Salts, crystalline forms of salts, pharmaceutical compositions thereof, and uses of HCV inhibitors

Abstract

The application belongs to the technical field of medicine, and relates to a salt of a hepatitis C inhibitor compound, a crystal form of the salt, a pharmaceutical composition of the salt, and application of the salt in preparation of a medicine for preventing, treating, curing or reducing HCV infection or a disease related to hepatitis C. The salt of the compound and the crystal form of the salt can significantly improve the pharmacokinetics and other properties of the compound, and have better drug properties.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a salt of a hepatitis C inhibitor compound, the crystal form of the salt, a pharmaceutical composition thereof, and its use in the preparation of a medicament for the prevention, treatment, or relief of HCV infection or diseases related to hepatitis C. Background Technology

[0002] HCV is a major human pathogen, estimated to infect approximately 170 million people globally, five times the number infected with human immunodeficiency virus type 1 (HIV-1). The majority of these HCV-infected individuals will develop severe, progressive liver disease, including cirrhosis and hepatocellular carcinoma. Therefore, chronic HCV infection is a leading cause of premature death from liver disease worldwide.

[0003] Example 5 of Chinese Patent CN105968101A discloses a compound represented by formula (I), which, as a drug-resistant pangenotypic HCV inhibitor, has a significant effect on the treatment of hepatitis C virus (HCV) infection or hepatitis C disease.

[0004]

[0005] However, subsequent studies revealed that the compound of formula (I) prepared in patent CN105968101A was amorphous, with poor solid morphology, affecting post-processing and formulation procedures; in addition, the compound had poor solubility and pharmacokinetic data, affecting drug efficacy. These factors caused numerous inconveniences for subsequent drug development. Summary of the Invention

[0006] This invention provides salts formed by the compounds of formula (I) with acids, including phosphates, hydrochlorides, sulfates, methanesulfonates, p-toluenesulfonates, maleates, and benzenesulfonates. In particular, this invention provides phosphates of the compounds of formula (I) that exhibit better pharmacokinetic properties compared to other salts. Especially, crystal form B of the phosphates of formula (IA) significantly improves the stability and pharmacokinetic properties of the compounds, thereby exhibiting superior drug-like properties.

[0007] Specifically, the present invention relates to salts of compounds of formula (I), crystal form B of phosphates of formula (IA), and pharmaceutical compositions comprising said salts or crystal forms thereof, and also to their use in the preparation of medicaments for the prevention, treatment, or relief of diseases associated with HCV infection or hepatitis C.

[0008] On the one hand, the present invention provides a salt of the compound shown in formula (I),

[0009]

[0010] The salts mentioned are phosphates, hydrochlorides, sulfates, methanesulfonates, p-toluenesulfonates, maleates, and benzenesulfonates.

[0011] In some embodiments, the salt of the compound represented by formula (I) of the present invention is a phosphate.

[0012] In some embodiments, the molar ratio of the compound of formula (I) in the phosphate of this invention to phosphoric acid is 1:2 to 1:4.

[0013] In some other embodiments, the molar ratio of the compound of formula (I) in the phosphate of this invention to phosphoric acid is 1:2 or 1:(8 / 3).

[0014] In some other embodiments, the molar ratio of the compound of formula (I) in the phosphate of this invention to phosphoric acid is 1:2.

[0015] In some other embodiments, the molar ratio of the compound of formula (I) in the phosphate of this invention to phosphoric acid is 1:(8 / 3).

[0016] On the other hand, the present invention provides a crystal form B of the phosphate shown in formula (IA).

[0017]

[0018] The X-ray powder diffraction pattern of crystal form B includes the following diffraction peaks at the 2θ angle: 3.49°±0.2°, 6.89°±0.2°, 9.15°±0.2°, 10.24°±0.2° and 12.16°±0.2°.

[0019] In some embodiments, the X-ray powder diffraction pattern of phosphate crystal form B shown in formula (IA) contains the following diffraction peaks at the 2θ angle: 3.49°±0.2°, 6.89°±0.2°, 7.33°±0.2°, 9.15°±0.2°, 10.24°±0.2°, 10.77°±0.2°, 12.16°±0.2°, 13.44°±0.2°, 14.65°±0.2°, 15.20°±0.2°, 16.22°±0.2°, 17.21°±0.2°, 17.58°±0.2°, 17.94°±0.2°, 18.64°±0.2°, and 19.58°±0.2°.

[0020] In some embodiments, the X-ray powder diffraction pattern of phosphate crystal form B shown in formula (IA) contains the following diffraction peaks at the 2θ angle: 3.49°±0.2°, 6.40°±0.2°, 6.89°±0.2°, 7.33°±0.2°, 9.15°±0.2°, 9.87°±0.2°, 10.24°±0.2°, 10.77°±0.2°, 12.16°±0.2°, 12.72°±0.2°, 13.44°±0.2°, 14.65°±0.2°. °, 15.20°±0.2°, 15.40°±0.2°, 16.22°±0.2°, 16.83°±0.2°, 17.21°±0.2°, 17.58°±0.2°, 17.94°±0.2°, 18.64°±0.2°, 19.58°±0.2°, 21.11°±0.2°, 21.91°±0.2°, 23.24°±0.2°, 24.35°±0.2°, 25.65°±0.2° and 27.05°±0.2°.

[0021] In some embodiments, the crystal form B of the phosphate shown in formula (IA) has essentially the following properties: Figure 3 The X-ray powder diffraction pattern shown.

[0022] In some embodiments, the differential scanning calorimeter of phosphate crystal form B as shown in formula (IA) contains an endothermic peak at 227.22 °C ± 3 °C.

[0023] In some embodiments, the crystal form B of the phosphate shown in formula (IA) has essentially the following properties: Figure 4 The differential scanning calorimetry (DSC) heatmap shown is shown.

[0024] In some embodiments, the thermogravimetric analysis of phosphate crystal form B as shown in formula (IA) shows a weight loss of 1.83% ± 0.5% in the range of 30-150°C.

[0025] In some embodiments, the crystal form B of the phosphate shown in formula (IA) has essentially the following properties: Figure 5 The thermogravimetric analysis diagram is shown.

[0026] On the other hand, the present invention provides an amorphous form of the phosphate shown in formula (IA).

[0027]

[0028] On the other hand, the present invention provides a crystal form A of the phosphate shown in formula (IA).

[0029]

[0030] The X-ray powder diffraction pattern of crystal form A includes the following diffraction peaks at the 2θ angle: 3.41°±0.2°, 6.76°±0.2°, 8.74°±0.2°, 10.10°±0.2° and 16.82°±0.2°.

[0031] In some embodiments, the X-ray powder diffraction pattern of phosphate crystal form A shown in formula (IA) contains the following diffraction peaks at the 2θ angle: 3.41°±0.2°, 6.76°±0.2°, 7.51°±0.2°, 8.74°±0.2°, 10.10°±0.2°, 10.39°±0.2°, 13.48°±0.2°, 14.71°±0.2°, 16.82°±0.2°, 17.68°±0.2°, 20.80°±0.2°, 23.62°±0.2°, 24.75°±0.2°, and 27.09°±0.2°.

[0032] In some embodiments, the X-ray powder diffraction pattern of phosphate crystal form A shown in formula (IA) contains the following diffraction peaks at the 2θ angle: 3.41°±0.2°, 6.76°±0.2°, 7.51°±0.2°, 8.74°±0.2°, 9.27°±0.2°, 10.10°±0.2°, 10.39°±0.2°, 12.53°±0.2°, 13.48°±0.2°, 14.71°±0.2°, 15.02°±0.2°, 16.24°±0.2°, 16.82°±0.2°, 17. 68°±0.2°, 18.84°±0.2°, 20.04°±0.2°, 20.52°±0.2°, 20.80°±0.2°, 21.39°±0.2°, 21.77°±0.2°, 22.90°±0.2°, 23.62°±0.2°, 23.89°±0.2°, 24.55°±0.2°, 24.75°±0.2°, 26.74°±0.2°, 27.09°±0.2°, 27.81°±0.2°, 28.18°±0.2°, and 30.12°±0.2°.

[0033] In some embodiments, the crystalline form A of the phosphate shown in formula (IA) has essentially the following properties: Figure 1 The X-ray powder diffraction pattern shown.

[0034] In some embodiments, the differential scanning calorimeter of phosphate crystal form A as shown in formula (IA) contains an endothermic peak at 225.33 °C ± 3 °C.

[0035] In some embodiments, the crystalline form A of the phosphate shown in formula (IA) has essentially the following properties: Figure 2 The differential scanning calorimetry (DSC) heatmap shown is shown.

[0036] On the other hand, the present invention provides a crystal form D of the phosphate shown in formula (IA).

[0037]

[0038] The X-ray powder diffraction pattern of crystal form D includes the following diffraction peaks at the 2θ angle: 3.37°±0.2°, 6.67°±0.2°, 16.62°±0.2°, 23.32°±0.2° and 33.53°±0.2°.

[0039] In some embodiments, the X-ray powder diffraction pattern of the phosphate crystal form D shown in formula (IA) contains the following diffraction peaks at the 2θ angle: 3.37°±0.2°, 6.67°±0.2°, 16.62°±0.2°, 18.60°±0.2°, 19.97°±0.2°, 21.87°±0.2°, 23.32°±0.2°, 25.64°±0.2°, 26.71°±0.2°, and 33.53°±0.2°.

