Acid addition salts and crystalline forms targeting fibroblast activating proteins and uses thereof

Abstract

The invention discloses a pharmaceutically acceptable acid addition salt of a compound shown in a formula (I) and a crystal form of the pharmaceutically acceptable acid addition salt. The inventor of the invention researches and develops a medicine (a compound shown as a formula (I)) for treating related diseases caused by expression of FAP, and in order to find a solid form with better druggability, various acid addition salts of the compound shown as the formula (I) and crystal forms of the salts are obtained. The preparation purity of the acid addition salt and the crystal form of the acid addition salt is obviously improved, the stability is obviously improved, and physical properties are more beneficial to preparation. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to an acid addition salt and a crystal form of a fibroblast activation protein targeted thereto and uses thereof. Background Art

[0002] Fibroblast activation protein (FAP, also known as fibroblast activation protein α, FAPα) is highly overexpressed on cancer-associated fibroblasts (CAFs) in solid tumors, but is generally not expressed in normal tissues and benign tumors. Tumor stromal CAFs can promote tumor cell growth and invasion and have become an important target for tumor intervention. Overexpression of the tumor biomarker FAP is a prominent feature of CAFs, making FAP a promising target for CAF-targeted tumor diagnosis and therapy.

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

[0004] Small-molecule FAP-selective (targeted) inhibitors that have undergone structural modification and optimized screening offer 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, stability, shelf life, exposure, bioavailability, or extended half-life). Therefore, further development of pharmaceutically acceptable salts or crystalline forms targeting fibroblast activation protein is necessary to facilitate further drug development. Summary of the Invention

[0005] The present invention aims to solve at least one of the technical problems existing in the prior art to a certain extent. One object of the present invention is to provide an acid addition salt and a crystal form of a fibroblast activation protein.

[0006] The following is a summary of some aspects of the present invention and is not intended to be limiting. These and other aspects are described in greater detail below. All references in this specification are incorporated herein by reference in their entirety. In the event of a discrepancy between the disclosure of this specification and a reference, the disclosure of this specification shall prevail.

[0007] The inventors of the present invention previously screened for drugs targeting fibroblast activation protein and obtained the compound represented by formula (I). However, this compound often exists in an oily, amorphous form, which is not conducive to accurate sampling, resulting in poor product stability. Long-term storage also reduces its purity and increases impurities. Based on this, the present invention screened the compound for crystalline forms and identified the optimal crystalline form. These crystalline forms exhibit improved stability and higher purity compared to the compound represented by formula (I).

[0008] The present invention provides acid addition salts and crystal forms targeting fibroblast activation protein, which can be used to diagnose and / or treat and / or prevent diseases that express fibroblast activation protein, such as fibrosarcoma, 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 the first aspect of the present invention, the present invention provides a pharmaceutically acceptable acid addition salt of a compound represented by formula (I),

[0010]

[0011] The inventors of the present invention have developed a drug (a compound represented by formula (I)) for treating diseases related to the expression of FAP. In order to find a solid form with better drugability, the inventors have obtained various acid addition salts of the compound represented by formula (I) and the crystalline forms of its salts through extensive experimental studies.

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

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

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

[0015] According to an embodiment of the present invention, the acid addition salt includes phosphate, sulfate, hydrobromide, or p-toluenesulfonate of the compound represented by formula (I).

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

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

[0018] The "2θ or 2θ angle" mentioned in the present disclosure refers to the diffraction angle, θ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2θ is ±0.20 (including the case where the number exceeds 2 decimal places after rounding).

[0019] According to an embodiment 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 a range value between any two ratios thereof.

[0020] According to an embodiment of the present invention, the acid addition salt is a p-toluenesulfonate crystalline form A of the compound represented by formula (I), and its 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 a p-toluenesulfonate crystalline form A of the compound represented by formula (I), and its 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°, and 26.32±0.2°.

[0022] According to an embodiment of the present invention, the acid addition salt is a p-toluenesulfonate crystalline form A of the compound represented by formula (I), and its 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°, and 26.32±0.2°.

[0023] According to an embodiment of the present invention, the acid addition salt is the p-toluenesulfonate crystalline form A of the compound represented by 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 crystalline form A, and its DSC graph contains one or more endothermic signals at 102.1°C±3°C and 138.0°C±3°C.

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

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

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

[0028] In some embodiments, the acid addition salt of the present invention is a p-toluenesulfonate salt of the compound represented by formula (I), Form A, wherein the molar ratio of the compound represented by formula (I) to p-toluenesulfonic acid in the p-toluenesulfonate salt 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 a p-toluenesulfonate salt of the compound represented by formula (I), Form A, wherein the molar ratio of the compound represented by formula (I) to p-toluenesulfonic acid in the p-toluenesulfonate salt Form A is 1:1.

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

[0030] According to an embodiment of the present invention, the acid addition salt is the p-toluenesulfonate crystalline form B of the compound represented by formula (I), and its 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 a p-toluenesulfonate crystalline form B of the compound represented by formula (I), and its 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°, and 24.38±0.2°.

[0032] According to an embodiment of the present invention, the acid addition salt is a p-toluenesulfonate crystalline form B of the compound represented by formula (I), and its 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°, and 24.38±0.2°.

[0033] According to an embodiment of the present invention, the acid addition salt is the p-toluenesulfonate crystalline form B of the compound represented by 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 crystalline form B, and its DSC graph contains one or more endothermic signals at 89.3°C±3°C and 130.4°C±3°C.

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

[0036] According to an embodiment of the present invention, the acid addition salt is a p-toluenesulfonate crystalline form B of the compound represented by formula (I), and the p-toluenesulfonate crystalline 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 a p-toluenesulfonate crystalline form B of the compound represented by formula (I), wherein the molar ratio of the compound represented by formula (I) to p-toluenesulfonic acid in the p-toluenesulfonate crystalline form B is 1:(0.33-3).

[0038] In some embodiments, the acid addition salt of the present invention is a p-toluenesulfonate salt of the compound represented by formula (I), Form B, wherein the molar ratio of the compound represented by formula (I) to p-toluenesulfonic acid in the p-toluenesulfonate salt 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 a p-toluenesulfonate salt of the compound represented by formula (I), Form B, wherein the molar ratio of the compound represented by formula (I) to p-toluenesulfonic acid in the p-toluenesulfonate salt Form B is 1:1.

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

[0040] 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), and its 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 a phosphate crystal form A of the compound represented by 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°, 18.59±0.2°, and 23.52±0.2°.

[0042] 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), 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°, and 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 represented by 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 graph contains one or more endothermic signals of 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 Figure 4-1 The X-ray powder diffraction pattern is 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), and the phosphate crystal form A has an XRPD analysis data table substantially 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 Figure 4-2 TGA and DSC graphs are shown.

[0048] According to an embodiment of the present invention, the acid addition salt is the phosphate crystal form B of the compound represented by 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 graph includes one or more endothermic signals at 56.2°C±3°C and 151.9°C±3°C.

[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 Figure 5-1 The X-ray powder diffraction pattern is shown.

[0051] In some embodiments, the acid addition salt of the present invention is a phosphate crystal form B of the compound represented by formula (I), wherein the molar ratio of the compound represented by 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 a phosphate salt of the compound of formula (I) in Form B, wherein the molar ratio of the compound of formula (I) to phosphoric acid in 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 a phosphate salt of the compound of formula (I) in Form B, wherein the molar ratio of the compound of formula (I) to phosphoric acid in 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 Figure 5-2 TGA and DSC graphs are shown.

[0054] 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 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 graph includes one or more endothermic signals at 59.8°C±3°C and 182.6°C±3°C.

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

[0057] In some embodiments, the acid addition salt of the present invention is a phosphate crystal form C of the compound represented by formula (I), wherein the molar ratio of the compound represented by 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 a phosphate salt of the compound of formula (I) in Form C, wherein the molar ratio of the compound of formula (I) to phosphoric acid in the phosphate salt 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 a phosphate salt of the compound of formula (I) in Form C, wherein the molar ratio of the compound of formula (I) to phosphoric acid in the phosphate salt Form C is 1:2.7.

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

[0060] According to an embodiment of the present invention, the acid addition salt is sulfate crystal form A of the compound represented by formula (I), and its 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 sulfate crystalline form A of the compound represented by 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°, and 20.78±0.2°.

[0062] According to an embodiment of the present invention, the acid addition salt is sulfate crystalline form A of the compound represented by 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°, and 29.76±0.2°.

[0063] According to an embodiment of the present invention, the acid addition salt is sulfate crystal form A of the compound represented by 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 graph contains one or more endothermic signals at 68.2°C±3°C and 207.3°C±3°C.

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

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

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

[0068] In some embodiments, the acid addition salt of the present invention is a sulfate salt of the compound of formula (I) in Form A, wherein the molar ratio of the compound of formula (I) to sulfuric acid in the sulfate salt 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 a sulfate salt of the compound of formula (I) in Form A, wherein the molar ratio of the compound of formula (I) to sulfuric acid in the sulfate salt Form A is 1:0.7.

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

[0070] According to an embodiment of the present invention, the acid addition salt is sulfate crystal form B of the compound represented by formula (I), and its 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 a sulfate crystalline form B of the compound represented by 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°, and 28.96±0.2°.

[0072] According to an embodiment of the present invention, the acid addition salt is a sulfate crystalline form B of the compound represented by 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°, and 28.96±0.2°.

[0073] According to an embodiment of the present invention, the acid addition salt is sulfate crystal form B of the compound represented by 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 graph contains one or more endothermic signals at 76.5°C±3°C and 142.2°C±3°C.

