FGFR4 inhibitor acid salts and their preparation and use

Abstract

The present invention relates to an acid salt of an FGFR4 inhibitor and its preparation and use. The FGFR4 inhibitor is a compound having a structure represented by formula (I) N-((3S,4S)-3-((6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(3-methoxy-3-methylazetidin-1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide, and the acid salt is a p-toluenesulfonate, which can greatly improve the physical and chemical properties such as solubility and bioavailability of the compound represented by formula (I) in free form, and meet the needs of clinical drug formulation development. The p-toluenesulfonate of the present invention has very important clinical use value, and is expected to promote the development of a new family of FGFR4 small molecule inhibitors. [Formula 1] TIFF2024544707000010.tif51170

Description

Detailed Description of the Invention

[0001] [Technical field] The present invention belongs to the field of drug development, and specifically relates to an acid salt of an FGFR4 inhibitor and its preparation method and use. [Background technology]

[0002] Fibroblast growth factors (FGFs) are a family of 22 structurally related polypeptides with distinct biological activities. Their corresponding FGF receptors (FGFRs) belong to the receptor tyrosine kinase (RPTK) family. Four receptors, FGFR1, FGFR2, FGFR3, and FGFR4, have been identified. Interaction with their corresponding ligand, FGF, triggers receptor dimerization and autophosphorylation, initiating multiple downstream signaling cascades, including MAPK and AKT. Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths in China and one of the cancers with the fastest annual increase in incidence. The current first-line treatment regimen is sorafenib, and there are no approved second-line drugs, so targeted anticancer drugs are still needed. While FGF19 is overexpressed in 5%-10% of HCC patients, FGFR4 is the dominant FGFR present in human hepatocytes, and its high expression in hepatocytes is thought to correlate with the aggressiveness of HCC. Therefore, FGFR4 plays a very important role in liver cancer. The interaction between FGF19 and FGFR4 is also thought to be correlated with the invasiveness of other types of cancer (e.g., gastric cancer, prostate cancer, lung cancer, colorectal cancer, pancreatic cancer, and ovarian cancer).

[0003] At present, highly selective FGFR4 inhibitors can effectively treat cancer diseases caused by abnormalities in the FGFR4 signaling pathway and avoid related side effects such as hyperphosphatemia caused by FGFR1-3 inhibition. Highly selective FGFR4 small molecule inhibitors have great prospects for use in the field of tumor targeted therapy. As a good drug candidate, FGFR4 inhibitors can meet the needs of liver cancer and other tumor targeted drugs both in China and abroad, and also bring the advantages of excellent safety and higher specificity.

[0004] After a long period of research, Abbisko Therapeutics Co., Ltd. has invented a small molecule compound with a novel structure and highly selective FGFR4 inhibitory effect, the relevant patent of which is WO2018113584A1 (international publication date: June 28, 2018), and its representative compounds are as follows:

[0005] [ka]

[0006] The compound N-((3S,4S)-3-((6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(3-methoxy-3-methylazetidin-1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide (compound represented by formula (I)) has significantly improved inhibitory activity against FGFR4 target and selectivity against other FGFR1-3 kinase receptors, and can meet the current needs in China and overseas for targeted treatment of tumors such as liver cancer, prostate cancer, pancreatic cancer, esophageal cancer, gastric cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, skin cancer, glioblastoma or rhabdomyosarcoma.

[0007] However, at the time of filing the patent application, raw materials and processes suitable for clinical and industrial use had not been developed, and no further research had been conducted into whether the compound represented by formula (I) was suitable for drug development. Subsequent research by the inventors revealed that the free base compound disclosed in WO2018113584A1 was poorly soluble in water and physiological solvents, had relatively low bioavailability, and was unable to meet clinical requirements and was not suitable for the development of clinical formulations. Therefore, in order to meet the needs of clinical research and commercially available drug formulations, it is urgent to further study the aggregation state of the drug to improve the physical and chemical properties of the compound, meet the needs of pharmaceutical or clinical use, and develop compounds having salt forms or crystalline forms suitable for drug development, thereby overcoming the deficiencies in the prior art. [Summary of the Invention]