[0040] In some embodiments, the X-ray powder diffraction pattern of the phosphate crystal form D shown in formula (IA) contains the following diffraction peaks at 2θ angles: 3.37°±0.2°, 6.04°±0.2°, 6.67°±0.2°, 9.18°±0.2°, 10.00°±0.2°, 13.30°±0.2°, 15.39°±0.2°, 16.62°±0.2°, 18. 60°±0.2°, 19.97°±0.2°, 20.66°±0.2°, 21.87°±0.2°, 23.32°±0.2°, 23.82°±0.2°, 25.13°±0.2°, 25.64°±0.2°, 26.71°±0.2°, 27.74°±0.2°, 30.25°±0.2° and 33.53°±0.2°.

[0041] In some embodiments, the crystal form D of the phosphate shown in formula (IA) has essentially the following characteristics: Figure 6 The X-ray powder diffraction pattern shown.

[0042] On the other hand, the present invention provides a crystal form E of the phosphate shown in formula (IA).

[0043]

[0044] The X-ray powder diffraction pattern of crystal form E includes the following diffraction peaks at the 2θ angle: 3.35°±0.2°, 6.62°±0.2°, 22.89°±0.2° and 23.79°±0.2°.

[0045] In some embodiments, the X-ray powder diffraction pattern of phosphate crystal form E shown in formula (IA) contains the following diffraction peaks at the 2θ angle: 3.35°±0.2°, 6.62°±0.2°, 9.15°±0.2°, 12.11°±0.2°, 16.46°±0.2°, 18.07°±0.2°, 22.89°±0.2°, 23.28°±0.2°, and 23.79°±0.2°.

[0046] In some embodiments, the X-ray powder diffraction pattern of phosphate crystal form E shown in formula (IA) includes the following diffraction peaks at the 2θ angle: 3.35°±0.2°, 6.62°±0.2°, 9.15°±0.2°, 12.11°±0.2°, 15.60°±0.2°, 16.46°±0.2°, 17.33°±0.2°, 18.07°±0.2°, 20.56°±0.2°, 22.06°±0.2°, 22.89°±0.2°, 23.28°±0.2°, 23.79°±0.2°, 25.04°±0.2°, 25.55°±0.2°, 30.29°±0.2°, and 33.52°±0.2°.

[0047] In some embodiments, the crystal form E of the phosphate shown in formula (IA) has essentially the following characteristics: Figure 7 The X-ray powder diffraction pattern shown.

[0048] On the other hand, the present invention provides a crystal form N1 of the phosphate shown in formula (IA).

[0049]

[0050] The X-ray powder diffraction pattern of the crystal form N1 includes the following diffraction peaks at the 2θ angle: 6.35°±0.2°, 7.67°±0.2°, 10.34°±0.2°, 16.31°±0.2° and 17.73°±0.2°.

[0051] In some embodiments, the X-ray powder diffraction pattern of the phosphate crystal form N1 shown in formula (IA) contains the following diffraction peaks at the 2θ angle: 6.35°±0.2°, 7.67°±0.2°, 8.92°±0.2°, 10.34°±0.2°, 12.50°±0.2°, 13.40°±0.2°, 16.31°±0.2°, 17.73°±0.2°, 19.02°±0.2°, 20.55°±0.2°, 22.27°±0.2°, 23.79°±0.2°, 24.42°±0.2°, and 25.88°±0.2°.

[0052] In some embodiments, the phosphate crystal form N1 shown in formula (IA) has essentially the following characteristics: Figure 8 The X-ray powder diffraction pattern shown.

[0053] In some embodiments, the differential scanning calorimeter of the phosphate crystal form N1 shown in formula (IA) contains an endothermic peak at 223.05 °C ± 3 °C.

[0054] In some embodiments, the phosphate crystal form N1 shown in formula (IA) has essentially the following characteristics: Figure 9 The differential scanning calorimetry (DSC) heatmap shown is shown.

[0055] In some embodiments, the thermogravimetric analysis of the phosphate crystal form N1 shown in formula (IA) shows a weight loss of 6.76% ± 0.5% in the range of 30-193°C.

[0056] In some embodiments, the phosphate crystal form N1 shown in formula (IA) has essentially the following characteristics: Figure 10 The thermogravimetric analysis diagram is shown.

[0057] On the other hand, the present invention provides a crystal form N2 of the phosphate shown in formula (IA).

[0058]

[0059] The X-ray powder diffraction pattern of the N2 crystal form includes the following diffraction peaks at the 2θ angle: 6.47°±0.2°, 10.22°±0.2°, 16.37°±0.2°, 17.59°±0.2° and 22.82°±0.2°.

[0060] In some embodiments, the X-ray powder diffraction pattern of the phosphate crystal form N2 shown in formula (IA) contains the following diffraction peaks at the 2θ angle: 6.47°±0.2°, 7.42°±0.2°, 8.26°±0.2°, 8.92°±0.2°, 10.22°±0.2°, 12.69°±0.2°, 14.22°±0.2°, 14.82°±0.2°, 15.64°±0.2°, 16.37°±0.2°, 17.59°±0.2°, 19.42°±0.2°, 20.32°±0.2°, 20.92°±0.2°, 22.82°±0.2°, 23.79°±0.2°, 24.43°±0.2°, and 25.15°±0.2°.

[0061] In some embodiments, the phosphate N2 of formula (IA) has essentially the following crystal form: Figure 11 The X-ray powder diffraction pattern shown.

[0062] In some embodiments, the differential scanning calorimeter of the phosphate crystal form N2 shown in formula (IA) contains an endothermic peak at 226.28 °C ± 3 °C.

[0063] In some embodiments, the phosphate N2 of formula (IA) has essentially the following crystal form: Figure 12 The differential scanning calorimetry (DSC) heatmap shown is shown.

[0064] In some implementations, the thermogravimetric analysis of the phosphate crystal form N2 shown in formula (IA) shows a weight loss of 6.99% ± 0.5% in the range of 30-212°C.

[0065] In some embodiments, the phosphate N2 of formula (IA) has essentially the following crystal form: Figure 13 The thermogravimetric analysis diagram is shown.

[0066] On the other hand, the present invention provides a crystal form N5 of the phosphate shown in formula (IA).

[0067]

[0068] The X-ray powder diffraction pattern of the crystal form N5 includes the following diffraction peaks at the 2θ angle: 3.37°±0.2°, 6.57°±0.2°, 10.24°±0.2°, 17.86°±0.2° and 21.41°±0.2°.

[0069] In some embodiments, the X-ray powder diffraction pattern of the phosphate crystal form N5 shown in formula (IA) contains the following diffraction peaks at the 2θ angle: 3.37°±0.2°, 6.57°±0.2°, 7.35°±0.2°, 8.49°±0.2°, 9.06°±0.2°, 10.24°±0.2°, 16.28°±0.2°, 17.86°±0.2°, 20.58°±0.2°, 21.41°±0.2°, 22.97°±0.2°, and 24.55°±0.2°.

[0070] In some embodiments, the X-ray powder diffraction pattern of the phosphate crystal form N5 shown in formula (IA) contains the following diffraction peaks at the 2θ angle: 3.37°±0.2°, 6.57°±0.2°, 7.35°±0.2°, 8.49°±0.2°, 9.06°±0.2°, 10.24°±0.2°, 12.18°±0.2°, 13.02°±0.2°, 14.67°±0.2°. 2°, 15.45°±0.2°, 16.28°±0.2°, 17.86°±0.2°, 19.61°±0.2°, 20.18°±0.2°, 20.58°±0.2°, 21.41°±0.2°, 22.97°±0.2°, 23.83°±0.2°, 24.55°±0.2°, 25.40°±0.2° and 25.88°±0.2°.

[0071] In some embodiments, the phosphate crystal form N5 shown in formula (IA) has essentially the following characteristics: Figure 14 The X-ray powder diffraction pattern shown.

[0072] In some embodiments, the differential scanning calorimeter of the phosphate crystal form N5 shown in formula (IA) contains an endothermic peak at 223.05 °C ± 3 °C.

[0073] In some embodiments, the phosphate crystal form N5 shown in formula (IA) has essentially the following characteristics: Figure 15 The differential scanning calorimetry (DSC) heatmap shown is shown.

[0074] In some implementations, the thermogravimetric analysis of the phosphate crystal form N5 shown in formula (IA) shows a weight loss of 5.49% ± 0.5% in the range of 30–198 °C.

[0075] In some embodiments, the phosphate crystal form N5 shown in formula (IA) has essentially the following characteristics: Figure 16 The thermogravimetric analysis diagram is shown.

[0076] On the other hand, the present invention provides a crystal form N6 of the phosphate shown in formula (IA).

[0077]

[0078] The X-ray powder diffraction pattern of the N6 crystal form includes the following diffraction peaks at the 2θ angle: 3.38°±0.2°, 6.60°±0.2°, 10.25°±0.2°, 16.49°±0.2° and 23.17°±0.2°.

[0079] In some embodiments, the X-ray powder diffraction pattern of the phosphate crystal form N6 shown in formula (IA) contains the following diffraction peaks at the 2θ angle: 3.38°±0.2°, 6.60°±0.2°, 7.43°±0.2°, 8.52°±0.2°, 10.25°±0.2°, 16.49°±0.2°, 17.97°±0.2°, 22.75°±0.2°, 23.17°±0.2°, 24.48°±0.2°, and 24.85°±0.2°.

