Phosphate or polymorphic form of imidazo [1, 2-a] pyridine compound

Abstract

The invention provides a phosphate of a compound shown in a formula (I) and a polymorphic substance of the phosphate, and the phosphate and the polymorphic substance of the phosphate have excellent hygroscopicity, solubility and stability, have excellent druggability and are suitable for industrial production and storage. In addition, the phosphate and the polymorph thereof have excellent pharmacokinetic properties.

Description

[0001] This application claims the right of priority from the following prior patent applications:

[0002] A prior application filed by the applicant with the China National Intellectual Property Administration on December 18, 2023, with the patent application number 202311742946.0 and the title "Phosphate Salt of Imidazo[1,2-a]pyridine Compounds or Its Polymorphs".

[0003] The entire text of the above prior patent applications is incorporated into this application by reference. Technical Field

[0004] The present invention relates to a phosphate salt of an imidazo[1,2-a]pyridine compound or its polymorph. Background Art

[0005] Gastrointestinal inflammatory diseases or gastric acid-related diseases such as peptic ulcer, gastric / duodenal ulcer, gastritis, gastroesophageal reflux disease (GERD), and non-erosive reflux disease (NERD) are the most common digestive system diseases. To address the problems of traditional proton pump inhibitors (PPIs), in recent studies on proton pump inhibitors (PPIs), the interest and demand for potassium-competitive acid blockers (P-CABs, proton pump inhibitors) are increasing. This drug has a mechanism of inhibiting gastric acid secretion by reversibly binding to H + / K + ATPase. In particular, different from irreversible proton pump inhibitors (PPIs), reversible proton pump inhibitors (P-CABs) have a fast onset mechanism and are convenient to take regardless of whether they are taken before or after meals, and are expected to achieve good therapeutic effects.

[0006] (Azetidin-1-yl)(8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)methanone (Zastaprazan) is an innovative potassium ion-competitive acid blocker (P-CAB). Currently, a Phase III clinical trial for erosive esophagitis is underway. Existing data show that Zastaprazan has the advantages of a fast onset, good acid suppression effect, long-lasting action, and few adverse reactions, and can be extended to the treatment of duodenal ulcer, Helicobacter pylori infection, and non-erosive gastroesophageal reflux disease in the future.

[0007] However, during the research process, the inventors found that the free base of Zastaprazan and its citrate have extremely low solubility, and its citrate will change color under light conditions, and the citrate anhydrous crystal form will undergo crystal transformation under high humidity conditions. These properties are not conducive to the manufacture, preservation, and drug development of the product.

[0008] Based on the above problems, it is necessary to further develop other salt forms or crystal forms with high solubility and good stability to provide better options for the development of this drug. SUMMARY OF THE INVENTION

[0009] To solve the above technical problems, the present invention provides a salt of the compound represented by formula (I) or a polymorph thereof; the salt is a phosphate.

[0010]

[0011] According to an embodiment of the present invention, the salt of the compound represented by formula (I) is the monophosphate of the compound represented by formula (I) or the diphosphate of the compound represented by formula (I).

[0012] According to an embodiment of the present invention, the polymorph of the salt of the compound represented by formula (I) is the polymorph of the monophosphate of the compound represented by formula (I) or the polymorph of the diphosphate of the compound represented by formula (I).

[0013] According to an embodiment of the present invention, the polymorphs of the compound represented by formula (I) are diphosphate crystal form A, monophosphate crystal form B, phosphate crystal form C, phosphate crystal form D, phosphate crystal form E, diphosphate crystal form F, and monophosphate crystal form G of the compound represented by formula (I).

[0014] According to an embodiment of the present invention, in the phosphate crystal form C, phosphate crystal form D, and phosphate crystal form E of the compound represented by formula (I), the ratio of the compound represented by formula (I) to phosphoric acid can be 1:1 or 1:2.

[0015] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the diphosphate crystal form A has characteristic diffraction peaks at the following 2θ angles: 6.6° ± 0.2°, 9.0° ± 0.2°, 10.5° ± 0.2°, 11.7° ± 0.2°, 13.8° ± 0.2°, 20.9° ± 0.2°.

[0016] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the diphosphate crystal form A further includes one, two, or more characteristic diffraction peaks at the following 2θ angles: 14.6° ± 0.2°, 15.2° ± 0.2°, 18.0° ± 0.2°, 18.5° ± 0.2°, 19.9° ± 0.2°, 20.2° ± 0.2°, 22.2° ± 0.2°, 22.6° ± 0.2°, 23.5° ± 0.2°, 27.2° ± 0.2°.

[0017] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the diphosphate crystal form A has characteristic diffraction peaks at the following 2θ angles: 6.6° ± 0.2°, 9.0° ± 0.2°, 10.5° ± 0.2°, 11.7° ± 0.2°, 13.8° ± 0.2°, 20.9° ± 0.2°, 23.5° ± 0.2°, 27.2° ± 0.2°; preferably, the X-ray powder diffraction pattern of the diphosphate crystal form A has characteristic diffraction peaks at the following 2θ angles: 6.6° ± 0.2°, 9.0° ± 0.2°, 10.5° ± 0.2°, 11.7° ± 0.2°, 13.8° ± 0.2°, 18.0° ± 0.2°, 18.5° ± 0.2°, 19.9° ± 0.2°, 20.9° ± 0.2°, 23.5° ± 0.2°, 27.2° ± 0.2°.

[0018] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the diphosphate crystal form A has characteristic diffraction peaks at the following 2θ angles: 6.6° ± 0.2°, 9.0° ± 0.2°, 10.5° ± 0.2°, 11.7° ± 0.2°, 13.8° ± 0.2°, 14.6° ± 0.2°, 15.2° ± 0.2°, 18.0° ± 0.2°, 18.5° ± 0.2°, 19.9° ± 0.2°, 20.2° ± 0.2°, 20.9° ± 0.2°, 22.2° ± 0.2°, 22.6° ± 0.2°, 23.5° ± 0.2°, 27.2° ± 0.2°.

[0019] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the diphosphate crystal form A has characteristic diffraction peaks at the following 2θ angles: 6.6° ± 0.2°, 9.0° ± 0.2°, 13.8° ± 0.2°, 20.9° ± 0.2°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the diphosphate crystal form A further includes characteristic diffraction peaks at one, two or more of the following 2θ angles: 10.5° ± 0.2°, 19.9° ± 0.2°, 22.6° ± 0.2°, 23.5° ± 0.2°, 27.2° ± 0.2°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the diphosphate crystal form A further includes characteristic diffraction peaks at one, two or more of the following 2θ angles: 11.7° ± 0.2°, 14.6° ± 0.2°, 15.2° ± 0.2°, 18.0° ± 0.2°, 18.5° ± 0.2°, 20.2° ± 0.2°, 22.2° ± 0.2°, 23.0° ± 0.2°, 25.2° ± 0.2°, 26.4° ± 0.2°, 29.2° ± 0.2°. According to an embodiment of the present invention, the X-ray powder diffraction pattern analysis data of the diphosphate crystal form A is shown in Table 1. According to an embodiment of the present invention, the diphosphate crystal form A has substantially asFigure 1 The X-ray powder diffraction pattern shown. According to an embodiment of the present invention, the differential scanning calorimetry curve of the diphosphate crystal form A includes an endothermic peak at 197.2 °C ± 3 °C. According to an embodiment of the present invention, the differential scanning calorimetry curve of the diphosphate crystal form A is as shown Figure 2 shown.

[0020] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the monophosphate crystal form B has characteristic diffraction peaks at the following 2θ angles: 8.1° ± 0.2°, 10.8° ± 0.2°, 11.5° ± 0.2°, 17.6° ± 0.2°, 22.0° ± 0.2°, 22.6° ± 0.2°; preferably, the X-ray powder diffraction pattern of the monophosphate crystal form B has characteristic diffraction peaks at the following 2θ angles: 8.1° ± 0.2°, 10.8° ± 0.2°, 11.5° ± 0.2°, 15.9° ± 0.2°, 16.8° ± 0.2°, 17.6° ± 0.2°, 22.0° ± 0.2°, 22.6° ± 0.2°.

[0021] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the monophosphate crystal form B further includes characteristic diffraction peaks at one, two or more of the following 2θ angles: 11.8° ± 0.2°, 19.4° ± 0.2°, 19.8° ± 0.2°, 21.1° ± 0.2°, 23.1° ± 0.2°, 23.9° ± 0.2°, 24.5° ± 0.2°, 25.3° ± 0.2°, 26.9° ± 0.2°.

[0022] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the monophosphate crystal form B has characteristic diffraction peaks at the following 2θ angles: 8.1° ± 0.2°, 10.8° ± 0.2°, 11.5° ± 0.2°, 11.8° ± 0.2°, 15.9° ± 0.2°, 16.8° ± 0.2°, 17.6° ± 0.2°, 19.4° ± 0.2°, 19.8° ± 0.2°, 21.1° ± 0.2°, 22.0° ± 0.2°, 22.6° ± 0.2°, 23.1° ± 0.2°, 23.9° ± 0.2°, 24.5° ± 0.2°, 25.3° ± 0.2°, 26.9° ± 0.2°.

[0023] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the monophosphate crystal form B has characteristic diffraction peaks at the following 2θ angles: 10.8° ± 0.2°, 11.5° ± 0.2°, 17.6° ± 0.2°, 21.9° ± 0.2°, 22.0° ± 0.2°, 22.6° ± 0.2°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the monophosphate crystal form B further includes one, two or more characteristic diffraction peaks at the following 2θ angles: 8.1° ± 0.2°, 15.9° ± 0.2°, 16.8° ± 0.2°, 23.1° ± 0.2°, 25.3° ± 0.2°, 26.9° ± 0.2°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the monophosphate crystal form B further includes one, two or more characteristic diffraction peaks at the following 2θ angles: 7.9° ± 0.2°, 11.8° ± 0.2°, 18.0° ± 0.2°, 19.4° ± 0.2°, 19.8° ± 0.2°, 21.1° ± 0.2°, 23.9° ± 0.2°, 24.5° ± 0.2°, 27.5° ± 0.2°, 32.9° ± 0.2°. According to an embodiment of the present invention, the X-ray powder diffraction pattern analysis data of the monophosphate crystal form B is shown in Table 2. According to an embodiment of the present invention, the monophosphate crystal form B has an X-ray powder diffraction pattern substantially as Figure 3 shown. According to an embodiment of the present invention, the differential scanning calorimetry curve of the monophosphate crystal form B of the present invention contains an endothermic peak at 206.9°C ± 3°C (for example Figure 4 ). According to an embodiment of the present invention, the differential scanning calorimetry curve of the monophosphate crystal form B is as Figure 4 shown.