[0008] In order to solve the problems in the prior art, the inventors have further studied the aggregation state of the compound represented by formula (I), N-((3S,4S)-3-((6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(3-methoxy-3-methylazetidin-1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide. Through long-term research, the inventors unexpectedly found that p-toluenesulfonate salt can significantly improve the solubility and bioavailability of the free compound represented by formula (I), and its physical and chemical properties such as hygroscopicity and chemical stability can meet the needs of industrial production and the needs of clinical drug formulation development. The p-toluenesulfonate salt of the present invention is widely used in the manufacture of drugs for treating cancer, particularly liver cancer, prostate cancer, pancreatic cancer, esophageal cancer, gastric cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, skin cancer, glioblastoma or rhabdomyosarcoma, and has very important clinical value, which is expected to promote the development of new FGFR4 small molecule inhibitors.

[0009] In a first aspect of the present invention, there is provided a p-toluenesulfonate salt of a compound represented by formula (I).

[0010] [ka]

[0011] In a preferred embodiment, the p-toluenesulfonate salt of the compound represented by formula (I) is a crystalline compound. In a more preferred embodiment, the X-ray powder diffraction pattern (XRPD) of the p-toluenesulfonate salt of the compound represented by formula (I) includes peaks located at diffraction angles (2θ) of 9.02±0.2°, 17.18±0.2°, 17.68±0.2°, 19.60±0.2°, and 22.90±0.2°.

[0012] In an even more preferred embodiment, the X-ray powder diffraction pattern (XRPD) of the compound p-toluenesulfonate represented by formula (I) includes peaks located at diffraction angles (2θ) of 9.02±0.2°, 17.18±0.2°, 17.68±0.2°, 19.60±0.2°, 22.90±0.2°, 10.60±0.2°, 12.72±0.2°, 18.56±0.2°, 21.22±0.2°, and 24.90±0.2°.

[0013] In a further preferred embodiment, the X-ray powder diffraction pattern (XRPD) of the compound p-toluenesulfonate represented by formula (I) includes peaks located at diffraction angles (2θ) of 9.02±0.2°, 17.18±0.2°, 17.68±0.2°, 19.60±0.2°, and 22.90±0.2°, 10.60±0.2°, 12.72±0.2°, 18.56±0.2°, 21.22±0.2°, 24.90±0.2°, 15.32±0.2°, 23.82±0.2°, 24.12±0.2°, 24.60±0.2°, and 25.58±0.2°.

[0014] In a preferred embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt of the compound represented by formula (I) has the following peaks: 9.02±0.2°, 10.60±0.2°, 12.04±0.2°, 12.72±0.2°, 15.32±0.2°, 17.18±0.2°, 17.68±0.2°, 18.56±0.2°, 19.60±0.2°, 20.60±0.2°. The peaks located at diffraction angles (2θ) of 2°, 21.22±0.2°, 22.90±0.2°, 23.82±0.2°, 24.12±0.2°, 24.60±0.2°, 24.90±0.2°, 25.58±0.2°, 27.78±0.2°, 29.04±0.2°, 31.48±0.2°, 36.60±0.2° and 38.16±0.2°.

[0015] In the most preferred embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt of the compound represented by formula (I) is essentially the same as the peaks at the diffraction angles (2θ) shown in Table 1, and the diffraction angles (2θ) and related intensity data (±0.2°) are as follows:

[0016] [Table 1]

[0017] In a preferred embodiment, the unit cell of the compound p-toluenesulfonate represented by formula (I) is P1, with a = 9.079(3) Å, b = 10.561(3) Å, and c = 10.882(3) Å, and the volume of the unit cell is 908.1(4) Å.

[0018] In a preferred form, the p-toluenesulfonate salt of the compound represented by formula (I) is a hydrate.

[0019] In a more preferred embodiment, each molecule of the hydrate of p-toluenesulfonate of the compound represented by the formula (I) contains 1 to 3 water molecules.

[0020] In a more preferred embodiment, each molecule of the hydrate of p-toluenesulfonate of the compound represented by formula (I) contains one, two or three water molecules.