[0080] In some embodiments, the X-ray powder diffraction pattern of the phosphate crystal form N6 shown in formula (IA) contains the following diffraction peaks at the 2θ angle: 3.38°±0.2°, 6.60°±0.2°, 7.43°±0.2°, 8.52°±0.2°, 9.07°±0.2°, 10.25°±0.2°, 14.55°±0.2°, 14.89°±0.2°, 15.63°±0.2°, 16.49°±0.2°, 17.05°±0.2°, 17.63°±0.2°. 2°, 17.97°±0.2°, 18.58°±0.2°, 19.78°±0.2°, 20.44°±0.2°, 21.50°±0.2°, 22.75°±0.2°, 23.17°±0.2°, 24.48°±0.2°, 24.85°±0.2°, 25.57°±0.2°, 26.27°±0.2°, 27.39°±0.2°, 28.02°±0.2°, 29.39°±0.2° and 30.87°±0.2°.

[0081] In some embodiments, the phosphate N6 of formula (IA) has essentially the following crystal form: Figure 17 The X-ray powder diffraction pattern shown.

[0082] In some embodiments, the differential scanning calorimeter of the phosphate crystal form N6 shown in formula (IA) contains an endothermic peak at 223.74 °C ± 3 °C.

[0083] In some embodiments, the phosphate N6 of formula (IA) has essentially the following crystal form: Figure 18 The differential scanning calorimetry (DSC) heatmap shown is shown.

[0084] In some implementations, the thermogravimetric analysis of the phosphate crystal form N6 shown in formula (IA) shows a weight loss of 4.69% ± 0.5% in the range of 30–196 °C.

[0085] In some embodiments, the phosphate N6 of formula (IA) has essentially the following crystal form: Figure 19 The thermogravimetric analysis diagram is shown.

[0086] On the other hand, the present invention provides a pharmaceutical composition comprising the crystalline form of the salt or phosphate of the present invention or the amorphous form of the phosphate of the present invention.

[0087] In some embodiments, the present invention provides a pharmaceutical composition comprising the salt of the present invention or the crystalline form B of the phosphate of the present invention or the amorphous form of the phosphate of the present invention.

[0088] In some preferred embodiments, the present invention provides a pharmaceutical composition comprising either crystal form B of the phosphate of the present invention or an amorphous form of the phosphate of the present invention.

[0089] In another aspect, the present invention provides a method for preparing a salt of the compound represented by formula (I) of the present invention, comprising reacting the compound represented by formula (I) with an acid in a suitable solvent.

[0090] In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.

[0091] In other embodiments, the pharmaceutical composition of the present invention further comprises other anti-HCV drugs.

[0092] In some embodiments, other anti-HCV drugs described in this invention include interferon, ribavirin, interleukin-2, interleukin-6, interleukin-12, compounds that promote type 1 helper T cell responses, interfering RNA, antisense RNA, imiquimod, inosine 5'-monophosphate dehydrogenase inhibitors, amantadine, rimantadine, bavitimab, hepatitis C immunoglobulin, and Civacir. TMBoprevir, Tetraprevir, Ingbuvir, Smepivir, Anavivir, Vaniprevir, Faldaprevir, Danopvir, Sovaprevir, Vedroprevir, BZF-961, GS-9256, Narlaprevir, ANA975, SH229, GSK-2336805, Ciluprevir, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, Modithromycin, VBY-3 76. TMC-649128, mericitabine, sofosbuvir, INX-189, IDX-184, IDX102, R-1479, UNX-08189, PSI-6130, PSI-938, PSI-879, nesbuvir, HCV-371 , VCH-916, lomibuvir, MK-3281, dasabuvir, ABT-072, filibuvir, deleobuvir, tegobuvir, A-837093, JKT-109, Gl-59728, GL-60667, TMC 647055, Radipasvir, Setrobuvir, Alisporivir, BIT-225, ACH-3422, MK-2748, ABP-560, TVB-2640, ID-12, PPI-383, A-848837, RG-7795, BC-2125, Alloferon, Nivolumab, WF-10, Nizoralide, Multiferon, Nevirapine, ACH-3422, Alabavirvir, MK-3682, GS-9857, CD-AdNS3, RG-101, MBL-HCV1, CIGB-230 The following are listed: TG-2349, procvax, CB-5300, miravirsen, chronvac-C, MK-1075, ACH-0143422, WS-007, MK-7680, MK-2248, IDX-21459, MK-8876, GSK-2878175, MBX-700, AL-335, AL-704, SB-9200, ITX-5061, or combinations thereof; the interferon is interferon α-2b, PEGylated interferon α, interferon α-2a, PEGylated interferon α-2a, complex α-interferon, interferon γ, or combinations thereof.

[0093] On the other hand, the present invention provides the use of the salt of the present invention, or crystal form B of the phosphate of the present invention, or the pharmaceutical composition of the present invention in the preparation of a medicament for the prevention, treatment, or relief of HCV infection or hepatitis C-related diseases.

[0094] The solvents used in the preparation methods of the salts and / or their crystal forms described in this invention are not particularly limited; any solvent capable of dissolving the starting material to a certain extent without affecting its properties is included in this invention. Furthermore, many similar modifications, equivalent substitutions, or solvents, solvent combinations, and different proportions of solvent combinations described in this invention are considered to be within the scope of this invention. This invention provides preferred solvents for each reaction step.

[0095] The preparation experiments of the salt or its crystal form described in this invention are described in detail in the Examples section. Furthermore, this invention provides pharmacological testing experiments (such as pharmacokinetic experiments) of the salt or its crystal form. Experiments have demonstrated that the salt or its crystal form described in this invention possesses good stability and pharmacokinetic properties.

[0096] Definitions and general terms

[0097] Unless otherwise stated, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents and publications related to this invention are incorporated herein by reference in their entirety. Although any methods and substances similar to or identical to those described herein may be used in the practice or testing of this invention, preferred methods, apparatus, and substances are described herein.

[0098] "Crystal form" or "crystalline shape" refers to a solid having a highly regular chemical structure, including, but not limited to, single-component or multi-component crystals, and / or polymorphs of compounds, solvates, hydrates, inclusion compounds, eutectics, salts, solvates of salts, and hydrates of salts. The crystalline form of a substance can be obtained by many methods known in the art. These methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a confined space, such as in nanopores or capillaries, crystallization on a surface or template, such as on a polymer, crystallization in the presence of additives such as co-crystallized antimolecules, desolventization, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, grinding, and solvent drop grinding, etc.

[0099] "Solvent" refers to a substance (typically a liquid) that can completely or partially dissolve another substance (typically a solid). Solvents used in the implementation of this invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, etc.

[0100] An antisolvent is a fluid that promotes the precipitation of a product (or product precursor) from a solvent. Antisolvents can include cold gases, fluids that promote precipitation through chemical reactions, or fluids that reduce the solubility of a product in a solvent; they can be the same liquid as the solvent but at a different temperature, or they can be a different liquid from the solvent.

[0101] Crystal forms can be identified using a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.

[0102] X-ray powder diffraction (XRPD) can detect changes in crystal form, crystallinity, and crystal structure, and is a commonly used method for identifying crystal forms. The peak positions of XRPD spectra depend primarily on the crystal structure and are relatively insensitive to experimental details, while their relative peak heights depend on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystal form of the present invention is characterized by an XRPD pattern with certain peak positions, which is essentially as shown in the XRPD patterns provided in the accompanying drawings. Furthermore, the measurement of 2θ in the XRPD spectra can be subject to experimental error; the measurement of 2θ in XRPD spectra may vary slightly between different instruments and different samples, therefore the value of 2θ cannot be considered absolute. Based on the instrument used in this experiment, there is an error tolerance of ±0.2° for the diffraction peaks.

[0103] Differential scanning calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference (commonly α-Al₂O₃) as a function of temperature by continuously heating or cooling under programmed control. The height of the endothermic peak in a DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystal form described in this invention is characterized by a DSC plot with characteristic peak positions, which is essentially as shown in the DSC plots provided in the accompanying drawings. However, DSC spectra can be subject to experimental error; the peak positions and peak values ​​may vary slightly between different instruments and different samples. Therefore, the peak positions or peak values ​​of the endothermic peaks in the DSC should not be considered absolute. Depending on the instrument used in this experiment, there is an error tolerance of ±3°C for the endothermic peaks.

[0104] Thermogravimetric analysis (TGA) is a technique used under programmed control to determine the change in mass of a substance with temperature. It is suitable for examining the loss of solvent in crystals or the sublimation and decomposition of samples, and can infer the presence of water of crystallization or crystallization solvent in the crystal. The mass change shown by the TGA curve depends on many factors, including sample preparation and instrumentation; the mass change detected by TGA varies slightly between different instruments and different samples, with an error tolerance of ±0.5%. Based on the instrument used in this experiment, the mass change introduced by the instrument has an error tolerance of ±0.1%.

[0105] In the context of this invention, the 2θ values ​​in X-ray powder diffraction patterns are all in degrees (°).

[0106] The term “basically as shown” means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks are shown in an X-ray powder diffraction pattern, DSC pattern, Raman spectrum, or infrared spectrum.

[0107] When referring to a spectrum or / and the data appearing in the graph, a "peak" refers to a feature that a person skilled in the art can identify and that is not attributable to background noise.

