Crystal form of tetrahydroisoquinoline compound and use thereof

Abstract

Disclosed in the present invention are a crystal form of a tetrahydroisoquinoline compound and a use thereof. The present invention provides methanesulfonate crystal form A, p-toluenesulfonate crystal form A, p-toluenesulfonate crystal form B, and p-toluenesulfonate crystal form E of a compound represented by formula (I). The crystal form of the present invention has the advantages such as high purity, strong stability, high solubility, reproducible preparation, and excellent performance. The crystal form of the present invention exhibits significantly higher solubility in water, fasted-state simulated intestinal fluid, and simulated gastric fluid compared to a free base. In the pharmacokinetic study in rats, the systemic exposure dosage of the crystal form of the present invention is significantly superior to that of the free base, and the overall pharmacokinetic property is unexpectedly improved.

Description

Crystal forms of tetrahydroisoquinolinyl compounds and their applications

[0001] This application claims priority to Chinese Patent Application No. 2024101777213, filed on February 8, 2024, and Chinese Patent Application No. 2025100079558, filed on January 2, 2025. The entire text of the above-mentioned Chinese patent application is incorporated herein by reference. Technical Field

[0002] The present invention relates to the field of medicinal chemistry, and specifically to a compound of formula I: p-toluenesulfonate and methanesulfonate of N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1-hydrogen)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide [English chemical name: N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide], as well as p-toluenesulfonate crystalline form A, p-toluenesulfonate crystalline form B, p-toluenesulfonate crystalline form E, methanesulfonate crystalline form A and applications thereof. Background Art

[0003] Voltage-gated potassium (Kv) channels are among the most important and critical channels in various physiological processes. The KCNQ family (Kv7 channels) consists of five members (KCNQ1–5). The Kv7 protein consists of six transmembrane segments: S1-S4 form the voltage-sensitive domain (VSD), S5-S6 form the pore domain (PD), and a short N-terminus and a long C-terminus are present in cells. Kv7 channels are not uniformly expressed throughout the body. For example, Kv7.1 expression has been detected in vascular smooth muscle cells of many rodent and human arteries and in cardiac tissue. In central, peripheral and sensory neurons, Kv7.2 / 7.3 channels are highly expressed and are the basis of M currents. Mutations in the KCNQ2 or KCNQ3 genes will lead to neuronal hyperexcitation, thereby causing epilepsy. Kv7.4 is expressed in the cochlea and is essential for normal hearing. Many congenital deafness cases are caused by mutations in KCNQ4. In addition, Kv7.4 is the main functional regulator of many smooth muscle tissues. Kv7.5 is expressed in neurons and is mainly involved in delayed afterhyperpolarization. It is also located in skeletal muscle, blood vessels and smooth muscle. In arterial smooth muscle, Kv7.5 protein forms a complex with Kv7.4 protein.

[0004] N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1-hydrogen)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (structure shown in the figure below, hereinafter referred to as the compound of Formula I) is a selective KCNQ potassium channel opener in clinical trials. Related indications include epilepsy, major depressive disorder (MDD), and potentially other neurological diseases. Completed studies have shown that the activity of the compound of Formula I is approximately 20 times higher than that of retigabine, which is also a KCNQ2 / 3 opener. The compound of Formula I also has good KCNQ2 / 3 and KCNQ 4 / 5 selectivity and good safety. In addition, preclinical in vitro and in vivo data showed that the compound of Formula I can prevent MES-induced epileptic seizure behavior in ICR mice and 6-Hz-induced epileptic seizures in C57BL / 6 mice in a dose-dependent manner.

[0005] The same compound can form different salts, and different salts can have one or more crystalline forms. Various salt forms and crystalline forms of a drug molecule exhibit unique physicochemical properties, including but not limited to melting point, solubility, dissolution rate, optical and mechanical properties, hygroscopicity, particle morphology, density, and flowability. These properties have a direct impact on the processing and manufacturability of the drug molecule. Different crystalline forms also exhibit different solid-state stability, chemical stability, and bioavailability. These factors can significantly affect the drug's efficacy and toxicology. During the drug development stage, inventors will comprehensively evaluate the solid-state stability, chemical stability, solubility, and in vivo exposure of various salt forms and crystalline forms to select the most suitable salt form and corresponding crystalline form.

[0006] The invention of salt forms and crystal forms of the compound of Formula I is of great significance for the treatment of various neurological diseases. Currently, there are no reports on the salt forms of the compound of Formula I and their crystal forms. The present invention provides salt forms and corresponding crystal forms of the compound of Formula I, which can further optimize the drugability, safety, and efficacy of the compound. Summary of the Invention

[0007] In view of the shortcomings of the existing free base of the compound of formula I in terms of solubility and drugability, the present invention provides a crystalline form of the compound of formula I and its application. The crystalline form of the present invention has good crystallinity, solid-state stability, good solubility and pharmacokinetic properties.