[0021] As the invention-creation of the present application, the applicant designates a crystal of p-toluenesulfonate salt of compound represented by formula (I) having any one of the X-ray powder diffraction data described above as crystalline form A (Form A), and the obtained crystal has been physically characterized by DSC, TGA and XRPD, and is shown to be a well-crystalline solid. The DSC and TGA results, as shown in Figures 1 and 2, indicate that the crystalline form of the acid salt of compound represented by formula (I) is a monohydrate.

[0022] In a second aspect of the present invention, there is provided a method for producing p-toluenesulfonate of the compound represented by formula (I), 1) dissolving or dispersing the compound represented by formula (I) in a free form in an aqueous solvent or an appropriate organic solvent, and adding p-toluenesulfonic acid or a p-toluenesulfonic acid solution to the system to form a salt, or adding the compound represented by formula (I) in a free form to a p-toluenesulfonic acid solution to form a salt; 2) collecting the p-toluenesulfonate salt of the compound represented by formula (I), which is the solid product precipitated during the salt formation reaction, or obtaining the p-toluenesulfonate salt of the compound represented by formula (I), which is the solid product, by causing supersaturation in the salt formation system.

[0023] In a preferred embodiment, the method for producing supersaturation in the salt-forming system in step 2) includes one or more of adding seed crystals, volatilizing the solvent, adding a poor solvent, and lowering the temperature.

[0024] In a preferred embodiment, the p-toluenesulfonate salt of the compound represented by formula (I), which is the solid product obtained above, is a crystalline p-toluenesulfonate salt of the compound represented by formula (I).

[0025] In a preferred embodiment, the organic solvent used in the salt formation process in step 1) is selected from organic solvents such as alcohols, chloroalkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzenes, amides, and sulfoxides, or a mixture thereof.

[0026] In a preferred embodiment, the suitable organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, dichloromethane, acetonitrile, acetone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, 2-methoxyethyl ether or a mixture thereof.

[0027] In a third aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of the p-toluenesulfonate salt of the compound of formula (I) and a pharmaceutically acceptable carrier.

[0028] In a fourth aspect, the present invention provides the use of p-toluenesulfonate salt of the compound of formula (I) in the manufacture of an FGFR4 inhibitor medicament.

[0029] In a fifth aspect of the present invention, there is provided use of p-toluenesulfonate salt of compound of formula (I) in the manufacture of a medicament for treating liver cancer, prostate cancer, pancreatic cancer, esophageal cancer, gastric cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, skin cancer, glioblastoma or rhabdomyosarcoma.

[0030] In a sixth aspect, the present invention provides a method for treating liver cancer, prostate cancer, pancreatic cancer, esophageal cancer, gastric cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, skin cancer, glioblastoma, or rhabdomyosarcoma, which method comprises administering to a patient in need of treatment a therapeutically effective amount of p-toluenesulfonate of compound represented by formula (I) or the pharmaceutical composition. [Brief explanation of the drawings]

[0031] [Figure 1]1 is a differential scanning calorimetry diagram of p-toluenesulfonate (Form A) of the compound represented by formula (I), in which the X axis represents temperature (° C.) and the Y axis represents heat flow (W / G). [Figure 2] 1 is a thermogravimetric analysis diagram of p-toluenesulfonate (Form A) of the compound represented by formula (I), in which the X axis represents temperature (° C.) and the Y axis represents the weight loss rate (%). [Figure 3] 1 shows an X-ray powder diffraction pattern of p-toluenesulfonate (Form A) of the compound represented by formula (I), in which the X axis represents the diffraction peak angle 2θ value (°) and the Y axis represents the peak intensity. [Figure 4] 1 shows a simulated X-ray diffraction powder diffraction pattern (bottom) of a single crystal of p-toluenesulfonate (Form A) of the compound represented by formula (I) and a measured XRPD pattern (top) of p-toluenesulfonate (Form A) of the compound represented by formula (I). The abscissa represents 2θ values ​​(°), and the ordinate represents peak intensity. [Figure 5] FIG. 1 is a unit cell diagram of a single crystal of p-toluenesulfonate (Form A) of the compound represented by formula (I). [Figure 6] 1 shows a DVS pattern of p-toluenesulfonate salt of the compound of formula (I) (Form A), in which the abscissa represents relative humidity (%) and the ordinate represents weight change (%). [Figure 7] 1 shows time / solubility curves for p-toluenesulfonate salt (Form A) of compound of formula (I) and free form of compound of formula (I) in a 25% PEG300 / 5% Solutol HS15 / 70% water solvent. The abscissa is time (hours) and the ordinate is concentration (mg / mL). DETAILED DESCRIPTION OF THE INVENTION