[0108] "Substantially pure" means that a crystal form substantially contains no other crystal forms, i.e., the purity of the crystal form is at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or the crystal form contains other crystal forms whose percentage in the total volume or total weight of the crystal form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

[0109] "Substantially free of" means that one or more other crystal forms account for less than 20%, or less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01% of the total volume or weight of the crystal form.

[0110] In an X-ray powder diffraction (XRPD) pattern, "relative intensity" or "relative peak height" refers to the ratio of the intensity of the other peaks to the intensity of the first strongest peak when the intensity of the first strongest peak is 100%.

[0111] In the context of this invention, when the terms "about" or "approximately" are used, whether or not they are used, it means within 10% of a given value or range, appropriately within 5%, and particularly within 1%. Alternatively, for those skilled in the art, the term "about" or "approximately" means within an acceptable standard error of the average. Whenever a number with a value of N is disclosed, any number having a value within N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, or N+ / -10% is explicitly disclosed, where "+ / -" refers to addition or subtraction.

[0112] In this invention, "room temperature" refers to a temperature ranging from approximately 20°C to approximately 30°C.

[0113] Pharmaceutical compositions, formulations, administration and uses of salts of the compounds described in this invention and their crystal forms.

[0114] The pharmaceutical compositions of the present invention are characterized by a salt of the compound represented by formula (I) or a crystalline form of the phosphate described in the present invention, and a pharmaceutically acceptable carrier, excipient, or excipient. The amount of the salt of the compound or the crystalline form of the phosphate described in the present invention in the pharmaceutical compositions of the present invention can effectively and detectably treat or alleviate diseases associated with HCV infection or hepatitis C in patients.

[0115] As described in this invention, pharmaceutically acceptable compositions of this invention further comprise pharmaceutically acceptable carriers, excipients, or excipients, such as those used in this invention, including any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder, or lubricant, etc., suitable for a particular target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of this literature demonstrate that different carriers can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. Except for any conventional carrier media that are incompatible with the salts or crystal forms of the compounds of the present invention, such as those that produce any adverse biological effects or interactions with any other component of a pharmaceutically acceptable composition in a harmful manner, their use is also within the scope of this invention.

[0116] Substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffering substances such as phosphates; glycine; sorbic acid; potassium sorbate; mixtures of partial glycerides of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as carboxymethyl cellulose. Sodium cellulose, ethyl cellulose, and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate; colorants; release agents; coatings; sweeteners; flavorings; fragrances; preservatives and antioxidants.

[0117] The pharmaceutical compositions of the present invention may be capsules, tablets, pills, powders, granules, and aqueous suspensions or solutions; and may be administered via the following routes: oral administration, injection administration, inhalation spray, topical administration, rectal administration, nasal administration, sublingual administration, vaginal administration, or via implantable cassette.

[0118] Oral administration can be in the following forms: tablets, pills, capsules, dispersible powders, granules or suspensions, syrups and elixirs, etc.; topical administration can be in the following forms: ointments, gels, medicated plasters, etc.

[0119] The salts or crystal forms thereof of the present invention are preferably formulated in a dosage unit form to reduce the uniformity of dosage and administration. The term "dosage unit form" here refers to the physical dispersion unit of the drug required for the patient to receive adequate treatment. However, it should be understood that the total daily dosage of the salts or crystal forms of the compounds represented by formula (I) of the present invention, or the pharmaceutical compositions of the present invention, will be determined by the attending physician based on reliable medical judgment. The specific effective dosage level for any particular patient or organism will depend on many factors including the condition being treated and its severity, the activity of the salts or crystal forms of the specific compounds, the specific composition used, the patient's age, weight, health status, sex, and dietary habits, the time of administration, the route of administration, and the excretion rate of the salts or crystal forms of the specific compounds used, the duration of treatment, whether the drug is used in combination therapy or in combination with salts or crystal forms of potent compounds, and other factors known in the pharmaceutical field.

[0120] This invention provides the use of salts or crystal forms of the compounds of this invention, or pharmaceutical compositions thereof, in the preparation of medicaments that can be used to inhibit the HCV replication process and / or inhibit the function of HCV viral proteins; the HCV replication process includes HCV entry, HCV uncoating, HCV translation, HCV replication, HCV assembly, or HCV release; the HCV viral proteins are selected from metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, or NS5B, as well as the internal ribosome entry site (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV viral replication. Any compound or pharmaceutical composition of this invention can be used to treat hepatitis C virus (HCV) infection or hepatitis C disease.

[0121] This invention relates to a treatment method comprising administering a salt or crystalline form of the compound of the invention, or a pharmaceutical composition thereof, further comprising administering other HCV drugs to a patient, thereby allowing the compound of the invention to be used in combination with other anti-HCV drugs, wherein said anti-HCV drugs include interferon, ribavirin, interleukin-2, interleukin-6, interleukin-12, compounds that promote type 1 helper T cell responses, interfering RNA, antisense RNA, imiquimod, inosine 5'-monophosphate dehydrogenase inhibitors, amantadine, rimantadine, bavitimab, hepatitis C immunoglobulin, and Civacir. TMBoprevir, Tilaprevir, Ingbuvir, Smepivir, Anavivir, Vaniprevir, Faldaprevir, Danoprevir, Sovaprevir, Vedroprevir, BZF-961, GS-9256, Narlaprevir, ANA975, SH229, GSK-2336805, Ciluprevir, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, Mod ithromycin, VBY-376, TMC-649128, mericitabine, sofosbuvir, INX-189, IDX-184, IDX102, R-1479, UNX-08189, PSI-6130, PSI-938, PSI-879, nesbuvir, HCV-371, VCH-916, lomibuvir, MK-3281, dasabuvir, ABT-072, filibuvir, deleobuvir, tegobuvir, A-8370 93, JKT-109, GL-59728, GL-60667, TMC647055, Radipasvir, Setrobuvir, Alisporivir, BIT-225, ACH-3422, MK-2748, ABP-560, TVB-2640, ID-12, PPI-383, A-848837, RG-7795, BC-2125, Alloferon, Nivolumab, WF-10, Nizoral, Multiferon, Nevirapine, ACH-3422, Alaborvir, M K-3682, GS-9857, CD-AdNS3, RG-101, MBL-HCV1, CIGB-230, TG-2349, Procvax, CB-5300, Miravirsen, Chronvac-C, MK-1075, ACH-0143422, WS-007, MK-7680, MK-2248, IDX-21459, MK-8876, GSK-2878175, MBX-700, AL-335, AL-704, SB-9200, ITX-5061, or combinations thereof. The interferon mentioned therein is interferon α-2b, PEGylated interferon α, interferon α-2a, PEGylated interferon α-2a, complex α-interferon, interferon γ, or combinations thereof.

[0122] The treatment method, which includes administration of a salt or crystalline form of the salt or a pharmaceutical composition comprising the compounds of the present invention, further includes administration of other anti-HCV drugs, wherein the other anti-HCV drugs may be administered in combination with the compounds of the present invention or pharmaceutical compositions thereof, either as a single dosage form or as part of a multi-dosage form. Other anti-HCV drugs may be administered simultaneously with or at different times than the compounds of the present invention. In the latter case, administration may be staggered, such as at intervals of 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, or 2 months.

[0123] The "effective amount" or "effective dose" of a salt or crystal form of a compound of the present invention, or a pharmaceutically acceptable composition, refers to an effective amount for treating or reducing the severity of one or more of the conditions mentioned in the present invention. According to the methods of the present invention, compounds and compositions can be administered at any dosage and via any route of administration to effectively treat or reduce the severity of a disease. The precise amount required will vary depending on the patient's condition, such as the patient's general condition, the severity of the infection, specific factors, the route of administration, etc. Compounds or compositions may be administered in combination with one or more other therapeutic agents, as discussed in the present invention. Attached Figure Description

[0124] Figure 1 The image shows the X-ray powder diffraction (XRPD) pattern of crystal form A of the phosphate shown in formula (IA).

[0125] Figure 2 The differential scanning calorimetry (DSC) curve is shown for crystal form A of the phosphate represented by formula (IA).

[0126] Figure 3 The image shows the X-ray powder diffraction (XRPD) pattern of phosphate crystal form B as shown in formula (IA).

[0127] Figure 4 The differential scanning calorimetry (DSC) curve is shown for crystal form B of the phosphate represented by formula (IA).

[0128] Figure 5 The thermogravimetric analysis (TGA) diagram shows the crystal form B of the phosphate represented by formula (IA).

[0129] Figure 6 The image shows the X-ray powder diffraction (XRPD) pattern of crystal form D of the phosphate shown in formula (IA).

[0130] Figure 7 The image shows the X-ray powder diffraction (XRPD) pattern of crystal form E of the phosphate shown in formula (IA).

[0131] Figure 8The image shows the X-ray powder diffraction (XRPD) pattern of the phosphate crystal form N1 shown in formula (IA).

[0132] Figure 9 The differential scanning calorimetry (DSC) curve is shown for the crystal form N1 of the phosphate represented by formula (IA).

[0133] Figure 10 The thermogravimetric analysis (TGA) diagram shows the crystal form N1 of the phosphate represented by formula (IA).

[0134] Figure 11 The image shows the X-ray powder diffraction (XRPD) pattern of the phosphate crystal form N2 as shown in formula (IA).

[0135] Figure 12 The differential scanning calorimetry (DSC) curve is shown for the phosphate crystal form N2 as represented by formula (IA).