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

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

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

[0078] In some embodiments, the acid addition salt of the present invention is a sulfate salt of the compound of formula (I) in Form B, wherein the molar ratio of the compound of formula (I) to sulfuric acid in the sulfate salt 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 a sulfate salt of the compound of formula (I) in Form B, wherein the molar ratio of the compound of formula (I) to sulfuric acid in the sulfate salt Form B is 1:2.2.

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

[0080] According to an embodiment of the present invention, the acid addition salt is the hydrobromide salt form A of the compound represented by formula (I), and its 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 a hydrobromide salt crystalline form A of the compound represented by formula (I), and its 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 a hydrobromide salt crystalline form A of the compound represented by formula (I), and its 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°, and 31.79±0.2°.

[0083] According to an embodiment of the present invention, the acid addition salt is the hydrobromide salt form A of the compound represented by 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 crystalline form A, and its DSC graph includes an endothermic signal at 66.8°C±3°C.

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

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

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

[0088] In some embodiments, the acid addition salt of the present invention is a hydrobromide salt of the compound represented by formula (I), Form A, wherein the molar ratio of the compound represented by formula (I) to hydrobromic acid in the hydrobromide salt 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 a hydrobromide salt of the compound represented by formula (I), Form A, wherein the molar ratio of the compound represented by formula (I) to hydrobromic acid in the hydrobromide salt Form A is 1:2.5.

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

[0090] In the second aspect of the present invention, the present invention provides a pharmaceutically acceptable crystalline form of a compound represented by formula (I),

[0091]

[0092] According to an embodiment of the present invention, the crystal form is 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 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 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 crystalline form is free crystalline form A, and the free crystalline form A has a weight loss of 0.6±0.1% at 100°C.

[0096] According to an embodiment of the present invention, the crystalline form is free crystalline form A, and the free crystalline form A comprises an endothermic signal of 204.3±3°C.

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

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

[0099] According to an embodiment of the present invention, the crystalline form is a free crystalline form A, and the free crystalline form A has substantially Figure 10-2 TGA and DSC graphs are shown.

[0100] According to an embodiment of the present invention, the crystal form is 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 crystalline form is a free crystalline form B, and the free crystalline form B has substantially the following Figure 11 The X-ray powder diffraction pattern is shown.

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

[0105] According to an embodiment of the present invention, the crystal form is 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°, and 26.69±0.2°.

[0108] According to an embodiment of the present invention, the crystalline form is free crystalline form C, and the free crystalline form C 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 free crystal form C, and the free crystal form C comprises an endothermic signal of 82.2°C±3°C to 101.8°C±3°C.

[0110] In an optional embodiment of the present invention, the crystalline form is a free crystalline form C, and the free crystalline form C comprises an endothermic signal of 25°C±3°C to 101.8°C±3°C. Exemplarily, the free crystalline form C comprises an endothermic signal of 25°C to 101.8°C.

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

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

[0113] According to an embodiment of the present invention, the crystalline form is a free crystalline form C, and the free crystalline form C has substantially the following Figure 12-2 TGA and DSC graphs are shown.

[0114] According to an embodiment of the present invention, the crystal form is 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 free-state crystal form D, and the free-state crystal form D 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 free crystal form D, and the free crystal form D comprises an endothermic signal of 199.7°C±3°C.

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

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

[0121] According to an embodiment of the present invention, the crystalline form is a free crystalline form D, and the free crystalline form D has substantially the following Figure 13-2 TGA and DSC graphs are shown.

[0122] According to an embodiment of the present invention, the crystal form is 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 crystalline form is free crystalline form E, and the free crystalline form E has a weight loss of 7.4±0.1% at 150°C.

[0126] According to an embodiment of the present invention, the crystalline form is free crystalline form E, and the free crystalline form E comprises one or more endothermic signals of 108.4°C±3°C and 205.0°C±3°C.

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

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

[0129] According to an embodiment of the present invention, the crystalline form is a free crystalline form E, and the free crystalline form E has substantially the following Figure 14-2 TGA and DSC graphs are shown.

[0130] According to an embodiment of the present invention, the crystal form is 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 free-state crystal form F, and the free-state crystal form F has a weight loss of 3.0±0.1% at 120°C.

[0133] According to an embodiment of the present invention, the crystalline form is a free-state crystalline form F, and the free-state crystalline form F comprises one or more endothermic signals of 65.4°C±3°C and 168.7°C±3°C.

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

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

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

[0137] According to an embodiment of the present invention, the crystal form is 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 the 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 the 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 crystalline form is free crystalline form G, and the free crystalline form G 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 free crystal form G, and the free crystal form G comprises an endothermic signal of 196.1°C±3°C.

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

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

[0144] According to an embodiment of the present invention, the crystalline form is a free crystalline form G, and the free crystalline form G has substantially the following Figure 16-2 TGA and DSC graphs are shown.

[0145] In its third aspect, the present invention provides a pharmaceutical composition. According to an embodiment of the present invention, the pharmaceutical composition comprises a pharmaceutically acceptable acid addition salt of the compound represented by Formula (I) described in the first aspect, or the crystalline form described in the second aspect. The pharmaceutical composition of the present invention can treat or prevent diseases related to FAP expression.

[0146] According to an embodiment of the present invention, the pharmaceutical composition further includes a pharmaceutically acceptable excipient.

[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 crystalline 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 represented by formula (I), or any crystalline form or amorphous form described herein, or any combination of the salt, crystalline form, and amorphous form.

[0148] In the fourth aspect of the present invention, the present invention proposes the use of a pharmaceutically acceptable acid addition salt of the compound represented by formula (I) described in the first aspect, the crystalline form described in the second aspect, or the pharmaceutical composition described in the third aspect in the preparation of one or more drugs; the drugs are used to treat and / or prevent related diseases caused by the expression of FAP.

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

[0150] According to an embodiment 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 its fifth aspect, the present invention provides the use of a pharmaceutically acceptable acid addition salt of the compound of formula (I) according to the first aspect, the crystalline form according to the second aspect, or the pharmaceutical composition according to the third aspect for inhibiting FAP. The pharmaceutically acceptable acid addition salt, crystalline form, or pharmaceutical composition of the compound of formula (I) of the present invention can be used to inhibit FAP in vivo or in vitro.

[0153] In the sixth aspect of the present invention, the present invention proposes the use of the pharmaceutically acceptable acid addition salt of the compound represented by formula (I) described in the first aspect, the crystal form described in the second aspect, or the pharmaceutical composition described in the third aspect in preventing and / or treating related diseases caused by the expression of FAP.

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

[0155] According to an embodiment 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 the seventh aspect of the present invention, the present invention proposes a pharmaceutically acceptable acid addition salt of the compound represented by formula (I) described in the first aspect, the crystal form described in the second aspect, or the pharmaceutical composition described in the third aspect, for use in expressing related diseases caused by FAP.

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

[0159] According to an embodiment 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] As used herein, "treatment" refers to the use of a drug or compound to obtain a desired pharmacological and / or physiological effect. The effect may be preventive in terms of completely or partially preventing a disease or its symptoms, and / or therapeutic in terms of partially or completely curing a disease and / or the adverse effects caused by the disease. As used herein, "treatment" covers diseases in mammals, particularly humans, and includes: (a) preventing the occurrence of a disease or condition in an individual who is susceptible to the disease but has not yet been diagnosed with the disease; (b) inhibiting the disease, such as arresting the progression of the disease; or (c) alleviating the disease, such as alleviating the symptoms associated with the disease. "Treatment" as used herein covers any medication that administers a drug or compound to an individual to treat, cure, alleviate, improve, reduce or inhibit the individual's disease, including but not limited to administering a drug containing a compound described herein to an individual in need.

[0162] In its eighth aspect, the present invention provides a method for inhibiting FAP, or preventing and / or treating related diseases caused by FAP expression. According to an embodiment of the present invention, the method comprises administering to a subject in need thereof a pharmaceutically acceptable acid addition salt of the compound of formula (I) described in the first aspect, the crystalline form described in the second aspect, or the pharmaceutical composition 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, that is evaluated for treatment and / or 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 infection, and the like. The subject can be a human, but also includes other mammals, particularly mammals that can be used as laboratory models of human diseases, such as mice, rats, and the like.

[0164] The effective amount of the acid addition salt, crystalline form, or pharmaceutical composition of the present invention may vary depending on the mode of administration and the severity of the disease to be treated. The preferred effective amount can be determined by one of ordinary skill in the art based on various factors (e.g., through clinical trials). Such 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, the route of administration, and the like. For example, depending on the exigencies of the treatment, several divided 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 the expression of FAP are selected from tumors and cancers expressing FAP.

[0166] According to an embodiment 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 purity of various acid addition salts of the compound represented by formula (I) is significantly improved, the stability is significantly improved, and the physical properties are more conducive to formulation.

[0170] 2. Further research was conducted on the preparation, drug metabolism properties and physicochemical properties of various acid addition salts of the compound represented by formula (I) and their crystalline forms. It was found that various salts of the compound represented by formula (I) and their crystalline forms have the advantages of suitable water solubility for drugability, good stability and good pharmacokinetics.

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

[0172] Definitions and General Terms

[0173] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0174] It will be further appreciated that certain features of the invention, which, for clarity, are described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which, for brevity, are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0175] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0176] The following definitions apply to the present invention unless otherwise indicated. For purposes of the present invention, the chemical elements are defined according to the Periodic Table of the Elements, CAS version, and Handbook of Chemical Physics, 75th Ed., 1994. Additionally, general principles of organic chemistry are described 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 specified or clearly contradicted by context, the articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more." Thus, as used herein, these articles refer to one or more than one (i.e., at least one) of the objects. For example, "a component" refers to one or more components, i.e., more than one component may be contemplated for use or use in implementing the described embodiments.