[0008] The present invention solves the above technical problems through the following technical solutions.

[0009] The present invention provides a mesylate crystalline form A of a compound of formula I,

[0010] The mesylate salt crystalline form A uses Cu-Kα radiation, and the X-ray powder diffraction pattern represented by 2θ has diffraction peaks at the following positions: 5.60°±0.2°, 12.31°±0.2°, and 15.40°±0.2°.

[0011] In one embodiment, the X-ray powder diffraction pattern of the mesylate salt form A expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 9.47°±0.2°, 10.99°±0.2°, 17.57°±0.2°, and 19.15°±0.2°.

[0012] In one embodiment, the X-ray powder diffraction pattern of the mesylate salt form A expressed in 2θ angles has diffraction peaks at the following positions: 5.60°±0.2°, 9.47°±0.2°, 10.99°±0.2°, 12.31°±0.2°, 15.40°±0.2°, 17.57°±0.2°, and 19.15°±0.2°.

[0013] In one embodiment, the X-ray powder diffraction pattern of the mesylate salt form A expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 14.86°±0.2°, 17.12°±0.2°, 18.33°±0.2°, 22.42°±0.2°, and 22.94°±0.2°.

[0014] In one embodiment, the X-ray powder diffraction pattern of the mesylate salt form A expressed in 2θ angles has diffraction peaks at the following positions: 5.60°±0.2°, 9.47°±0.2°, 10.99°±0.2°, 12.31°±0.2°, 14.86°±0.2°, 15.40°±0.2°, 17.12°±0.2°, 17.57°±0.2°, 18.33°±0.2°, 19.15°±0.2°, 22.42°±0.2°, and 22.94°±0.2°.

[0015] In one embodiment, the X-ray powder diffraction pattern of the mesylate salt form A expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 7.35°±0.2°, 11.36°±0.2°, 19.66°±0.2°, 20.10°±0.2°, 21.78°±0.2°, 26.69°±0.2°, and 28.95°±0.2°.

[0016] In one embodiment, the X-ray powder diffraction pattern of the mesylate salt form A expressed in 2θ angles has diffraction peaks at the following positions: 5.60°±0.2°, 7.35°±0.2°, 9.47°±0.2°, 10.99°±0.2°, 11.36°±0.2°, 12.31°±0.2°, 14.86°±0.2°, 15.40°±0.2° °, 17.12°±0.2°, 17.57°±0.2°, 18.33°±0.2°, 19.15°±0.2°, 19.66°±0.2°, 20.10°±0.2°, 21.78°±0.2°, 22.42°±0.2°, 22.94°±0.2°, 26.69°±0.2°, 28.95°±0.2°.

[0017] In one embodiment, the X-ray powder diffraction pattern of the mesylate salt form A expressed in 2θ angles has diffraction peaks at the following positions: 5.60°±0.2°, 7.35°±0.2°, 9.47°±0.2°, 10.99°±0.2°, 11.36°±0.2°, 12.31°±0.2°, 13.48°±0.2°, 14.02°±0.2°, 14.86°±0.2°, 15.40°±0.2°, 16.45°±0.2°, 17.12°±0.2°. °, 17.57°±0.2°, 18.33°±0.2°, 19.15°±0.2°, 19.66°±0.2°, 20.10°±0.2°, 20.66°±0.2°, 21.78°±0.2°, 22.42°±0.2°, 22.94°±0.2°, 23.44°±0.2°, 26.69°±0.2°, 27.18°±0.2°, 28.95°±0.2°, 34.31°±0.2°, and 36.14°±0.2°.

[0018] In one embodiment, the X-ray powder diffraction pattern of the mesylate salt form A expressed in 2θ angles has the diffraction peaks shown in the following table:

[0019] In one embodiment, the X-ray powder diffraction pattern of the mesylate salt form A expressed in 2θ angles is substantially as shown in FIG3 .

[0020] In one embodiment, the mesylate salt form A obtains an X-ray powder diffraction pattern using the following parameters:

[0021] In one embodiment, the differential scanning calorimetry of the mesylate salt form A has an endothermic peak at a peak value of 213.85°C±3°C.

[0022] In one embodiment, the differential scanning calorimetry of the mesylate salt form A has an endothermic peak at 213.85°C±3°C, and the heat of fusion is 66.99 J / g.

