invention provides pharmaceutically acceptable acid addition salts of compounds of formula (I) as described in the first aspect, crystal forms as described in the second aspect, or pharmaceutical compositions as described in the third aspect for expressing diseases associated with FAP.

[0158] According to an embodiment of the present invention, the related diseases caused by FAP expression are selected from tumors and cancers that express FAP.

[0159] According to embodiments of the present invention, the tumor or cancer expressing FAP is selected from at least one of melanoma, esophageal cancer, breast cancer, bile duct cancer, lung cancer, liver cancer, colorectal cancer, fibrosarcoma, osteosarcoma, pancreatic cancer, ovarian cancer, head and neck cancer, and neuroendocrine tumors.

[0160] According to an embodiment of the present invention, the tumor or cancer expressing FAP is selected from at least one of fibrosarcoma, osteosarcoma, pancreatic cancer, and ovarian cancer.

[0161] In this document, “treatment” means the use of a drug or compound to achieve a desired pharmacological and / or physiological effect. This effect may be preventative in terms of complete or partial prevention of a disease or its symptoms, and / or therapeutic in terms of partial or complete cure of a disease and / or adverse effects caused by the disease. As used herein, “treatment” covers diseases in mammals, particularly humans, including: (a) prevention of disease or the onset of a disease in individuals who are susceptible but have not yet been diagnosed with the disease; (b) inhibition of disease, such as blocking disease progression; or (c) relief of disease, such as reducing symptoms associated with the disease. As used herein, “treatment” encompasses any administration of a drug or compound to an individual to treat, cure, relieve, improve, reduce, or inhibit the individual’s disease, including but not limited to administration of a drug containing a compound described herein to an individual in need.

[0162] In an eighth aspect of the invention, a method is provided for inhibiting FAP, or preventing and / or treating diseases related to FAP expression. According to embodiments of the invention, the method comprises administering to a desired subject a pharmaceutically acceptable acid addition salt of a compound of formula (I) as described in the first aspect, a crystalline form as described in the second aspect, or a pharmaceutical composition as described in the third aspect.

[0163] It should be noted that the terms "subject," "individual," "object," and "patient" are used interchangeably herein and refer to an animal, preferably a mammal, being evaluated for treatment and / or being treated. In one embodiment, the mammal is a human. The terms "subject," "individual," "object," and "patient" include, but are not limited to, individuals with cancer, individuals with autoimmune diseases, individuals with pathogen infections, etc. Subjects can be humans, but also include other mammals, particularly mammals that can be used as laboratory models of human diseases, such as mice, rats, etc.

[0164] The effective amount of the acid addition salt, crystal form, or pharmaceutical composition described in this invention can vary depending on the administration method and the severity of the disease to be treated. A preferred effective amount can be determined by those skilled in the art based on various factors (e.g., through clinical trials). These factors include, but are not limited to: pharmacokinetic parameters of the active ingredient, such as bioavailability, metabolism, and half-life; the severity of the disease to be treated, the patient's weight, the patient's immune status, and the route of administration. For example, due to the urgency of the treatment condition, several separate doses may be administered daily, or the dose may be reduced proportionally.

[0165] According to an embodiment of the present invention, the related diseases caused by FAP expression are selected from tumors and cancers that express FAP.

[0166] According to embodiments of the present invention, the tumor or cancer expressing FAP is selected from at least one of melanoma, esophageal cancer, breast cancer, bile duct cancer, lung cancer, liver cancer, colorectal cancer, fibrosarcoma, osteosarcoma, pancreatic cancer, ovarian cancer, head and neck cancer, and neuroendocrine tumors.

[0167] According to an embodiment of the present invention, the tumor or cancer expressing FAP is selected from at least one of fibrosarcoma, osteosarcoma, pancreatic cancer, and ovarian cancer.

[0168] Beneficial effects:

[0169] 1. The preparation of various acid addition salts of the compound shown in formula (I) has significantly improved purity, stability, and physical properties that are more conducive to formulation.

[0170] 2. Further studies were conducted on the preparation, drug metabolism properties, and physicochemical properties of various acid addition salts of the compound shown in formula (I) and their crystal forms. It was found that various salts of the compound shown in formula (I) and their crystal forms have advantages such as suitable drug-like water solubility, good stability, and good pharmacokinetics.

[0171] 3. The crystal form of the present invention has the advantages of suitable drug-like water solubility, good stability, and good pharmacokinetics. Its purity is significantly improved, and its physical properties are more conducive to formulation.

[0172] Definitions and general terms

[0173] Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice the invention. The invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0174] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0175] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0176] Unless otherwise stated, the following definitions will apply in this invention. For the purposes of this invention, chemical elements are defined according to the periodic table, CAS version, and the Handbook of Chemical Physics, 75th Ed., 1994. Additionally, general principles of organic chemistry are found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito, 1999, and "March's Advanced Organic Chemistry," Michael B. Smith and Jerry March, John Wiley & Sons, New York, 2007, all of which are incorporated herein by reference.

[0177] Unless otherwise stated or there is a clear conflict in the context, the articles “a,” “an,” and “described” as used herein are intended to include “at least one” or “one or more.” Therefore, these articles as used herein refer to articles for one or more (i.e., at least one) objects. For example, “a component” refers to one or more components, meaning that more than one component may be considered for use or adoption in the implementation of the described embodiments.

[0178] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0179] In this document, the terms “optionally,” “optionally,” or “optional” generally refer to an event or condition that may, but may not, occur, and the description includes both cases in which the event or condition occurs and cases in which the event or condition does not occur. Unless otherwise specified, wedge-shaped solid lines are used. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid.

[0180] In this document, the term "pharmaceutically acceptable acid addition salt" refers to a salt formed by the compound of formula (I) of this invention with a pharmaceutically acceptable non-toxic acid, including but not limited to various organic and inorganic acid salts described in this invention.

[0181] In this document, the term "acid addition salt of the compound represented by formula (I)" refers to a salt formed by the reaction of the compound represented by formula (I) (free base) with various suitable organic or inorganic acids, including but not limited to the hydrochloride, sulfate, phosphate, fumarate, 1,2-ethanedisulfonate, benzenesulfonate, 2-hydroxyethanesulfonate, ethanesulfonate, etc., described in this invention. The term "acid addition salt of the compound represented by formula (I)" includes the amorphous or crystalline form of the salt, its solvate form (e.g., hydrate form), and its polymorphic form. For example, the hydrochloride salt of the compound represented by formula (I) includes the amorphous form, various crystalline forms, various solvates, various hydrates, and also the polymorphic form of the salt.

[0182] In this document, the term "crystal form" or "crystalline shape" refers to a solid having a highly regular chemical structure, including but not limited to, single-component or multi-component crystals, and / or polymorphs of compounds, solvates, hydrates, inclusion compounds, eutectics, salts, solvates of salts, and hydrates of salts. The crystalline form of a substance can be obtained by many methods known in the art. These methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a confined space, such as in nanopores or capillaries, crystallization on a surface or template; crystallization, for example, on polymers, in the presence of additives such as co-crystallized antimolecules, desolventization, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, grinding, and solvent drop grinding, etc.

[0183] In this paper, the term "amorphous" or "amorphous form" refers to a substance formed when its particles (molecules, atoms, ions) are arranged non-periodically in three-dimensional space, exhibiting a diffuse X-ray powder diffraction pattern without sharp peaks. Amorphous matter is a special physical form of solid matter, and its locally ordered structural features suggest a close connection to crystalline substances. Amorphous forms of matter can be obtained through many methods known in the art. These methods include, but are not limited to, quenching, antisolvent flocculation, ball milling, spray drying, freeze drying, wet granulation, and solid dispersion techniques.

[0184] In this document, the term "solvent" refers to a substance (typically a liquid) that can completely or partially dissolve another substance (typically a solid). Solvents used in the implementation of this invention include, but are not limited to, water, acetic acid, ethyl acetate, acetone, acetonitrile, methanol, toluene, isopropanol, tetrahydrofuran, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methyl ethyl ketone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, xylene, mixtures thereof, etc.

[0185] In this document, the term "antisolvent" refers to a fluid that promotes the precipitation of a product (or product precursor) from a solvent. Antisolvents may include cold gases, fluids that promote precipitation through chemical reactions, or fluids that reduce the solubility of a product in a solvent; they may be the same liquid as the solvent but at a different temperature, or they may be a different liquid from the solvent.

[0186] In this document, the term "solvent" refers to a compound having a solvent on its surface, in its lattice, or both on its surface and in its lattice. The solvent can be water, acetic acid, ethyl acetate, acetone, acetonitrile, methanol, toluene, isopropanol, tetrahydrofuran, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, xylene, and mixtures thereof, etc. A specific example of a solvate is a hydrate, wherein the solvent on its surface, in its lattice, or both on its surface and in its lattice is water. A hydrate may or may not have other solvents besides water on its surface, in its lattice, or both on its surface and in its lattice.

[0187] Crystalline or amorphous forms can be identified using a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.

[0188] X-ray powder diffraction (XRPD) can detect changes in crystal form, crystallinity, and crystal structure, and is a commonly used method for identifying crystal forms. The peak positions of XRPD spectra depend primarily on the crystal structure and are relatively insensitive to experimental details, while their relative peak heights depend on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystal form of the present invention is characterized by an XRPD pattern with certain peak positions, which is essentially as shown in the XRPD patterns provided in the accompanying drawings. Furthermore, the measurement of 2θ in the XRPD spectra can be subject to experimental error; the measurement of 2θ in XRPD spectra may vary slightly between different instruments and different samples, therefore the value of 2θ cannot be considered absolute. Based on the instrument used in this experiment, there is an error tolerance of ±0.2° for the diffraction peaks.