[0178] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0179] As used herein, the terms "optionally," "optional," or "optionally" generally mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed key Indicates the relative configuration of a stereocenter.

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

[0181] As used herein, the term "acid addition salt of the compound of formula (I)" refers to a salt formed by the reaction of the compound of 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 herein. The "acid addition salt of the compound of formula (I)" includes an amorphous form or a crystalline form of the salt, including a solvate form thereof (e.g., a hydrate form), and also includes a polymorphic form of the salt. For example, the hydrochloride salt of the compound of formula (I) includes an amorphous form, various crystalline forms, various solvates, various hydrates of such salt, and also includes a polymorphic form of such salt.

[0182] As used herein, the term "crystal form" or "crystalline form" refers to a solid having a highly regular chemical structure, including but not limited to single-component or multi-component crystals, and / or polymorphs, solvates, hydrates, inclusion compounds, co-crystals, salts, solvates of salts, and hydrates of salts of a compound. Crystalline forms of a substance can be obtained by many methods known in the art. Such 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; for example, on a polymer, crystallization in the presence of an additive such as a co-crystallization countermolecule, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, grinding, and solvent drop grinding.

[0183] As used herein, the term "amorphous" or "amorphous form" refers to a substance formed when the particles (molecules, atoms, ions) of a substance are arranged in a three-dimensional space without periodicity, and has a diffuse X-ray powder diffraction pattern without peaks. Amorphous is a special physical form of solid matter, and its locally ordered structural characteristics suggest that it is inextricably linked to crystalline substances. Amorphous forms of substances can be obtained by many methods known in the art. Such methods include, but are not limited to, quenching, antisolvent flocculation, ball milling, spray drying, freeze drying, wet granulation, and solid dispersion technology.

[0184] As used herein, the term "solvent" refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid). Solvents useful in the practice of the present invention include, but are not limited to, water, acetic acid, ethyl acetate, acetone, acetonitrile, methanol, toluene, isopropyl alcohol, tetrahydrofuran, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butyl alcohol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropyl alcohol, methyl ethyl ketone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, xylene, mixtures thereof, and the like.

[0185] In this article, the term "anti-solvent" refers to a fluid that promotes precipitation of a product (or product precursor) from a solvent. The anti-solvent can include a cold gas, or a fluid that promotes precipitation by a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it can be the same liquid as the solvent but at a different temperature, or it can be a liquid different from the solvent.

[0186] As used herein, the term "solvate" refers to a compound having a solvent on the surface, in the crystal lattice, or both on the surface and in the crystal lattice, wherein the solvent may 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, methylpyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, xylene, and mixtures thereof. A specific example of a solvate is a hydrate, in which the solvent on the surface, in the crystal lattice, or both on the surface and in the crystal lattice is water. A hydrate may or may not have other solvents other than water on the surface, in the crystal lattice, or both on the surface and in the crystal lattice of the substance.

[0187] Crystalline or amorphous forms can be identified by a variety of technical means, 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, dissolution calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.

[0188] X-ray powder diffraction (XRPD) can detect information such as changes in crystal form, crystallinity, and crystalline state, and is a common means of identifying crystal forms. The peak position of the XRPD pattern depends primarily on the structure of the crystal form and is relatively insensitive to experimental details, while its relative peak height depends 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 substantially as shown in the XRPD pattern provided in the accompanying drawings of the present invention. At the same time, the measurement of 2θ of the XRPD pattern may have experimental errors, and the measurement of 2θ of the XRPD pattern may be slightly different between different instruments and different samples, so the numerical value of the 2θ cannot be considered absolute. According to the instrument conditions used in this experiment, there is an error tolerance of ±0.2° for the diffraction peak.

[0189] Differential scanning calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference material (usually α-Al2O3) as a function of temperature by continuously heating or cooling the sample under program control. The height of the endothermic peak (or endothermic signal) of 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 crystalline form of the present invention is characterized by a DSC graph with a characteristic peak position, which is substantially as shown in the DSC graph provided in the accompanying drawings of the present invention. At the same time, DSC spectra may have experimental errors, and the peak positions and peak values ​​of the DSC spectra may vary slightly between different instruments and different samples. Therefore, the peak position or peak value of the DSC endothermic peak cannot be considered absolute. According to the instrument conditions used in this experiment, the endothermic peak has an error tolerance of ±3°.

[0190] Thermogravimetric analysis (TGA) is a technique that measures the mass change of a substance with temperature under program control. It is suitable for examining the loss of solvent from crystals or the sublimation or decomposition of a sample, and can infer the presence of water of crystallization or solvent in the crystals. 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 samples. Due to the instrumentation used in this test, the mass change has an error tolerance of ±0.1%.

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

[0192] As used herein, 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, or a DSC pattern, or a Raman spectrum pattern, or an infrared spectrum pattern are shown in the pattern.

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

[0194] In the context of the present invention, when or whether the word "about" or "approximately" is used, it means within 10%, suitably within 5%, and especially within 1% of a given value or range. Alternatively, for those of ordinary skill in the art, the term "about" or "approximately" means within an acceptable standard error of the mean. Whenever a number having a value of N is disclosed, any number having a value of N + / - 1%, N + / - 2%, N + / - 3%, N + / - 5%, N + / - 7%, N + / - 8% or N + / - 10% is specifically disclosed, where "+ / -" means plus or minus.

[0195] Unless otherwise indicated, the structural formulas described herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformers)): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, and (Z) and (E) conformers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformers) are within the scope of the present invention.

[0196] Depending on the specific conditions being treated, these agents can be formulated into liquid or solid dosage forms and administered systemically or topically. As known to those skilled in the art, the multiple medicaments can be delivered in the form of regular or sustained slow release. Multiple technologies of formulation and administration can be found in "Remington: The Science and Practice of Pharmacy" (20th edition) Lippincott, Williams & Wilkins (2000). Multiple suitable approaches may include: via inhalation spray, transdermal, or transmucosal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injection, and intrathecal, direct intraventricular, intravenous, intraarticular, intrasternal, intrasynovial, intrahepatic, intralesional, intracranial, intraperitoneal, intranasal or intraocular injection or other delivery modes.

[0197] For injection, the various agents disclosed herein can be formulated and diluted in various aqueous solutions, for example, in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For such transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation, such penetrants being generally known in the art.

[0198] Pharmaceutical compositions suitable for use in the present disclosure include compositions containing an effective amount of the active ingredient to achieve its intended purpose. Determination of such effective amounts is well within the capabilities of those skilled in the art, particularly in light of the detailed disclosure provided herein. Generally, the compounds according to the present invention are effective over a wide dosage range. For example, in the treatment of adults, dosages of 0.01 to 1000 milligrams (mg), 0.5 to 100 mg, 1 to 50 mg per day, and 5 to 40 mg per day are examples of dosages that may be used. A non-limiting dose is 10 to 30 mg per day. The exact dosage 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 preference and experience of the attending physician.

[0199] In addition to the active ingredients, the pharmaceutical compositions may also contain suitable pharmaceutically acceptable carriers, including auxiliary materials and adjuvants that facilitate processing the active compounds into pharmaceutically acceptable preparations.

[0200] In many embodiments of the methods of the present disclosure, the subject treated by the methods of the present disclosure is ideally a human subject, although it should be understood that the methods described herein are effective for all vertebrate species, which are intended to be included in the term "subject." Thus, a "subject" can include a human subject for various medical purposes, such as a prophylactic treatment for treating an existing condition or disease or for preventing the onset of a condition or disease, or an animal (non-human) subject for medical, veterinary, or developmental purposes. Suitable animal subjects include mammals, including but not limited to primates, such as humans, monkeys, and apes; bovines, such as cattle and oxen; ovines, such as sheep; caprines, such as goats; porcines, such as pigs and hogs; equines, such as horses, donkeys, and zebras; felines, including wild and domestic cats; canines, including dogs; lagomorphs, including rabbits and hares; and rodents, including mice and rats. An animal can be a transgenic animal. In some embodiments, the subject is a human, including but not limited to fetal, neonatal, infant, adolescent, and adult subjects. Furthermore, a "subject" can include a patient suffering from or suspected of suffering from a condition or disease. Therefore, the terms "subject" and "patient" are used interchangeably herein. In some embodiments, the subject is a human. In other embodiments, the subject is a non-human.

[0201] As used herein, the term "treating" can include reversing, alleviating, inhibiting the progression of, preventing or reducing the disease or condition to which the term applies or one or more symptoms or manifestations of the disease or condition.

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

[0203] As used herein, the term "treatment" of any disease or condition refers to all conditions that can slow down, interrupt, prevent, control or stop the progression of a disease or condition, but does not necessarily mean that all symptoms of all diseases or conditions disappear, and it also includes preventative treatment of the symptoms, especially in patients who are susceptible to such diseases or disorders. In some embodiments, it refers to improving a disease or condition (i.e., slowing down or preventing or alleviating the development of a disease or condition or at least one of its clinical symptoms). In other embodiments, "treatment" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treatment" refers to regulating a disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing parameters of the body) or both. In other embodiments, "treatment" refers to preventing or delaying the onset, occurrence or worsening of a disease or condition.

[0204] As used herein, the term "therapeutically effective amount" or "therapeutically effective dose" refers to an amount of a compound of the present invention that is capable of eliciting a biological or medical response in an individual (e.g., reducing or inhibiting enzyme or protein activity, or ameliorating symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease, etc.). In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount that, when administered to an individual, is effective for: (1) at least partially alleviating, inhibiting, preventing, and / or ameliorating (i) a condition or disease mediated by FAP, or (ii) associated with FAP activity, or (iii) characterized by abnormal activity of FAP; or (2) reducing or inhibiting the activity of FAP; or (3) reducing or inhibiting the expression of FAP. In another embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a cell, or an organ, or a non-cellular biological substance, or a medium, is effective for at least partially reducing or inhibiting the activity of FAP; or at least partially reducing or inhibiting the expression of FAP.