[0136] Figure 13 The thermogravimetric analysis (TGA) diagram shows the crystalline form N2 of phosphate represented by formula (IA).

[0137] Figure 14 The image shows the X-ray powder diffraction (XRPD) pattern of the phosphate crystal form N5 as shown in formula (IA).

[0138] Figure 15 The differential scanning calorimetry (DSC) curve is shown for the N5 crystal form of the phosphate shown in formula (IA).

[0139] Figure 16 The thermogravimetric analysis (TGA) diagram shows the crystal form N5 of the phosphate represented by formula (IA).

[0140] Figure 17 The image shows the X-ray powder diffraction (XRPD) pattern of the phosphate crystal form N6 as shown in formula (IA).

[0141] Figure 18 The differential scanning calorimetry (DSC) curve is shown for the N6 crystal form of the phosphate shown in formula (IA).

[0142] Figure 19 The thermogravimetric analysis (TGA) diagram shows the crystal form N6 of the phosphate represented by formula (IA).

[0143] Figure 20 The XRPD spectra of the factors affecting phosphate crystal form B as shown in formula (IA) of Example 18 are shown from top to bottom as XRPD spectra corresponding to 30 days of light, 30 days of high humidity, 30 days of high temperature and 0 days.

[0144] Figure 21The XRPD spectra of the amorphous influencing factors of phosphate shown in formula (IA) of Example 18 are as follows, from top to bottom: XRPD spectra corresponding to 15 days of light, 15 days of high humidity, 15 days of high temperature, 10 days of light, 10 days of high humidity, 10 days of high temperature, 5 days of light, 5 days of high humidity, 5 days of high temperature and 0 days. Detailed Implementation

[0145] The present invention will be further illustrated by means of embodiments below, but the invention is not limited to the scope of the embodiments described herein.

[0146] The X-ray powder diffraction analysis method used in this invention is as follows: X-ray powder diffraction (XRPD) patterns are collected on a Dutch PANalytical Empyrean X-ray diffractometer equipped with an automated 3*15 zero-background sample holder and a transmission / reflection sample stage. The radiation source used is (Cu, kα, ... 1.540598; 1.544426; Kα2 / Kα1 intensity ratio: 0.50), where the voltage is set at 45KV and the current at 40mA. The X-ray beam divergence, i.e., the effective size of the X-ray confinement on the sample, is 10mm. Using the θ-θ continuous scanning mode, an effective 2θ range of 3° to 40° is obtained. An appropriate amount of sample is placed in the circular groove of the zero-background sample holder under environmental conditions (approximately 18℃ to 32℃), and a clean glass slide is gently pressed to obtain a flat plane. The zero-background sample holder is then fixed. The sample is scanned at a step size of 0.0167° within the 2θ range of (3~40°) ± 0.2° to generate a conventional XRPD pattern. The software used for data collection is Data Collector, and the data is analyzed and displayed using Data Viewer and HighScore Plus. In the X-ray powder diffraction pattern, the vertical axis represents the diffraction intensity expressed in counts, and the horizontal axis represents the diffraction angle 2θ expressed in degrees (°).

[0147] The differential scanning calorimetry (DSC) analysis method used in this invention is as follows: A TA Instruments Q2000 differential scanning calorimeter is used for DSC. The sample (approximately 1 mg to 3 mg) is placed in an aluminum dish, and the weight is accurately recorded. The dish is covered with a lid, then pressed shut, and the sample is transferred to the instrument for measurement. The sample cell is equilibrated at 30°C and heated to a final temperature of 300°C at a rate of 10°C / min under nitrogen purging. In the DSC graph, the horizontal axis represents temperature (°C), and the vertical axis represents the heat flow per unit mass of the substance (W / g).

[0148] The thermogravimetric analysis (TGA) method used in this invention is as follows: Thermogravimetric analysis is performed using a TA Instruments Q500 thermogravimetric analyzer. An appropriate amount of sample is placed in a platinum sample pan, and the temperature is increased at a rate of 10°C / min under a nitrogen atmosphere, with a temperature range of 30 to 300°C. In the TGA graph, the horizontal axis represents temperature (°C), and the vertical axis represents mass percentage (%).

[0149] The Dynamic Vapor Adsorption Analysis (DVS) method used in this invention is as follows: The DVS isothermal adsorption equilibrium curve testing method is employed. The instrument used is a DVS-INTRINSIC. Under conditions of 25.0℃, the relative humidity changes from 0% to 95% (0%-95.0%-0%), starting at 0% relative humidity and decreasing in 10% steps to reach 95% relative humidity, then decreasing again in 10% steps to return to 0% relative humidity. Equilibrium is considered reached when the absolute value of the sample weight change (dm / dt) per unit time is less than 0.1% under a specific relative humidity condition, and then the process proceeds to the next relative humidity level. The method detects the change in hygroscopicity of the product under cyclic conditions of relative humidity (0%-95.0%-0%).

[0150] The abbreviations used in this instruction manual are as follows:

[0151] HCl (hydrochloric acid); H2SO4 (sulfuric acid); H3PO4 (phosphoric acid); MsOH (methanesulfonic acid); PTSA (p-toluenesulfonic acid); MA (maleic acid); BSA (benzenesulfonic acid); min (minutes); M (mol / L); mmol (millomoles); mL (milliliters); h (hours); g (grams).

[0152] Example

[0153] The compound shown in formula (I) was obtained by referring to the synthesis method of Example 5 in Chinese Patent CN105968101A.

[0154] Unless otherwise specified, the crystal forms or amorphous forms of the phosphates of the compounds represented by formula (I) in this specification are the crystal forms or amorphous forms of the phosphates represented by formula (IA) formed by the compounds represented by formula (I) and 8 / 3 molecules of phosphoric acid.

[0155]

[0156] Unless otherwise specified, the room temperature in this instruction manual is 20℃~30℃.

[0157] Example 1: Preparation of compound (I)·2H3PO4

[0158] 0.50 g of compound (I) (0.559 mmol, 1.0 eq) was dissolved in 5 mL of ethanol. A mixture of 0.14 g of phosphoric acid (1.42 mmol, 2.56 eq) and 5 mL of ethanol was added dropwise at room temperature. After the addition was complete, a white solid precipitated. The mixture was stirred at room temperature for 12 h and then filtered. The wet product was dried to obtain 0.60 g of yellowish-white solid. Ion chromatography analysis showed that the phosphate content was 18.4%, indicating that it was a phosphate formed by compound (I) and two molecules of phosphoric acid.

[0159] Example 2 Preparation of compound (I)·2MsOH

[0160] 0.50 g of compound (I) (0.559 mmol, 1.0 eq) was dissolved in 10 mL of ethyl acetate. A mixture of 0.12 g of methanesulfonic acid (1.25 mmol, 2.24 eq) and 5 mL of ethyl acetate was added dropwise at room temperature. After the addition was complete, a pink solid precipitated. The mixture was stirred at room temperature for 4 h, filtered, and the wet product was dried to give 0.60 g of pink solid. 1 HNMR indicates that it is a methanesulfonate formed by compound (I) and two molecules of methanesulfonic acid.

[0161] 1 H NMR (400MHz, CDCl3): δ (ppm) 15.00 (s, 1H), 14.80–13.92 (m, 3H), 8.77–8.55 (m, 1H), 7.91 (dd, J = 40.0, 11.9Hz, 2H), 7. 80–7.59(m,2H),7.57–7.33(m,6H),7.21(s,1H),6.13(s,1H),5.62(dd,J=54.2,35.0Hz,1H),5.43(dd,J=13.5,7.0Hz, 2H),5.30(d,J=10.5Hz,1H),4.83–4.19(m,2H),3.75(d,J=38.8Hz,2H),3.64(s,3H),3.62–3.38(m,3H),3.30(s,3H),3 .23–3.03(m,4H),2.55–2.27(m,9H),2.24–1.90(m,8H),1.71(d,J=59.4Hz,2H),1.42–1.30(m,3H),1.16–0.78(m,6H).

[0162] Example 3 Preparation of compound (I)·2H2SO4

[0163] 0.50 g of compound (I) (0.559 mmol, 1.0 eq) was dissolved in 10 mL of ethyl acetate. A mixture of 0.12 g of concentrated sulfuric acid (1.22 mmol, 2.19 eq) and 10 mL of ethyl acetate was added dropwise at room temperature. After the addition was complete, a pink solid precipitated. The mixture was stirred at room temperature for 2 h and then filtered. The wet product was dried to obtain 0.54 g of pink solid. Ion chromatography showed that the sulfate content was 18%, indicating that it was a sulfate formed by compound (I) and two molecules of sulfuric acid.

[0164] Example 4 Preparation of compound (I)·2HCl

[0165] 0.50 g of compound (I) (0.559 mmol, 1.0 eq) was dissolved in 10 mL of ethyl acetate. A mixture of 0.6 mL of 2 M hydrochloric acid (1.20 mmol, 2.14 eq) and 10 mL of ethyl acetate was added dropwise at room temperature. After the addition was complete, a pink solid precipitated. The mixture was stirred at room temperature for 2 h and then filtered. The wet product was dried to obtain 0.54 g of pink solid. Ion chromatography showed that the chlorine content was 8.11%, indicating that it was the hydrochloride salt formed by compound (I) and two molecules of hydrochloric acid.