[0032] [Specific embodiment] Drugs differ in bioavailability, solubility, melting point, chemical and physical stability, etc. depending on their crystalline form, which further affects the safety and efficacy of the drug. In order to develop a salt form or crystalline form suitable for drug development, the inventors have intensively studied the compound represented by formula (I), N-((3S,4S)-3-((6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-(3-methoxy-3-methylazetidin-1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide, and screened a large number of salt forms and crystalline forms of the compound represented by formula (I). As a result, it was found that the p-toluenesulfonate salt can significantly improve the physical and chemical properties, such as solubility and bioavailability, of the free compound represented by formula (I). The physical and chemical properties, such as hygroscopicity and chemical stability, can also meet the needs of industrial production and the needs of clinical drug formulation development. This is expected to promote the development of a new family of FGFR4 small molecule inhibitors.

[0033] DETAILED DESCRIPTION: Unless stated to the contrary, terms used in the following specification and claims shall have the following meanings.

[0034] A "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, and other components, such as physiologically / pharmaceutically acceptable carriers and excipients, to facilitate administration to a living body and contribute to the absorption of the active ingredients, thereby further exerting their biological activity.

[0035] "Polycrystalline forms" refer to crystalline forms that have the same chemical composition but differ in the spatial arrangement of the molecules, atoms, and / or ions that make up the crystal. Although polycrystalline forms have the same chemical composition, their packing and geometric arrangements differ, and they may exhibit different physical properties, such as melting point, shape, color, density, hardness, deformability, stability, solubility, dissolution rate, and similar properties. Both polycrystalline forms may be monotropic or tautomeric, depending on their temperature-stability relationship. In a monotropic system, the relative stability between the two solid phases remains unchanged with temperature. Conversely, in a tautomeric system, a transition temperature exists, at which the stability of the two phases changes. The phenomenon of a compound existing in different crystalline structures is called drug polycrystallization.

[0036] The various crystalline structures of the present invention can be distinguished from one another using various analytical techniques known to those skilled in the art, including, but not limited to, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and / or thermogravimetric analysis (TGA).

[0037] Methods and Materials 1.1. X-ray powder diffraction Those skilled in the art will recognize that X-ray powder diffraction patterns may be obtained with measurement errors depending on the measurement conditions used. The intensities of X-ray powder diffraction patterns can vary depending on the conditions of the materials used. Relative intensities may also vary depending on the experimental conditions, and correspondingly, accurate intensities are not taken into account. Furthermore, the measurement error in conventional X-ray powder diffraction angles is typically about 5% or less, and such measurement errors are considered to apply to the diffraction angles. Therefore, the crystal structures of the present invention are not limited to those that provide X-ray powder diffraction patterns that are completely identical to those shown in the drawings disclosed herein. Any crystal structure that has an X-ray powder diffraction pattern that is essentially identical to that disclosed in the drawings is within the scope of the present invention. Those skilled in the art should be able to determine that an X-ray powder diffraction pattern is essentially identical to that shown in the drawings. Other appropriate standard calibrations are known to those skilled in the art. However, relative intensities may vary depending on the size and shape of the crystal.