[0024] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the phosphate crystal form C has characteristic diffraction peaks at the following 2θ angles: 7.4° ± 0.2°, 9.3° ± 0.2°, 11.8° ± 0.2°, 13.9° ± 0.2°, 18.7° ± 0.2°, 26.2° ± 0.2°.

[0025] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the phosphate crystal form C further includes one, two or more characteristic diffraction peaks at the following 2θ angles: 12.5° ± 0.2°, 14.8° ± 0.2°, 17.0° ± 0.2°, 22.4° ± 0.2°, 23.6° ± 0.2°, 26.9° ± 0.2°, 27.7° ± 0.2°.

[0026] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the phosphate crystal form C has characteristic diffraction peaks at the following 2θ angles: 7.4° ± 0.2°, 9.3° ± 0.2°, 11.8° ± 0.2°, 12.5° ± 0.2°, 13.9° ± 0.2°, 14.8° ± 0.2°, 17.0° ± 0.2°, 18.7° ± 0.2°, 20.6° ± 0.2°, 22.4° ± 0.2°, 23.6° ± 0.2°, 26.2° ± 0.2°, 26.9° ± 0.2°, 27.7° ± 0.2°.

[0027] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the phosphate crystal form C has characteristic diffraction peaks at the following 2θ angles: 7.4° ± 0.2°, 9.3° ± 0.2°, 13.9° ± 0.2°, 18.7° ± 0.2°, 26.2° ± 0.2°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the phosphate crystal form C further includes characteristic diffraction peaks at one, two or more of the following 2θ angles: 11.8° ± 0.2°, 20.6° ± 0.2°, 22.4° ± 0.2°, 23.6° ± 0.2°, 27.7° ± 0.2°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the phosphate crystal form C further includes characteristic diffraction peaks at one, two or more of the following 2θ angles: 12.5° ± 0.2°, 12.9° ± 0.2°, 14.8° ± 0.2°, 15.1° ± 0.2°, 15.6° ± 0.2°, 17.0° ± 0.2°, 20.9° ± 0.2°, 22.9° ± 0.2°, 24.5° ± 0.2°, 25.8° ± 0.2°, 26.9° ± 0.2°, 27.3° ± 0.2°.

[0028] According to an embodiment of the present invention, the X-ray powder diffraction pattern analysis data of the phosphate crystal form C is shown in Table 3. According to an embodiment of the present invention, the phosphate crystal form C has substantially as Figure 7 the X-ray powder diffraction pattern shown. According to an embodiment of the present invention, after the phosphate crystal form C is dried at 40°C for 4 h, there is a tendency to turn into crystal form A (as Figure 8 ).

[0029] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the phosphate crystal form D has characteristic diffraction peaks at the following 2θ angles: 7.4° ± 0.2°, 12.9° ± 0.2°, 14.6° ± 0.2°, 14.9° ± 0.2°, 22.5° ± 0.2°, 23.7° ± 0.2°.

[0030] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the phosphate crystal form D further includes the following characteristic diffraction peaks at one, two or more 2θ angles: 11.8° ± 0.2°, 15.7° ± 0.2°, 17.5° ± 0.2°, 18.9° ± 0.2°, 19.2° ± 0.2°, 19.9° ± 0.2°, 21.9° ± 0.2°, 24.7° ± 0.2°, 24.9° ± 0.2°, 26.1° ± 0.2°.

[0031] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the phosphate crystal form D has characteristic diffraction peaks at the following 2θ angles: 7.4° ± 0.2°, 11.8° ± 0.2°, 12.9° ± 0.2°, 14.6° ± 0.2°, 14.9° ± 0.2°, 15.7° ± 0.2°, 17.5° ± 0.2°, 18.9° ± 0.2°, 19.2° ± 0.2°, 19.9° ± 0.2°, 21.9° ± 0.2°, 22.5° ± 0.2°, 23.7° ± 0.2°, 24.7° ± 0.2°, 24.9° ± 0.2°, 26.1° ± 0.2°.

[0032] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the phosphate crystal form D has characteristic diffraction peaks at the following 2θ angles: 7.4° ± 0.2°, 12.9° ± 0.2°, 14.6° ± 0.2°, 14.9° ± 0.2°, 22.5° ± 0.2°, 23.7° ± 0.2°, 26.1° ± 0.2°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the phosphate crystal form D further includes the following characteristic diffraction peaks at one, two or more 2θ angles: 17.5° ± 0.2°, 18.9° ± 0.2°, 19.0° ± 0.2°, 19.2° ± 0.2°, 24.7° ± 0.2°, 24.9° ± 0.2°, 25.1° ± 0.2°, 27.0° ± 0.2°, 30.2° ± 0.2°.

[0033] According to an embodiment of the present invention, the X-ray powder diffraction pattern analysis data of the phosphate crystal form D is shown in Table 4. According to an embodiment of the present invention, the phosphate crystal form D has an X-ray powder diffraction pattern substantially as Figure 9 shown. According to an embodiment of the present invention, the differential scanning calorimetry curve of the phosphate crystal form D contains endothermic peaks at 133.7°C ± 3°C, 144.7°C ± 3°C, 194.8°C ± 3°C (as Figure 11 ). According to an embodiment of the present invention, the differential scanning calorimetry curve of the phosphate crystal form D is as Figure 11 shown.

[0034] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the phosphate crystal form E has characteristic diffraction peaks at the following 2θ angles: 6.4° ± 0.2°, 8.9° ± 0.2°, 14.2° ± 0.2°, 19.3° ± 0.2°, 20.3° ± 0.2°.

[0035] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the phosphate crystal form E further includes characteristic diffraction peaks at one, two or more of the following 2θ angles: 12.4° ± 0.2°, 17.4° ± 0.2°, 17.9° ± 0.2°, 18.3° ± 0.2°, 19.5° ± 0.2°, 21.1° ± 0.2°, 24.5° ± 0.2°, 25.1° ± 0.2°, 25.8° ± 0.2°, 27.4° ± 0.2°.

[0036] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the phosphate crystal form E has characteristic diffraction peaks at the following 2θ angles: 6.4° ± 0.2°, 8.9° ± 0.2°, 12.4° ± 0.2°, 14.2° ± 0.2°, 17.4° ± 0.2°, 17.9° ± 0.2°, 18.3° ± 0.2°, 19.3° ± 0.2°, 19.5° ± 0.2°, 20.3° ± 0.2°, 21.1° ± 0.2°, 24.5° ± 0.2°, 25.1° ± 0.2°, 25.8° ± 0.2°, 27.4° ± 0.2°.

[0037] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the phosphate crystal form E has characteristic diffraction peaks at the following 2θ angles: 6.4° ± 0.2°, 14.2° ± 0.2°, 19.3° ± 0.2°, 20.3° ± 0.2°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the phosphate crystal form E further includes characteristic diffraction peaks at one, two or more of the following 2θ angles: 8.9° ± 0.2°, 18.3° ± 0.2°, 19.5° ± 0.2°, 24.5° ± 0.2°, 25.1° ± 0.2°, 25.8° ± 0.2°, 27.4° ± 0.2°.

[0038] According to an embodiment of the present invention, the X-ray powder diffraction pattern analysis data of the phosphate crystal form E is shown in Table 5. According to an embodiment of the present invention, the phosphate crystal form E has an X-ray powder diffraction pattern substantially as Figure 13 shown.

[0039] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the diphosphate crystal form F has characteristic diffraction peaks at the following 2θ angles: 4.1° ± 0.2°, 12.4° ± 0.2°, 13.7° ± 0.2°, 16.6° ± 0.2°.

[0040] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the diphosphate crystal form F further includes the following characteristic diffraction peaks at one, two or more 2θ angles: 8.2° ± 0.2°, 10.1° ± 0.2°, 17.6° ± 0.2°, 20.4° ± 0.2°, 20.8° ± 0.2°, 24.2° ± 0.2°, 25.7° ± 0.2°.

[0041] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the diphosphate crystal form F has characteristic diffraction peaks at the following 2θ angles: 4.1° ± 0.2°, 8.2° ± 0.2°, 10.1° ± 0.2°, 12.4° ± 0.2°, 13.7° ± 0.2°, 16.6° ± 0.2°, 17.6° ± 0.2°, 20.4° ± 0.2°, 20.8° ± 0.2°, 24.2° ± 0.2°, 25.7° ± 0.2°.

[0042] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the diphosphate crystal form F has characteristic diffraction peaks at the following 2θ angles: 4.1° ± 0.2°, 13.7° ± 0.2°, 16.6° ± 0.2°, 24.2° ± 0.2°, 25.7° ± 0.2°. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the diphosphate crystal form F further includes the following characteristic diffraction peaks at one, two or more 2θ angles: 8.2° ± 0.2°, 10.1° ± 0.2°, 12.4° ± 0.2°, 17.2° ± 0.2°, 17.6° ± 0.2°, 20.4° ± 0.2°, 20.8° ± 0.2°, 22.4° ± 0.2°, 25.0° ± 0.2°, 27.8° ± 0.2°, 29.3° ± 0.2°, 29.9° ± 0.2°, 31.7° ± 0.2°, 38.0° ± 0.2°, 38.5° ± 0.2°, 42.4° ± 0.2°, 42.9° ± 0.2°.