[0189] Differential scanning calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference (commonly α-Al₂O₃) as a function of temperature under programmed control by continuously heating or cooling. The height of the endothermic peak (or endothermic signal) in the DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystal form described in this invention is characterized by a DSC plot with characteristic peak positions, which is essentially as shown in the DSC plot provided in the accompanying drawings. However, DSC spectra can be subject to experimental error; the peak positions and peak values ​​of DSC spectra may vary slightly between different instruments and different samples. Therefore, the peak positions or peak values ​​of the endothermic peaks in the DSC should not be considered absolute. Depending on the instrument used in this experiment, there is an error tolerance of ±3° for the endothermic peaks.

[0190] Thermogravimetric analysis (TGA) is a technique used under programmed control to determine the change in mass of a substance with temperature. It is suitable for examining the loss of solvent in crystals or the sublimation and decomposition of samples, and can infer the presence of water of crystallization or crystallization solvent in the crystal. The mass change shown by the TGA curve depends on many factors, including sample preparation and instrumentation; the mass change detected by TGA varies slightly between different instruments and different samples. Based on the instrument used in this experiment, there is an error tolerance of ±0.1% for the mass change.

[0191] In the context of this invention, the 2θ values ​​in X-ray powder diffraction patterns are all in degrees (°).

[0192] In this document, the term "substantially 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 99% of the peaks in an X-ray powder diffraction pattern, DSC pattern, Raman spectrum, or infrared spectrum are shown in its figure.

[0193] When referring to a spectrum or / and the data appearing in the graph, a "peak" refers to a feature that a person skilled in the art can identify and that is not attributable to background noise.

[0194] In the context of this invention, when the terms "about" or "approximately" are used, whether or not they are used, it means within 10% of a given value or range, appropriately within 5%, and particularly within 1%. Alternatively, for those skilled in the art, the term "about" or "approximately" means within an acceptable standard error range of the average. Whenever a number with a value of N is disclosed, any number having a value within N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, or N+ / -10% is explicitly disclosed, where "+ / -" means addition or subtraction.

[0195] Unless otherwise indicated, the structural formulas described in this invention include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compounds of this invention, or its enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers), is within the scope of this invention.

[0196] Depending on the specific condition being treated, these agents can be formulated into liquid or solid dosage forms and administered systemically or locally. As is known to those skilled in the art, the plurality of agents can be delivered in a timed or sustained slow-release manner. Various formulation and administration techniques can be found in Remington: Pharmaceutical Sciences and Practice (20th Edition), Lippincott, Williams & Wilkins (2000). Multiple suitable routes may include: inhalation spray, transdermal, or transmucosal administration; parenteral delivery, including intramuscular, subcutaneous, and intramedullary injection; and intrathecal, direct intraventricular, intravenous, intra-articular, intrasternal, intrasynovial, intrahepatic, intralesional, intracranial, intraperitoneal, intranasal, or intraocular injections or other delivery modalities.

[0197] For injection, the various reagents disclosed herein can be prepared and diluted in various aqueous solutions, such as physiologically compatible buffers like Hank's solution, Ringer's solution, or physiological saline buffer. For such transmucosal administration, a permeabilizing agent suitable for the barrier to be penetrated is used in the formulation, such permeabilizing agents are generally known in the art.

[0198] The pharmaceutical compositions applicable to this disclosure include multiple compositions containing an effective amount of an active ingredient to achieve their intended purpose. The determination of the multiple effective amounts is entirely within the competence of those skilled in the art, particularly based on the detailed disclosure provided in this specification. Generally, the multiple compounds according to the invention are effective over a wide dosage range. For example, in the treatment of adults, multiple doses of 0.01 to 1000 mg, 0.5 to 100 mg, 1 to 50 mg daily, and 5 to 40 mg daily are examples of possible doses. A non-limiting dose is 10 to 30 mg daily. The exact dose will depend on the route of administration, the form of administration of the compound, the subject to be treated, the weight of the subject to be treated, the bioavailability, adsorption, distribution, metabolism, and excretion (ADME) toxicity of the compound(s), and the preferences and experience of the attending physician.

[0199] In addition to the plurality of active ingredients, the plurality of pharmaceutical compositions may also contain a plurality of suitable pharmaceutically acceptable carriers, the carriers including a plurality of excipients and adjuvants that facilitate the processing of the plurality of active compounds into a plurality of pharmaceutically acceptable formulations.

[0200] In many embodiments of the methods disclosed herein, the object treated by the methods of this disclosure is ideally a human object, although it should be understood that the various methods described herein are effective for all vertebrate species, which are intended to be included in the term "object". Thus, an "object" can include a human object for various medical purposes, such as: for treating an existing condition or disease, or for a preventative treatment to prevent the onset of a condition or disease, or an animal (non-human) object for medical, veterinary, or developmental purposes. Suitable animal objects include: mammals, including but not limited to: primates, such as humans, monkeys, apes, etc.; bovids, such as cattle, oxen, etc.; sheep, such as sheep, etc.; caprines, such as goats, etc.; hogs, such as pigs, hogs, etc.; equines, such as horses, donkeys, zebras, etc.; felines, including wildcats and domestic cats; canines, including dogs; rabbits, including rabbits, hares, etc.; and rodents, including mice, rats, etc. An animal may be a transgenic animal. In some embodiments, the object is a human being, including but not limited to: fetuses, newborns, infants, adolescents, and adult objects. Furthermore, "object" can include a patient who has or is suspected of having a condition or disease. Therefore, the terms "object" and "patient" are used interchangeably herein. In some embodiments, the object is a human being. In other embodiments, the object is a non-human being.

[0201] As used in this specification, the term "treatment" may include reversing, alleviating, or inhibiting the development of the disease, preventing or reducing the disease or the condition to which the term applies, or one or more symptoms or manifestations of the disease or condition.

[0202] "Prevention" means not causing a disease, condition, symptom, or manifestation or worsening of its severity. Therefore, the presently disclosed compounds can be administered preventively to prevent or reduce the occurrence or recurrence of the disease or condition.

[0203] As used herein, the term "treatment" for any disease or condition refers to anything that can slow, interrupt, prevent, control, or stop the progression of the disease or condition, but does not necessarily mean the complete disappearance of all symptoms of the disease or condition. It also includes preventative treatment of said symptoms, particularly in patients susceptible to such diseases or disorders. In some embodiments, "treatment" refers to improving the disease or condition (i.e., slowing, preventing, or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" refers to alleviating or improving at least one bodily parameter, including bodily parameters that may not be perceptible to the patient. In still other embodiments, "treatment" refers to regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters), or both. In still other embodiments, "treatment" refers to preventing or delaying the onset, occurrence, or worsening of the disease or condition.

[0204] As used herein, the term "therapeutic effective amount" or "therapeutic effective dose" refers to the amount of the compound of the present invention capable of evoking a biological or medical response in an individual (e.g., reducing or inhibiting enzyme or protein activity, or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease, etc.). In a non-limiting embodiment, the term "therapeutic effective amount" means an amount that, when administered to an individual, is effective in: (1) at least partially alleviating, inhibiting, preventing, and / or improving (i) symptoms or diseases mediated by FAP, or (ii) associated with FAP activity, or (iii) characterized by abnormal FAP activity; or (2) reducing or inhibiting FAP activity; or (3) reducing or inhibiting FAP expression. In another embodiment, the term "therapeutic effective amount" means an effective amount of the compound of the present invention that, when administered to cells, or organs, or non-cellular biological substances, or mediators, at least partially reduces or inhibits FAP activity; or at least partially reduces or inhibits FAP expression.

[0205] As used in this invention, the terms "compound" and "administered" should be understood as referring to the provision of the compound of this invention or a prodrug of the compound of this invention to an individual in need of it. It should be recognized that those skilled in the art can treat diseases currently expressing FAP, such as fibrosarcoma, osteosarcoma, pancreatic cancer, ovarian cancer, etc., by using effective amounts of the compounds of this invention.

[0206] Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. Attached Figure Description

[0207] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which:

[0208] Figure 1-1 The nuclear magnetic resonance spectrum of NYM030 in Example 1 of this invention;

[0209] Figure 1-2 The LC-MS spectrum of NYM030 in Preparation Example 1 of this invention;

[0210] Figure 1-3 The XRPD image of NYM030 in Example 1 of this invention;

[0211] Figure 1-4 The HPLC chromatogram of NYM030 in Preparation Example 1 of this invention is shown below. Figure 16-3 ;

[0212] Figure 1-5 TGA and DSC images of NYM030 in Example 1 of this invention were prepared.

[0213] Figure 2-1 This is the XRPD image of p-toluenesulfonate crystal form A in Example 1 of the present invention;

[0214] Figure 2-2 The TGA and DSC images are of p-toluenesulfonate crystal form A in Example 1 of this invention;

[0215] Figure 2-3 For example, in Example 1 of this invention, p-toluenesulfonate crystal form A... 1 H NMR spectrum;

[0216] Figure 3-1 This is the XRPD image of p-toluenesulfonate crystal form B in Example 1 of the present invention;

[0217] Figure 3-2 The TGA and DSC images are of p-toluenesulfonate crystal form B in Example 1 of this invention;

[0218] Figure 3-3 For example, in Example 1 of this invention, p-toluenesulfonate crystal form B... 1 H NMR spectrum;

[0219] Figure 4-1 This is the XRPD image of phosphate crystal form A in Example 1 of the present invention;

[0220] Figure 4-2 The TGA and DSC images are of phosphate crystal form A in Example 1 of this invention;

[0221] Figure 4-3 For phosphate crystal form A in Example 1 of the present invention 1 H NMR spectrum;

[0222] Figure 5-1 This is the XRPD image of phosphate crystal form B in Example 1 of the present invention;

[0223] Figure 5-2 The TGA and DSC images are of phosphate crystal form B in Example 1 of this invention;

[0224] Figure 5-3 For phosphate crystal form B in Example 1 of this invention 1 H NMR spectrum;

[0225] Figure 6-1 This is the XRPD image of phosphate crystal form C in Example 1 of the present invention;

[0226] Figure 6-2 The TGA and DSC images are of phosphate crystal form C in Example 1 of this invention;

[0227] Figure 6-3 For the phosphate crystal form C in Example 1 of this invention 1 H NMR spectrum;