[0038] The crystalline forms of the compounds of the present invention were characterized by their X-ray powder diffraction patterns. Therefore, X-ray powder diffraction patterns of the salts were obtained on a Bruker D8 Discover X-ray powder diffractometer equipped with a GADDS (General Area Diffraction Detector System) CS operating in reflection mode using Cu Kα radiation (1.54 Å). Scanning was performed at a tube voltage of 40 kV and a current of 40 mA. The sample was scanned for 60 seconds within the 2θ range of 3.0° to 40°. The diffractometer was calibrated using corundum standards for peak positions expressed in terms of 2θ. All analyses were typically performed between 20°C and 30°C. Data were acquired and integrated using GADDS for WNT software version 4.1.14T. Diffraction patterns were analyzed using DiffracPlus software with Eva version 9.0.0.2, published in 2003.

[0039] XRPD samples were typically prepared by placing the sample on a single-crystal silicon wafer and pressing the sample powder with a glass plate or equivalent to ensure the sample surface was flat and of appropriate height. The sample holder was then placed in a Bruker XRPD instrument, and an X-ray powder diffraction pattern was acquired using the instrument parameters described above. Measurement discrepancies associated with the results of such X-ray powder diffraction analyses arise from multiple factors, including (a) errors in sample preparation (e.g., sample height), (b) instrument error, (c) calibration difference, (d) operator error (including errors incurred when measuring peak positions), and (e) material properties (e.g., preferred orientation error). Calibration error and sample height error often result in all peaks shifting in the same direction. Typically, this calibration factor will match the measured peak positions with the expected peak positions, within the expected 2θ value of ±0.2°.

[0040] 1.2. Differential scanning calorimetry (DSC) Differential scanning calorimetry (DSC) experiments were performed by TA Instruments TMThe measurements were performed on a Model Q2000. Samples (approximately 1-6 mg) were weighed into aluminum trays, recorded to the nearest 1 mg, and transferred to the DSC. The instrument was purged with nitrogen gas at 50 mL / min. Data were collected from room temperature to 350°C at a heating rate of 10°C / min. The endothermic peaks were plotted downward. However, those skilled in the art will recognize that the observed onset and maximum temperatures in DSC measurements vary to some extent depending on the heating rate, crystal shape and purity, and other measurement parameters.

[0041] 1.3, Thermogravimetric analysis (TGA) Thermogravimetric analysis (TGA) experiments were performed using TA Instruments TM The experiment was carried out on a Model Q500. Samples (approximately 10-30 mg) were placed in a pre-tared platinum tray. The instrument accurately measured the sample weight and recorded it to the nearest 1 mg‰. The furnace was purged with nitrogen gas at 100 mL / min. Data were collected from room temperature to 300 °C at a heating rate of 10 °C / min.

[0042] 1.4. Dynamic Vapor Sorption (DVS) The experimental method for characterizing the acid salt of the compound of crystalline formula (I) using dynamic vapor sorption (DVS) involves taking a small amount of powder of the acid salt of the compound of crystalline formula (I) and placing it in a precision sample pan that is set up with the instrument. After the sample is loaded, it is transferred to the instrument for measurement. All instruments used in this patent for dynamic vapor sorption are DVS Intrinsic models. The experimental parameters are set to use nitrogen gas as the carrier gas, a constant temperature of 25°C, and a mass percentage change rate per unit time (dm / dt) of 0.01% / min as the criteria for reaching equilibrium. A programmed humidity change cycle is set with an initial relative humidity of 0% and an end-point relative humidity of 90%, with two cycles, each with a change in RH of 10%.

[0043] The reagents in the examples of the present invention are known and commercially available as commercial industrial or analytical reagents, or can be synthesized using or according to methods known in the art, and the API raw materials can be produced according to patent WO2018113584A1.

[0044] Unless otherwise specified, all reactions herein are carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, solvents are dry solvents, and temperatures are in degrees Celsius (°C). As used herein, the term "room temperature" or "RT" refers to an ambient temperature of 20-25°C (68-77°F).

[0045] The present invention will be described in more detail and completely by the following examples, which are used to illustrate only specific embodiments of the present invention and should not be construed as limiting the scope of the present invention in any way.