[0166] Example 5 Preparation of compound (I) · 2MA

[0167] 0.50 g of compound (I) (0.559 mmol, 1.0 eq) was dissolved in 10 mL of ethyl acetate. A mixture of 142 mg maleic acid (1.22 mmol, 2.19 eq) and 5 mL of ethyl acetate was added dropwise at -4 °C. After stirring at room temperature for 20 h, the mixture was filtered and the wet product was dried to give 0.59 g of pale yellow solid. 1 HNMR indicates that it is a maleate salt formed by compound (I) and two molecules of maleic acid.

[0168] 1H NMR (400MHz, CDCl3): δ (ppm) 8.65 (s, 1H), 7.70 (s, 1H), 7.55–7.28 (m, 7H), 7.02 (s, 1H), 6.79 (s, 1H), 6. 39–6.33(m,5H),5.46(dt,J=29.2,25.7Hz,4H),4.76–4.68(m,2H),4.40–4.24(m,1H),4.03–3.81(m,2H) ,3.73(s,1H),3.69(s,3H),3.50(dd,J=33.7,5.6Hz,4H),3.30(s,3H),3.26(s,1H),3.19(s,2H),3.10(s ,2H),2.84–2.73(m,2H),2.39(s,3H),2.28–2.010(m,4H),1.29(d,J=9.0Hz,4H),1.01(d,J=4.2Hz,6H).

[0169] Example 6 Preparation of compound (I) · 2BSA

[0170] 0.50 g of compound (I) (0.559 mmol, 1.0 eq) was dissolved in 10 mL of ethyl acetate. A mixture of 194 mg benzenesulfonic acid (1.23 mmol, 2.20 eq) and 5 mL of ethyl acetate was added dropwise at -4 °C. After stirring at room temperature for 18 h, the mixture was filtered and the wet product was dried to give 0.61 g of white solid. 1 HNMR indicates that it is a benzenesulfonate formed by compound (I) and two molecules of benzenesulfonic acid.

[0171] 1H NMR (400MHz, CDCl3): δ (ppm) 15.03 (s, 1H), 14.80–13.92 (m, 3H), 8.66 (s, 1H), 7.92–7.80 (m, 6H), 7.71 (s, 1H), 7.58– 7.29(m,11H),7.02(s,1H),6.79(s,1H),6.35(s,1H),5.43(dt,J=29.2,25.7Hz,4H),4.78–4.70(m,2H),4.46–4.26( m,1H),4.05–3.80(m,2H),3.74(s,1H),3.67(s,3H),3.49(dd,J=33.7,5.6Hz,4H),3.30(s,3H),3.26(s,1H),3.19(s ,2H),3.10(s,2H),2.84–2.73(m,2H),2.39(s,3H),2.27–2.08(m,4H),1.27(d,J=9.0Hz,4H),1.02(d,J=4.2Hz,6H).

[0172] Example 7 Preparation of compound (I) · 2PTSA

[0173] 0.46 g of compound (I) (0.514 mmol, 1.0 eq) was dissolved in 10 mL of ethyl acetate. A mixture of 194 mg of p-toluenesulfonic acid (1.13 mmol, 2.19 eq) and 5 mL of ethyl acetate was added dropwise at room temperature. After the addition was complete, the mixture was filtered directly under vacuum and the wet product was dried to give 0.60 g of white solid. 1 HNMR indicates that it is a p-toluenesulfonate formed by compound (I) and two molecules of p-toluenesulfonic acid.

[0174] 1H NMR (400MHz, CDCl3): δ (ppm) 15.08 (s, 1H), 14.81–13.94 (m, 3H), 8.66 (s, 1H), 7.90 (d, J = 7.8Hz, 4H), 7.71 (s, 1H), 7.58–7.29 ( m,7H),7.21(d,J=7.7Hz,4H),7.02(s,1H),6.79(s,1H),6.35(s,1H),5.44(dt,J=29.2,25.7Hz,4H),4.78–4.70(m,2H),4.45– 4.24(m,1H),4.04–3.81(m,2H),3.74(s,1H),3.68(s,3H),3.49(dd,J=33.7,5.6Hz,4H),3.30(s,3H),3.26(s,1H),3.19(s,2H ),3.10(s,2H),2.84–2.73(m,2H),2.39(s,3H),2.37(s,6H),2.27–2.07(m,4H),1.29(d,J=9.0Hz,4H),1.01(d,J=4.2Hz,6H).

[0175] Example 8 Preparation of the phosphate shown in formula (IA) (compound (I)·(8 / 3)H3PO4)

[0176] 3.00 g of compound (I) (3.35 mmol, 1.0 eq) was dissolved in 26.7 mL of acetone. A mixture of 1.16 g of phosphoric acid (10.05 mmol, 3.0 eq) and 3.3 mL of acetone was added dropwise at room temperature. After the addition was complete, a white solid precipitated. The mixture was stirred for 0.5 h, then 1 mL of water was added, and the mixture was heated to 60 °C and stirred for 24 h. After the reaction cooled to room temperature, the mixture was filtered and dried to obtain 3.50 g of a white solid powder. Ion chromatography analysis showed a phosphate content of 23.05%, indicating that it is a phosphate formed by compound (I) and 8 / 3 molecules of phosphoric acid, i.e., the phosphate shown in formula (IA).

[0177] Example 9: Phosphate crystal form B as shown in formula (IA)

[0178] 1. Preparation of phosphate crystal form B as shown in formula (IA)

[0179] 10.01 g of solid phosphate (as shown in formula (IA)), 60 mL of acetone, and 10 mL of water were added to a 400 mL glass reactor. The mixture was stirred until dissolved at 150 rpm and 55 °C. 40 mL of acetone was added dropwise over 1 hour, and the mixture was stirred for 11 hours. Then, 200 mL of acetone was added dropwise over 12 hours. After the addition was complete, the temperature was linearly lowered to 25 °C over 4 hours. The entire mixture was filtered, and the wet product was vacuum dried at 60 °C for 21 hours to obtain 9.10 g of a white, flaky crystalline solid of form B.

[0180] 2. Identification of phosphate crystal form B as shown in formula (IA)

[0181] (1) Empyrean X-ray powder diffraction (XRPD) analysis: Using Cu-Kα radiation, the following characteristic peaks, expressed in terms of angle 2θ, are observed: 3.49°, 6.40°, 6.89°, 7.33°, 9.15°, 9.87°, 10.24°, 10.77°, 12.16°, 12.72°, 13.44°, 14.65°, 15.20°, 15.40°, 16.22°, 16.83°, 17.21°, 17.58°, 17.94°, 18.64°, 19.58°, 21.11°, 21.91°, 23.24°, 24.35°, 25.65°, 27.05°. An error tolerance of ±0.2° exists. The obtained X-ray powder diffraction pattern is basically as follows: Figure 3 As shown.

[0182] (2) Differential scanning calorimetry (DSC) analysis using TA Q2000: The heating rate was 10℃ / min, and the resulting DSC curves were basically as follows: Figure 4 As shown, there is an endothermic peak at 227.22℃, with an error tolerance of ±3℃.

[0183] (3) Thermogravimetric analysis (TGA) was performed using a TA Q500: the heating rate was 10℃ / min, and the obtained TGA curves were basically as follows. Figure 5 As shown, the weight loss is approximately 1.83% in the range of 30-150℃, with an error tolerance of ±0.5%.

[0184] Example 10: Phosphate crystal form A shown in formula (IA)

[0185] 1. Preparation of phosphate crystal form A as shown in formula (IA)

[0186] 1.00 g of solid phosphate (the phosphate shown in formula (IA)), 3 mL of acetone, and 1 mL of water were added to a 100 mL glass bottle. The mixture was heated to 65 °C until completely dissolved. 12 mL of acetone was added dropwise, and the mixture was stirred at 65 °C for 39 h. Then, 5 mL of acetone was added dropwise, and the mixture was stirred at 65 °C for 7 h. Finally, 10 mL of acetone was added dropwise, and the mixture was stirred at 65 °C for 15 h. The mixture was then cooled to room temperature and filtered. The filter cake was washed with 5 mL of acetone / water (V / V = 30 / 1) solution and dried to obtain 0.99 g of off-white solid powder. Ion chromatography analysis showed that the phosphate content was 22.32%, indicating that it is crystal form A of the phosphate shown in formula (IA).

[0187] 2. Identification of phosphate crystal form A as shown in formula (IA)

[0188] (1) Identification by Empyrean X-ray powder diffraction (XRPD): Using Cu-Kα radiation, the following characteristic peaks, expressed in terms of angle 2θ, are observed: 3.41°, 6.76°, 7.51°, 8.74°, 9.27°, 10.10°, 10.39°, 12.53°, 13.48°, 14.71°, 15.02°, 16.24°, 16.82°, 17.68°, 1 The X-ray powder diffraction patterns obtained are 8.84°, 20.04°, 20.52°, 20.80°, 21.39°, 21.77°, 22.90°, 23.62°, 23.89°, 24.55°, 24.75°, 26.74°, 27.09°, 27.81°, 28.18°, and 30.12°, with an error tolerance of ±0.2°. The resulting patterns are essentially as follows: Figure 1 As shown.

[0189] (2) Differential scanning calorimetry (DSC) analysis using TA Q2000 confirmed that at a heating rate of 10℃ / min, the obtained DSC curves were essentially as follows: Figure 2 As shown, there is an endothermic peak at 225.33℃, with an error tolerance of ±3℃.