[0023] In one embodiment, the differential scanning calorimetry diagram of the mesylate salt form A is shown in FIG2 .

[0024] In one embodiment, the thermogravimetric analysis of the mesylate salt form A shows a weight loss of 0.85% when the temperature is raised to 180°C.

[0025] In one embodiment, the thermogravimetric analysis diagram of the mesylate salt form A is substantially as shown in FIG2 .

[0026] In a certain embodiment, the mesylate salt form A is obtained by the following parameters to obtain a TGA and / or DSC pattern of the crystalline form;

[0027] In a certain embodiment, the mesylate salt crystalline form A is an anhydrous crystalline form of a single salt.

[0028] The present invention provides a p-toluenesulfonate crystalline form A of a compound of formula I;

[0029] The p-toluenesulfonate crystalline form A uses Cu-Kα radiation, and the X-ray powder diffraction pattern represented by 2θ has diffraction peaks at the following positions: 5.17°±0.2°, 10.40°±0.2°, and 18.34°±0.2°.

[0030] In a certain embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form A expressed in 2θ angle further has diffraction peaks at one or more of the following positions: 8.55°±0.2°, 14.19°±0.2°.

[0031] In one embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form A expressed in 2θ angles has diffraction peaks at the following positions: 5.17°±0.2°, 8.55°±0.2°, 10.40°±0.2°, 14.19°±0.2°, and 18.34°±0.2°.

[0032] In a certain embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form A expressed in 2θ angle further has diffraction peaks at one or more of the following positions: 7.04°±0.2°, 17.56°±0.2°.

[0033] In one embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form A expressed in 2θ angles has diffraction peaks at the following positions: 5.17°±0.2°, 7.04°±0.2°, 8.55°±0.2°, 10.40°±0.2°, 14.19°±0.2°, 17.56°±0.2°, and 18.34°±0.2°.

[0034] In one embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form A expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 11.16°±0.2°, 14.61°±0.2°, 15.14°±0.2°, 19.85°±0.2°, 21.01°±0.2°, 22.21°±0.2°, 22.58°±0.2°, and 24.65°±0.2°.

[0035] In one embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form A expressed in 2θ angles has diffraction peaks at the following positions: 5.17°±0.2°, 7.04°±0.2°, 8.55°±0.2°, 10.40°±0.2°, 11.16°±0.2°, 14.19°±0.2°, 14.61°±0.2°, 15.14°±0.2°, 17.56°±0.2°, 18.34°±0.2°, 19.85°±0.2°, 21.01°±0.2°, 22.21°±0.2°, 22.58°±0.2°, and 24.65°±0.2°.

[0036] In a certain embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form A expressed in 2θ angles has diffraction peaks at the following positions: 5.17°±0.2°, 7.04°±0.2°, 7.98°±0.2°, 8.55°±0.2°, 10.40°±0.2°, 11.16°±0.2°, 11.51°±0.2°, 13.15°±0.2°, 14.19°±0.2°, 14.61°±0.2°, 15.14°±0.2°, 16.15°±0.2°, 17.56°±0.2°, 18.34°±0.2°. °, 19.52°±0.2°, 19.85°±0.2°, 20.44°±0.2°, 21.01°±0.2°, 21.56°±0.2°, 22.21°±0.2°, 22.58°±0.2°, 23.75°±0.2°, 24.65°±0.2°, 25.38°±0.2°, 26.45°±0.2°, 26.96°±0.2°, 28.82°±0.2°, 30.53°±0.2°, 31.81°±0.2°, 35.27°±0.2°, and 37.51°±0.2°.

[0037] In one embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form A expressed in 2θ angles has the diffraction peaks shown in the following table:

[0038] In one embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form A expressed at 2θ angles is substantially as shown in FIG6 .

[0039] In a certain embodiment, the p-toluenesulfonate salt form A is obtained by the following parameters to obtain an XRPD pattern of the crystalline form;

[0040] In one embodiment, the differential scanning calorimetry of the p-toluenesulfonate crystalline form A has an endothermic peak at a peak value of 223.99°C±3°C.

[0041] In one embodiment, the differential scanning calorimetry of the p-toluenesulfonate salt form A has an endothermic peak at 223.99°C±3°C, and the heat of fusion is 68.20 J / g.

[0042] In one embodiment, the differential scanning calorimetry diagram of the p-toluenesulfonate salt form A is shown in FIG5 .

[0043] In one embodiment, the thermogravimetric analysis diagram of the p-toluenesulfonate salt form A is substantially as shown in FIG5 .