[0043] According to an embodiment of the present invention, the X-ray powder diffraction pattern analysis data of the diphosphate crystal form F is shown in Table 6. According to an embodiment of the present invention, the diphosphate crystal form F has substantially as Figure 15 shown in the X-ray powder diffraction pattern. According to an embodiment of the present invention, the differential scanning calorimetry chart of the diphosphate crystal form F contains endothermic peaks at 136.7°C ± 3°C and 196.3°C ± 3°C (as Figure 18 ). According to an embodiment of the present invention, the differential scanning calorimetry chart of the diphosphate crystal form F is as Figure 18 shown.

[0044] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the monophosphate crystal form G has characteristic diffraction peaks at the following 2θ angles: 7.6° ± 0.2°, 10.8° ± 0.2°, 13.9° ± 0.2°, 20.8° ± 0.2°, 24.2° ± 0.2°.

[0045] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the monophosphate crystal form G further includes one, two or more characteristic diffraction peaks at the following 2θ angles: 13.0° ± 0.2°, 14.5° ± 0.2°, 15.4° ± 0.2°, 15.9° ± 0.2°, 17.3° ± 0.2°, 18.0° ± 0.2°, 19.7° ± 0.2°, 23.4° ± 0.2°, 24.7° ± 0.2°, 26.5° ± 0.2°, 30.8° ± 0.2°.

[0046] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the monophosphate crystal form G further includes one, two or more characteristic diffraction peaks at the following 2θ angles: 8.4° ± 0.2°, 13.0° ± 0.2°, 13.4° ± 0.2°, 14.5° ± 0.2°, 15.4° ± 0.2°, 15.9° ± 0.2°, 17.0° ± 0.2°, 17.3° ± 0.2°, 17.6° ± 0.2°, 18.0° ± 0.2°, 18.4° ± 0.2°, 19.1° ± 0.2°, 19.7° ± 0.2°, 20.5° ± 0.2°, 21.0° ± 0.2°, 21.2° ± 0.2°, 21.9° ± 0.2°, 22.7° ± 0.2°, 23.0° ± 0.2°, 23.4° ± 0.2°, 23.7° ± 0.2°, 24.7° ± 0.2°, 25.4° ± 0.2°, 26.5° ± 0.2°, 27.0° ± 0.2°, 27.6° ± 0.2°, 28.0° ± 0.2°, 29.3° ± 0.2°, 29.6° ± 0.2°, 30.8° ± 0.2°, 31.1° ± 0.2°, 31.9° ± 0.2°, 32.5° ± 0.2°, 33.6° ± 0.2°, 34.4° ± 0.2°, 35.0° ± 0.2°, 35.4° ± 0.2°, 36.4° ± 0.2°.

[0047] According to an embodiment of the present invention, the X-ray powder diffraction pattern of the monophosphate crystal form G has characteristic diffraction peaks at the following 2θ angles: 7.6° ± 0.2°, 10.8° ± 0.2°, 13.0° ± 0.2°, 13.9° ± 0.2°, 14.5° ± 0.2°, 15.4° ± 0.2°, 15.9° ± 0.2°, 17.3° ± 0.2°, 18.0° ± 0.2°, 19.7° ± 0.2°, 20.8° ± 0.2°, 23.4° ± 0.2°, 24.2° ± 0.2°, 24.7° ± 0.2°, 26.5° ± 0.2°, 30.8° ± 0.2°.

[0048] According to an embodiment of the present invention, the X-ray powder diffraction pattern analysis data of the monophosphate crystal form G are shown in Table 7. According to an embodiment of the present invention, the monophosphate crystal form G of the present invention has an X-ray powder diffraction pattern substantially as Figure 19 shown. According to an embodiment of the present invention, the differential scanning calorimetry curve of the monophosphate crystal form G of the present invention contains endothermic peaks at 120.2°C ± 3°C, 188.7°C ± 3°C, and 197.3°C ± 3°C (as Figure 20 ). According to an embodiment of the present invention, the differential scanning calorimetry curve of the monophosphate crystal form G is as Figure 20 shown.

[0049] The present invention also provides a pharmaceutical composition, which comprises a salt of the compound represented by the above formula (I) or a polymorph thereof, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant or a combination thereof.

[0050] According to an embodiment of the present invention, the pharmaceutical composition is used for preventing and / or treating diseases caused by excessive gastric acid secretion; preferably, the disease is a gastrointestinal inflammatory disease or a gastric acid-related disease.

[0051] According to an embodiment of the present invention, the gastrointestinal inflammatory disease or gastric acid-related disease includes but is not limited to peptic ulcer, gastric and duodenal ulcer, non-steroidal anti-inflammatory drug (NSAID)-induced ulcer, Helicobacter pylori infection, functional dyspepsia, Zollinger-Ellison syndrome, gastritis, gastroesophageal reflux disease (GERD) and non-invasive reflux disease (NERD).

[0052] The present invention also provides the use of a salt of the compound represented by the above formula (I) or a polymorph thereof or the above pharmaceutical composition in the preparation of a drug for preventing and / or treating diseases caused by excessive gastric acid secretion; preferably, the disease is a gastrointestinal inflammatory disease or a gastric acid-related disease.

[0053] According to an embodiment of the present invention, the gastrointestinal inflammatory disease or gastric acid-related disease includes but is not limited to peptic ulcer, gastric and duodenal ulcer, non-steroidal anti-inflammatory drug (NSAID)-induced ulcer, Helicobacter pylori infection, functional dyspepsia, Zollinger-Ellison syndrome, gastritis, gastroesophageal reflux disease (GERD), and non-invasive reflux disease (NERD).

[0054] The present invention also provides a method for preventing and / or treating a disease caused by excessive gastric acid secretion, the method comprising administering to a patient an effective amount of a salt of the compound represented by formula (I) above or a polymorph thereof or the above-mentioned pharmaceutical composition; preferably, the disease is a gastrointestinal inflammatory disease or a gastric acid-related disease.

[0055] According to an embodiment of the present invention, the gastrointestinal inflammatory disease or gastric acid-related disease includes but is not limited to peptic ulcer, gastric and duodenal ulcer, non-steroidal anti-inflammatory drug (NSAID)-induced ulcer, Helicobacter pylori infection, functional dyspepsia, Zollinger-Ellison syndrome, gastritis, gastroesophageal reflux disease (GERD), and non-invasive reflux disease (NERD).

[0056] The present invention also provides a method for preparing a phosphate salt of the compound represented by formula (I) above, the method comprising:

[0057] Mixing the compound represented by formula (I) with phosphoric acid to obtain the phosphate salt of the compound represented by formula (I).

[0058] The present invention also provides a method for preparing a diphosphate salt of the compound represented by formula (I) above, the method comprising:

[0059] Mixing a solution of the compound represented by formula (I) with a phosphoric acid solution to obtain the diphosphate salt of the compound represented by formula (I);

[0060] The molar ratio of the compound represented by formula (I) to phosphoric acid is 1:1.5 to 1:2.3, for example 1:1.5.

[0061] According to an embodiment of the present invention, the solution of the compound represented by formula (I) is prepared as follows: dissolving the compound represented by formula (I) in an alcohol solvent to form a solution of the compound represented by formula (I); preferably, the alcohol solvent is methanol, ethanol, n-butanol, n-propanol, isopropanol, etc.

[0062] According to an embodiment of the present invention, the phosphoric acid solution is prepared as follows: dissolving phosphoric acid in an alcohol solvent to form a phosphoric acid solution; preferably, the alcohol solvent is methanol, ethanol, n-butanol, etc.

[0063] The present invention also provides a method for preparing a polymorph of the phosphate salt of the compound represented by formula (I) above, the method comprising:

[0064] Mix the compound represented by formula (I) with phosphoric acid and crystallize to obtain the polymorph of the phosphate of the compound represented by formula (I).

[0065] The present invention also provides a method for preparing a polymorph of the diphosphate of the compound represented by formula (I) above, and the preparation method includes:

[0066] Mix the solution of the compound represented by formula (I) with a phosphoric acid solution and crystallize to obtain the polymorph of the diphosphate of the compound represented by formula (I) (for example, crystal form A of the diphosphate);

[0067] The molar ratio of the compound represented by formula (I) to phosphoric acid is 1:1.5 to 1:2.3, for example 1:1.5.

[0068] According to an embodiment of the present invention, after mixing the solution of the compound represented by formula (I) with a phosphoric acid solution, stir, perform solid-liquid separation to obtain a solid, and dry to obtain the polymorph of the diphosphate of the compound represented by formula (I).

[0069] According to an embodiment of the present invention, the drying method is vacuum drying, for example, vacuum drying at room temperature; the drying time is preferably overnight. According to an embodiment of the present invention, the solid-liquid separation is filtration, centrifugation, etc.

[0070] According to an embodiment of the present invention, the solution of the compound represented by formula (I) is prepared as follows: dissolve the compound represented by formula (I) in an alcohol solvent to form a solution of the compound represented by formula (I); preferably, the alcohol solvent is methanol, ethanol, n-butanol, n-propanol, isopropanol, etc.

[0071] According to an embodiment of the present invention, the phosphoric acid solution is prepared as follows: dissolve phosphoric acid in an alcohol solvent to form a phosphoric acid solution; preferably, the alcohol solvent is methanol, ethanol, n-butanol, etc.

[0072] According to an embodiment of the present invention, the preparation method is specifically: mix the solution of the compound represented by formula (I) with a phosphoric acid solution, stir for 1 day, centrifuge to obtain a solid, and vacuum dry at room temperature overnight to obtain the polymorph of the diphosphate of the compound represented by formula (I);

[0073] Preferably, mix the n-propanol solution of the compound represented by formula (I) with the phosphoric acid ethanol solution, stir for 1 day, centrifuge to obtain a solid, and vacuum dry at room temperature overnight to obtain crystal form A of the diphosphate of the compound represented by formula (I); the molar ratio of the compound represented by formula (I) to phosphoric acid is 1:1.5.

[0074] The present invention also provides a method for preparing a polymorph of the monophosphate of the compound represented by formula (I) above, and the preparation method includes:

[0075] Mix the solution of the compound shown in formula (I) with phosphoric acid solution, and crystallize to obtain the polymorph of the phosphate of the compound shown in formula (I);

[0076] The molar ratio of the compound shown in formula (I) to phosphoric acid is 1:0.8 to 1:1.2, for example, 1:1.1.