[0205] As used herein, the terms "administering" and "administering" a compound should be understood as providing a compound of the present invention or a prodrug of a compound of the present invention to an individual in need thereof. It should be understood that one skilled in the art can treat a disease currently expressing FAP, such as fibrosarcoma, osteosarcoma, pancreatic cancer, ovarian cancer, etc., by administering an effective amount of a compound of the present invention.

[0206] Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0208] Figure 1-1 This is the nuclear magnetic resonance spectrum of NYM030 in Preparation Example 1 of the present invention;

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

[0210] Figure 1-3 This is the XRPD pattern of NYM030 in Preparation Example 1 of the present invention;

[0211] Figure 1-4 The HPLC spectrogram of NYM030 in Preparation Example 1 of the present invention is shown in Figure 16-3 ;

[0212] Figure 1-5 The TGA and DSC diagrams of NYM030 in Preparation Example 1 of the present invention are shown;

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

[0214] Figure 2-2 The TGA and DSC diagrams of the p-toluenesulfonate crystalline form A in Example 1 of the present invention are shown;

[0215] Figure 2-3 For the p-toluenesulfonate crystalline form A in Example 1 of the present invention 1 H NMR spectra;

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

[0217] Figure 3-2 The TGA and DSC diagrams of the p-toluenesulfonate crystalline form B in Example 1 of the present invention are shown;

[0218] Figure 3-3 For the p-toluenesulfonate crystal form B in Example 1 of the present invention 1 H NMR spectra;

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

[0220] Figure 4-2 The TGA and DSC diagrams of the phosphate crystal form A in Example 1 of the present invention are shown;

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

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

[0223] Figure 5-2 The TGA and DSC diagrams of the phosphate crystal form B in Example 1 of the present invention are shown;

[0224] Figure 5-3 is the phosphate crystal form B in Example 1 of the present invention 1 H NMR spectra;

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

[0226] Figure 6-2 The TGA and DSC diagrams of the phosphate crystal form C in Example 1 of the present invention are shown;

[0227] Figure 6-3 The phosphate crystal form C in Example 1 of the present invention is 1 H NMR spectra;

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

[0229] Figure 7-2 The TGA and DSC diagrams of sulfate crystal form A in Example 1 of the present invention are shown;

[0230] Figure 7-3 is the sulfate crystal form A in Example 1 of the present invention 1 H NMR spectra;

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

[0232] Figure 8-2 The TGA and DSC diagrams of the sulfate crystal form B in Example 1 of the present invention are shown;

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

[0234] Figure 8-4 LC-MS diagram of sulfate salt form B in Example 1 of the present invention;

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

[0236] Figure 9-2 The TGA and DSC diagrams of the hydrobromide salt form A in Example 1 of the present invention are shown;

[0237] Figure 9-3 The hydrobromide salt form A in Example 1 of the present invention is 1 H NMR spectra;

[0238] Figure 9-4 LC-MS diagram of hydrobromide salt form A in Example 1 of the present invention;

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

[0240] Figure 10-2 The TGA and DSC diagrams of the free crystalline form A in Example 2 of the present invention are shown;

[0241] Figure 10-3 The free form A in Example 2 of the present invention 1 H NMR spectra;

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

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

[0244] Figure 12-2 The TGA and DSC diagrams of the free form C in Example 2 of the present invention are shown;

[0245] Figure 12-3 The free form C in Example 2 of the present invention 1 H NMR spectra;

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

[0247] Figure 13-2 The TGA and DSC diagrams of the free-state crystalline form D in Example 2 of the present invention are shown;

[0248] Figure 13-3 The free state crystal form D in Example 2 of the present invention is 1 H NMR spectra;

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

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

[0251] Figure 13-6 : XRPD patterns of the free form D in Example 2 of the present invention before and after VS testing;

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

[0253] Figure 14-2 The TGA and DSC diagrams of the free crystalline form E in Example 2 of the present invention are shown;

[0254] Figure 14-3 The free form E in Example 2 of the present invention 1 H NMR spectra;

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

[0256] Figure 15-2 The TGA and DSC diagrams of the free form F in Example 2 of the present invention are shown;

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

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

[0259] Figure 16-2 The TGA and DSC diagrams of the free form G in Example 2 of the present invention are shown;

[0260] Figure 16-3 The free form G in Example 2 of the present invention 1 H NMR spectra;

[0261] Figure 17 The results of the in vitro anti-tumor cell viability of NYM030 in Test Example 2 of the present invention are as follows;

[0262] Figure 18 This is a trend chart of tumor volume in each group in Test Example 3 of the present invention;

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

[0264] Figure 20 The changes in tumor volume of SJSA-1 tumor-bearing mice in Test Example 4 of the present invention;

[0265] Figure 21 The weight changes of SJSA-1 tumor-bearing mice in Test Example 4 of the present invention;

[0266] Figure 22 The figure shows the weight changes of ICR mice in Test Example 5 of the present invention. DETAILED DESCRIPTION

[0267] The following embodiments of the present invention are described in detail. The embodiments described below are exemplary and are only used to explain the present invention, and are not to be construed as limiting the present invention. Where specific techniques or conditions are not specified in the embodiments, the techniques or conditions described in the literature in this field or the product specifications are used. Where the manufacturer of the reagents or instruments is not specified, all are conventional products that can be obtained commercially.

[0268] General experiments

[0269] 1. Instrument information and methods

[0270] Dynamic moisture sorption / desorption analysis (DVS)

[0271] Dynamic moisture sorption / desorption analysis was performed using a DVS Intrinsic (SMS, UK). The test used a gradient profile with humidity changes from 50% to 95% to 0% to 50%, with each gradient increasing by 10% within the 0% to 90% range. The gradient endpoint was determined using the dm / dt method, with a dm / dt of less than 0.002% maintained for 10 minutes, or a maximum of 180 minutes per gradient. After the test, the samples were analyzed by XRPD to confirm any changes in the solid form.

[0272] X-ray powder diffraction (XRPD)

[0273] The solid samples were analyzed using a Bruker D8 Advance X-ray powder diffractometer (Bruker, Germany) or a Panalytical EMPYREAN X-ray diffractometer (PANalytical, UK). The 2θ scanning angle ranged from 3° to 45°, using Cu target Kα1 radiation, a voltage of 40 kV, a current of 40 mA, and a zero-background sample pan.

[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 equilibrated open aluminum sample pan and automatically weighed in the TGA furnace. The sample was heated to the final temperature at a rate of 10°C / min. A nitrogen purge rate of 60 mL / min was applied to the sample and 40 mL / min was applied to the balance.

[0276] Differential Scanning Calorimetry (DSC): A TA Discovery 250 (TA, US) differential scanning calorimeter was used. A 1-2 mg 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 a nitrogen purge rate of 50 mL / min.

[0277] Polarized light microscopy (PLM)

[0278] The polarizing microscope model is Nikon Ci-POL (Nikon, JP). A small amount of sample is placed on a glass slide and the sample morphology is observed using a suitable lens.

[0279] NMR analysis ( 1 H NMR) method

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

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

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

[0283]

[0284] NYM030 molecular structure (its NMR spectrum is shown in Figure 1-1 , LC-MS spectrum see Figure 1-2 )

[0285] Synthesis route:

[0286] Step 1:

[0287]

[0288] Compound (1) (6.00 g) was dissolved in 50.0 mL of THF, and NMM (3.23 g) and methylsulfonyl 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 organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain compound (2) (7.50 g).

[0289] Step 2:

[0290]

[0291] A mixture of compound (2) (7.50 g) and MeNH2 (52.2 g, 504 mmol, 50.0 mL, 30.0% purity) 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, followed by filtration to afford compound (3) (6.2 g) as a colorless oil.

[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 the solution. The reaction mixture was stirred at 20°C for 12 hours, diluted with 150 mL of water, and extracted with ethyl acetate. The organic layer after extraction was washed with brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a residue. The residue was separated and purified by column chromatography to obtain compound (4) (12.0 g).

[0295] Step 4:

[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 the 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 organic layer after extraction was washed with 100 mL of brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a 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 the solution under N2 purge. The resulting suspension was degassed under vacuum and purged with hydrogen several times. Under H2 purge, the mixture was stirred at 20°C for 12 hours, filtered, and the filtrate was freed from the solvent under vacuum to obtain a residue. Purification by prep-HPLC gave compound (6) (4.70 g).

[0301] Step 6:

[0302]

[0303] Compound (6) (650 mg) and compound (7) (1.03 g) were dissolved in 5.00 mL of DMF 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 7:

[0305]

[0306] Compound (8) (600 mg) was dissolved in 6.00 mL of MeCN solvent, and TsOH·H2O (390 mg) was added to the 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 the solution, and the mixture was stirred at 25°C for 12 hours to obtain a reaction mixture. After removing the solvent under vacuum, the resulting product was ground in 10 mL of MTBE solvent to obtain solid compound (12) (512 mg).

[0310] Step 9:

[0311]

[0312] Compound (9) (350 mg) and compound (12) (291 mg, 521 μmol, 1.00 eq) obtained in the above step were dissolved in 3.00 mL of DMF 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 obtain compound (NYM030) (60.0 mg, purity 99.6%). The XRPD pattern is shown in FIG. Figure 1-3 , the HPLC spectrum of NYM030 is shown in Figure 1-4 , TGA and DSC diagrams are shown in Figure 1-5 .