[0044] In a certain embodiment, the p-toluenesulfonate salt form A is obtained by the following parameters to obtain a TGA and / or DSC pattern of the crystalline form;

[0045] In a certain embodiment, the p-toluenesulfonate crystalline form A is an anhydrous crystalline form of a single salt.

[0046] The present invention provides a p-toluenesulfonate crystalline form B of a compound of formula I;

[0047] The p-toluenesulfonate salt form B uses Cu-Kα radiation, and the X-ray powder diffraction pattern represented by 2θ has diffraction peaks at the following positions: 13.44°±0.2°, 17.28°±0.2°, and 17.38°±0.2°.

[0048] In one embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form B expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 5.64°±0.2°, 14.49°±0.2°, 15.13°±0.2°, 20.45°±0.2°, 21.15°±0.2°, and 22.15°±0.2°.

[0049] In one embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form B expressed in 2θ angles has diffraction peaks at the following positions: 5.64°±0.2°, 13.44°±0.2°, 14.49°±0.2°, 15.13°±0.2°, 17.28°±0.2°, 17.38°±0.2°, 20.45°±0.2°, 21.15°±0.2°, and 22.15°±0.2°.

[0050] In one embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form B expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 7.84°±0.2°, 10.11°±0.2°, 11.36°±0.2°, 12.03°±0.2°, 13.60°±0.2°, 18.58°±0.2°, and 23.97°±0.2°.

[0051] In one embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form B expressed in 2θ angles has diffraction peaks at the following positions: 5.64°±0.2°, 7.84°±0.2°, 10.11°±0.2°, 11.36°±0.2°, 12.03°±0.2°, 13.44°±0.2°, 13.60°±0.2°, 14.49°±0.2°, 15.13°±0.2°, 17.28°±0.2°, 17.38°±0.2°, 18.58°±0.2°, 20.45°±0.2°, 21.15°±0.2°, 22.15°±0.2°, and 23.97°±0.2°.

[0052] In one embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form B expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 5.09°±0.2°, 9.22°±0.2°, 10.87°±0.2°, 16.21°±0.2°, 19.55°±0.2°, 22.89°±0.2°, 25.03°±0.2°, and 27.08°±0.2°.

[0053] In one embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form B expressed in 2θ angles has diffraction peaks at the following positions: 5.09°±0.2°, 5.64°±0.2°, 7.84°±0.2°, 9.22°±0.2°, 10.11°±0.2°, 10.87°±0.2°, 11.36°±0.2°, 12.03°±0.2°, 13.44°±0.2°, 13.60°±0.2°, 14.4 9°±0.2°, 15.13°±0.2°, 16.21°±0.2°, 17.28°±0.2°, 17.38°±0.2°, 18.58°±0.2°, 19.55°±0.2°, 20.45°±0.2°, 21.15°±0.2°, 22.15°±0.2°, 22.89°±0.2°, 23.97°±0.2°, 25.03°±0.2°, and 27.08°±0.2°.

[0054] In a certain embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form B expressed in 2θ angles has diffraction peaks at the following positions: 5.09°±0.2°, 5.64°±0.2°, 7.06°±0.2°, 7.84°±0.2°, 9.22°±0.2°, 10.11°±0.2°, 10.87°±0.2°, 11.36°±0.2°, 12.03°±0.2°, 13.44°±0.2°, 13.60°±0.2°, 14.49°±0.2°, 15.13°±0.2°, 16.21°±0.2°. °, 17.28°±0.2°, 17.38°±0.2°, 18.58°±0.2°, 19.55°±0.2°, 20.45°±0.2°, 21.15°±0.2°, 22.15°±0.2°, 22.89°±0.2°, 23.97°±0.2°, 25.03°±0.2°, 27.08°±0.2°, 29.19°±0.2°, 30.07°±0.2°, 30.73°±0.2°, 31.60°±0.2°, 35.97°±0.2°, and 37.84°±0.2°.

[0055] In one embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form B expressed in 2θ angles has the diffraction peaks shown in the following table:

[0056] In one embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form B expressed in 2θ angles is substantially as shown in FIG9 .

[0057] In a certain embodiment, the p-toluenesulfonate salt Form B is obtained by the following parameters to obtain an XRPD pattern of the crystalline form;

[0058] In one embodiment, the differential scanning calorimetry of the p-toluenesulfonate salt form B has an endothermic peak at 222.98°C±3°C, and the heat of fusion is 54.52 J / g.

[0059] In one embodiment, the differential scanning calorimetry diagram of the p-toluenesulfonate salt form B is shown in FIG8 .

[0060] In one embodiment, the thermogravimetric analysis diagram of the p-toluenesulfonate salt form B is substantially as shown in FIG8 .