[0077] The present invention also provides a method for preparing crystalline form B of the monophosphate of the compound shown in formula (I) above, and the preparation method includes:

[0078] Mix the solution of the compound shown in formula (I) with phosphoric acid solution, perform solid-liquid separation to obtain a solid, and dry it to obtain crystalline form B of the phosphate of the compound shown in formula (I);

[0079] The molar ratio of the compound shown in formula (I) to phosphoric acid is 1:0.8 to 1:1.2, for example, 1:1.1.

[0080] According to the embodiment of the present invention, the drying method is vacuum drying, for example, vacuum drying at room temperature; the drying time is preferably overnight. According to the embodiment of the present invention, the solid-liquid separation is filtration, centrifugation, etc.

[0081] According to the embodiment of the present invention, the solution of the compound shown in formula (I) is prepared as follows: dissolve the compound shown in formula (I) in an alcohol solvent to form a solution of the compound shown in formula (I); preferably, the alcohol solvent is methanol, ethanol, n-butanol, n-propanol, isopropanol, etc.; preferably, the concentration of the solution of the compound shown in formula (I) is 0.01 mol / L - 2.0 mol / L, for example, 0.06 mol / L.

[0082] According to the embodiment of the present invention, the phosphoric acid solution is prepared as follows: dissolve phosphoric acid in an alcohol solvent to form a phosphoric acid solution; preferably, the alcohol solvent is methanol, ethanol, n-butanol, etc.; preferably, the concentration of the phosphoric acid solution is 0.1 mol / L - 5 mol / L, for example, 1 mol / L.

[0083] According to the embodiment of the present invention, the preparation method is specifically: mix the solution of the compound shown in formula (I) with the phosphoric acid solution, stir for 1 day, centrifuge to obtain a solid, and vacuum dry at room temperature overnight to obtain crystalline form B of the phosphate of the compound shown in formula (I).

[0084] The present invention also provides a method for preparing crystalline form C of the phosphate of the compound shown in formula (I) above, and the preparation method includes:

[0085] Dissolve crystalline form A of the diphosphate of the compound shown in formula (I) above in solvent-1, stir, perform solid-liquid separation to obtain a solid, and dry it to obtain crystalline form C of the phosphate of the compound shown in formula (I).

[0086] According to an embodiment of the present invention, Solvent-1 is selected from DMSO (dimethyl sulfoxide), a mixed solvent of DMSO and isopropyl ether, and a mixed solvent of DMSO and toluene.

[0087] According to an embodiment of the present invention, the drying method is vacuum drying; the drying temperature is preferably room temperature to 40 °C. According to an embodiment of the present invention, the solid-liquid separation is filtration, centrifugation, etc.

[0088] According to an embodiment of the present invention, the mass-volume ratio of the diphosphate crystal form A of the compound represented by formula (I) to Solvent-1 is 80 mg: 1 mL to 120 mg: 1 mL, such as 100 mg: 1 mL.

[0089] According to an embodiment of the present invention, the specific preparation method is as follows: Dissolve the diphosphate crystal form A of the compound represented by formula (I) in DMSO, stir for 1 day, centrifuge to obtain a solid, and vacuum dry to obtain the diphosphate crystal form C of the compound represented by formula (I).

[0090] The present invention also provides a preparation method of the phosphate crystal form D of the compound represented by formula (I) above, and the preparation method includes:

[0091] Dissolve the diphosphate crystal form A of the compound represented by formula (I) in Solvent-2, then add Solvent-3, filter, stir, perform solid-liquid separation after precipitating a solid, and dry to obtain the phosphate crystal form D of the compound represented by formula (I).

[0092] According to an embodiment of the present invention, Solvent-2 and Solvent-3 are the same or different and are independently selected from n-heptane, cyclohexane, chloroform, dichloromethane, toluene, cyclohexane, and methanol.

[0093] According to an embodiment of the present invention, Solvent-2 and / or Solvent-3 is a pre-heat-treated solvent; preferably, the solvent temperature is 40 °C - 60 °C, such as 50 °C.

[0094] According to an embodiment of the present invention, the mass-volume ratio of the diphosphate crystal form A of the compound represented by formula (I) to Solvent-2 is 18 mg: 1 mL to 22 mg: 1 mL, such as 20 mg: 1 mL.

[0095] According to an embodiment of the present invention, the drying method is vacuum drying, such as vacuum drying at room temperature. According to an embodiment of the present invention, the solid-liquid separation is filtration, centrifugation, etc.

[0096] According to an embodiment of the present invention, the specific preparation method is as follows: Dissolve the diphosphate crystal form A in n-heptane at 50 °C (to form a suspension), add (such as dropwise add) methanol at 50 °C until the solution is clear; after filtering the clear solution, stir at room temperature for 1 day; after precipitating a solid, perform centrifugal separation, and vacuum dry the solid at room temperature to obtain the phosphate crystal form D.

[0097] The present invention also provides a method for preparing phosphate crystal form E of the compound shown in the above formula (I), and the preparation method includes:

[0098] Adding diphosphate crystal form A of the compound shown in the above formula (I) into solvent-4, filtering, stirring, cooling at a low temperature, precipitating a solid, separating the solid from the liquid, and drying to obtain phosphate crystal form E of the compound shown in the formula (I).

[0099] According to an embodiment of the present invention, solvent-4 is selected from alcohol solvents, such as methanol, ethanol, etc.

[0100] According to an embodiment of the present invention, solvent-4 is selected from the following mixed solvents: methanol / tetrahydrofuran, methanol / acetonitrile, methanol / isopropyl ether, methanol / dioxane, methanol / butyl formate, methanol / ethyl acetate, methanol / toluene, methanol / chloroform.

[0101] According to an embodiment of the present invention, the mass-volume ratio of diphosphate crystal form A of the compound shown in the formula (I) to solvent-4 is 14.4 mg:1.8 mL to 21.6 mg:1.8 mL, such as 20 mg:1.8 mL.

[0102] According to an embodiment of the present invention, solvent-4 is a preheated solvent; preferably, the solvent temperature is 40°C - 60°C.

[0103] According to an embodiment of the present invention, the temperature range of low-temperature cooling is -20°C to 4°C; preferably, it is cooled at 4°C and then at -15°C in sequence.

[0104] According to an embodiment of the present invention, the drying method is vacuum drying, such as vacuum drying at room temperature. According to an embodiment of the present invention, the solid-liquid separation is filtration, centrifugation, etc.

[0105] According to an embodiment of the present invention, the specific preparation method is: adding diphosphate crystal form A into preheated ethanol; filtering and stirring the solution; cooling at 4°C and -15°C in sequence; after precipitating a solid, centrifuging and vacuum drying at room temperature to obtain phosphate crystal form E.

[0106] The present invention also provides a method for preparing diphosphate crystal form F of the compound shown in the above formula (I), and the preparation method includes:

[0107] Dissolving diphosphate crystal form A of the compound shown in the above formula (I) in solvent-5, then adding solvent-6, stirring, separating the solid from the liquid to obtain a solid, and drying to obtain phosphate crystal form F of the compound shown in the formula (I).

[0108] According to an embodiment of the present invention, solvent-5 is selected from DMF (N,N-dimethylformamide).

[0109] According to an embodiment of the present invention, Solvent-6 is selected from chloroform.

[0110] According to an embodiment of the present invention, the volume ratio of Solvent-5 to Solvent-6 is 1:5 - 20, for example, 1:10.

[0111] According to an embodiment of the present invention, the drying method is vacuum drying, for example, vacuum drying at room temperature. According to an embodiment of the present invention, the solid-liquid separation is filtration, centrifugation, etc.

[0112] According to an embodiment of the present invention, the preparation method is specifically as follows:

[0113] Add the diphosphate crystal form A of the compound shown in formula (I) to DMF (until the sample is completely dissolved), then add (for example, dropwise) chloroform, stir at room temperature, perform solid-liquid separation to obtain a solid, and vacuum dry the solid at room temperature to obtain phosphate crystal form F.

[0114] The present invention also provides a preparation method of phosphate crystal form G of the compound shown in the above formula (I), and the preparation method includes:

[0115] Dissolve the diphosphate crystal form A of the compound shown in the above formula (I) in Solvent-7, then add Solvent-8, filter, stir, centrifuge to obtain a solid, and dry to obtain phosphate crystal form G of the compound shown in formula (I).

[0116] According to an embodiment of the present invention, Solvent-7 is selected from ethylene glycol dimethyl ether and acetone.

[0117] According to an embodiment of the present invention, Solvent-8 is selected from water.

[0118] According to an embodiment of the present invention, Solvent-7 and / or Solvent-8 is a pre-treated solvent; preferably, the solvent temperature is 40°C - 60°C, for example, 50°C.

[0119] According to an embodiment of the present invention, the mass-volume ratio of the diphosphate crystal form A of the compound shown in formula (I) to Solvent-7 is 18 mg:1 mL - 22 mg:1 mL, for example, 20 mg:1 mL.

[0120] According to an embodiment of the present invention, the drying method is vacuum drying, for example, vacuum drying at room temperature. According to an embodiment of the present invention, the solid-liquid separation is filtration, centrifugation, etc.

[0121] According to an embodiment of the present invention, the preparation method is specifically as follows: Dissolve the diphosphate crystal form A in ethylene glycol dimethyl ether at 50°C (to form a suspension), add (for example, dropwise) water at 50°C until the solution is clear; filter the clear solution, stir at room temperature; centrifuge to obtain a solid, and vacuum dry the solid at room temperature to obtain phosphate crystal form G.