[0313] Example 1: Preparation and characterization of pharmaceutically acceptable acid addition salts of compounds of formula (I)

[0314] 1. p-Toluenesulfonate Crystalline Form A / B

[0315] 1.1 Approximately 46.0 mg of the compound of formula (I) prepared in Preparation Example 1 and 9.8 mg of p-toluenesulfonic acid were weighed separately, added to 1.0 mL of THF / water (v / v, 4 / 1), stirred at room temperature for 2 days, and cooled at -4°C to obtain p-toluenesulfonate salt Form A.

[0316] Among them, the XRPD pattern of p-toluenesulfonate crystal form A is as follows Figure 2-1 The XRPD data are shown in Table 1, the TGA and DSC data are shown in Figure 2-2 As shown, 1 H-NMR was tested in DMSO-d6 and the results were as follows Figure 2-3 TGA results showed an 11.4% weight loss when heated to 150°C, with possible decomposition occurring after 230°C. DSC results revealed endothermic signals at 102.1°C and 138°C (peak temperatures). Form A of the p-toluenesulfonate salt transformed into an amorphous form upon heating to 125°C.

[0317] The NMR integration results showed that characteristic peaks of p-toluenesulfonic acid ligand appeared at 2.28 ppm, 7.10 ppm, and 7.47 ppm. According to 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 of 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 Approximately 45.8 mg of the compound of formula (I) prepared in Preparation Example 1 and 9.8 mg of p-toluenesulfonic acid were weighed separately, added to 1.0 mL of THF / water (v / v, 4 / 1), suspended at room temperature for 2 days, and then cooled at -15°C to obtain p-toluenesulfonate salt Form B.

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

[0322] The NMR integration results showed that characteristic peaks of p-toluenesulfonic acid ligand appeared at 2.28 ppm, 7.10 ppm, and 7.47 ppm. According to 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 form A / B / C

[0326] 2.1 Approximately 46.1 mg of the compound of formula (I) prepared in Preparation Example 1 and 50 μL of phosphoric acid (1 M phosphoric acid solution diluted in ethanol) were weighed and added to 1 mL of ethylene glycol monomethyl ether / MTBE (v / v, 1 / 1), stirred at room temperature for 3 days, the suspension was centrifuged, and the solid was vacuum dried to obtain phosphate crystal form A.

[0327] Among them, the XRPD pattern of phosphate crystal form A is as follows Figure 4-1 The XRPD data are shown in Table 3, the TGA and DSC data are shown in Table 3. Figure 4-2 As shown, 1 H-NMR was tested in DMSO-d6 and the results were as follows Figure 4-3 The TGA results showed that the sample had a weight loss of 13.5% when heated to 180°C; the DSC results showed that the sample had endothermic signals at 70.6°C, 126.8°C, 191.4°C, 208.2°C and 229.2°C (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 Approximately 46.0 mg of the compound of formula (I) prepared in Preparation Example 1 and 50 μL of phosphoric acid (1 M phosphoric acid solution diluted in ethanol) were weighed separately, added to 1 mL of ethylene glycol monomethyl ether / MTBE (v / v, 1 / 1), and stirred at room temperature for 2 days. The suspension was centrifuged and the solid was vacuum dried to obtain phosphate crystal form B.

[0331] Among them, the XRPD pattern of phosphate crystal form B is as follows Figure 5-1 As shown, TGA and DSC diagrams are as follows Figure 5-2 As shown, 1 H-NMR was tested in DMSO-d6 and the results were as follows Figure 5-3 The TGA results showed that the sample had a weight loss of 3.3% when heated to 120°C; the DSC results showed that the sample had endothermic signals at 56.2°C and 151.9°C (peak temperature).

[0332] Ion chromatography results showed that the mass proportion of phosphate ions in this sample was 9.22%. Based on the ion chromatography results, the molar ratio of free phosphate ions was calculated to be approximately 1:1. In summary, it can be seen that phosphate crystal form B is a solid containing adsorbed solvent.

[0333] 2.3 Approximately 91.8 mg of the compound of formula (I) prepared in Preparation Example 1 and 300 μL of phosphoric acid (1 M phosphoric acid solution diluted in ethanol) were weighed separately, added to 2 mL of ethylene glycol monomethyl ether / MTBE (v / v, 1 / 1), and stirred at room temperature for 2 days. The suspension was centrifuged and the solid was vacuum dried to obtain phosphate crystal form C.

[0334] Among them, the XRPD pattern of phosphate crystal form C is as follows Figure 6-1 As shown, TGA and DSC diagrams are as follows Figure 6-2 As shown, 1 H-NMR was tested in DMSO-d6 and the results were as follows Figure 6-3 The TGA results showed that the sample had a weight loss of 9.0% when heated to 150°C; the DSC results showed that the sample had endothermic signals at 59.8°C and 182.6°C (peak temperature).

[0335] The ion chromatography results showed that the mass proportion of phosphate ions in the sample was 19.8%. According to the ion chromatography results, the molar ratio of free state to phosphate ions was approximately 1:2.7.

[0336] 3. Sulfate crystal form A / B

[0337] 3.1 Approximately 45.5 mg of the compound of formula (I) prepared in Preparation Example 1 and 50 μL of aqueous sulfuric acid were weighed, added to 1.0 mL of acetone, and stirred at room temperature for 2 days. The suspension was centrifuged, and the solid was vacuum dried to obtain sulfate salt Form A.

[0338] Among them, the XRPD pattern of sulfate crystal form A is as follows Figure 7-1 The XRPD data are shown in Table 4, the TGA and DSC data are shown in Table 4. Figure 7-2 As shown, 1 H-NMR was tested in DMSO-d6 and the results were as follows Figure 7-3 The TGA results showed that the sample had a weight loss of 7.7% when heated to 120°C; the DSC results showed that the sample had endothermic signals at 68.2°C and 207.3°C (peak temperature).

[0339] The ion chromatography results showed that sulfate ions accounted for 6.37% by mass, and the calculated ratio of compound to sulfate ion 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 Approximately 91.7 mg of the compound of formula (I) prepared in Preparation Example 1 and 300 μL of aqueous sulfuric acid were weighed, added to 2.0 mL of acetone, and stirred at room temperature for 2 days. The suspension was centrifuged, and the solid was vacuum dried to obtain sulfate salt Form B.

[0343] Among them, the XRPD pattern of sulfate crystal form B is as follows Figure 8-1 The XRPD data are shown in Table 5, the TGA and DSC data are shown in Table 5. Figure 8-2 As shown, 1 H-NMR was tested in DMSO-d6 and the results were as follows Figure 8-3 As shown, LC-MS pictures are as follows Figure 8-4 TGA results showed a 6.1% weight loss when the sample was heated to 120°C; DSC results showed endothermic signals at 76.5°C and 142.2°C (peak temperatures). The residual solid of sulfate Form B after oscillating in water for 2 hours did not undergo a crystalline transformation.

[0344] The ion chromatography results showed that the mass proportion of sulfate ions in the sample was 17.6%. According to the ion chromatography results, the ratio of free state to sulfate ions was 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 Form A

[0348] About 46.0 mg of the compound of formula (I) prepared in Preparation Example 1 and 150 μL of hydrobromic acid (1 M hydrobromic acid solution diluted in 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 vacuum dried to obtain hydrobromide salt Form A.

[0349] Among them, the XRPD pattern of hydrobromide salt form A is as follows Figure 9-1 The XRPD data are shown in Table 6, the TGA and DSC data are shown in Table 6. Figure 9-2 As shown, 1 H-NMR was tested in DMSO-d6 and the results were as follows Figure 9-3 As shown, LC-MS pictures are as follows Figure 9-4 TGA results showed a 9.0% weight loss when the sample was heated to 150°C; DSC results revealed an endothermic signal at 66.8°C (peak temperature). Ion chromatography results indicated a 16.5% bromide ion content. Based on the ion chromatography results, the ratio of free bromide to bromide ion was calculated to be approximately 1:2.5.

[0350] Table 6: XRPD analysis data of hydrobromide salt 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 Free Crystalline Form of Compound of Formula (I)

[0353] 1. Free crystal form A

[0354] About 100.2 mg of the compound of formula (I) prepared in Preparation Example 1 was weighed, 1 mL of tetrahydrofuran / water (v / v, 2 / 1) solvent was added, and the mixture was stirred at room temperature. After the solid precipitated, 3 ml of tetrahydrofuran / water (v / v, 2 / 1) solvent was added and stirred at room temperature for 1 day. After the suspension was centrifuged, the solid was vacuum dried at room temperature to obtain free crystalline Form A.

[0355] Among them, the XRPD pattern of free form A is as follows Figure 10-1 The XRPD data are shown in Table 7, and the TGA and DSC patterns are shown in Table 7. Figure 10-2 As shown, 1 H-NMR was tested in DMSO-d6 and the results were as follows Figure 10-3 The TGA results showed that the sample had a weight loss of 0.6% when heated to 100°C; the DSC results showed that the sample had an endothermic signal at 204.3°C (peak temperature).

[0356] Table 7: XRPD analysis data of free 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 crystal form B

[0359] About 45.8 mg of the compound of formula (I) prepared in Preparation Example 1 was weighed, 2 mL of acetone was added, and the mixture was suspended at a low temperature of 10° C. for 7 days. The suspension was centrifuged to obtain free crystalline Form B.

[0360] Among them, the XRPD pattern of free form B is as follows Figure 11 The XRPD data are shown in Table 8.

[0361] Table 8: XRPD analysis data of free 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] About 70.0 mg of the compound of formula (I) prepared in Preparation Example 1 was weighed, 3.0 mL of dimethylformamide / water (v / v, 1 / 2) solvent was added, and the mixture was stirred at 10° C. for 3 days. After the suspension was centrifuged, the solid was vacuum dried at room temperature for 3 days to obtain free crystalline Form C.