[0228] Figure 7-1 This is the XRPD image of sulfate crystal form A in Example 1 of the present invention;

[0229] Figure 7-2 The TGA and DSC images are of sulfate crystal form A in Example 1 of this invention;

[0230] Figure 7-3 For sulfate crystal form A in Example 1 of this invention 1 H NMR spectrum;

[0231] Figure 8-1 This is the XRPD image of sulfate crystal form B in Example 1 of the present invention;

[0232] Figure 8-2 The TGA and DSC images are of sulfate crystal form B in Example 1 of this invention;

[0233] Figure 8-3 For sulfate crystal form B in Example 1 of this invention 1 H NMR spectrum;

[0234] Figure 8-4 This is the LC-MS image of sulfate crystal form B in Example 1 of the present invention;

[0235] Figure 9-1 This is the XRPD image of hydrobromide crystal form A in Example 1 of the present invention;

[0236] Figure 9-2 The TGA and DSC images are of hydrobromide crystal form A in Example 1 of this invention;

[0237] Figure 9-3 For example, in Embodiment 1 of the present invention, the hydrobromide crystal form A is... 1 H NMR spectrum;

[0238] Figure 9-4 This is the LC-MS image of hydrobromide crystal form A in Example 1 of the present invention;

[0239] Figure 10-1 This is the XRPD image of free crystal form A in Example 2 of the present invention;

[0240] Figure 10-2 The TGA and DSC images are of free crystal form A in Example 2 of this invention;

[0241] Figure 10-3 For the free crystal form A in Example 2 of this invention 1 H NMR spectrum;

[0242] Figure 11 This is the XRPD image of free crystal form B in Example 2 of the present invention;

[0243] Figure 12-1 This is the XRPD image of the free crystal form C in Example 2 of the present invention;

[0244] Figure 12-2 The TGA and DSC images are of the free crystal form C in Example 2 of this invention;

[0245] Figure 12-3 The free crystal form C in Example 2 of this invention 1 H NMR spectrum;

[0246] Figure 13-1 This is the XRPD image of the free crystal form D in Example 2 of the present invention;

[0247] Figure 13-2 The TGA and DSC diagrams are shown for the free crystal form D in Example 2 of this invention.

[0248] Figure 13-3 The free crystal form D in Example 2 of this invention 1 H NMR spectrum;

[0249] Figure 13-4 This is a PLM diagram of the free crystal form D in Example 2 of the present invention;

[0250] Figure 13-5 This is the DVS curve of the free crystal form D in Example 2 of the present invention;

[0251] Figure 13-6 These are XRPD images of the free crystal form D before and after the VS test in Example 2 of this invention;

[0252] Figure 14-1 This is the XRPD image of the free crystal form E in Example 2 of the present invention;

[0253] Figure 14-2 The TGA and DSC images are of the free crystal form E in Example 2 of this invention;

[0254] Figure 14-3 For the free crystal form E in Example 2 of this invention 1 H NMR spectrum;

[0255] Figure 15-1 This is the XRPD image of the free crystal form F in Example 2 of the present invention;

[0256] Figure 15-2 The TGA and DSC images are of the free crystal form F in Example 2 of this invention;

[0257] Figure 15-3 For the free crystal form F in Example 2 of the present invention 1 H NMR spectrum;

[0258] Figure 16-1 This is the XRPD image of the free crystal form G in Example 2 of the present invention;

[0259] Figure 16-2 The TGA and DSC images are of the free crystal form G in Example 2 of this invention;

[0260] Figure 16-3 For the free crystal form G in Example 2 of this invention 1 H NMR spectrum;

[0261] Figure 17 The cell viability results of NYM030 in vitro antitumor activity in Test Example 2 of this invention;

[0262] Figure 18 This is a trend graph of tumor volume in each group in test example 3 of the present invention;

[0263] Figure 19 This is a graph showing the trend of body weight change in each group of mice in Test Example 3 of this invention;

[0264] Figure 20 This is a test example 4 of the present invention showing the changes in tumor volume in SJSA-1 tumor-bearing mice;

[0265] Figure 21 The following is a description of the weight changes in SJSA-1 tumor-bearing mice in Test Example 4 of this invention;

[0266] Figure 22 This shows the weight change of ICR mice in Test Example 5 of this invention. Detailed Implementation

[0267] The embodiments of the present invention are described in detail below. These embodiments are exemplary and are only used to explain the present invention, and should not be construed as limiting the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the art or according to the product instructions. Reagents or instruments used, unless otherwise specified, are all commercially available conventional products.

[0268] General Experiment

[0269] 1. Instrument Information and Methods

[0270] Dynamic moisture adsorption-desorption analysis (DVS)

[0271] Dynamic moisture adsorption-desorption analysis was performed using DVS Intrinsic (SMS, UK). The test employed a gradient mode with humidity variations of 50%-95%-0%-50%. Within the 0% to 90% range, each gradient represented a 10% change in humidity. The gradient endpoint was determined using the dm / dt method, with a dm / dt value less than 0.002% maintained for 10 minutes as the endpoint, or each gradient lasting a maximum of 180 minutes. After the test, XRPD analysis was performed on the samples to confirm whether the solid form had changed.

[0272] X-ray powder diffraction (XRPD)

[0273] The solid samples obtained in the experiment were analyzed using a Bruker D8 Advance (Bruker, GER) or Panalytical EMPYREAN (PANalytical, UK) X-ray powder diffractometer. The 2θ scanning angle ranged from 3° to 45°, the test method was Cu target Kα1 X-ray, the voltage was 40 kV, the current was 40 mA, and the sample disk was a zero-background sample disk.

[0274] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)

[0275] Thermogravimetric analysis (TGA): The thermogravimetric analyzer was a TA Discovery 550 (TA, US). 2-5 mg of sample was placed in a pre-equilibrated open aluminum sample pan and automatically weighed inside the TGA furnace. The sample was heated to the final temperature at a rate of 10 °C / min, with nitrogen purging at 60 mL / min at the sample location and 40 mL / min at the balance location.

[0276] Differential Scanning Calorimetry (DSC): The differential scanning calorimeter was a TA Discovery 250 (TA, US). 1-2 mg of sample was accurately weighed and placed in a perforated DSC Tzero sample pan. The sample was heated to the final temperature at a rate of 10 °C / min, with nitrogen purging at a rate of 50 mL / min.

[0277] Polarizing microscopy analysis (PLM)

[0278] The polarizing microscope used was a Nikon Ci-POL (Nikon, JP). A small amount of sample was placed on a glass slide, and a suitable lens was selected to observe the sample morphology.

[0279] Nuclear magnetic resonance analysis (NMR) 1 H NMR method

[0280] Several milligrams of solid sample were dissolved in dimethyl sulfoxide-d6 solvent and analyzed by nuclear magnetic resonance on a Bruker AVANCE NEO 400 (Bruker, GER).

[0281] Preparation Example 1: Preparation method of compound (I)

[0282] 1. Preparation process of compound (I) (i.e., compound NYM030 molecule)

[0283]

[0284] The molecular structure of NYM030 (its NMR spectrum is shown in [reference]). Figure 1-1 LC-MS spectra are shown below. Figure 1-2 )

[0285] Synthesis route:

[0286] Step 1:

[0287]

[0288] Compound (1) (6.00 g) was dissolved in 50.0 mL of THF solvent, and NMM (3.23 g) and methanesulfonyl methanesulfonate (5.56 g) were added. The mixture was stirred at 20 °C for 2 hours. The reaction solution was diluted with H2O (50.0 mL) and extracted with ethyl acetate. The extracted organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum evaporation to obtain compound (2) (7.50 g).

[0289] Step Two:

[0290]

[0291] The mixture of compound (2) (7.50 g) and MeNH2 (52.2 g, 504 mmol, 50.0 mL, purity 30.0%) was stirred in a sealed tube at 70 °C for 12 hours. The reaction mixture was then quenched with 1.00 M HCl and the pH was adjusted to 7. The mixture was then filtered to obtain a colorless oily compound (3) (6.2 g).

[0292] Step 3:

[0293]

[0294] Compound (4-1) (10.0 g) was dissolved in 100 mL of MeCN solvent, and Cs₂CO₃ (19.4 g) and BnBr (6.79 g) were added to this solution. The reaction mixture was stirred at 20 °C for 12 hours, then diluted with 150 mL of water and extracted with ethyl acetate. The extracted organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum evaporation to obtain the residue. The residue was separated and purified by column chromatography to obtain compound (4) (12.0 g).

[0295] Step Four:

[0296]

[0297] Compound (3) (5.60 g) and compound (4) (7.45 g) were dissolved in 50.0 mL of dioxane, and Pd2(dba)3 (1.99 g), Xphos (1.04 g), and Cs2CO3 (14.2 g) were added to this solution. The mixture was stirred at 100 °C for 12 hours. The reaction product was diluted with 100 mL of water and extracted with ethyl acetate. The extracted organic layer was washed with 100 mL of brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum evaporation to obtain the residue. The residue was purified by prep-HPLC (TFA reagent) to obtain compound (5) (4.24 g).

[0298] Step 5:

[0299]

[0300] Compound (5) (7.00 g) was dissolved in 70.0 mL of THF solvent, and Pd / C (700 mg, 10% purity) was added to this solution under N2 purging. The resulting suspension was degassed under vacuum and purged several times with hydrogen. The mixture was stirred at 20 °C for 12 hours under H2 purging, filtered, and the solvent was removed from the filtrate under vacuum to obtain the residue. The residue was purified by prep-HPLC to obtain compound (6) (4.70 g).

[0301] Step Six:

[0302]

[0303] Compound (6) (650 mg) and compound (7) (1.03 g) were dissolved in 5.00 mL of LMF solvent, and HATU (864 mg) and DIEA (390 mg) were added to the solution. The mixture was stirred at 20 °C for 1 hour, and then the solvent was removed under vacuum. The mixture was purified by prep-HPLC (TFA reagent) to obtain compound (8) (624 mg).