[0122] Beneficial effects

[0123] The present invention provides phosphates of the compound represented by formula (I) and polymorphs of the phosphates. The phosphates and their polymorphs have excellent hygroscopicity (almost no hygroscopicity), solubility, stability (including high-temperature stability, high-humidity stability, light stability, etc.), have excellent drug-forming properties, and are suitable for industrial production, manufacturing, and preservation. Moreover, the phosphates and their polymorphs have excellent pharmacokinetic properties, such as higher blood drug concentration, higher bioavailability, etc. Brief description of the drawings

[0124] Figure 1 It is the X-ray powder diffraction (XRPD) pattern of the diphosphate polymorph A of the compound represented by formula (I).

[0125] Figure 2 It is the differential scanning calorimetry / thermogravimetric analysis (DSC / TGA) pattern of the diphosphate polymorph A of the compound represented by formula (I).

[0126] Figure 3 It is the X-ray powder diffraction (XRPD) pattern of the monophosphate polymorph B of the compound represented by formula (I).

[0127] Figure 4 It is the differential scanning calorimetry / thermogravimetric analysis (DSC / TGA) pattern of the monophosphate polymorph B of the compound represented by formula (I).

[0128] Figure 5 It is the nuclear magnetic resonance hydrogen spectrum ( 1 1H NMR) pattern of the diphosphate polymorph A of the compound represented by formula (I).

[0129] Figure 6 It is the nuclear magnetic resonance hydrogen spectrum ( 1 1H NMR) pattern of the monophosphate polymorph B of the compound represented by formula (I).

[0130] Figure 7 It is the X-ray powder diffraction (XRPD) pattern of the phosphate polymorph C of the compound represented by formula (I).

[0131] Figure 8 It is the change process of the X-ray powder diffraction (XRPD) pattern of the phosphate polymorph C of the compound represented by formula (I) during the drying process.

[0132] Figure 9 It is the X-ray powder diffraction (XRPD) pattern of the phosphate polymorph D of the compound represented by formula (I).

[0133] Figure 10 It is the nuclear magnetic resonance hydrogen spectrum ( 11H NMR spectrum

[0134] Figure 11 Differential scanning calorimetry / thermogravimetric analysis (DSC / TGA) curve of phosphate crystal form D of the compound represented by formula (I).

[0135] Figure 12 Change process of X-ray powder diffraction (XRPD) pattern during heating of phosphate crystal form D of the compound represented by formula (I).

[0136] Figure 13 X-ray powder diffraction (XRPD) pattern of phosphate crystal form E of the compound represented by formula (I).

[0137] Figure 14 Change process of X-ray powder diffraction (XRPD) pattern during drying of phosphate crystal form E of the compound represented by formula (I).

[0138] Figure 15 X-ray powder diffraction (XRPD) pattern of phosphate crystal form F of the compound represented by formula (I).

[0139] Figure 16 Change process of X-ray powder diffraction (XRPD) pattern during heating of phosphate crystal form F of the compound represented by formula (I).

[0140] Figure 17 Change process of X-ray powder diffraction (XRPD) pattern during standing at room temperature of phosphate crystal form F of the compound represented by formula (I).

[0141] Figure 18 Differential scanning calorimetry / thermogravimetric analysis (DSC / TGA) curve of phosphate crystal form F of the compound represented by formula (I).

[0142] Figure 19 X-ray powder diffraction (XRPD) pattern of phosphate crystal form G of the compound represented by formula (I).

[0143] Figure 20 Differential scanning calorimetry / thermogravimetric analysis (DSC / TGA) curve of phosphate crystal form G of the compound represented by formula (I).

[0144] Figure 21 Dynamic vapor sorption (DVS) curve of diphosphate crystal form A of the compound represented by formula (I).

[0145] Figure 22 Dynamic vapor sorption (DVS) curve of citrate crystal form C2

[0146] Figure 23 Ion chromatography diagram of phosphate crystal form A of the compound represented by formula (I).

[0147] Figure 24 Ion chromatogram of phosphate crystal form B of the compound represented by formula (I).

[0148] Figure 25 Ion chromatogram of phosphate crystal form F of the compound represented by formula (I).

[0149] Figure 26 Ion chromatogram of phosphate crystal form G of the compound represented by formula (I). Detailed implementation manners

[0150] The technical solutions of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only used to illustrate and explain the present invention exemplarily, and should not be construed as limiting the protection scope of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection of the present invention.

[0151] Unless otherwise specified, the raw materials and reagents used in the following embodiments are all commercially available products, or can be prepared by known methods.

[0152] The common name of the compound represented by formula (I) is Zastaprazan, and the CAS number is 2133852-18-1.

[0153] The explanations of the abbreviations used in the present invention are as follows: XRPD: X-ray powder diffraction; DSC: differential scanning calorimetry; TGA: thermogravimetric analysis; 1 H NMR: nuclear magnetic resonance hydrogen spectrum; DVS: dynamic vapor sorption.

[0154] The X-ray powder diffraction pattern described in the present invention is collected on a Panalytical Empyrean X-ray powder diffractometer. The method parameters of the X-ray powder diffraction described in the present invention are as follows:

[0155] X-ray reflection parameters: Cu, Kα; Kα1 1.540598; Kα2 1.544426; Kα2 / Kα1 intensity ratio: 0.50; voltage: 45 kilovolts (kV); current: 40 milliamperes (mA); scanning range: from 3.0 to 40.0 degrees or from 3.0 to 60.0 degrees; step size: 0.026° / second.

[0156] The differential scanning calorimetry (DSC) pattern described in the present invention is collected on a TA Q2000. The method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:

[0157] Scanning rate: 10°C / min; protective gas: nitrogen.

[0158] The thermogravimetric analysis (TGA) graph described in the present invention was collected on a TA Q500. The method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:

[0159] Scanning rate: 10 °C / min; protective gas: nitrogen.

[0160] The dynamic vapor sorption (DVS) graph described in the present invention was collected on an Intrinsic dynamic vapor sorption instrument produced by SMS (Surface Measurement Systems Ltd.). The method parameters of the dynamic vapor sorption instrument are as follows:

[0161] Temperature: 25 °C; carrier gas, flow rate: N2, 200 mL / min; mass change per unit time: 0.002% / min; relative humidity range: 0% RH - 95% RH - 0% RH.

[0162] Example 1

[0163] Preparation method of diphosphate crystal form A: Weigh 218 mg of the compound shown in formula (I) and add it to 10.0 mL of n-propanol, then add 900 μL of phosphoric acid ethanol solution (1 mol / L). After stirring for 1 day, centrifuge the suspension, and dry the solid under vacuum at room temperature overnight. The obtained solid is diphosphate crystal form A.

[0164] The X-ray powder diffraction data of diphosphate crystal form A obtained in this example is shown in Table 1, and its XRPD graph is as Figure 1 shown.

[0165] Table 1 X-ray powder diffraction data of crystal form A

[0166]

[0167] The DSC / TGA of diphosphate crystal form A is as Figure 2 shown. An endothermic peak appears in the DSC when heated to around 197.2 °C, and there is a 0.1% weight loss in the TGA when heated to 150 °C.

[0168] The 1 1H NMR of diphosphate crystal form A is as Figure 5 shown.

[0169] The ion chromatography of crystal form A is as Figure 23 shown. It can be seen from the figure that the content of phosphate is 33.3%. Through analysis, it can be known that crystal form A contains two molecules of phosphate (the molecular weight of the free base is 362.48, the molecular weight of phosphoric acid is 97.99, and the theoretical content of phosphate in the diphosphate is 35%). Thus, it can be judged that crystal form A is diphosphate.

[0170] Example 2

[0171] Preparation method of monophosphate crystal form B: Weigh 218 mg of the compound shown in formula (I), add it to 10.0 mL of n-propanol, then add 660 μL of phosphoric acid ethanol solution (1 mol / L). After stirring for 1 day, centrifuge the suspension, and dry the solid under vacuum at room temperature overnight. The obtained solid is monophosphate crystal form B.

[0172] The X-ray powder diffraction data of the monophosphate crystal form B obtained in this example is shown in Table 2, and its XRPD pattern is as Figure 3 shown.

[0173] Table 2 X-ray powder diffraction data of crystal form B

[0174]

[0175]

[0176] The DSC / TGA of monophosphate crystal form B is as Figure 4 shown. An endothermic peak appears in the DSC when heated to around 206.9 °C, and there is basically no weight loss in the TGA when heated to 150 °C.

[0177] The 1 1H NMR of monophosphate crystal form B is as Figure 6 shown.

[0178] The ion chromatography of crystal form B is as Figure 24 shown. It can be seen from the figure that the content of phosphate is 20.3%. Through analysis, it is known that crystal form B contains one molecule of phosphate (the molecular weight of the free base is 362.48, the molecular weight of phosphoric acid is 97.99, and the theoretical content of phosphate in monophosphate is 21%). Thus, it can be judged that crystal form B is monophosphate or monophosphate.

[0179] Example 3

[0180] Preparation method of phosphate crystal form C: Weigh 20 mg of diphosphate crystal form A respectively, add 0.2 mL of DMSO, suspend and stir at room temperature for 1 day, centrifuge the suspension, and dry the solid under vacuum at room temperature or 40 °C. The obtained solid is phosphate crystal form C.

[0181] The X-ray powder diffraction data of the phosphate crystal form C obtained in this example is shown in Table 3, and its XRPD pattern is as Figure 7 shown.

[0182] Table 3 X-ray powder diffraction data of crystal form C

[0183]

[0184] From the XRPD results, the wet sample is in phosphate crystal form C, and there is a tendency to transform into diphosphate crystal form A after drying at 40 °C ( Figure 8 ).

[0185] Example 4

[0186] Preparation method of phosphate crystal form D: Weigh 20 mg of diphosphate crystal form A, add 1 mL of n-heptane at 50 °C to form a suspension, and then gradually add preheated methanol at 50 °C dropwise until the solution becomes clear; filter the clear solution and stir at room temperature for 1 day; after sufficient solid precipitates, centrifuge the suspension and vacuum-dry the solid at room temperature. The obtained solid is phosphate crystal form D.

[0187] The X-ray powder diffraction data of the phosphate crystal form D obtained in this example are shown in Table 4, and its XRPD pattern is as Figure 9 shown.

[0188] Table 4 X-ray powder diffraction data of crystal form D

[0189]

[0190]

[0191] The 1 1H NMR of phosphate crystal form D is as Figure 10 shown.