[0365] Among them, the XRPD pattern of free form C is as follows Figure 12-1 The XRPD data are shown in Table 9, the TGA and DSC data are shown in Table 9. Figure 12-2 As shown, 1 H-NMR was tested in DMSO-d6 and the results were as follows Figure 12-3 The TGA results showed that the sample had a 9.1% weight loss when heated to 150°C; the DSC results showed that the sample had a broad endothermic signal at 25°C to 120°C.

[0366] Table 9: XRPD analysis data of free form 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 crystal form D

[0369] About 200.1 mg of the compound of formula (I) prepared in Preparation Example 1 was weighed, 6.0 mL of acetone solvent was added, and the mixture was stirred at 10° C. for 3 days. After the suspension was centrifuged, the solid was vacuum dried at room temperature for 3 days to obtain free crystalline Form D.

[0370] Among them, the XRPD pattern of free crystal form D is as follows: Figure 13-1 The XRPD data are shown in Table 10, the TGA and DSC diagrams are shown in Table 11. Figure 13-2 As shown, 1 H-NMR was tested in DMSO-d6 and the results were as follows Figure 13-3 As shown in the PLM diagram Figure 13-4 As shown, the DVS curve is as follows Figure 13-5 As shown, the XRPD images before and after VS test are as follows Figure 13-6 As shown. TGA results showed that the sample lost 1.0% weight when heated to 100°C; DSC results showed that the sample had an endothermic signal at 199.7°C (peak temperature). PLM results showed that the free form D was long rod-shaped particles with a length of about 10μm, and its crystalline state was good. DVS results showed that the free form D gained 1.12% weight at 80% RH, gained 3.06% weight at 95% RH, and lost 1.97% weight at 0% RH. The sample was less hygroscopic; there was no significant change in the XRPD results before and after the DVS experiment, indicating that its crystal form was less affected by humidity and had good stability. NMR results showed that it was consistent with the reference spectrum, with no obvious organic solvent residue.

[0371] Table 10: XRPD analysis data of free 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] About 200.2 mg of the compound of formula (I) prepared in Preparation Example 1 was weighed, 1 mL of tetrahydrofuran / water (v / v, 2 / 1) solvent was added, and the mixture was stirred at room temperature. After the solid precipitated, 3 ml of tetrahydrofuran / water (v / v, 2 / 1) solvent was added and stirred at room temperature for 7 days. After the suspension was centrifuged, the solid was vacuum dried at room temperature to obtain the free crystalline Form E.

[0375] Among them, the XRPD pattern of free crystal form E is as follows Figure 14-1 The XRPD data are shown in Table 11, the TGA and DSC diagrams are shown in Figure 14-2 As shown, 1 H-NMR was tested in DMSO-d6 and the results were as follows Figure 14-3 As shown. TGA results showed a 7.4% weight loss when the sample was heated to 150°C; DSC results showed endothermic signals at 108.4°C and 205.0°C (peak temperatures). NMR results were consistent with the reference spectrum, with tetrahydrofuran signal peaks at 1.76 and 3.59 ppm. XRPD analysis of the free-state Form E after heating to 150°C and then cooling to room temperature showed significant changes.

[0376] Table 11: XRPD analysis data of free 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 crystal form F

[0379] About 100.1 mg of the compound of formula (I) prepared in Preparation Example 1 was weighed, 1.0 mL of tetrahydrofuran / water (v / v, 1 / 1) solvent was added, and the mixture was suspended at room temperature for 15 h. 3.0 mL of tetrahydrofuran / water (v / v, 1 / 1) solvent was added and the mixture was suspended for 24 h. After the suspension was centrifuged, the solid was vacuum dried at 40 ° C for 3 days to obtain free crystalline Form F.

[0380] Among them, the XRPD pattern of free form F is as follows Figure 15-1 The XRPD data are shown in Table 12, the TGA and DSC diagrams are shown in Table 13. Figure 15-2 As shown, 1 H-NMR was tested in DMSO-d6 and the results were as follows Figure 15-3 As shown. TGA results showed a 3.0% weight loss when the sample was heated to 120°C; DSC results showed endothermic signals at 65.4°C and 168.7°C (peak temperatures). Heating test results showed that the free-state Form F, after being heated to 120°C and then cooled to room temperature, showed no significant change in XRPD results. NMR analysis revealed no significant residual organic solvent peaks.

[0381] Table 12: XRPD analysis data of free 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-state crystalline form G was obtained by weighing 100.2 mg of the free-state crystalline form D, adding 2.0 mL of acetonitrile solution, suspending the mixture at room temperature for 3 days, centrifuging the suspension, and then drying the mixture under vacuum at room temperature.

[0385] Among them, the XRPD pattern of free crystal form G is as follows Figure 16-1 The XRPD data are shown in Table 13, the TGA and DSC diagrams are shown in Table 14. Figure 16-2 As shown, 1 H-NMR was tested in DMSO-d6 and the results were as follows Figure 16-3 The TGA results showed that the sample had a weight loss of 1.1% when heated to 100°C; the DSC results showed that the sample had an endothermic signal at 196.1°C (peak temperature).

[0386] Table 13: XRPD analysis data of free 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 test of the crystalline form of the compound of formula (I)

[0389] The acid addition salt crystalline form of the compound of formula (I) prepared in Example 1 and the free crystalline form of the compound of formula (I) prepared in Example 2 were subjected to stability testing. Appropriate samples of the different crystalline 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 the corresponding number of days. XRPD characterization was then performed. The results showed that both the acid addition salt crystalline form and the free crystalline form of the present invention exhibited high stability.

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

[0391] The XRPD pattern of the remaining solid was unchanged when the free-state Form G was shaken in 0.9% saline and water at 40°C. The XRPD pattern of the remaining solid was unchanged when the free-state Form G was added to 0.9% saline and shaken at 25°C for three days. This indicates that the free-state Form D maintains its crystalline structure over extended periods of time 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, which has a strong affinity for FAP, was used as a positive control.

[0397] FAP (purchased from ACROBiosystems Inc.) was coupled to the surface of a CM5 chip. The running buffer consisted of 50 mM Tris, 150 mM NaCl, 0.05% P20 (Tween 20), and 5% DMSO, pH 7.2-7.4. A series of different concentrations of the test samples BR102910 (a selective fibroblast activation protein (FAP) inhibitor, purchased from MedChemExpress LLC) and NYM030 molecules were prepared. A series of different concentrations of the test sample solutions were diluted in equal proportions (maximum concentration: 70 nM, dilution ratio: 2, 5 different concentrations), and the samples were injected and the affinity of the test samples BR102910 and NYM030 to FAP was measured. The affinity of the test samples BR102910 and NYM030 to FAP is represented by the equilibrium dissociation constant KD (Kd / Ka) value, where Kd is the dissociation constant and Ka is the binding constant. The smaller the KD value, the higher the affinity of the compound to the protein.

[0398] The test results are shown in Table 16 below. NYM030 showed low nanomolar affinity for FAP and had higher affinity for FAP than 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 cells were counted using a Vi-Cell XR cell counter. The cell suspension was adjusted to the appropriate concentration. The culture medium used to culture different cells 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 incubated at 37°C, 5% CO2, and 95% humidity for 24 hours.

[0403] Prepare a series of serial dilutions of the test article stock solution (NYM030 in DMSO, 6 mg / ml) in a 1:3 ratio with DMSO. Each dilution is then diluted 100-fold with culture medium. Finally, add 10 μl of the corresponding 100-fold dilution to each well of each cell line. Plate three replicates at each drug concentration and incubate in a 37°C, 5% CO2 incubator for 72 hours.

[0404] After 72 hours of drug treatment, according to the instructions of the CTG (CELL TITER-GLO) cell viability assay, 50 μl of pre-melted and room temperature CTG solution was added to each well and mixed on a microplate shaker for 2 minutes. After standing at room temperature for 10 minutes, the fluorescence signal value was measured using an Envision 2104 plate reader.

[0405] The results of NYM030 in vitro anti-tumor activity test and cell viability test are shown in Table 18, Figure 17 As shown, the results showed that NYM030 had a strong in vitro anti-tumor effect on ES-2, SJSA-1, and 5637 cells, and could significantly inhibit the proliferation of ES-2, SJSA-1, and 5637 cells. Among them, the inhibitory activity against ES-2 was the highest, while the anti-tumor activity against HS746T and SHP-77 cells was low, demonstrating the specific anti-tumor activity of NYM030.

[0406] Table 17: Cell line culture information

[0407]

[0408]

[0409] Table 18: In vitro anti-tumor activity IC of NYM030 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: NYM030 drug efficacy experiment in HT1080 tumor model

[0412] The HT1080 model, provided by Suzhou Hengjia Biotechnology Co., Ltd., is a subcutaneous xenograft HT1080 tumor model established in BALB / c nude mice. This model is a mouse model derived from human fibrosarcoma cells. Twenty female HT1080 xenograft human fibrosarcoma mice were randomly selected for the experiment. Tumor size was measured before the experiment and the mice were ranked according to tumor size. Sixteen mice with tumors of appropriate size were selected and divided into three groups: G1, G2, and G3. Group G1 (treatment group) consisted of six tumor-bearing mice. Each animal received a tail vein injection of NYM030 in saline at a dose of approximately 10 mg / kg. The drug dosage was calculated based on the body weight of each tumor-bearing mouse. Group G2 (positive control group) consisted of six tumor-bearing mice. Each animal received a tail vein injection of irinotecan in saline at a dose of approximately 5 mg / kg. (NYM030 and irinotecan were administered at the same molar ratio, i.e., the same cytotoxic drug dosage). In the G3 group (control group), four tumor mice were injected with physiological saline solution through the tail vein of each animal. The dosage was close to that of the G1 and G2 groups, and the injection time of each group was recorded. The tumor volume (long diameter and short diameter) and body weight of the G1, G2, and G3 groups were measured before administration and 2, 4, 6, 8, 10, 12, and 14 days after administration. The status of the mice was observed at the same time, and accurate records were kept. The long diameter and short diameter of the tumor measured during the tumor efficacy evaluation were used to calculate the tumor volume. The calculation formula is as follows: Tumor volume (TV) = a × b 2 / 2 (a is the long diameter, b is the short diameter). The trend diagram of tumor volume in each group is shown in Figure 18 , the weight change trend of mice is shown in Figure 19 It can be seen that NYM030 inhibits tumor growth more significantly than irinotecan and normal saline, and there is no significant change in the weight of mice, indicating that NYM030 has a good anti-tumor effect and good safety.