[0304] Step Seven:

[0305]

[0306] Compound (8) (600 mg) was dissolved in 6.00 mL of MeCN solvent, and TsOH·H2O (390 mg) was added to this solution. The mixture was stirred at 20 °C for 12 hours, and the solvent was removed under vacuum to obtain compound (9) (712 mg).

[0307] Step 8:

[0308]

[0309] Compound (10) (500 mg) was dissolved in 5 mL of THF solvent; DIEA (247 mg) and compound (11) (308 mg) were added to this solution, and the mixture was stirred at 25 °C for 12 hours to obtain a reaction mixture. After removing the solvent under vacuum, the obtained product was ground in 10 mL of MTBE solvent to obtain solid compound (12) (512 mg).

[0310] Step Nine:

[0311]

[0312] Compound (9) (350 mg) and compound (12) (291 mg, 521 μmol, 1.00 eq) obtained in the above steps were dissolved in 3.00 mL of LDM solvent, and triethylamine (TEA) (158 mg) was added to the solution. The mixture was stirred at 20 °C for 2 hours. The mixture was purified by prep-HPLC (TFA reagent) to give compound (NYM030) (60.0 mg, purity 99.6%), and the XRPD chromatogram is shown in [Figure not provided]. Figure 1-3 The HPLC chromatogram of NYM030 is shown below. Figure 1-4 See TGA and DSC charts. Figure 1-5 .

[0313] Example 1: Preparation and characterization of pharmaceutically acceptable acid addition salt of compound (I)

[0314] 1. p-Toluenesulfonate crystal form A / B

[0315] 1.1 Weigh approximately 46.0 mg of the compound of formula (I) prepared in Preparation Example 1 and 9.8 mg of p-toluenesulfonic acid, add them to 1.0 mL of THF / water (v / v, 4 / 1), stir at room temperature for 2 days, and cool at -4 °C to obtain p-toluenesulfonate crystal form A.

[0316] The XRPD diagram of p-toluenesulfonate crystal form A is shown below. Figure 2-1 As shown in Table 1, the XRPD data is shown in Table 1, and the TGA and DSC charts are shown in Table 2. Figure 2-2 As shown, 1 H-NMR was obtained in DMSO-d6 as follows Figure 2-3 As shown. TGA results indicate that the sample loses 11.4% of its weight when heated to 150℃, and may decompose after 230℃; DSC results show endothermic signals at 102.1℃ and 138℃ (peak temperatures). Toluenesulfonate crystal form A transforms into an amorphous form upon heating to 125℃.

[0317] The NMR integration results showed characteristic peaks of the p-toluenesulfonic acid ligand at 2.28 ppm, 7.10 ppm, and 7.47 ppm. Based on the integration results, the molar ratio of the compound to p-toluenesulfonic acid was calculated to be 1:1.

[0318] Table 1: XRPD analysis data for p-toluenesulfonate crystal form A

[0319] Angle [°2Th.] Rel.Intensity[%] 5.76 100.0 11.61 59.6 11.98 30.7 17.34 23.7 21.23 21.3 20.71 20.8 26.32 20.4 24.87 18.7 20.30 17.9 8.17 17.6

[0320] 1.2 Weigh approximately 45.8 mg of the compound of formula (I) prepared in Preparation Example 1 and 9.8 mg of p-toluenesulfonic acid, respectively, add them to 1.0 mL of THF / water (v / v, 4 / 1), suspend at room temperature for 2 days, and cool at -15 °C to obtain p-toluenesulfonate crystal form B.

[0321] The XRPD diagram of p-toluenesulfonate crystal form B is shown below. Figure 3-1 As shown in Table 2, the XRPD data is shown in Table 2, and the TGA and DSC charts are shown in Table 3. Figure 3-2 As shown, 1 H-NMR was obtained in DMSO-d6 as follows Figure 3-3 As shown. TGA results showed a 7.9% weight loss when the sample was heated to 160℃; DSC results showed endothermic signals at 89.3℃ and 130.4℃ (peak temperatures). The remaining solid of p-toluenesulfonate B after shaking in water for 2 hours did not undergo a crystal transformation.

[0322] The NMR integration results showed characteristic peaks of the p-toluenesulfonic acid ligand at 2.28 ppm, 7.10 ppm, and 7.47 ppm. Based on the integration results, the molar ratio of the compound to p-toluenesulfonic acid was calculated to be 1:1.

[0323] Table 2: XRPD analysis data of p-toluenesulfonate crystal form B

[0324] Angle [°2Th.] Rel.Intensity[%] 13.48 100.0 6.71 48.8 20.26 44.2 11.65 30.6 8.60 25.5 24.38 23.7 23.04 22.4 20.92 22.1 21.99 19.8 17.67 18.2

[0325] 2. Phosphate crystal forms A / B / C

[0326] 2.1 Weigh approximately 46.1 mg of the compound of formula (I) prepared in Preparation Example 1 and 50 μL of phosphoric acid (1M phosphoric acid solution diluted with ethanol), add it to 1 mL of ethylene glycol methyl ether / MTBE (v / v, 1 / 1), stir at room temperature for 3 days, centrifuge the suspension, and vacuum dry the solid to obtain phosphate crystal form A.

[0327] The XRPD diagram of phosphate crystal form A is shown below. Figure 4-1 As shown in Table 3, the XRPD data is shown in Table 3, and the TGA and DSC charts are shown in Table 4. Figure 4-2 As shown, 1 H-NMR was obtained in DMSO-d6 as follows Figure 4-3 As shown. TGA results show that the sample lost 13.5% weight when heated to 180℃; DSC results show that the sample had endothermic signals at 70.6℃, 126.8℃, 191.4℃, 208.2℃ and 229.2℃ (peak temperature).

[0328] Table 3: XRPD analysis data of phosphate crystal form A

[0329] Angle [°2Th.] Rel.Intensity[%] 3.33 100.0 3.97 99.0 6.19 96.6 5.18 84.1 9.16 74.3 23.52 71.0 18.59 67.2 15.67 59.2 11.92 51.6 12.87 51.1

[0330] 2.2 Weigh approximately 46.0 mg of the compound of formula (I) prepared in Preparation Example 1 and 50 μL of phosphoric acid (1M phosphoric acid solution diluted with ethanol), add it to 1 mL of ethylene glycol methyl ether / MTBE (v / v, 1 / 1), stir at room temperature for 2 days, centrifuge the suspension, and vacuum dry the solid to obtain phosphate crystal form B.

[0331] The XRPD diagram of phosphate crystal form B is shown below. Figure 5-1 As shown, the TGA chart and DSC chart are as follows: Figure 5-2 As shown, 1 H-NMR was obtained in DMSO-d6 as follows Figure 5-3 As shown. TGA results show that the sample lost 3.3% of its weight when heated to 120℃; DSC results show that the sample had endothermic signals at 56.2℃ and 151.9℃ (peak temperature).

[0332] Ion chromatography results showed that the phosphate ion content of the sample was 9.22%, and the molar ratio of free phosphate ions to phosphate ions was calculated to be approximately 1:1. Therefore, phosphate crystal form B is a solid containing adsorbed solvent.

[0333] 2.3 Weigh approximately 91.8 mg of the compound of formula (I) prepared in Preparation Example 1 and 300 μL of phosphoric acid (1M phosphoric acid solution diluted with ethanol), add it to 2 mL of ethylene glycol methyl ether / MTBE (v / v, 1 / 1), stir at room temperature for 2 days, centrifuge the suspension, and vacuum dry the solid to obtain phosphate crystal form C.

[0334] The XRPD diagram of phosphate crystal form C is shown below. Figure 6-1 As shown, the TGA chart and DSC chart are as follows: Figure 6-2 As shown, 1 H-NMR was obtained in DMSO-d6 as follows Figure 6-3 As shown in the figure. TGA results show that the sample lost 9.0% of its weight when heated to 150℃; DSC results show that the sample had endothermic signals at 59.8℃ and 182.6℃ (peak temperature).

[0335] Ion chromatography results showed that the mass percentage of phosphate ions in the sample was 19.8%, and the molar ratio of free phosphate ions to phosphate ions was calculated to be approximately 1:2.7 based on the ion chromatography results.

[0336] 3. Sulfate crystal form A / B

[0337] 3.1 Weigh approximately 45.5 mg of the compound of formula (I) prepared in Preparation Example 1 and 50 μL of sulfuric acid aqueous solution, add them to 1.0 mL of acetone and stir at room temperature for 2 days. Centrifuge the suspension and dry the solid under vacuum to obtain sulfate crystal form A.

[0338] The XRPD diagram of sulfate crystal form A is shown below. Figure 7-1 As shown in Table 4, the XRPD data is shown in Table 4, and the TGA and DSC charts are shown in Table 4. Figure 7-2 As shown, 1 H-NMR was obtained in DMSO-d6 as follows Figure 7-3 As shown in the figure. TGA results show that the sample lost 7.7% of its weight when heated to 120℃; DSC results show that the sample had endothermic signals at 68.2℃ and 207.3℃ (peak temperature).

[0339] Ion chromatography results showed that sulfate ions accounted for 6.37% of the total mass, and the calculated ratio of the compound to sulfate ions was 1:0.7.

[0340] Table 4: XRPD analysis data of sulfate crystal form A

[0341] Angle [°2Th.] Rel.Intensity[%] 20.78 100.0 9.30 85.5 10.75 83.4 13.20 71.0 13.61 71.0 14.74 67.2 8.15 66.3 11.69 66.0 29.76 57.9 29.20 56.0

[0342] 3.2 Weigh approximately 91.7 mg of the compound of formula (I) prepared in Preparation Example 1 and 300 μL of sulfuric acid aqueous solution, add them to 2.0 mL of acetone and stir at room temperature for 2 days. Centrifuge the suspension and dry the solid under vacuum to obtain sulfate crystal form B.