[0192] The DSC / TGA of phosphate crystal form D is as Figure 11 shown. Endothermic peaks appear near 133.7 °C and 144.7 °C during DSC heating, and there is an endothermic signal for melting at about 194.8 °C; the weight loss of TGA is 3.1% when heated to 150 °C.

[0193] When phosphate crystal form D is heated to 160 °C at 20 °C / min and held at a constant temperature for 10 min, the XRPD transforms into diphosphate crystal form A, and it remains in diphosphate crystal form A after cooling to room temperature ( Figure 12 ).

[0194] Example 5

[0195] Preparation method of phosphate crystal form E: Weigh 20 mg of diphosphate crystal form A respectively, add it to 1.8 mL of preheated ethanol until the solid is completely dissolved; filter the clear solution and stir at room temperature for 2 h; then cool the solution at 4 °C and -15 °C in sequence; after sufficient solid precipitates, centrifuge the suspension and vacuum-dry the solid at room temperature. The obtained solid is phosphate crystal form E.

[0196] The X-ray powder diffraction data of the phosphate crystal form E obtained in this example are shown in Table 5, and its XRPD pattern is as Figure 13 shown.

[0197] X-ray powder diffraction data of crystal form E in Table 5

[0198]

[0199]

[0200] Phosphate crystal form E turns into diphosphate crystal form A after being vacuum-dried at room temperature for 1 day, and turns into diphosphate crystal form A after cooling to room temperature ( Figure 14 ).

[0201] Example 6

[0202] Preparation method of phosphate crystal form F: Weigh 20 mg of diphosphate crystal form A respectively, add DMF to completely dissolve the sample, then dropwise add 10 times the volume of chloroform (the volume of chloroform is 10 times the volume of DMF), stir at room temperature for 1 day, centrifuge the suspension and vacuum-dry the solid at room temperature for 1 day. The obtained solid is phosphate crystal form F.

[0203] The X-ray powder diffraction data of phosphate crystal form F obtained in this example are shown in Table 6, and its XRPD pattern is as Figure 15 shown:[[]]

[0204] X-ray powder diffraction data of crystal form F in Table 6

[0205]

[0206] Phosphate crystal form F is heated to 165 °C at 20 °C / min and kept at a constant temperature for 10 min, and its XRPD turns into diphosphate crystal form A. After cooling to room temperature, most of it is diphosphate crystal form A ( Figure 16 ).

[0207] XRPD results show that phosphate crystal form F turns into phosphate crystal form D after being placed at room temperature for 8 days ( Figure 17 ).

[0208] The DSC / TGA of phosphate crystal form F is as Figure 18 shown. An endothermic peak appears in the DSC when heated to around 136.7, and there is a melting endothermic signal at about 196.3 °C; the TGA loses 3.1% of its weight when heated to 150 °C.

[0209] The ion chromatography of crystal form F is as Figure 25 shown. It can be seen from the figure that the content of phosphate is 31.7%. Analysis shows that crystal form F contains two molecules of phosphate (the molecular weight of the free base is 362.48, the molecular weight of phosphoric acid is 97.99, and the theoretical content of phosphate in diphosphate is 35%). It can be judged from this that crystal form F is diphosphate.

[0210] Example 7

[0211] Preparation method of phosphate crystal form G: Weigh 20 mg of diphosphate crystal form A respectively, add 1.0 mL of ethylene glycol dimethyl ether at 50 °C to form a suspension, and then gradually add preheated water at 50 °C dropwise until the solution becomes clear; filter the clear solution and stir at room temperature for 1 day; centrifuge the suspension and vacuum-dry the solid at room temperature. The obtained solid is phosphate crystal form G.

[0212] The X-ray powder diffraction data of the phosphate crystal form G obtained in this example are shown in Table 7, and its XRPD pattern is as Figure 19 shown:

[0213] Table 7 X-ray powder diffraction data of crystal form G

[0214]

[0215] The DSC / TGA of phosphate crystal form G is as Figure 20 shown. There is a relatively broad endothermic accompanied by exothermic thermal signal from 50 °C to about 180 °C, and endothermic melting signals at about 189 °C and 197 °C; the TGA loses 3.4% of its weight when heated to 150 °C and may decompose after 290 °C.

[0216] The ion chromatography of crystal form G is as Figure 26 shown. It can be seen from the figure that the content of phosphate radical is 20.1%. Through analysis, it is known that crystal form G contains one molecule of phosphate radical (the molecular weight of the free base is 362.48, the molecular weight of phosphoric acid is 97.99, and the theoretical content of phosphate radical in monophosphate is 21%). Thus, it can be judged that crystal form G is monophosphate or mono-phosphate.

[0217] Hygroscopicity investigation of Example 8

[0218] Hygroscopicity study of diphosphate crystal form A and citrate crystal form C2 of patent KR2496869.

[0219] Take 10 mg of diphosphate crystal form A prepared in Example 1 of the present invention and citrate crystal form C2 in patent KR10-2496869 respectively for dynamic vapor sorption (DVS) test. The results are shown in Table 8. The DVS of diphosphate crystal form A is as Figure 21 shown, and the DVS of citrate crystal form C2 of patent KR10-2496869 is as Figure 22 shown.

[0220] Table 8

[0221] Type of salt Weight gain at 80% relative humidity Weight gain at 95% relative humidity Crystal form change before and after DVS Diphosphate crystal form A 0.1664％ 0.2789％ Unchanged Citrate crystal form C2 0.398％ 1.963％ Changed

[0222] The results show that: for the citrate crystal form C2 of Patent KR10-2496869, the weight gain due to moisture absorption reaches 1.963% at 95% relative humidity and the crystal form changes. However, the diphosphate crystal form A of the present invention has no or almost no hygroscopicity, its hygroscopicity is significantly better than that of the citrate crystal form C2, and the crystal form is not easily transformed under high humidity, which is convenient for the long-term storage of drugs.

[0223] Example 9 Solubility Investigation

[0224] Comparative study on the solubility of diphosphate crystal form A, monophosphate crystal form B, free base and citrate crystal form C2 in the present invention.

[0225] The diphosphate crystal form A prepared in Example 1, the monophosphate crystal form B prepared in Example 2, the free base and the citrate crystal form C2 samples were respectively prepared into saturated solutions with high-purity water, and the content of the samples in the saturated solutions was determined by high-performance liquid chromatography after 24 hours. The experimental results are shown in Table 9.

[0226] Table 9

[0227] Type of salt Free base Citrate crystal form C2 Monophosphate crystal form B Diphosphate crystal form A Solubility 0.0044 mg / mL 0.0018 mg / mL 5.27 mg / mL > 25 mg / mL

[0228] It can be seen from the above results that: the solubility of diphosphate crystal form A and monophosphate crystal form B of the present invention is much greater than that of the free base and citrate crystal form C2.

[0229] For the development of injectables, the solubility of the active pharmaceutical ingredient is crucial. Especially for small-volume injections, in order to meet the requirements of patient compliance, the injection volume is usually no more than 5 mL. Therefore, the significantly improved solubility of the new salt form provided by the present invention is conducive to the further development of small-volume injections and reduces the injection volume.

[0230] Example 10 Stability Investigation

[0231] Comparative study on the stability of diphosphate crystal form A, monophosphate crystal form B, free base and citrate crystal form C2 in the present invention.

[0232] Take diphosphate crystal form A, monophosphate crystal form B, free base and citrate crystal form C2 and place them respectively under high temperature (60 °C), accelerated experiment (40 °C, 75% RH), high humidity (25 °C / 90% RH) and light (illuminance is 4500 ± 500 lx, ultraviolet light ≥ 0.7 w / m 2 ) conditions for 15 days, and sample to detect the appearance, purity and crystal form of the samples. The experimental results are shown in Table 10.

[0233] Table 10

[0234]

[0235]

[0236] It can be seen from the above results that the citrate crystal form C2 undergoes crystal transformation under high humidity conditions and color change (off-white) under light conditions, while the diphosphate crystal form A in the present invention shows no changes in purity, crystal form, and appearance after being placed under high temperature, high humidity, accelerated, and light conditions, indicating that the diphosphate crystal form A is more suitable for subsequent production, manufacturing, and storage.

[0237] Meanwhile, in the high humidity experiment for purity determination of the free base as an influencing factor, the content of the impurity with an RRT of 1.82 increased to 1.34% at 14 days; in the light experiment for influencing factors (7 days, 14 days), the color turned yellow. However, the diphosphate crystal form A and the monophosphate crystal form B showed no obvious changes under the four influencing factor conditions.

[0238] Example 11 In vivo Pharmacokinetic Test of the Compounds of the Present Invention

[0239] The experimental animals were male Sprague-Dawley (SD) rats, 6 to 8 weeks old, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. They were randomly divided into 4 groups based on body weight, with 6 animals in each group. Among them, 3 groups were respectively given citrate C2, monophosphate crystal form B, and diphosphate crystal form A by gavage, and the dosing doses were all 10 mg / kg; the last group was given diphosphate crystal form A by intravenous injection, and the dosing dose was 5 mg / kg. The compound solvent was water for injection.

[0240] Before the start of the pharmacokinetic experiment, the rats were fasted overnight. Blood samples of 0.20 mL were collected at regular intervals by carotid artery puncture, and the blood sampling time points were 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h. The blood samples were collected into sample tubes containing EDTA, immediately centrifuged at 4000 rpm for 5 minutes at 4°C, and then the plasma was transferred to another sample tube and stored at -20°C or below.

[0241] The methods and instruments used are as follows:

[0242] Instrument: LC-MS / MS-05 (TQ6500+);

[0243] Chromatographic column: ACQUITY UPLC HSS T3 1.8 μm 2.1 * 50 mm;

[0244] Mass spectrometry method: ESI positive;

[0245] Mobile phase: 0.1% FA (formic acid) water / 0.1% acetonitrile;

[0246] Quantification method: internal standard method.

[0247] The experimental results are shown in Table 11.