[0190] Example 11: Phosphate crystal form D as shown in formula (IA)

[0191] 1. Preparation of phosphate crystal form D as shown in formula (IA)

[0192] 52 mg of solid phosphate crystal form B of formula (IA) was added to 5 mL of tetrahydrofuran, stirred at 25 °C for 2 days, and filtered to obtain 20 mg of off-white solid powder of solid phosphate crystal form D of formula (IA).

[0193] 2. Identification of phosphate crystal form D as shown in formula (IA)

[0194] Empyrean X-ray powder diffraction (XRPD) analysis using Cu-Kα radiation revealed the following characteristic peaks, expressed in terms of angle 2θ: 3.37°, 6.04°, 6.67°, 9.18°, 10.00°, 13.30°, 15.39°, 16.62°, 18.60°, 19.97°, 20.66°, 21.87°, 23.32°, 23.82°, 25.13°, 25.64°, 26.71°, 27.74°, 30.25°, and 33.53°. An error tolerance of ±0.2° was observed. The obtained X-ray powder diffraction pattern was essentially as follows. Figure 6 As shown.

[0195] Example 12: Phosphate crystal form E shown in formula (IA)

[0196] 1. Preparation of phosphate crystal form E as shown in formula (IA)

[0197] 25 mg of solid phosphate (the phosphate shown in formula (IA)) was added to 2 mL of tetrahydrofuran, stirred at 50 °C for 3 days, and filtered to obtain 20 mg of off-white solid powder of phosphate crystal form E shown in formula (IA).

[0198] 2. Identification of phosphate crystal form E as shown in formula (IA)

[0199] Empyrean X-ray powder diffraction (XRPD) analysis using Cu-Kα radiation revealed the following characteristic peaks, expressed in terms of angle 2θ: 3.35°, 6.62°, 9.15°, 12.11°, 15.60°, 16.46°, 17.33°, 18.07°, 20.56°, 22.06°, 22.89°, 23.28°, 23.79°, 25.04°, 25.55°, 30.29°, and 33.52°. An error tolerance of ±0.2° was observed. The obtained X-ray powder diffraction pattern was essentially as follows: Figure 7 As shown.

[0200] Example 13 shows the amorphous phosphate of formula (IA).

[0201] Add 2g of solid phosphate (phosphate crystal form B as shown in formula (IA)) and 30mL of methanol to a 250mL flask. After dissolving at room temperature, rotary evaporate at 50℃ to obtain the amorphous solid of phosphate as shown in formula (IA).

[0202] Example 14 shows the phosphate crystal form N1 of formula (IA).

[0203] 1. Preparation of phosphate crystal form N1 as shown in formula (IA)

[0204] 1.20 g of amorphous phosphate solid of formula (IA) was added to a 50 mL glass bottle, followed by 30 mL of 1,4-dioxane. The mixture was stirred at 50 °C for 2 days, filtered, and the wet product was dried at room temperature for 1 day to obtain 0.65 g of yellow phosphate crystalline N1 solid powder of formula (IA).

[0205] 2. Identification of phosphate crystal form N1 as shown in formula (IA)

[0206] (1) Empyrean X-ray powder diffraction (XRPD) analysis: Using Cu-Kα radiation, the following characteristic peaks, expressed in terms of angle 2θ, are observed: 6.35°, 7.67°, 8.92°, 10.34°, 12.50°, 13.40°, 16.31°, 17.73°, 19.02°, 20.55°, 22.27°, 23.79°, 24.42°, 25.88°. An error tolerance of ±0.2° exists. The obtained X-ray powder diffraction pattern is basically as follows: Figure 8 As shown.

[0207] (2) Differential scanning calorimetry (DSC) analysis using TA Q2000: The heating rate was 10℃ / min, and the resulting DSC curves were basically as follows: Figure 9 As shown, there is an endothermic peak at 223.05℃, with an error tolerance of ±3℃.

[0208] (3) Thermogravimetric analysis (TGA) was performed using a TA Q500: the heating rate was 10℃ / min, and the obtained TGA curves were basically as follows. Figure 10 As shown, the weight loss is approximately 6.76% in the range of 30-193℃, with an error tolerance of ±0.5%.

[0209] Preparation of phosphate crystal form N2 as shown in Formula (IA) in Example 15

[0210] 1. Preparation of the phosphate crystal form N2 shown in formula (IA)

[0211] Add 500 mg of solid phosphate (phosphate crystal form B as shown in formula (IA)) to a 100 mL glass bottle, add 15 mL of 1,4-dioxane and 1 mL of purified water, and stir at room temperature until dissolved. Add 20 mL of 1,4-dioxane dropwise, and an oily substance forms at the bottom. Stir at 60 °C for 10 hours, then stir with the bottle open until the solvent evaporates to half its volume. Filter the entire mixture, and dry the wet product at room temperature for 1 day to obtain a pale yellow-green solid powder of phosphate crystal form N2 as shown in formula (IA).

[0212] 2. Identification of the phosphate crystal form N2 shown in formula (IA)

[0213] (1) Empyrean X-ray powder diffraction (XRPD) analysis: Using Cu-Kα radiation, the following characteristic peaks, expressed in terms of angle 2θ, are observed: 6.47°, 7.42°, 8.26°, 8.92°, 10.22°, 12.69°, 14.22°, 14.82°, 15.64°, 16.37°, 17.59°, 19.42°, 20.32°, 20.92°, 22.82°, 23.79°, 24.43°, 25.15°. An error tolerance of ±0.2° exists. The obtained X-ray powder diffraction pattern is basically as follows: Figure 11 As shown.

[0214] (2) Differential scanning calorimetry (DSC) analysis using TA Q2000: The heating rate was 10℃ / min, and the resulting DSC curves were basically as follows: Figure 12 As shown, there is an endothermic peak at 226.28℃, with an error tolerance of ±3℃.

[0215] (3) Thermogravimetric analysis (TGA) was performed using a TA Q500: the heating rate was 10℃ / min, and the obtained TGA curves were basically as follows. Figure 13 As shown, the weight loss is approximately 6.99% in the range of 30-212℃, with an error tolerance of ±0.5%.

[0216] Example 16 shows the phosphate crystal form N5 (IA).

[0217] 1. Preparation of phosphate crystal form N5 as shown in formula (IA)

[0218] Add 50 mg of solid phosphate (phosphate crystal form B as shown in formula (IA)) and 0.1 mL of DMF to a 5 mL EP tube, stir and dissolve at room temperature, add 2 mL of butanone and the solid precipitates, stir at 60 °C for 2 days and filter, dry the wet product at room temperature for 1 day to obtain a white solid powder of phosphate crystal form N5 as shown in formula (IA).

[0219] 2. Identification of phosphate crystal form N5 as shown in formula (IA)

[0220] (1) Empyrean X-ray powder diffraction (XRPD) analysis: Using Cu-Kα radiation, the following characteristic peaks, expressed in terms of angle 2θ, are observed: 3.37°, 6.57°, 7.35°, 8.49°, 9.06°, 10.24°, 12.18°, 13.02°, 14.67°, 15.45°, 16.28°, 17.86°, 19.61°, 20.18°, 20.58°, 21.41°, 22.97°, 23.83°, 24.55°, 25.40°, 25.88°. An error tolerance of ±0.2° is present. The obtained X-ray powder diffraction pattern is basically as follows: Figure 14 As shown.

[0221] (2) Differential scanning calorimetry (DSC) analysis using TA Q2000: The heating rate was 10℃ / min, and the resulting DSC curves were basically as follows: Figure 15 As shown, there is an endothermic peak at 223.05℃, with an error tolerance of ±3℃.

[0222] (3) Thermogravimetric analysis (TGA) was performed using a TA Q500: the heating rate was 10℃ / min, and the obtained TGA curves were basically as follows. Figure 16 As shown, the weight loss is approximately 5.49% in the range of 30-198℃, with an error tolerance of ±0.5%.

[0223] Example 17 shows the phosphate crystal form N6 (IA).

[0224] 1. Preparation of phosphate crystal form N6 as shown in formula (IA)

[0225] Add 400 mg of amorphous solid of phosphate (formula (IA)) and 10 mL of sec-butanol to a 50 mL glass bottle. Stir at 50 °C for 2 days and then filter to obtain 300 mg of white solid of phosphate (formula (IA)) crystalline N6.

[0226] 2. Identification of phosphate crystal form N6 as shown in formula (IA)

[0227] (1) Empyrean X-ray powder diffraction (XRPD) analysis: Using Cu-Kα radiation, the following characteristic peaks, expressed in terms of angle 2θ, are observed: 3.38°, 6.60°, 7.43°, 8.52°, 9.07°, 10.25°, 14.55°, 14.89°, 15.63°, 16.49°, 17.05°, 17.63°, 17.97°, 18.58°, 19.78°, 20.44°, 21.50°, 22.75°, 23.17°, 24.48°, 24.85°, 25.57°, 26.27°, 27.39°, 28.02°, 29.39°, 30.87°. An error tolerance of ±0.2° exists. The obtained X-ray powder diffraction pattern is basically as follows: Figure 17 As shown.

[0228] (2) Differential scanning calorimetry (DSC) analysis using TA Q2000: The heating rate was 10℃ / min, and the resulting DSC curves were basically as follows: Figure 18 As shown, there is an endothermic peak at 223.74℃, with an error tolerance of ±3℃.