[0343] The XRPD diagram of sulfate crystal form B is shown below. Figure 8-1 As shown in Table 5, the XRPD data is shown in Table 5, and the TGA and DSC charts are shown in Table 6. Figure 8-2 As shown, 1 H-NMR was obtained in DMSO-d6 as follows Figure 8-3 As shown, the LC-MS graph is as follows. Figure 8-4 As shown. TGA results showed a 6.1% weight loss when the sample was heated to 120℃; DSC results showed endothermic signals at 76.5℃ and 142.2℃ (peak temperature). The remaining solid of sulfate crystal form B did not undergo a crystal form transformation after oscillation in water for 2 hours.

[0344] Ion chromatography results showed that the mass percentage of sulfate ions in the sample was 17.6%, and the ratio of free sulfate ions to sulfate ions was calculated to be approximately 1:2.2.

[0345] Table 5: XRPD analysis data of sulfate crystal form B

[0346] Angle [°2Th.] Rel.Intensity[%] 11.48 100.0 20.58 99.3 17.48 76.8 15.75 73.3 16.68 73.3 24.57 69.9 28.96 69.9 7.74 69.4 13.20 69.4 7.11 68.2

[0347] 4. Hydrobromide crystal form A

[0348] Approximately 46.0 mg of the compound of formula (I) prepared in Preparation Example 1 and 150 μL of hydrobromic acid (1M hydrobromic acid solution diluted with ethanol) were weighed and stirred in 1.0 mL of acetone at room temperature for 2 days. The suspension was centrifuged and the solid was dried under vacuum to obtain hydrobromide crystal form A.

[0349] The XRPD diagram of hydrobromide crystal form A is shown below. Figure 9-1 As shown in Table 6, the XRPD data is shown in Table 6, and the TGA and DSC graphs are shown in Table 6. Figure 9-2 As shown, 1 H-NMR was obtained in DMSO-d6 as follows Figure 9-3 As shown, the LC-MS graph is as follows. Figure 9-4 As shown. TGA results showed a 9.0% weight loss when the sample was heated to 150℃; DSC results showed an endothermic signal at 66.8℃ (peak temperature). Ion chromatography results showed that the bromide ion content of the sample was 16.5%, and the ratio of free to bromide ions calculated from the ion chromatography results was approximately 1:2.5.

[0350] Table 6: XRPD analysis data of hydrobromide crystal form A

[0351] Angle [°2Th.] Rel.Intensity[%] 3.89 100.0 4.23 97.1 8.16 75.8 24.60 58.3 16.38 56.1 17.88 54.5 19.66 54.5 21.29 54.5 31.79 28.2

[0352] Example 2: Preparation and characterization of the free crystal form of compound (I)

[0353] 1. Free-state crystal form A

[0354] Weigh approximately 100.2 mg of the compound of formula (I) prepared in Preparation Example 1, add 1 mL of tetrahydrofuran / water (v / v, 2 / 1) solvent and stir at room temperature. After the solid precipitates, add 3 mL of tetrahydrofuran / water (v / v, 2 / 1) solvent and stir at room temperature for 1 day. After centrifuging the suspension, dry the solid under vacuum at room temperature to obtain free crystal form A.

[0355] The XRPD diagram of free crystal form A is shown below. Figure 10-1 As shown in Table 7, the XRPD data, TGA plot, and DSC plot are shown in Table 7. Figure 10-2 As shown, 1 H-NMR was obtained in DMSO-d6 as follows Figure 10-3 As shown in the figure. TGA results show that the sample lost 0.6% of its weight when heated to 100℃; DSC results show that the sample had an endothermic signal at 204.3℃ (peak temperature).

[0356] Table 7: XRPD analytical data of free crystal form A

[0357] Angle(°2Th) Rel.Intensity(%) 5.39 100.0 12.10 48.4 4.67 36.5 16.08 22.4 11.18 21.6 15.56 21.6 17.32 21.2 20.80 16.1 12.87 15.3 14.23 14.5

[0358] 2. Free-state crystal form B

[0359] Weigh approximately 45.8 mg of the compound of formula (I) prepared in Preparation Example 1, add 2 mL of acetone and suspend at a low temperature of 10°C for 7 days. After centrifugation of the suspension, free crystal form B is obtained.

[0360] The XRPD diagram of free crystal form B is shown below. Figure 11 As shown in Table 8, the XRPD data is as follows.

[0361] Table 8: XRPD analytical data of free crystal form B

[0362] Angle(°2Th) Rel.Intensity(%) 12.47 100.0 13.73 72.5 16.84 51.6 9.16 51.4 16.08 40.8 16.47 40.0 20.61 37.9 7.59 35.5 4.38 31.0 8.27 28.2

[0363] 3. Free crystal form C

[0364] Weigh approximately 70.0 mg of the compound of formula (I) prepared in Preparation Example 1, add 3.0 mL of dimethylformamide / water (v / v, 1 / 2) solvent, stir at 10 °C for 3 days, centrifuge the suspension, and then vacuum dry the solid at room temperature for 3 days to obtain free crystalline form C.

[0365] The XRPD diagram of the free crystal form C is shown below. Figure 12-1 As shown in Table 9, the XRPD data, TGA chart, and DSC chart are shown in Table 9. Figure 12-2 As shown, 1 H-NMR was obtained in DMSO-d6 as follows Figure 12-3 As shown in the figure. TGA results show that the sample lost 9.1% of its weight when heated to 150℃; DSC results show that the sample has a wide endothermic signal between 25℃ and 120℃.

[0366] Table 9: XRPD analytical data of free crystalline C

[0367] Angle(°2Th) Rel.Intensity(%) 22.69 100.0 24.11 89.5 15.61 84.5 18.57 81.7 24.55 78.9 26.69 76.5 14.82 73.7 18.00 72.6 11.05 71.9 4.98 69.8

[0368] 4. Free state crystal form D

[0369] Weigh approximately 200.1 mg of the compound of formula (I) prepared in Preparation Example 1, add 6.0 mL of acetone solvent, stir at 10 °C for 3 days, centrifuge the suspension, and then vacuum dry the solid at room temperature for 3 days to obtain free crystal form D.

[0370] The XRPD diagram of the free crystal form D is shown below. Figure 13-1 As shown in Table 10, the XRPD data, TGA chart, and DSC chart are shown in Table 10. Figure 13-2 As shown, 1 H-NMR was obtained in DMSO-d6 as follows Figure 13-3 As shown in the PLM diagram Figure 13-4 As shown in the figure, the DVS curve is as follows: Figure 13-5 As shown, the XRPD graphs before and after the VS test are as follows. Figure 13-6 As shown. TGA results showed a 1.0% weight loss when the sample was heated to 100℃; DSC results showed an endothermic signal at 199.7℃ (peak temperature). PLM results showed that the free crystal form D consisted of long rod-shaped particles with a length of about 10μm, exhibiting good crystallinity. DVS results showed that the free crystal form D gained 1.12% weight at 80% RH, 3.06% weight at 95% RH, and lost 1.97% weight at 0% RH, indicating low hygroscopicity. XRPD results showed no significant change before and after the DVS experiment, indicating that its crystal form is less affected by humidity and has good stability. NMR results were consistent with the reference spectrum, with no obvious organic solvent residue.

[0371] Table 10: XRPD analytical data of free crystal form D

[0372] Angle(°2Th) Rel.Intensity(%) 13.85 100.0 15.75 45.4 4.05 24.8 18.76 20.2 18.49 19.7 9.49 18.3 5.39 17.7 6.93 17.2 11.18 16.3 10.85 15.5

[0373] 5. Free crystal form E

[0374] Weigh approximately 200.2 mg of the compound of formula (I) prepared in Preparation Example 1, add 1 mL of tetrahydrofuran / water (v / v, 2 / 1) solvent and stir at room temperature. After the solid precipitates, add 3 mL of tetrahydrofuran / water (v / v, 2 / 1) solvent and stir at room temperature for 7 days. After centrifuging the suspension, dry the solid under vacuum at room temperature to obtain the free crystal form E.

[0375] The XRPD diagram of the free crystal form E is shown below. Figure 14-1 As shown in Table 11, the XRPD data, TGA chart, and DSC chart are shown in Table 11. Figure 14-2 As shown, 1 H-NMR was obtained in DMSO-d6 as follows Figure 14-3 As shown in the figure. TGA results showed a 7.4% weight loss when the sample was heated to 150℃; DSC results showed endothermic signals at 108.4℃ and 205.0℃ (peak temperatures). NMR results were consistent with the reference spectrum, with tetrahydrofuran signal peaks at 1.76 and 3.59 ppm. After heating the free crystalline form E to 150℃ and then cooling it to room temperature, XRPD tests showed significant changes.

[0376] Table 11: XRPD analytical data of free crystal form E

[0377] Angle(°2Th) Rel.Intensity(%) 4.67 100.0 5.33 30.6 15.23 19.4 10.11 19.3 13.96 19.0 10.72 15.0 22.40 14.2 17.09 12.4 12.10 12.0 15.67 11.8

[0378] 6. Free-state crystal form F

[0379] Weigh approximately 100.1 mg of the compound of formula (I) prepared in Preparation Example 1, add 1.0 mL of tetrahydrofuran / water (v / v, 1 / 1) solvent and suspend at room temperature for 15 h, then add 3.0 mL of tetrahydrofuran / water (v / v, 1 / 1) solvent and continue suspending for 24 h. After centrifugation of the suspension, the solid is dried under vacuum at 40 °C for 3 days to obtain free crystalline form F.

[0380] The XRPD diagram of the free crystal form F is shown below. Figure 15-1 As shown in Table 12, the XRPD data, TGA chart, and DSC chart are shown in Table 12. Figure 15-2 As shown, 1 H-NMR was obtained in DMSO-d6 as follows Figure 15-3 As shown. TGA results showed a 3.0% weight loss when the sample was heated to 120℃; DSC results showed endothermic signals at 65.4℃ and 168.7℃ (peak temperatures). Heating experiments showed that after heating the free crystalline form F to 120℃ and then cooling it to room temperature, XRPD tests showed no significant change. NMR spectroscopy showed no obvious residual organic solvent peaks.