[0248] Table 11 PK parameters of different salt forms

[0249]

[0250] As can be seen from the data in Table 11, the oral bioavailability of diphosphate crystal form A and monophosphate crystal form B in the examples has significant advantages compared with citrate crystal form C2. Drugs with high oral bioavailability can achieve the expected drug effect at lower dosing doses; and lower dosing doses can reduce the cost of medication.

[0251] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims

1. A phosphate salt of the compound represented by formula (I) or a polymorph thereof; The phosphate of the compound represented by formula (I) is a diphosphate of the compound represented by formula (I); Preferably, the polymorph of the phosphate of the compound represented by formula (I) is a polymorph of the monophosphate of the compound represented by formula (I) or a polymorph of the diphosphate of the compound represented by formula (I); Preferably, the polymorph of the phosphate of the compound represented by formula (I) is diphosphate form A, monophosphate form B, phosphate form C, phosphate form D, phosphate form E, diphosphate form F, and monophosphate form G of the compound represented by formula (I).

2. The phosphate or polymorph thereof according to claim 1, characterized in that The X-ray powder diffraction pattern of the diphosphate crystalline form A has characteristic diffraction peaks at the following 2θ angles: 6.6°±0.2°, 9.0°±0.2°, 10.5°±0.2°, 11.7°±0.2°, 13.8°±0.2°, 20.9°±0.2°; preferably, the X-ray powder diffraction pattern of the diphosphate crystalline form A also includes the following one, two or more characteristic diffraction peaks at 2θ angles: 14.6°±0.2°, 15.2°±0.2°, 18.0°±0.2°, 18.5°±0.2°, 19.9°±0.2°, 20.2°±0.2°, 22.2°±0.2°, 22.6°±0.2°, 23.5°±0.2°, 27.2°±0.2°; Preferably, the X-ray powder diffraction pattern of the diphosphate crystalline form A has characteristic diffraction peaks at the following 2θ angles: 6.6°±0.2°, 9.0°±0.2°, 10.5°±0.2°, 11.7°±0.2°, 13.8°±0.2°, 20.9°±0.2°, 23.5°±0.2°, 27.2°±0.2°; ... The line powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.6°±0.2°, 9.0°±0.2°, 10.5°±0.2°, 11.7°±0.2°, 13.8°±0.2°, 18.0°±0.2°, 18.5°±0.2°, 19.9°±0.2°, 20.9°±0.2°, 23.5°±0.2°, 27.2°±0.2°; Preferably, the X-ray powder diffraction pattern of the diphosphate crystalline form A has characteristic diffraction peaks at the following 2θ angles: 6.6°±0.2°, 9.0°±0.2°, 10.5°±0.2°, 11.7°±0.2°, 13.8°±0.2°, 14.6°±0.2°, 15.2°±0.2°, 18.0°±0.2°, 18.5°±0.2°, 19.9°±0.2°, 20.2°±0.2°, 20.9°±0.2°, 22.2°±0.2°, 22.6°±0.2°, 23.5°±0.2°, 27.2°±0.2°; Preferably, the X-ray powder diffraction pattern of the diphosphate crystalline form A has characteristic diffraction peaks at the following 2θ angles: 6.6°±0.2°, 9.0°±0.2°, 13.8°±0.2°, 20.9°±0.2°; Preferably, the X-ray powder diffraction pattern of the diphosphate crystalline form A also includes one, two or more characteristic diffraction peaks at the following 2θ angles: 10.5°±0.2°, 19.9°±0.2°, 22.6°±0.2°, 23.5°±0.2°, 27.2 °±0.2°; preferably, the X-ray powder diffraction pattern of the diphosphate crystalline form A further comprises the following one, two or more characteristic diffraction peaks at 2θ angles: 11.7°±0.2°, 14.6°±0.2°, 15.2°±0.2°, 18.0°±0.2°, 18.5°±0.2°, 20.2°±0.2°, 22.2°±0.2°, 23.0°±0.2°, 25.2°±0.2°, 26.4°±0.2°, 29.2°±0.2°; Preferably, the X-ray powder diffraction pattern analysis data of the diphosphate crystal form A is shown in Table 1; Preferably, the diphosphate crystalline form A has an X-ray powder diffraction pattern substantially as shown in FIG1 ; Preferably, the differential scanning calorimetry diagram of the diphosphate crystalline form A comprises an endothermic peak at 197.2°C ± 3°C; Preferably, the differential scanning calorimetry diagram of the diphosphate crystal form A is shown in Figure 2.

3. The phosphate or polymorph thereof according to claim 1, characterized in that: The X-ray powder diffraction pattern of the monophosphate crystal form B has characteristic diffraction peaks at the following 2θ angles: 8.1°±0.2°, 10.8°±0.2°, 11.5°±0.2°, 17.6°±0.2°, 22.0°±0.2°, 22.6°±0.2°; preferably, the X-ray powder diffraction pattern of the monophosphate crystal form B has characteristic diffraction peaks at the following 2θ angles: 8.1°±0.2°, 10.8°±0.2°, 11.5°±0.2°, 15.9°±0.2°, 16.8°±0.2°, 17.6°±0.2°, 22.0°±0.2°, 22.6°±0.2°; Preferably, the X-ray powder diffraction pattern of the monophosphate crystal form B further includes one, two or more of the following characteristic diffraction peaks at 2θ angles: 11.8°±0.2°, 19.4°±0.2°, 19.8°±0.2°, 21.1°±0.2°, 23.1°±0.2°, 23.9°±0.2°, 24.5°±0.2°, 25.3°±0.2°, 26.9°±0.2°; Preferably, the X-ray powder diffraction pattern of the monophosphate crystal form B has characteristic diffraction peaks at the following 2θ angles: 8.1°±0.2°, 10.8°±0.2°, 11.5°±0.2°, 11.8°±0.2°, 15.9°±0.2°, 16.8°±0.2°, 17.6°±0.2°, 19.4°±0.2°, 19.8°±0.2°, 21.1°±0.2°, 22.0°±0.2°, 22.6°±0.2°, 23.1°±0.2°, 23.9°±0.2°, 24.5°±0.2°, 25.3°±0.2°, 26.9°±0.2°; Preferably, the X-ray powder diffraction pattern of the monophosphate crystal form B has characteristic diffraction peaks at the following 2θ angles: 10.8°±0.2°, 11.5°±0.2°, 17.6°±0.2°, 21.9°±0.2°, 22.0°±0.2°, 22.6°±0.2°; preferably, the X-ray powder diffraction pattern of the monophosphate crystal form B also includes the following one, two or more characteristic diffraction peaks at 2θ angles: 8.1°±0.2°, 15.9°±0.2°, 16.8°±0.2°, 23. 1°±0.2°, 25.3°±0.2°, 26.9°±0.2°; preferably, the X-ray powder diffraction pattern of the monophosphate crystal form B also includes the following one, two or more characteristic diffraction peaks at 2θ angles: 7.9°±0.2°, 11.8°±0.2°, 18.0°±0.2°, 19.4°±0.2°, 19.8°±0.2°, 21.1°±0.2°, 23.9°±0.2°, 24.5°±0.2°, 27.5°±0.2°, 32.9°±0.2°; Preferably, the X-ray powder diffraction pattern analysis data of the monophosphate crystal form B is shown in Table 2; Preferably, the monophosphate crystalline form B has an X-ray powder diffraction pattern substantially as shown in Figure 3; Preferably, the differential scanning calorimetry diagram of the monophosphate crystal form B comprises an endothermic peak at 206.9°C±3°C (eg, FIG. 4 ).

4. The phosphate or polymorph thereof according to claim 1, characterized in that: The X-ray powder diffraction pattern of the phosphate crystal form C has characteristic diffraction peaks at the following 2θ angles: 7.4°±0.2°, 9.3°±0.2°, 11.8°±0.2°, 13.9°±0.2°, 18.7°±0.2°, 26.2°±0.2°; Preferably, the X-ray powder diffraction pattern of the phosphate crystal form C further includes the following one, two or more characteristic diffraction peaks at 2θ angles: 12.5°±0.2°, 14.8°±0.2°, 17.0°±0.2°, 22.4°±0.2°, 23.6°±0.2°, 26.2°±0.2°, 26.9°±0.2°, 27.7°±0.2°; Preferably, the X-ray powder diffraction pattern of the phosphate crystal form C has characteristic diffraction peaks at the following 2θ angles: 7.4°±0.2°, 9.3°±0.2°, 11.8°±0.2°, 12.5°±0.2°, 13.9°±0.2°, 14.8°±0.2°, 17.0°±0.2°, 18.7°±0.2°, 20.6°±0.2°, 22.4°±0.2°, 23.6°±0.2°, 26.2°±0.2°, 26.9°±0.2°, 27.7°±0.2°; Preferably, the X-ray powder diffraction pattern of the phosphate crystal form C has characteristic diffraction peaks at the following 2θ angles: 7.4°±0.2°, 9.3°±0.2°, 13.9°±0.2°, 18.7°±0.2°, 26.2°±0.2°; Preferably, the X-ray powder diffraction pattern of the phosphate crystal form C also includes the following one, two or more characteristic diffraction peaks at 2θ angles: 11.8°±0.2°, 20.6°±0.2°, 22.4°±0.2°, 23.6°±0.2°, 27.7°±0.2°; Preferably, the X-ray powder diffraction pattern analysis data of the phosphate crystal form C is shown in Table 3; Preferably, the phosphate crystal form C has an X-ray powder diffraction pattern substantially as shown in Figure 7; Preferably, after being dried at 40° C. for 4 h, the phosphate crystal form C tends to turn to the crystal form A (as shown in FIG. 8 ).