[0413] Test Example 4: NYM030 drug efficacy experiment in SJSA-1 tumor model

[0414] The experimental animal SJSA-1 model was provided by Sino-US Crown Biotechnology (Taicang) Co., Ltd. and is a female BALB / c nude mouse model in which humanized SJSA-1 cell lines were subcutaneously transplanted. BALB / c nude mice were inoculated subcutaneously on the right side of the back with 2×10 6 SJSA-1 cells, tumors grow to an average volume of approximately 100 mm 3 .

[0415] The experiment was divided into negative control and 3 doses of NYM030 (10 mg / kg, 3 mg / kg and 1 mg / kg, prepared as dosing solution using 5% glucose solution) of their own single-drug groups, with 8 animals in each group. The drugs were administered by tail vein injection with a dosing volume of 10 μL / g for a total of two weeks, and the experiment ended on the 28th day. Specific dosing information is shown in Table 19. Before the start of dosing, all animals were weighed and the tumor volume was measured with a vernier caliper. The tumor volume (long diameter and short diameter) and body weight were measured before and after administration, and the effects of tumor growth and treatment on the normal behavior of the animals were observed, including the activity of the experimental animals, food and water intake, weight gain or loss, and other abnormal conditions. The efficacy was evaluated based on the inhibition rate of tumor volume (TGI), and the changes in animal weight (such as attached Figure 21 ) and mortality were evaluated for safety. 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 and control groups at a specific time point; tumor volume (TV) = a × b 2 / 2 (a is the major diameter, b is the minor diameter).

[0416] As attached Figure 20 As shown, on day 24, the tumor volume of mice in the negative control group exceeded 3000 mm 3 On day 24, the average tumor volume of the negative control group was 2997.74 mm 3 ; Each dose group of NYM030 (10 mg / kg, 3 mg / kg and 1 mg / kg) could significantly inhibit tumor growth, with TGIs of 60.69%, 46.59% and 44.46%, respectively. Among them, the high-dose group had a better tumor inhibition effect. There was no obvious weight loss in the negative control group and each dose group of NYM030, and no abnormal conditions occurred in the mice, indicating that NYM030 has good safety.

[0417] Table 19: Dosing Information

[0418] Group Number of animals Drug administration group Single dose (mg / kg) Dosage time (days) 01 8 5% glucose solution - Day 1.2.3.4.8.9.10.11 02 8 NYM030 1 Day 1.2.3.4.8.9.10.11 03 8 NYM030 3 Day 1.2.3.4.8.9.10.11 04 8 NYM030 10 Day 1.2.3.4.8.9.10.11

[0419] Test Example 5: Continuous drug administration toxicity experiment

[0420] The mouse model was 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. The animals' general indices (hair, activity level, diet, etc.) and mortality (time of death, etc.) were observed. The animals' weight changes were measured before administration, during the observation period, and before sacrifice at the end of the experiment. The mice were sacrificed on the last day of the experiment, and their heart, liver, spleen, lungs, and kidneys were dissected and observed for changes in their tissues. Figure 22 The change in body weight is used to evaluate the change in body weight at a certain time point compared to the body weight before the start of the experiment. The calculation formula is: change in body weight = body weight at the time of weighing / initial body weight * 100%.

[0421] like Figure 22 As shown, after 7 days of continuous administration, all mice showed no mortality or abnormal reactions, and no abnormalities were observed in their organs during autopsy. Furthermore, there was no significant change in body weight during the experiment. This indicates that NYM030 is a safe molecule.

[0422] Test Example 6: ICR mouse acute toxicity test

[0423] The mouse model used 6-8 week old female ICR mice purchased from Suzhou Hengjia Biotechnology Co., Ltd. Nine ICR mice were randomly divided into three groups, each containing three mice. The experimental group received 100 mg / kg NYM030, the positive control group received 50 mg / kg irinotecan, and the control group received normal saline. The animals were observed for general health (hair, activity level, diet, etc.), mortality (time of death, etc.), and body weight before and 2, 4, 6, and 8 days after dosing. The mice were sacrificed and autopsied on the final day of the experiment to examine all major organ abnormalities. During the eight days of observation, no mice died or had any abnormal reactions. Organ dissection revealed no abnormalities, and all mice had gained weight after the completion of the experiment. While the effective drug (cytotoxic drug) dose was consistent, the experimental group lost less weight than the positive control group. At the end of the experiment, the experimental group had gained weight compared to pre-dose, while the positive control group had not. This demonstrates the safety profile of NYM030.

[0424] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0425] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify 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), 2. The acid addition salt according to claim 1, characterized in that The acid addition salts include inorganic acid salts or organic acid salts; Optionally, the inorganic acid salt comprises phosphate, sulfate or hydrobromide; Optionally, the organic acid salt comprises p-toluenesulfonate; Optionally, the acid addition salt comprises a phosphate, sulfate, hydrobromide, or p-toluenesulfonate of the compound represented by formula (I); Optionally, the acid addition salt includes at least one of p-toluenesulfonate crystalline form A, p-toluenesulfonate crystalline form B, phosphate crystalline form A, phosphate crystalline form B, phosphate crystalline form C, sulfate crystalline form A, sulfate crystalline form B, hydrobromide crystalline form A, p-toluenesulfonate crystalline form A and p-toluenesulfonate crystalline form B of the compound represented by formula (I).

3. The acid addition salt according to claim 1, characterized in that The acid addition salt is a p-toluenesulfonate crystalline form A of the compound represented by formula (I), and its 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°; Optionally, the acid addition salt is a p-toluenesulfonate crystalline form A of the compound represented by formula (I), and its 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°, and 26.32±0.2°; Optionally, the acid addition salt is a p-toluenesulfonate crystalline form A of the compound represented by formula (I), and its 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°; Optionally, the acid addition salt is a p-toluenesulfonate salt of the compound represented by formula (I) in Form A, which has a weight loss of 11.4±0.1% at 150° C.; Optionally, the acid addition salt is p-toluenesulfonate crystalline form A, whose DSC chart contains one or more endothermic signals at 102.1°C ± 3°C and 138.0°C ± 3°C; Optionally, the acid addition salt is a p-toluenesulfonate salt of the compound represented by formula (I), Form A, which has an X-ray powder diffraction pattern substantially as shown in Figure 2-1; Optionally, the acid addition salt is the p-toluenesulfonate crystalline form A of the compound represented by formula (I), which has a TGA graph and a DSC graph substantially as shown in Figure 2-2.

4. The acid addition salt according to claim 1, characterized in that The acid addition salt is a p-toluenesulfonate crystalline form B of the compound represented by formula (I), and its 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°; Optionally, the acid addition salt is a p-toluenesulfonate salt form B of the compound represented by formula (I), and its 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°, and 24.38±0.2°; Optionally, the acid addition salt is a p-toluenesulfonate crystalline form B of the compound represented by formula (I), and its 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°; Optionally, the acid addition salt is a p-toluenesulfonate salt of the compound represented by formula (I) in Form B, which has a weight loss of 7.9±0.1% at 160° C.; Optionally, the acid addition salt is p-toluenesulfonate crystalline form B, and its DSC chart contains one or more endothermic signals of 89.3°C ± 3°C and 130.4°C ± 3°C; Optionally, the acid addition salt is a p-toluenesulfonate salt of the compound represented by formula (I), Form B, which has an X-ray powder diffraction pattern substantially as shown in FIG3-1; Optionally, the acid addition salt is the p-toluenesulfonate crystalline form B of the compound represented by formula (I), which has a TGA graph and a DSC graph substantially as shown in FIG3-2 .

5. The acid addition salt according to claim 1, characterized in that The acid addition salt is a phosphate crystal form A of the compound represented by 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°, and 6.19±0.2°; Optionally, the acid addition salt is a phosphate crystal form A of the compound represented by 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°, 18.59±0.2°, and 23.52±0.2°; Optionally, the acid addition salt is a phosphate crystal form A of the compound represented by 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°; Optionally, the acid addition salt is a phosphate salt of the compound represented by formula (I) in Form A, which has a weight loss of 13.5±0.1% at 180°C; Optionally, the acid addition salt is a phosphate crystal form A, and its DSC graph comprises one or more endothermic signals of 70.6°C±3°C, 126.8°C±3°C, 191.4°C±3°C, 208.2°C±3°C, and 229.2°C±3°C; Optionally, the acid addition salt is a phosphate salt of the compound represented by formula (I) in Form A, which has an X-ray powder diffraction pattern substantially as shown in FIG4-1; Optionally, the acid addition salt is the phosphate crystal form A of the compound represented by formula (I), which has a TGA graph and a DSC graph substantially as shown in FIG4-2 .