[0381] Table 12: XRPD analytical data of free crystal form F

[0382] Angle(°2Th) Rel.Intensity(%) 8.11 100.0 13.16 48.8 4.71 40.6 19.70 28.2 11.55 26.4 15.91 25.3 31.01 21.7 9.92 17.7

[0383] 7. Free crystal form G

[0384] The free crystalline form G was obtained by weighing 100.2 mg of free crystalline form D, adding 2.0 mL of acetonitrile solution, suspending it at room temperature for 3 days, centrifuging the suspension, and then vacuum drying it at room temperature.

[0385] The XRPD diagram of the free crystal form G is shown below. Figure 16-1 As shown in Table 13, the XRPD data, TGA chart, and DSC chart are shown in Table 13. Figure 16-2 As shown, 1 H-NMR was obtained in DMSO-d6 as follows Figure 16-3 As shown. TGA results show that the sample lost 1.1% of its weight when heated to 100℃; DSC results show that the sample had an endothermic signal at 196.1℃ (peak temperature).

[0386] Table 13: XRPD analytical data of free crystal form G

[0387] Angle(°2Th) Rel.Intensity(%) 12.14 100.0 7.79 60.4 4.22 53.1 8.07 51.7 9.41 48.1 13.19 46.2 16.20 45.0 8.76 45.0 20.24 43.1 10.96 40.4

[0388] Example 3: Stability testing of the crystal form of compound (I)

[0389] The stability of the acid addition salt crystal form of compound (I) prepared in Example 1 and the free crystal form of compound (I) prepared in Example 2 were tested. Appropriate amounts of samples of different crystal forms were weighed and placed under high temperature (60°C), long-term conditions (25°C / 60% RH), or accelerated conditions (40°C / 75% RH) for corresponding number of days, and then samples were taken for XRPD characterization. The results showed that both the acid addition salt crystal form and the free crystal form of the present invention exhibited high stability.

[0390] This embodiment exemplifies the test results of free crystal form D and free crystal form G. The XRPD results show that the amorphous raw material did not change after 30 days under high temperature and accelerated conditions. The free crystal form D did not change after 30 days under long-term and accelerated conditions. The free crystal form G transformed into free crystal form D after 5 days under long-term and accelerated conditions. The results after 30 days were similar to those after 5 days.

[0391] In one test, free crystalline form G was placed in 0.9% physiological saline and water and shaken at a constant temperature of 40°C; the remaining solid XRPD remained unchanged. Similarly, when free crystalline form G was added to 0.9% physiological saline and shaken at 25°C for 3 days, the remaining solid XRPD also remained unchanged. This demonstrates that free crystalline form D maintains its crystalline structure for a considerable period under high temperature and humidity conditions.

[0392] Table 14: XRPD Test Results

[0393]

[0394]

[0395] Test Example 1: SPR Affinity Test of NYM030 Drug Compound

[0396] The affinity of the NYM030 compound obtained in Preparation Example 1 for FAP was determined using the Biacore 8K protein interaction system. BR102910 was used as a positive control, which showed a strong affinity for FAP.

[0397] FAP (purchased from ACROBiosystems Inc) was coupled to the surface of the CM5 chip. The running buffer consisted of 50 mM Tris, 150 mM NaCl, 0.05% P2O (Tween 20), and 5% DMSO, pH 7.2-7.4. A series of different concentrations of the test sample BR102910 (a selective fibroblast activating protein (FAP) inhibitor, purchased from MedChemExpress LLC) and NYM030 molecules were prepared. A series of different concentrations of the test sample solution were diluted proportionally (the highest concentration was 70 nM, and the dilution ratio was 2 to 5 different concentrations). The samples were injected and the affinity of the test samples BR102910 and NYM030 for FAP was measured. The affinity of the test samples BR102910 and NYM030 for FAP is represented by the equilibrium dissociation constant KD (Kd / Ka), where Kd is the dissociation constant and Ka is the binding constant. The smaller the KD value, the higher the affinity between the compound and the protein.

[0398] The test results are shown in Table 16 below. NYM030 showed low nanomolar affinity for FAP, and higher affinity for FAP compared to BR102910.

[0399] Table 16: SPR Affinity Test Results

[0400] compound KD(nM) BR102910 60.93±5.61 NYM030 2.52±0.12

[0401] Test Example 2: Inhibitory Activity of NYM030 Drug on Tumor Cell Proliferation

[0402] ES-2 (ovarian cancer), HS746T (gastric cancer), SJSA-1 (osteosarcoma), 5637 (bladder cancer), and SHP-77 (lung cancer) cells in the exponential growth phase were collected and viable cell counted using a Vi-Cell XR cell counter. The cell suspension was adjusted to an appropriate concentration. The culture medium used for different cell types and the number of cells added per well are shown in Table 17. 90 μl of cell suspension was added to each well of a 96-well cell culture plate and cultured at 37°C, 5% CO2, and 95% humidity for 24 hours.

[0403] A series of serial dilutions were prepared using the test sample stock solution (6 mg / ml DMSO solution of NYM030) and DMSO at a ratio of 1:3. Each solution was then diluted 100-fold with culture medium. Finally, 10 μl of the corresponding 100-fold dilution was added to each well for each cell line, with three replicates for each drug concentration. The cells were then incubated at 37°C in a 5% CO2 incubator for 72 hours.

[0404] 72 hours after drug treatment, following the instructions for the CTG (CELL TITER-GLO) luminescence assay for cell viability, 50 μl of pre-melted and equilibrated CTG solution was added to each well. The solution was mixed with a microplate shaker for 2 minutes and allowed to stand at room temperature for 10 minutes before the fluorescence signal was measured using an Envision 2104 plate reader.

[0405] The results of the in vitro antitumor activity test and cell viability test of NYM030 are shown in Table 18. Figure 17 As shown, the results indicate that NYM030 has strong in vitro antitumor activity against ES-2, SJSA-1, and 5637 cells, and can significantly inhibit the proliferation of ES-2, SJSA-1, and 5637 cells. The inhibitory activity against ES-2 cells is the highest, while the antitumor activity against HS746T and SHP-77 cells is low, demonstrating the specific antitumor activity of NYM030.

[0406] Table 17: Cell line culture information

[0407]

[0408]

[0409] Table 18: In vitro antitumor activity of NYM030 (IC50) 50 Value and maximum inhibition rate

[0410] cell lines <![CDATA[IC 50 (μM)]]> Max inh. (%) ES-2 1.977 89.13％ HS746T >6 5.04％ SJSA-1 5.339 56.43％ 5637 2.949 67.10％ SHP-77 >6 8.15％

[0411] Test Example 3: Efficacy Experiment of NYM030 Drug in HT1080 Tumor Model

[0412] The HT1080 experimental animal model was provided by Suzhou Hengjia Biotechnology Co., Ltd. It is a subcutaneous ectopic xenograft model of HT1080 based on BALB / c nude mice, and is a mouse model constructed from human fibrosarcoma cells. Twenty female HT1080 ectopic human fibrosarcoma model mice were randomly selected for the experiment. Before the experiment, tumor size was measured, and mice were arranged in order of tumor size. Sixteen mice with tumors of suitable size were selected and divided into three groups: G1, G2, and G3. Group G1 (treatment group) consisted of six tumor-bearing mice, each receiving an intravenous injection of NYM030 in saline solution at a dose of approximately 10 mg / kg, calculated based on the weight of each tumor-bearing mouse. Group G2 (positive control group) consisted of six tumor-bearing mice, each receiving an intravenous injection of irinotecan in saline solution at a dose of approximately 5 mg / kg (the molar amounts of NYM030 and irinotecan were the same, i.e., the same dose of cytotoxic drug). Four mice in group G3 (control group) with tumors were injected with physiological saline solution via tail vein. The volume of the solution was similar to that in groups G1 and G2, and the injection time for each group was recorded. Tumor volume (long and short diameters) and body weight were measured in groups G1, G2, and G3 before administration and at 2, 4, 6, 8, 10, 12, and 14 days after administration. The mice's condition was also observed and accurately recorded. The long and short diameters of the tumor measured during the tumor efficacy evaluation period were used to calculate the tumor volume using the following formula: Tumor volume (TV) = a × b 2 / 2 (a is the major axis, b is the minor axis). See the trend chart of tumor volume for each group. Figure 18 The trend of mouse body weight change can be seen in the figure. Figure 19 As can be seen, NYM030 significantly inhibits tumor growth at a faster rate than irinotecan and saline, and the weight of mice did not change significantly, indicating that NYM030 has a good anti-tumor effect and good safety.

[0413] Test Example 4: Efficacy Experiment of NYM030 Drug in SJSA-1 Tumor Model

[0414] The experimental animal model SJSA-1 was provided by Crown Bioscience (Taicang) Co., Ltd., and is an animal model of female BALB / c nude mice with subcutaneous xenograft of human SJSA-1 cell line. BALB / c nude mice were subcutaneously inoculated with 2×10⁻⁶ cells on the right back. 6 SJSA-1 cells, tumors grew to an average volume of approximately 100 mm. 3 .

[0415] The experiment consisted of a negative control group and three single-drug groups of NYM030 at three different doses (10 mg / kg, 3 mg / kg, and 1 mg / kg, prepared using 5% glucose solution). Eight animals were in each group. Administration was via tail vein injection at a volume of 10 μL / g for two weeks, ending on day 28. Detailed administration information is shown in Table 19. Before administration, all animals were weighed, and tumor volume was measured using calipers. Tumor volume (long and short diameters) and body weight were measured before and after administration. Tumor growth and the effects of treatment on normal animal behavior were also observed, including activity level, feeding and drinking, weight gain or loss, and other abnormalities. Efficacy was evaluated based on the tumor volume inhibition rate (TGI) and changes in animal body weight (as shown in the attached table). Figure 21 Safety was evaluated based on the tumor suppression rate and mortality. The tumor inhibition rate (TGI%) was calculated using the following formula: TGI% = (1 - T / C) × 100%, where T and C are the average tumor volumes of the treatment group and control group at a specific time point, respectively; tumor volume (TV) = a × b 2 / 2 (a is the major axis and b is the minor axis).