[0229] (3) Thermogravimetric analysis (TGA) was performed using a TA Q500: the heating rate was 10℃ / min, and the obtained TGA curves were basically as follows. Figure 19 As shown, the weight loss is approximately 4.69% in the range of 30-196℃, with an error tolerance of ±0.5%.

[0230] Example 18: Experiment on the Influence Factors of Phosphate Crystal Form B and Amorphous Form as shown in Formula (IA)

[0231] According to the guidelines for drug formulation stability testing, experiments were conducted on the crystalline form B and amorphous form of the phosphate shown in formula (IA), including high temperature test, high humidity test and strong light irradiation test, to investigate the conditions affecting the stability of its crystalline form.

[0232] High temperature test: Take appropriate amounts of samples with different crystal forms, spread them evenly in a weighing bottle, and place them in a constant temperature and humidity chamber at 60±5℃ and RH75±5%. Then, take about 10mg of the above samples at 5, 10 and / or 15 (or 30) days to test their crystal form.

[0233] High humidity test: Take appropriate amounts of samples with different crystal forms, spread them evenly in a weighing bottle, and place them in a constant temperature and humidity chamber at 25℃ and RH 92.5±5%. Then, take about 10mg of the above samples at 5, 10 and / or 15 (or 30) days to test their crystal form.

[0234] Light irradiation test: Take appropriate amounts of samples of different crystal forms, spread them evenly in a weighing bottle, and expose them to visible light (4500 Lux ± 500 Lux) and ultraviolet light (1.7 W·h / m²). 2 The samples were placed in a constant temperature and humidity chamber (25℃, RH 60±5%), and then approximately 10 mg of the samples were collected at 5, 10, and / or 15 (or 30) days to test their crystal form. The experimental results are shown in Table 1.

[0235] Table 1 shows the experimental results of the influencing factors on phosphate crystal form B (IA) and amorphous phosphate (IA).

[0236]

[0237] The experimental results of the influencing factors of phosphate crystal form B and amorphous form as shown in formula (IA) are as follows: Figure 20 and 21 As shown. Crystal form B maintained its original crystal form under high temperature, high humidity, and light conditions; the amorphous form was also very stable and did not undergo crystal transformation.

[0238] Example 19 Pharmacokinetic evaluation of compound (I), phosphate B of formula (IA), and amorphous phosphate of formula (IA).

[0239] Pharmacokinetic data for the compound of formula (I), the phosphate of formula (IA) in crystal form B, and the amorphous form of the phosphate of formula (IA) were obtained. The method was as follows: Male beagle dogs were orally administered 5 mg / kg (calculated based on the amount of compound of formula (I)) via capsules. Five beagle dogs of each species were administered the test compound directly into capsules. Blood was collected from the forelimb vein at time points (0.25, 0.5, 1, 2.4, 6.8, and 24 hours after administration and collected in anticoagulant tubes containing EDTA-K2. Plasma samples were subjected to protein precipitation and centrifugation. The supernatant was then quantitatively analyzed using multiple reaction monitoring (MRM) on a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS / MS) system. Pharmacokinetic parameters were calculated using a non-compartmental model method with WinNonlin 6.3 software. The experimental results are shown in Table 2.

[0240] Table 2. Pharmacokinetic parameters of compound (I), phosphate crystal form B shown in formula (IA), and phosphate amorphous form shown in formula (IA) in beagle dogs.

[0241] Phosphate crystal form B shown in formula (IA) 3770 392 2 The phosphate amorphous form shown in formula (IA) 1070 134 2.2 Compound of formula (I) 564 75.6 2.4

[0242] Experimental results showed that, compared with compound (I), phosphate crystal form B shown in formula (IA) and phosphate amorphous form shown in formula (IA) had higher exposure levels (AUC) and peak plasma concentrations (C) in beagle dogs. max This indicates that the phosphate crystal form B shown in formula (IA) and the amorphous phosphate shown in formula (IA) are better absorbed orally than the compound of formula (I).

[0243] The above description is merely a basic explanation of the concept of this invention, and any equivalent modifications made based on the technical solution of this invention shall fall within the protection scope of this invention.

[0244] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0245] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. Salts of the compounds shown in formula (I), (I)， Its features are, The salt is a phosphate, wherein the molar ratio of the compound shown in formula (I) to phosphoric acid is 1:

2.

2. A crystal form B of the phosphate shown in formula (IA), (IA), Its features are, The X-ray powder diffraction pattern of crystal form B includes the following diffraction peaks at the 2θ angle: 3.49° ±0.2°, 6.89° ±0.2°, 9.15° ±0.2°, 10.24° ±0.2° and 12.16° ±0.2°.

3. The crystal form B according to claim 2, characterized in that, The X-ray powder diffraction pattern of crystal form B includes the following diffraction peaks at the 2θ angle: 3.49° ± 0.2°, 6.89° ± 0.2°, 7.33° ± 0.2°, 9.15° ± 0.2°, 10.24° ± 0.2°, 10.77° ± 0.2°, 12.16° ± 0.2°, 13.44° ± 0.2°, 14.65° ± 0.2°, 15.20° ± 0.2°, 16.22° ± 0.2°, 17.21° ± 0.2°, 17.58° ± 0.2°, 17.94° ± 0.2°, 18.64° ± 0.2°, and 19.58° ± 0.2°.

4. The crystal form B according to claim 2, characterized in that, The X-ray powder diffraction pattern of crystal form B contains the following diffraction peaks at the 2θ angle: 3.49° ± 0.2°, 6.40° ± 0.2°, 6.89° ± 0.2°, 7.33° ± 0.2°, 9.15° ± 0.2°, 9.87° ± 0.2°, 10.24° ± 0.2°, 10.77° ± 0.2°, 12.16° ± 0.2°, 12.72° ± 0.2°, 13.44° ± 0.2°, 14.65° ± 0.2°, 15.20° ± 0.2°, 15.40° ± 0.2°, 16.22° ± 0.2°, 16.83° ± 0.2°, 17.21° ± 0.2°. 0.2°, 17.58° ± 0.2°, 17.94° ± 0.2°, 18.64° ± 0.2°, 19.58° ± 0.2°, 21.11° ± 0.2°, 21.91° ± 0.2°, 23.24° ± 0.2°, 24.35° ± 0.2°, 25.65° ± 0.2° and 27.05° ± 0.2°.

5. The crystal form B according to claim 2, characterized in that, The crystal form B has an X-ray powder diffraction pattern that is essentially as shown in Figure 3.

6. The crystal form B according to claim 2, characterized in that, The differential scanning calorimetry (DSC) of crystal form B contains an endothermic peak at 227.22°C ± 3°C.

7. The crystal form B according to claim 2, characterized in that, The crystal form B has a differential scanning calorimeter that is substantially as shown in Figure 4.

8. An amorphous form of a phosphate of formula (IA), (IA).

9. A pharmaceutical composition comprising crystal form B of the salt of claim 1 or the phosphate of any one of claims 2-7 or the amorphous form of the phosphate of claim 8.

10. The pharmaceutical composition of claim 9, further comprising a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.

11. The pharmaceutical composition according to claim 9 or 10, further comprising other anti-HCV drugs; optionally, said other anti-HCV drugs are interferon, interleukin-2, interleukin-6, interleukin-12, compounds that promote the generation of type 1 helper T cell responses, interfering RNA, antisense RNA, imiquimod, inosine 5'-monophosphate dehydrogenase inhibitors, amantadine, rimantadine, bavitimab, hepatitis C immunoglobulin, Civacir TM Boprevir, Tetraprevir, Ingbuvir, Smepivir, Anavivir, Vaniprevir, Faldaprevir, Danoprevir, Sovaprevir, Vedroprevir, BZF-961, GS-9256, Narlaprevir, ANA975, SH229, GSK-2336805, Ciluprevir, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, Modithr omycin, VBY-376, TMC-649128, mericitabine, sofosbuvir, INX-189, IDX-184, IDX102, R-1479, UNX-08189, PSI-6130, PSI-938, PSI-87 9. nesbuvir, HCV-371, VCH-916, lomibuvir, MK-3281, dasabuvir, ABT-072, filibuvir, deleobuvir, tegobuvir, A-837093, JKT- 109, GL-59728, GL-60667, TMC647055, Radipasvir, Setrobuvir, BIT-225, ACH-3422, MK-2748, ABP-560, TVB-2640, ID-12, PPI-383, A-848837, RG-7795, BC-2125, Alloferon, Nivolumab, WF-10, Nizoral, Multiferon, Alabasvir, MK-3682, GS-9857, CD-AdNS3, RG-101, MBL-HC V1, CIGB-230, TG-2349, procvax, CB-5300, miravirsen, MK-1075, WS-007, MK-7680, MK-2248, IDX-21459, MK-8876, GSK-2878175, MBX-700, AL-335, AL-704, SB-9200, ITX-5061 or combinations thereof; wherein the interferon is interferon α-2b, PEGylated interferon α, interferon α-2a, PEGylated interferon α-2a, complex α-interferon, interferon γ or combinations thereof.

12. The pharmaceutical composition according to claim 11, wherein, The inosine 5'-monophosphate dehydrogenase inhibitor is ribavirin.

13. Use of the salt of claim 1, or crystal form B of the phosphate of any one of claims 2-7, or amorphous form of the phosphate of claim 8, or the pharmaceutical composition of any one of claims 9-12 in the preparation of a medicament for the prevention, treatment, cure, or relief of diseases associated with HCV infection or hepatitis C.

Images