6. The acid addition salt according to claim 1, characterized in that The acid addition salt is a phosphate crystal form B of the compound represented by formula (I), which has a weight loss of 3.3±0.1% at 120°C; Optionally, the acid addition salt is a phosphate crystal form B, and its DSC graph comprises one or more endothermic signals at 56.2°C ± 3°C and 151.9°C ± 3°C; Optionally, the acid addition salt is a phosphate salt of the compound represented by formula (I) in Form B, which has an X-ray powder diffraction pattern substantially as shown in FIG5-1; Optionally, the acid addition salt is the phosphate crystal form B of the compound represented by formula (I), which has a TGA graph and a DSC graph substantially as shown in FIG5-2.

7. The acid addition salt according to claim 1, characterized in that The acid addition salt is a phosphate crystal form C of the compound represented by formula (I), which has a weight loss of 9.0±0.1% at 150°C; Optionally, the acid addition salt is a phosphate crystal form C, and its DSC chart comprises one or more endothermic signals of 59.8°C ± 3°C and 182.6°C ± 3°C; Optionally, the acid addition salt is a phosphate salt of the compound represented by formula (I), Form C, which has an X-ray powder diffraction pattern substantially as shown in FIG6-1; Optionally, the acid addition salt is the phosphate crystal form C of the compound represented by formula (I), which has a TGA graph and a DSC graph substantially as shown in FIG6-2.

8. The acid addition salt according to claim 1, characterized in that The acid addition salt is a sulfate crystal form A of the compound represented by formula (I), and its 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°; Optionally, the acid addition salt is a sulfate crystalline form A of the compound represented by 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°; Optionally, the acid addition salt is a sulfate crystalline form A of the compound represented by 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°; Optionally, the acid addition salt is a sulfate salt of the compound represented by formula (I) in Form A, which has a weight loss of 7.7±0.1% at 120°C; Optionally, the acid addition salt is sulfate crystalline form A, and its DSC graph comprises one or more endothermic signals at 68.2°C ± 3°C and 207.3°C ± 3°C; Optionally, the acid addition salt is a sulfate salt of the compound represented by formula (I), Form A, which has an X-ray powder diffraction pattern substantially as shown in Figure 7-1; Optionally, the acid addition salt is sulfate crystalline form A of the compound represented by formula (I), which has a TGA graph and a DSC graph substantially as shown in FIG7-2 .

9. The acid addition salt according to claim 1, characterized in that The acid addition salt is a sulfate crystal form B of the compound represented by formula (I), and its 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°; Optionally, the acid addition salt is a sulfate crystalline form B of the compound represented by 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°, and 28.96±0.2°; Optionally, the acid addition salt is a sulfate crystalline form B of the compound represented by 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°; Optionally, the acid addition salt is a sulfate salt of the compound represented by formula (I) in Form B, which has a weight loss of 6.1±0.1% at 120° C.; Optionally, the acid addition salt is sulfate crystal form B, and its DSC graph contains one or more endothermic signals of 76.5°C ± 3°C and 142.2°C ± 3°C; Optionally, the acid addition salt is a sulfate salt of the compound represented by formula (I) in Form B, which has an X-ray powder diffraction pattern substantially as shown in FIG8-1; Optionally, the acid addition salt is sulfate crystal form B of the compound represented by formula (I), which has a TGA graph and a DSC graph substantially as shown in FIG8-2 .

10. The acid addition salt according to claim 1, characterized in that The acid addition salt is a hydrobromide salt crystalline form A of the compound represented by formula (I), and its 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°; Optionally, the acid addition salt is a hydrobromide salt crystalline form A of the compound represented by formula (I), and its 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°; Optionally, the acid addition salt is a hydrobromide salt crystalline form A of the compound represented by formula (I), and its 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°; Optionally, the acid addition salt is a hydrobromide salt of the compound represented by formula (I) in Form A, which has a weight loss of 9.0±0.1% at 150° C.; Optionally, the acid addition salt is hydrobromide salt form A, whose DSC graph comprises an endothermic signal at 66.8°C ± 3°C; Optionally, the acid addition salt is a hydrobromide salt of the compound represented by formula (I), Form A, which has an X-ray powder diffraction pattern substantially as shown in Figure 9-1; Optionally, the acid addition salt is the hydrobromide salt form A of the compound represented by formula (I), which has a TGA graph and a DSC graph substantially as shown in FIG9-2 .

11. A crystalline form of a compound represented by formula (I), 12. The crystal form according to claim 11, 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°, and 12.10±0.2°; Optionally, the crystalline form is free crystalline 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°, and 17.32±0.2°; Optionally, the crystalline form is free crystalline 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°, 20.80±0.2°; Optionally, the crystalline form is free crystalline form A, which has a weight loss of 0.6±0.1% at 100° C.; Optionally, the crystalline form is free crystalline form A, which comprises an endothermic signal of 204.3±3°C; Optionally, the crystalline form is free crystalline form A, which has an X-ray powder diffraction pattern substantially as shown in Figure 10-1; Optionally, the crystalline form is free crystalline form A, which has a TGA graph and a DSC graph substantially as shown in FIG10-2 .

13. The crystal form according to claim 11, 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: 12.47±0.2°, 13.73±0.2°, and 16.84±0.2°; Optionally, the crystalline form is free crystalline 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°; Optionally, the crystalline form is a free crystalline 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°, 20.61±0.2° Optionally, the crystalline form is free crystalline Form B, and the free crystalline Form B has an X-ray powder diffraction pattern substantially as shown in FIG11 .

14. The crystal form according to claim 11, 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: 15.61±0.2°, 22.69±0.2°, and 24.11±0.2°; Optionally, the crystalline form is a free crystalline 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°; Optionally, the crystalline form is a free crystalline 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°; Optionally, the crystalline form is free crystalline form C, which has a weight loss of 9.1±0.1% at 150°C; Optionally, the crystalline form is a free crystalline form C, which comprises an endothermic signal of 82.2°C ± 3°C to 101.8°C ± 3°C; Optionally, the crystalline form is a free crystalline form C, which has an X-ray powder diffraction pattern substantially as shown in FIG12-1; Optionally, the crystalline form is free crystalline form C, which has a TGA graph and a DSC graph substantially as shown in Figure 12-2.

15. The crystal form according to claim 11, 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°, 13.85±0.2°, and 15.75±0.2°; Optionally, the crystalline form is a free crystalline 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°, and 18.76±0.2°; Optionally, the crystalline form is a free crystalline 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°, 18.76±0.2°; Optionally, the crystalline form is free crystalline form D, which has a weight loss of 1.0±0.1% at 100° C.; Optionally, the crystalline form is a free crystalline form D, which comprises an endothermic signal of 199.7°C ± 3°C; Optionally, the crystalline form is a free crystalline form D, which has an X-ray powder diffraction pattern substantially as shown in FIG13-1; Optionally, the crystalline form is free crystalline form D, which has a TGA graph and a DSC graph substantially as shown in FIG13-2 .

16. The crystal form according to claim 11, 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°, and 15.23±0.2°; Optionally, the crystalline form is a free crystalline 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°, and 22.40±0.2°; Optionally, the crystalline form is a free crystalline 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°, 22.40±0.2°; Optionally, the crystalline form is free crystalline form E, which has a weight loss of 7.4±0.1% at 150°C; Optionally, the crystalline form is a free crystalline form E, which comprises one or more endothermic signals of 108.4°C ± 3°C and 205.0°C ± 3°C; Optionally, the crystalline form is free crystalline Form E, which has an X-ray powder diffraction pattern substantially as shown in Figure 14-1; Optionally, the crystalline form is free crystalline form E, which has a TGA graph and a DSC graph substantially as shown in FIG14-2 .

17. The crystal form according to claim 11, characterized in that 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°, and 13.16±0.2°; Optionally, the crystalline form is free crystalline 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°; Optionally, the crystalline form is free crystalline form F, which has a weight loss of 3.0±0.1% at 120°C; Optionally, the crystalline form is free crystalline form F, which comprises one or more endothermic signals of 65.4°C ± 3°C and 168.7°C ± 3°C; Optionally, the crystalline form is free crystalline form F, which has an X-ray powder diffraction pattern substantially as shown in Figure 15-1; Optionally, the crystalline form is free crystalline form F, which has a TGA graph and a DSC graph substantially as shown in FIG15-2 .

18. The crystal form according to claim 11, 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°, and 12.14±0.2°; Optionally, the crystalline form is free crystalline 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°; Optionally, the crystalline form is a free crystalline 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°, 20.24±0.2°; Optionally, the crystalline form is free crystalline form G, which has a weight loss of 1.1±0.1% at 100° C.; Optionally, the crystalline form is a free crystalline form G, which comprises an endothermic signal of 196.1°C ± 3°C; Optionally, the crystalline form is free crystalline Form G, which has an X-ray powder diffraction pattern substantially as shown in Figure 16-1; Optionally, the crystalline form is free crystalline form G, which has a TGA graph and a DSC graph substantially as shown in Figure 16-2.

19. A pharmaceutical composition, characterized in that A pharmaceutically acceptable acid addition salt of a compound represented by formula (I) according to any one of claims 1 to 10 or a crystalline form according to any one of claims 11 to 18; Optionally, a pharmaceutically acceptable excipient is further included.

20. Use of a pharmaceutically acceptable acid addition salt of a compound of formula (I) according to any one of claims 1 to 10, a crystalline form according to any one of claims 11 to 18, or a pharmaceutical composition according to claim 19 in the preparation of one or more drugs; The drug is used to treat and / or prevent related diseases caused by the expression of FAP; Optionally, the related disease caused by the expression of FAP is selected from tumors and cancers expressing FAP; Optionally, 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; Preferably, the tumor or cancer expressing FAP is selected from at least one of fibrosarcoma, osteosarcoma, pancreatic cancer and ovarian cancer.

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