[0416] As attached Figure 20 As shown, on day 24, some mice in the negative control group had tumor volumes exceeding 3000 mmHg. 3 They were euthanized. On day 24, the mean tumor volume in the negative control group was 2997.74 mm. 3 All doses of NYM030 (10 mg / kg, 3 mg / kg and 1 mg / kg) significantly inhibited tumor growth, with TGI of 60.69%, 46.59% and 44.46%, respectively. The high-dose group showed better tumor inhibition. No significant weight loss was observed in the negative control group and any of the NYM030 dose groups, and no abnormalities were observed in the mice, indicating that NYM030 has good safety.

[0417] Table 19: Dosage Information

[0418] Group Animal number Drug administration group Single dose (mg / kg) Dosage time (days) 01 8 5% glucose solution - Days 1, 2, 3, 4, 8, 9, 10, and 11 02 8 NYM030 1 Days 1, 2, 3, 4, 8, 9, 10, and 11 03 8 NYM030 3 Days 1, 2, 3, 4, 8, 9, 10, and 11 04 8 NYM030 10 Days 1, 2, 3, 4, 8, 9, 10, and 11

[0419] Test Example 5: Continuous Dosing Toxicity Experiment

[0420] The mouse model consisted of 6-8 week old female ICR mice purchased from Suzhou Hengjia Biotechnology Co., Ltd. Six ICR mice were randomly selected and administered NYM030 at a single dose of 10 mg / kg for 7 consecutive days. General animal indicators (hair condition, activity level, diet, etc.), mortality (time of death, etc.), and changes in body weight were observed (before administration, during observation, and before sacrifice at the end of the experiment). Mice were sacrificed on the last day of the experiment, and their tissue changes in major organs such as the heart, liver, spleen, lungs, and kidneys were observed through dissection. Figure 22 The change in body weight is used to evaluate the change in body weight at a certain point in time compared with the body weight before the start of the experiment. The calculation formula is: Change in body weight = Body weight at weighing / Initial body weight * 100%.

[0421] like Figure 22 As shown, after 7 days of continuous administration, none of the mice died or showed any abnormal reactions. Autopsy revealed no abnormalities in the organs, and there was no significant change in body weight during the experiment. This demonstrates that the NYM030 molecule has good safety profile.

[0422] Test Example 6: Acute Toxicity Experiment in ICR Rats

[0423] The mouse model was 6-8 week old female ICR mice purchased from Suzhou Hengjia Biotechnology Co., Ltd. Nine ICR mice were randomly selected and divided into three groups of three mice each. The experimental group was given 100 mg / kg NYM030, the positive control was given 50 mg / kg irinotecan, and the control group was given saline. General indicators (hair, activity level, diet, etc.), mortality (time of death, etc.), and body weight were observed in each group before administration and on days 2, 4, 6, and 8 after administration. On the last day of the experiment, the mice were sacrificed and dissected to observe any abnormalities in major organs. During the 8-day observation period, no mice died or showed any abnormal reactions. Dissection revealed no abnormalities in organs, and all mice gained body weight after the experiment. Under the premise of consistent effective drug (cytotoxic drug) dosage, the experimental group mice experienced less weight loss than the positive control group. At the end of the experiment, the experimental group mice gained body weight compared to before administration, while the positive control group did not. This indicates that NYM030 has good molecular safety.

[0424] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0425] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A pharmaceutically acceptable acid addition salt of a compound represented by formula (I), (I)； The acid addition salt is p-toluenesulfonate crystal form A of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 5.76±0.2°, 11.61±0.2°, 11.98±0.2°, 17.34±0.2°, 20.71±0.2°, 21.23±0.2°, 26.32±0.2°; The acid addition salt is p-toluenesulfonate crystal form B of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 6.71±0.2°, 8.60±0.2°, 11.65±0.2°, 13.48±0.2°, 20.26±0.2°, 23.04±0.2°, 24.38±0.2°; The acid addition salt is the phosphate crystal form A of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 3.33±0.2°, 3.97±0.2°, 5.18±0.2°, 6.19±0.2°, 9.16±0.2°, 18.59±0.2°, 23.52±0.2°; The acid addition salt is the phosphate crystal form B of the compound shown in formula (I), which has an X-ray powder diffraction pattern substantially as shown in Figure 5-1. The acid addition salt is the phosphate crystal form C of the compound shown in formula (I), which has an X-ray powder diffraction pattern substantially as shown in Figure 6-1. The acid addition salt is the sulfate crystal form A of the compound shown in formula (I), and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 8.15±0.2°, 9.30±0.2°, 10.75±0.2°, 13.20±0.2°, 13.61±0.2°, 14.74±0.2°, 20.78±0.2°; The acid addition salt is the sulfate crystal form B of the compound shown in formula (I), and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 11.48±0.2°, 15.75±0.2°, 16.68±0.2°, 17.48±0.2°, 20.58±0.2°, 24.57±0.2°, 28.96±0.2°; The acid addition salt is the hydrobromide crystal form A of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 3.89±0.2°, 4.23±0.2°, 8.16±0.2°, 16.38±0.2°, 17.88±0.2°, and 24.60±0.2°.

2. The acid addition salt according to claim 1, characterized in that, The acid addition salt is p-toluenesulfonate crystal form A of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 5.76±0.2°, 8.17±0.2°, 11.61±0.2°, 11.98±0.2°, 17.34±0.2°, 20.30±0.2°, 20.71±0.2°, 21.23±0.2°, 24.87±0.2°, 26.32±0.2°.

3. The acid addition salt according to claim 2, characterized in that, The acid addition salt is p-toluenesulfonate crystal form A of the compound shown in formula (I), which has a weight loss of 11.4 ± 0.1% at 150 °C.

4. The acid addition salt according to claim 2, characterized in that, The acid addition salt is p-toluenesulfonate crystal form A of the compound shown in formula (I), which has an X-ray powder diffraction pattern substantially as shown in Figure 2-1.

5. The acid addition salt according to claim 2, characterized in that, The acid addition salt is p-toluenesulfonate crystal form A of the compound shown in formula (I), which has the TGA diagram and DSC diagram shown in Figure 2-2.

6. The acid addition salt according to claim 1, characterized in that, The acid addition salt is p-toluenesulfonate crystal form B of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 6.71±0.2°, 8.60±0.2°, 11.65±0.2°, 13.48±0.2°, 17.67±0.2°, 20.26±0.2°, 20.92±0.2°, 21.99±0.2°, 23.04±0.2°, 24.38±0.2°.

7. The acid addition salt according to claim 6, characterized in that, The acid addition salt is p-toluenesulfonate crystal form B of the compound shown in formula (I), which has a weight loss of 7.9 ± 0.1% at 160 °C.

8. The acid addition salt according to claim 6, characterized in that, The acid addition salt is p-toluenesulfonate crystal form B of the compound shown in formula (I), which has an X-ray powder diffraction pattern substantially as shown in Figure 3-1.

9. The acid addition salt according to claim 6, characterized in that, The acid addition salt is p-toluenesulfonate crystal form B of the compound shown in formula (I), which has the TGA diagram and DSC diagram shown in Figure 3-2.

10. The acid addition salt according to claim 1, characterized in that, The acid addition salt is the phosphate crystal form A of the compound shown in formula (I), and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 3.33±0.2°, 3.97±0.2°, 5.18±0.2°, 6.19±0.2°, 9.16±0.2°, 11.92±0.2°, 12.87±0.2°, 15.67±0.2°, 18.59±0.2°, 23.52±0.2°.

11. The acid addition salt according to claim 10, characterized in that, The acid addition salt is the phosphate crystal form A of the compound shown in formula (I), which has a weight loss of 13.5 ± 0.1% at 180 °C.

12. The acid addition salt according to claim 10, characterized in that, The acid addition salt is the phosphate crystal form A of the compound shown in formula (I), which has an X-ray powder diffraction pattern substantially as shown in Figure 4-1.

13. The acid addition salt according to claim 10, characterized in that, The acid addition salt is the phosphate crystal form A of the compound shown in formula (I), which has the TGA diagram and DSC diagram shown in Figure 4-2.

14. The acid addition salt according to claim 1, characterized in that, The acid addition salt is the phosphate crystal form B of the compound shown in formula (I), which has a weight loss of 3.3 ± 0.1% at 120 °C.

15. The acid addition salt according to claim 14, characterized in that, The acid addition salt is the phosphate crystal form B of the compound shown in formula (I), which has the TGA diagram and DSC diagram shown in Figure 5-2.

16. The acid addition salt according to claim 1, characterized in that, The acid addition salt is the phosphate crystal form C of the compound shown in formula (I), which has a weight loss of 9.0 ± 0.1% at 150 °C.

17. The acid addition salt according to claim 16, characterized in that, The acid addition salt is the phosphate crystal form C of the compound shown in formula (I), which has the TGA diagram and DSC diagram shown in Figure 6-2.

18. The acid addition salt according to claim 1, characterized in that, The acid addition salt is the sulfate crystal form A of the compound shown in formula (I), and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 8.15±0.2°, 9.30±0.2°, 10.75±0.2°, 11.69±0.2°, 13.20±0.2°, 13.61±0.2°, 14.74±0.2°, 20.78±0.2°, 29.20±0.2°, 29.76±0.2°.

19. The acid addition salt according to claim 18, characterized in that, The acid addition salt is the sulfate crystal form A of the compound shown in formula (I), which has a weight loss of 7.7 ± 0.1% at 120 °C.

20. The acid addition salt according to claim 18, characterized in that, The acid addition salt is the sulfate crystal form A of the compound shown in formula (I), which has an X-ray powder diffraction pattern substantially as shown in Figure 7-1.