[0046] Preparation of specific examples Example 1 Preparation of p-toluenesulfonate of compound represented by formula (I) 5 mg of the free compound of Formula (I) was weighed and dissolved in 0.5 mL of ethyl acetate. 1.67 mg of p-toluenesulfonic acid was weighed and dissolved in 0.1 mL of tetrahydrofuran. The p-toluenesulfonic acid solution was slowly added to the solution of the compound of Formula (I) with stirring overnight. The mixture was filtered and the filter cake was dried in a vacuum drying cabinet at 40 °C and characterized by DSC, TGA, and XRPD. The DSC and TGA patterns of the obtained p-toluenesulfonate salt of the compound of Formula (I) are shown in Figures 1 and 2, respectively, and the XRPD diffraction pattern is shown in Figure 3.

[0047] Example 2 Preparation of p-toluenesulfonate of compound represented by formula (I) 2 g of the compound of formula (I) in free form was weighed and dissolved in 160 mL of ethyl acetate. 668 mg of p-toluenesulfonic acid was weighed and dissolved in 4 mL of tetrahydrofuran. The p-toluenesulfonic acid solution was slowly added to the solution of the compound of formula (I) with stirring. The mixture was stirred overnight and filtered. The filter cake was dried in a vacuum drying oven at 40°C. The XRPD diffraction pattern of the p-toluenesulfonate salt of the compound of formula (I) is consistent with that shown in Figure 3.

[0048] Example 3 Preparation of p-toluenesulfonate of compound represented by formula (I) 5 g of the compound of formula (I) in free form was weighed and dissolved / suspended in 400 mL of acetone. 1670 mg of p-toluenesulfonic acid was weighed and dissolved in 10 mL of tetrahydrofuran. The p-toluenesulfonic acid solution was slowly added to the solution of the compound of formula (I) with stirring, followed by stirring overnight. The mixture was filtered and the filter cake was dried in a vacuum drying cabinet at 40°C. The XRPD diffraction pattern of the p-toluenesulfonate salt of the compound of formula (I) is consistent with that shown in Figure 3.

[0049] Example 4. Single crystal production and characterization 150 mg of p-toluenesulfonate salt of the compound represented by formula (I) was weighed, 1 mL of solvent (composition: methanol:ethanol = 1:1, plus 2% water) was added, and the mixture was stirred at 50 °C for 15 min. The suspension was filtered through a 0.45 μm filter, and the filtrate was used as the mother liquor. 340 μL of the mother liquor was taken, and 260 μL of solvent was added. After uniform mixing, the mixture was cooled at room temperature and recrystallized to obtain single crystals.

[0050] A suitable single crystal was selected and detected using a Bruker APEX-II CCD single crystal diffractometer. The temperature was maintained at 220 K during data collection. The unit cell parameters of the compound p-toluenesulfonate represented by formula (I) are shown in Table 2. The single crystal XRPD simulation results are consistent with the XRPD results of the compound p-toluenesulfonate represented by formula (I), as shown in Figure 4, and the unit cell structure of the single crystal is shown in Figure 5. Table 2:

[0051] [Table 2]

[0052] Example 5 Moisture absorption behavior test

[0053] The hygroscopicity of compound p-toluenesulfonate (Form A) of formula (I) was evaluated by measuring the hygroscopic weight gain (weight gain after hygroscopic absorption / weight gain before hygroscopic absorption × 100%) at various relative humidities using a dynamic vapor sorption method. The results are shown in Figure 6. The experimental results demonstrate that compound p-toluenesulfonate (Form A) of formula (I) of the present invention exhibits good hygroscopicity, with a change in crystalline weight of essentially 2% or less as the relative humidity (%) increases, meeting the needs of industrial production and clinical formulation development.

[0054] Example 6 Stability Test The p-toluenesulfonate salt (Form A) of the compound represented by formula (I) and the free form of the compound represented by formula (I) were subjected to stability tests under high temperature and accelerated test conditions. The stability of the p-toluenesulfonate salt (Form A) of the compound represented by formula (I) and the free form of the compound represented by formula (I) was evaluated using chemical purity as an evaluation index. The experimental results are shown in Table 3:

[0055] [Table 3]

[0056] The above experimental results show that the compound of the present invention is stable under high temperature and accelerated test conditions for 14 days, and the chemical stability of the product meets the needs of industrial production and clinical drug formulation development.