5. The phosphate or polymorph thereof according to claim 1, characterized in that: The X-ray powder diffraction pattern of the phosphate crystal form D has characteristic diffraction peaks at the following 2θ angles: 7.4°±0.2°, 12.9°±0.2°, 14.6°±0.2°, 14.9°±0.2°, 22.5°±0.2°, 23.7°±0.2°; preferably, the X-ray powder diffraction pattern of the phosphate crystal form D also includes the following one, two or more characteristic diffraction peaks at 2θ angles: 11.8°±0.2°, 15.7°±0.2°, 17.5°±0.2°, 18.9°±0.2°, 19.2°±0.2°, 19.9°±0.2°, 21 .9°±0.2°, 24.7°±0.2°, 24.9°±0.2°, 26.1°±0.2°; preferably, the X-ray powder diffraction pattern of the phosphate crystal form D has characteristic diffraction peaks at the following 2θ angles: 7.4°±0.2°, 11.8,°±0.2°, 12.9°±0.2°, 14.6°±0.2°, 14.9°±0.2°, 15.7°±0.2°, 17.5°±0.2°, 18.9°±0.2°, 19.2°±0.2°, 19.9°±0.2°, 21.9°±0.2°, 22.5°±0.2°, 23. .7°±0.2°, 24.7°±0.2°, 24.9°±0.2°, 26.1°±0.2°; preferably, the X-ray powder diffraction pattern of the phosphate crystal form D has characteristic diffraction peaks at the following 2θ angles: 7.4°±0.2°, 12.9°±0.2°, 14.6°±0.2°, 14.9°±0.2°, 22.5°±0.2°, 23.7°±0.2°, 26.1°±0.2°; preferably, the X-ray powder diffraction pattern of the phosphate crystal form D also includes the following one, two or more characteristic diffraction peaks at 2θ angles: 17.5°±0.2°, 1 8.9°±0.2°, 19.0°±0.2°, 19.2°±0.2°, 24.7°±0.2°, 24.9°±0.2°, 25.1°±0.2°, 27.0°±0.2°, 30.2°±0.2°; preferably, the X-ray powder diffraction pattern analysis data of the phosphate crystal form D are shown in Table 4; preferably, the phosphate crystal form D has an X-ray powder diffraction pattern substantially as shown in Figure 9; preferably, the differential scanning calorimetry diagram of the phosphate crystal form D comprises endothermic peaks at 133.7°C±3°C, 144.7°C±3°C, and 194.8°C±3°C (as shown in Figure 11); And / or, the X-ray powder diffraction pattern of the phosphate crystal form E has characteristic diffraction peaks at the following 2θ angles: 6.4°±0.2°, 8.9°±0.2°, 14.2°±0.2°, 19.3°±0.2°, 20.3°±0.2°; preferably, the X-ray powder diffraction pattern of the phosphate crystal form E also includes the following one, two or more characteristic diffraction peaks at 2θ angles: 12.4°±0.2°, 17.4°±0.2°, 17.9°±0.2°, 18.3°±0.2 °, 19.5°±0.2°, 21.1°±0.2°, 24.5°±0.2°, 25.1°±0.2°, 25.8°±0.2°, 27.4°±0.2°; Preferably, the X-ray powder diffraction pattern of the phosphate crystal form E has characteristic diffraction peaks at the following 2θ angles: 6.4°±0.2°, 8.9°±0.2°, 12.4°±0.2°, 14.2°±0.2°, 17.4°±0.2°, 17.9°±0.2°, 18.3°±0.2 °, 19.3°±0.2°, 19.5°±0.2°, 20.3°±0.2°, 21.1°±0.2°, 24.5°±0.2°, 25.1°±0.2°, 25.8°±0.2°, 27.4°±0.2°; preferably, the X-ray powder diffraction pattern of the phosphate crystalline form E has characteristic diffraction peaks at the following 2θ angles: 6.4°±0.2°, 14.2°±0.2°, 19.3°±0.2°, 20.3°±0.2°; preferably, the phosphate The X-ray powder diffraction pattern of the phosphate crystal form E also includes the following one, two or more characteristic diffraction peaks at 2θ angles: 8.9°±0.2°, 18.3°±0.2°, 19.5°±0.2°, 24.5°±0.2°, 25.1°±0.2°, 25.8°±0.2°, 27.4°±0.2°; preferably, the X-ray powder diffraction pattern analysis data of the phosphate crystal form E are shown in Table 5; preferably, the phosphate crystal form E has an X-ray powder diffraction pattern substantially as shown in Figure 13.

6. The phosphate or polymorph thereof according to claim 1, characterized in that: The X-ray powder diffraction pattern of the diphosphate crystal form F has characteristic diffraction peaks at the following 2θ angles: 4.1°±0.2°, 12.4°±0.2°, 13.7°±0.2°, 16.6°±0.2°; preferably, the X-ray powder diffraction pattern of the diphosphate crystal form F also includes the following one, two or more characteristic diffraction peaks at 2θ angles: 8.2°±0.2°, 10.1°±0. 2°, 17.6°±0.2°, 20.4°±0.2°, 20.8°±0.2°, 24.2°±0.2°, 25.7°±0.2°; Preferably, the X-ray powder diffraction pattern of the diphosphate crystalline form F has characteristic diffraction peaks at the following 2θ angles: 4.1°±0.2°, 8.2°±0.2°, 10.1°±0.2°, 12.4°±0.2°, 13.7 °±0.2°, 16.6°±0.2°, 17.6°±0.2°, 20.4°±0.2°, 20.8°±0.2°, 24.2°±0.2°, 25.7°±0.2°; Preferably, the X-ray powder diffraction pattern of the diphosphate crystalline form F has characteristic diffraction peaks at the following 2θ angles: 4.1°±0.2°, 13.7°±0.2°, 16.6°±0.2° , 24.2°±0.2°, 25.7°±0.2°; preferably, the X-ray powder diffraction pattern analysis data of the diphosphate crystalline form F are shown in Table 6; preferably, the diphosphate crystalline form F has an X-ray powder diffraction pattern substantially as shown in FIG. 15; preferably, the differential scanning calorimetry diagram of the diphosphate crystalline form F comprises endothermic peaks at 136.7°±3°C and 196.3°±3°C (as shown in FIG. 18); And / or, the X-ray powder diffraction pattern of the monophosphate crystalline form G has characteristic diffraction peaks at the following 2θ angles: 7.6°±0.2°, 10.8°±0.2°, 13.9°±0.2°, 20.8°±0.2°, 24.2°±0.2°; preferably, the X-ray powder diffraction pattern of the monophosphate crystalline form G also includes one, two or more characteristic diffraction peaks at the following 2θ angles: 13.0°±0.2°, 1 4.5°±0.2°, 15.4°±0.2°, 15.9°±0.2°, 17.3°±0.2°, 18.0°±0.2°, 19.7°±0.2°, 23.4°±0.2°, 24.7°±0.2°, 26.5°±0.2°, 30.8°±0.2°; Preferably, the X-ray powder diffraction pattern of the monophosphate crystalline form G has characteristic diffraction peaks at the following 2θ angles: 7.6° ±0.2°,10.8°±0.2°,13.0°±0.2°,13.9°±0.2°,14.5°±0.2°,15.4°±0.2°,15.9°±0.2°,17.3°±0.2°,18.0°±0.2°,19.7°±0.2°,20.8°±0.2°,23.4°±0.2°,24.2°±0.2°,24.7°±0.2°,26 .5°±0.2°, 30.8°±0.2°; preferably, the X-ray powder diffraction pattern analysis data of the monophosphate crystal form G are shown in Table 7; preferably, the monophosphate crystal form G has an X-ray powder diffraction pattern substantially as shown in Figure 19; preferably, the differential scanning calorimetry diagram of the monophosphate crystal form G comprises endothermic peaks at 120.2℃±3℃, 188.7℃±3℃, and 197.3℃±3℃ (as shown in Figure 20).

7. A pharmaceutical composition comprising the phosphate salt of the compound of formula (I) or its polymorph according to any one of claims 1 to 6, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant or a combination thereof; Preferably, the pharmaceutical composition is used to prevent and / or treat a disease caused by excessive gastric acid secretion; preferably, the disease is a gastrointestinal inflammatory disease or a gastric acid-related disease; Preferably, the gastrointestinal inflammatory disease or gastric acid-related disease includes, but is not limited to, peptic ulcer, gastric and duodenal ulcer, nonsteroidal anti-inflammatory drug (NSAID)-induced ulcer, Helicobacter pylori infection, functional dyspepsia, Zollinger-Ellison syndrome, gastritis, gastroesophageal reflux disease (GERD) and non-invasive reflux disease (NERD).

8. Use of the phosphate salt of the compound of formula (I) or its polymorph according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 7 in the preparation of a drug for preventing and / or treating diseases caused by excessive secretion of gastric acid; Preferably, the disease is a gastrointestinal inflammatory disease or a gastric acid-related disease; Preferably, the gastrointestinal inflammatory disease or gastric acid-related disease includes, but is not limited to, peptic ulcer, gastric and duodenal ulcer, nonsteroidal anti-inflammatory drug (NSAID)-induced ulcer, Helicobacter pylori infection, functional dyspepsia, Zollinger-Ellison syndrome, gastritis, gastroesophageal reflux disease (GERD) and non-invasive reflux disease (NERD).

9. A method for preventing and / or treating a disease caused by excessive gastric acid secretion, the method comprising administering to a patient an effective amount of a phosphate salt of the compound of formula (I) or a polymorph thereof according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 7; Preferably, the disease is a gastrointestinal inflammatory disease or a gastric acid-related disease; Preferably, the gastrointestinal inflammatory disease or gastric acid-related disease includes, but is not limited to, peptic ulcer, gastric and duodenal ulcer, nonsteroidal anti-inflammatory drug (NSAID)-induced ulcer, Helicobacter pylori infection, functional dyspepsia, Zollinger-Ellison syndrome, gastritis, gastroesophageal reflux disease (GERD) and non-invasive reflux disease (NERD).

10. A method for preparing a phosphate salt of a compound of formula (I) or a polymorph thereof according to any one of claims 1 to 6; The preparation method of the phosphate comprises: The compound represented by formula (I) is mixed with phosphoric acid to obtain the phosphate of the compound represented by formula (I); The preparation method of the polymorph of the phosphate comprises: mixing the compound represented by formula (I) with phosphoric acid, and crystallizing to obtain the polymorph of the phosphate of the compound represented by formula (I).

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