21. The acid addition salt according to claim 18, characterized in that, The acid addition salt is the sulfate crystal form A of the compound shown in formula (I), which has the TGA diagram and DSC diagram shown in Figure 7-2.

22. The acid addition salt according to claim 1, characterized in that, The acid addition salt is the sulfate crystal form B of the compound shown in formula (I), and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 7.11±0.2°, 7.74±0.2°, 11.48±0.2°, 13.20±0.2°, 15.75±0.2°, 16.68±0.2°, 17.48±0.2°, 20.58±0.2°, 24.57±0.2°, 28.96±0.2°.

23. The acid addition salt according to claim 22, characterized in that, The acid addition salt is the sulfate crystal form B of the compound shown in formula (I), which has a weight loss of 6.1 ± 0.1% at 120 °C.

24. The acid addition salt according to claim 22, characterized in that, The acid addition salt is the sulfate crystal form B of the compound shown in formula (I), which has an X-ray powder diffraction pattern substantially as shown in Figure 8-1.

25. The acid addition salt according to claim 22, characterized in that, The acid addition salt is the sulfate crystal form B of the compound shown in formula (I), which has the TGA diagram and DSC diagram shown in Figure 8-2.

26. The acid addition salt according to claim 1, characterized in that, The acid addition salt is the hydrobromide crystal form A of the compound shown in formula (I), whose X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 3.89±0.2°, 4.23±0.2°, 8.16±0.2°, 16.38±0.2°, 17.88±0.2°, 19.66±0.2°, 21.29±0.2°, 24.60±0.2°, 31.79±0.2°.

27. The acid addition salt according to claim 26, characterized in that, The acid addition salt is the hydrobromide crystal form A of the compound shown in formula (I), which has a weight loss of 9.0 ± 0.1% at 150 °C.

28. The acid addition salt according to claim 26, characterized in that, The acid addition salt is the hydrobromide crystal form A of the compound shown in formula (I), which has an X-ray powder diffraction pattern substantially as shown in Figure 9-1.

29. The acid addition salt according to claim 26, characterized in that, The acid addition salt is the hydrobromide crystal form A of the compound shown in formula (I), which has the TGA diagram and DSC diagram shown in Figure 9-2.

30. A crystal form of the compound shown in formula (I), (I)； The crystal form is free crystal form A, and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 4.67±0.2°, 5.39±0.2°, 11.18±0.2°, 12.10±0.2°, 15.56±0.2°, 16.08±0.2°, 17.32±0.2°; The crystal form is free crystal form B, and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 9.16±0.2°, 12.47±0.2°, 13.73±0.2°, 16.08±0.2°, 16.47±0.2°, 16.84±0.2°, 20.61±0.2°; The crystal form is free crystal form C, and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 14.82±0.2°, 15.61±0.2°, 18.57±0.2°, 22.69±0.2°, 24.11±0.2°, 24.55±0.2°, 26.69±0.2°; The crystal form is free crystal form D, and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 4.05±0.2°, 5.39±0.2°, 9.49±0.2°, 13.85±0.2°, 15.75±0.2°, 18.49±0.2°, 18.76±0.2°; The crystal form is free crystal form E, and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 4.67±0.2°, 5.33±0.2°, 10.11±0.2°, 10.72±0.2°, 13.96±0.2°, 15.23±0.2°, 22.40±0.2°; The crystal form is free crystal form F, and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 4.71±0.2°, 8.11±0.2°, 9.92±0.2°, 11.55±0.2°, 13.16±0.2°, 15.91±0.2°, 19.70±0.2°, 31.01±0.2°; The crystal form is free crystal form G, and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 4.22±0.2°, 7.79±0.2°, 8.07±0.2°, 8.76±0.2°, 9.41±0.2°, 12.14±0.2°, 13.19±0.2°, and 16.20±0.2°.

31. The crystal form according to claim 30, characterized in that, The crystal form is free crystal form A, and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 4.67±0.2°, 5.39±0.2°, 11.18±0.2°, 12.10±0.2°, 12.87±0.2°, 14.23±0.2°, 15.56±0.2°, 16.08±0.2°, 17.32±0.2°, and 20.80±0.2°.

32. The crystal form according to claim 31, characterized in that, The crystal form is free crystal form A, which has a weight loss of 0.6 ± 0.1% at 100℃.

33. The crystal form according to claim 31, characterized in that, The crystal form is free crystal form A, which has an X-ray powder diffraction pattern that is essentially as shown in Figure 10-1.

34. The crystal form according to claim 31, characterized in that, The crystal form is free crystal form A, which has the TGA diagram and DSC diagram shown in Figure 10-2.

35. The crystal form according to claim 30, characterized in that, The crystal form is free crystal form B, and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 4.38±0.2°, 7.59±0.2°, 8.27±0.2°, 9.16±0.2°, 12.47±0.2°, 13.73±0.2°, 16.08±0.2°, 16.47±0.2°, 16.84±0.2°, and 20.61±0.2°.

36. The crystal form according to claim 35, characterized in that, The crystal form is free crystal form B, which has an X-ray powder diffraction pattern substantially as shown in Figure 11.

37. The crystal form according to claim 30, characterized in that, The crystal form is free crystal form C, and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 4.98±0.2°, 11.05±0.2°, 14.82±0.2°, 15.61±0.2°, 18.00±0.2°, 18.57±0.2°, 22.69±0.2°, 24.11±0.2°, 24.55±0.2°, 26.69±0.2°.

38. The crystal form according to claim 37, characterized in that, The crystal form is free crystal form C, which has a weight loss of 9.1 ± 0.1% at 150℃.

39. The crystal form according to claim 37, characterized in that, The crystal form is free crystal form C, which has an X-ray powder diffraction pattern that is essentially as shown in Figure 12-1.

40. The crystal form according to claim 37, characterized in that, The crystal form is free crystal form C, which has the TGA diagram and DSC diagram shown in Figure 12-2.

41. The crystal form according to claim 30, characterized in that, The crystal form is free crystal form D, and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 4.05±0.2°, 5.39±0.2°, 6.93±0.2°, 9.49±0.2°, 10.85±0.2°, 11.18±0.2°, 13.85±0.2°, 15.75±0.2°, 18.49±0.2°, and 18.76±0.2°.

42. The crystal form according to claim 41, characterized in that, The crystal form is free crystal form D, which has a weight loss of 1.0 ± 0.1% at 100℃.

43. The crystal form according to claim 41, characterized in that, The crystal form is free crystal form D, which has an X-ray powder diffraction pattern that is essentially as shown in Figure 13-1.

44. The crystal form according to claim 41, characterized in that, The crystal form is free crystal form D, which has the TGA diagram and DSC diagram shown in Figure 13-2.

45. The crystal form according to claim 30, characterized in that, The crystal form is free crystal form E, and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 4.67±0.2°, 5.33±0.2°, 10.11±0.2°, 10.72±0.2°, 12.10±0.2°, 13.96±0.2°, 15.23±0.2°, 15.67±0.2°, 17.09±0.2°, and 22.40±0.2°.

46. ​​The crystal form according to claim 45, characterized in that, The crystal form is free crystal form E, which has a weight loss of 7.4 ± 0.1% at 150℃.

47. The crystal form according to claim 45, characterized in that, The crystal form is free crystal form E, which has an X-ray powder diffraction pattern that is essentially as shown in Figure 14-1.

48. The crystal form according to claim 45, characterized in that, The crystal form is free crystal form E, which has the TGA diagram and DSC diagram shown in Figure 14-2.

49. The crystal form according to claim 30, characterized in that, The crystal form is free crystal form F, which has a weight loss of 3.0 ± 0.1% at 120℃.

50. The crystal form according to claim 49, characterized in that, The crystal form is free crystal form F, which has an X-ray powder diffraction pattern that is essentially as shown in Figure 15-1.

51. The crystal form according to claim 49, characterized in that, The crystal form is free crystal form F, which has the TGA diagram and DSC diagram shown in Figure 15-2.

52. The crystal form according to claim 30, characterized in that, The crystal form is free crystal form G, and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 4.22±0.2°, 7.79±0.2°, 8.07±0.2°, 8.76±0.2°, 9.41±0.2°, 10.96±0.2°, 12.14±0.2°, 13.19±0.2°, 16.20±0.2°, and 20.24±0.2°.

53. The crystal form according to claim 52, characterized in that, The crystal form is free crystal form G, which has a weight loss of 1.1 ± 0.1% at 100℃.

54. The crystal form according to claim 52, characterized in that, The crystal form is free crystal form G, which has an X-ray powder diffraction pattern that is essentially as shown in Figure 16-1.

55. The crystal form according to claim 52, characterized in that, The crystal form is free crystal form G, which has the TGA diagram and DSC diagram shown in Figure 16-2.

56. A pharmaceutical composition, characterized in that, A pharmaceutically acceptable acid addition salt comprising a compound of formula (I) as described in any one of claims 1 to 29 or a crystal form as described in any one of claims 30 to 55.

57. The pharmaceutical composition according to claim 56, characterized in that, This further includes pharmaceutically acceptable excipients.

58. The use of a pharmaceutically acceptable acid addition salt of the compound of formula (I) according to any one of claims 1 to 29, the crystal form according to any one of claims 30 to 55, or the pharmaceutical composition according to any one of claims 56 to 57 in the preparation of one or more pharmaceuticals; The drug is used to treat and / or prevent diseases associated with FAP expression.

59. The application according to claim 58, characterized in that, The diseases associated with FAP expression are selected from tumors and cancers that express FAP.

60. The application according to claim 59, characterized in that, The tumors or cancers expressing FAP are selected from at least one of melanoma, esophageal cancer, breast cancer, bile duct cancer, lung cancer, liver cancer, colorectal cancer, fibrosarcoma, osteosarcoma, pancreatic cancer, ovarian cancer, head and neck cancer, and neuroendocrine tumors.

61. The application according to claim 59, characterized in that, The tumors or cancers expressing FAP are selected from at least one of fibrosarcoma, osteosarcoma, pancreatic cancer, and ovarian cancer.

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