[0057] Example 7 Solubility Measurement 1) Solubility in water 2 mg of p-toluenesulfonate (Form A) of the compound of formula (I) and 2 mg of the compound of formula (I) in free form were weighed into 2 mL glass bottles, and 0.4 mL of water was added to each bottle. The bottles were stirred with a magnetic stirrer at room temperature for 24 hours, centrifuged, and the content in the liquid phase was measured. The experimental results are shown in Table 4:

[0058] [Table 4]

[0059] The above experimental results demonstrate that the p-toluenesulfonate salt (Form A) of compound of formula (I) has significantly higher water solubility than the free form of the compound of formula (I), and can meet the needs of clinical drug formulation development. 2) Solubility in physiological solvents 80 mg of p-toluenesulfonate salt of compound of formula (I) (Form A) and 80 mg of free compound of formula (I) were weighed into 4 mL glass vials, and 2 mL of solvent (25% PEG300 / 5% Solutol HS15 / 70% water) (v / v / v) was added to each vial. The vials were stirred at room temperature with a magnetic stirrer. Samples were taken at different time points, centrifuged, and the liquid content was measured. The results are shown in Figure 7. The experimental results showed that the solubility of p-toluenesulfonate salt of compound of formula (I) was significantly higher than that of free compound of formula (I), meeting the needs of clinical drug formulation development.

[0060] Example 8: Pharmacokinetics in Animals The p-toluenesulfonate salt (Form A) of the compound represented by formula (I) and the free form of the compound represented by formula (I) were each subjected to a PK experiment in monkeys at a dose of 200 mpk (amount as the free form compound). The experimental results are shown in Table 5.

[0061] [Table 5]

[0062] The above test results indicate that the p-toluenesulfonate salt of compound represented by formula (I) can significantly increase the exposure of the compound represented by formula (I) in free form in the bodies of monkeys, and therefore the bioavailability of compound represented by formula (I) in free form (p-toluenesulfonate salt (Form A)) is significantly higher than that of the compound represented by formula (I).

[0063] All documents related to the present invention are incorporated by reference in this application as if each document were incorporated individually. Furthermore, after reading the contents of the present invention, those skilled in the art may make various variations and modifications to the present invention, and it should be understood that these equivalents are also encompassed within the scope of the claims appended hereto.

Claims

1. A compound p-toluenesulfonate salt of formula (I), 【Chemical 1】 The compound p-toluenesulfonate represented by the formula (I) is a crystalline compound. A p-toluenesulfonic acid salt of the compound represented by formula (I).

2. The X-ray powder diffraction pattern (XRPD) of the compound p-toluenesulfonate represented by formula (I) is characterized by including peaks located at diffraction angles (2θ) of 9.02±0.2°, 17.18±0.2°, 17.68±0.2°, 19.60±0.2°, and 22.90±0.2°. The p-toluenesulfonic acid salt of the compound represented by formula (I) according to claim 1.

3. The X-ray powder diffraction pattern (XRPD) of the compound p-toluenesulfonate represented by formula (I) is characterized by including peaks located at diffraction angles (2θ) of 10.60±0.2°, 12.72±0.2°, 18.56±0.2°, 21.22±0.2°, and 24.90±0.2°. The p-toluenesulfonic acid salt of the compound represented by formula (I) according to claim 2.

4. The X-ray powder diffraction pattern (XRPD) of the compound p-toluenesulfonate represented by formula (I) is characterized by including peaks located at diffraction angles (2θ) of 15.32±0.2°, 23.82±0.2°, 24.12±0.2°, 24.60±0.2°, and 25.58±0.2°. The p-toluenesulfonic acid salt of the compound represented by formula (I) according to claim 3.

5. The X-ray powder diffraction pattern of the compound p-toluenesulfonate represented by formula (I) is 9.02±0.2°, 10.60±0.2°, 12.04±0.2°, 12.72±0.2°, 15.32±0.2°, 17.18±0.2°, 17.68±0.2°, 18.56±0.2°, 19.60±0.2°, 20.60±0.2°, 21.22±0.2°. 0.2°, 22.90±0.2°, 23.82±0.2°, 24.12±0.2°, 24.60±0.2°, 24.90±0.2°, 25.58±0.2°, 27.78±0.2°, 29.04±0.2°, 31.48±0.2°, 36.60±0.2° and 38.16±0.2°. The p-toluenesulfonic acid salt of the compound represented by formula (I) according to claim 1.

6. The unit cell of the compound p-toluenesulfonate represented by formula (I) is P1, with a = 9.079(3) Å, b = 10.561(3) Å, and c = 10.882(3) Å, and the volume of the unit cell is 908.1(4) Å. ３ characterized in that A p-toluenesulfonate salt of the compound represented by formula (I) according to any one of claims 1 to 5.

7. The compound p-toluenesulfonate represented by the formula (I) is a hydrate. A p-toluenesulfonate salt of the compound represented by formula (I) according to any one of claims 1 to 5.

8. The compound p-toluenesulfonate represented by formula (I) is a hydrate, and each molecule of the hydrate contains 1 to 3 water molecules. A p-toluenesulfonate salt of the compound represented by formula (I) according to any one of claims 1 to 5.

9. The compound p-toluenesulfonate represented by formula (I) is a hydrate, characterized in that each molecule of the hydrate contains one, two or three water molecules. A p-toluenesulfonate salt of the compound represented by formula (I) according to any one of claims 1 to 5.

10. A method for producing p-toluenesulfonate of the compound represented by formula (I) according to claim 1, comprising the steps of: 1) a step of dissolving or dispersing the compound represented by formula (I) in a free form in an aqueous solvent or an appropriate organic solvent, and adding p-toluenesulfonic acid or a p-toluenesulfonic acid solution to the system to form a salt, or adding the compound represented by formula (I) in a free form to a p-toluenesulfonic acid solution to form a salt; 2) collecting the p-toluenesulfonate salt of the compound represented by formula (I), which is a solid product precipitated during the salt formation reaction, or obtaining the p-toluenesulfonate salt of the compound represented by formula (I), which is a solid product, by causing supersaturation in the salt formation system.

11. In the step 2), the method for generating supersaturation in the salt-forming system is selected from one or more of the following: addition of seed crystals, evaporation of a solvent, addition of a poor solvent, and temperature reduction. The method of claim 10.

12. The suitable organic solvent used in step 1) is selected from the group consisting of alcohols, chloroalkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzenes, amides, sulfoxides, or mixtures thereof. The method of claim 10.

13. the suitable organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, dichloromethane, acetonitrile, acetone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, 2-methoxyethyl ether or a mixture thereof; The method of claim 12.

14. A pharmaceutical composition comprising a therapeutically effective amount of the p-toluenesulfonic acid salt of compound of formula (I) according to claim 1 and a pharmaceutically acceptable carrier.

15. Use of the p-toluenesulfonate salt of the compound represented by formula (I) according to claim 1 in the manufacture of an FGFR4 inhibitor drug.

16. Use of the p-toluenesulfonate salt of compound of formula (I) according to claim 1 in the manufacture of a medicament for treating liver cancer, prostate cancer, pancreatic cancer, esophageal cancer, gastric cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, skin cancer, glioblastoma or rhabdomyosarcoma.

17. 10. The compound p-toluenesulfonate of formula (I) according to claim 1 for treating liver cancer, prostate cancer, pancreatic cancer, esophageal cancer, gastric cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, skin cancer, glioblastoma or rhabdomyosarcoma, A therapeutically effective amount of the p-toluenesulfonic acid salt of the compound of formula (I) is administered to a patient in need of treatment.

18. 15. The pharmaceutical composition according to claim 14 for treating liver cancer, prostate cancer, pancreatic cancer, esophageal cancer, gastric cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, skin cancer, glioblastoma or rhabdomyosarcoma, A pharmaceutical composition to be administered in a therapeutically effective amount to a patient in need of treatment.

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