[0061] In a certain embodiment, the p-toluenesulfonate salt form B is obtained by the following parameters to obtain a TGA and / or DSC pattern of the crystalline form;

[0062] In a certain embodiment, the p-toluenesulfonate crystalline form B is an anhydrous crystalline form of a single salt.

[0063] The present invention provides a p-toluenesulfonate crystalline form E of a compound of formula I;

[0064] The p-toluenesulfonate salt form E uses Cu-Kα radiation, and the X-ray powder diffraction pattern represented by 2θ has diffraction peaks at the following positions: 5.60°±0.2°, 8.15°±0.2°, and 17.33°±0.2°.

[0065] In one embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form E expressed in 2θ angle further has diffraction peaks at one or more of the following positions: 11.31°±0.2°, 13.89°±0.2°, and 19.88°±0.2°.

[0066] In one embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form E expressed in 2θ angles has diffraction peaks at the following positions: 5.60°±0.2°, 8.15°±0.2°, 11.31°±0.2°, 13.89°±0.2°, 17.33°±0.2°, and 19.88°±0.2°.

[0067] In one embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form E expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 9.85°±0.2°, 10.02°±0.2°, 18.83°±0.2°, and 20.23°±0.2°.

[0068] In one embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form E expressed in 2θ angles has diffraction peaks at the following positions: 5.60°±0.2°, 8.15°±0.2°, 9.85°±0.2°, 10.02°±0.2°, 11.31°±0.2°, 13.89°±0.2°, 17.33°±0.2°, 18.83°±0.2°, 19.88°±0.2°, and 20.23°±0.2°.

[0069] In one embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form E expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 14.15°±0.2°, 16.12°±0.2°, 17.88°±0.2°, 22.33°±0.2°, 25.51°±0.2°, and 27.23°±0.2°.

[0070] In one embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form E expressed in 2θ angles has diffraction peaks at the following positions: 5.60°±0.2°, 8.15°±0.2°, 9.85°±0.2°, 10.02°±0.2°, 11.31°±0.2°, 13.89°±0.2°, 14.15°±0.2°, 16.12°±0.2°, 17.33°±0.2°, 17.88°±0.2°, 18.83°±0.2°, 19.88°±0.2°, 20.23°±0.2°, 22.33°±0.2°, 25.51°±0.2°, and 27.23°±0.2°.

[0071] In one embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form E expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 3.34°±0.2°, 16.43°±0.2°, 21.72°±0.2°, 22.87°±0.2°, 23.17°±0.2°, 23.99°±0.2°, 24.51°±0.2°, 30.48°±0.2°, 33.75°±0.2°, and 34.38°±0.2°.

[0072] In a certain embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form E expressed in 2θ angles has diffraction peaks at the following positions: 3.34°±0.2°, 5.60°±0.2°, 8.15°±0.2°, 9.85°±0.2°, 10.02°±0.2°, 11.31°±0.2°, 13.89°±0.2°, 14.15°±0.2°, 16.12°±0.2°, 16.43°±0.2°, 17.33°±0.2°, 17.8 8°±0.2°, 18.83°±0.2°, 19.88°±0.2°, 20.23°±0.2°, 21.72°±0.2°, 22.33°±0.2°, 22.87°±0.2°, 23.17°±0.2°, 23.99°±0.2°, 24.51°±0.2°, 25.51°±0.2°, 27.23°±0.2°, 30.48°±0.2°, 33.75°±0.2°, and 34.38°±0.2°.

[0073] In one embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form E expressed in 2θ angles has the diffraction peaks shown in the following table:

[0074] In one embodiment, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form E expressed in 2θ angles is substantially as shown in FIG10 .

[0075] In a certain embodiment, the p-toluenesulfonate salt form E is obtained by the following parameters to obtain an XRPD pattern of the crystalline form;

[0076] In one embodiment, the differential scanning calorimetry diagram of the p-toluenesulfonate salt form E has two endothermic peaks at 180.26°C±3°C and 224.05°C±3°C, respectively.

[0077] In one embodiment, the differential scanning calorimetry diagram of the p-toluenesulfonate salt form E has an endothermic peak at a peak value of 180.26°C±3°C, and a melting heat of 26.13 J / g; and an endothermic peak at a peak value of 224.05°C±3°C, and a melting heat of 59.89 J / g.

[0078] In one embodiment, the differential scanning calorimetry diagram of the p-toluenesulfonate salt form E is shown in FIG11 .

[0079] In one embodiment, the thermogravimetric analysis diagram of the p-toluenesulfonate salt form E is substantially as shown in FIG11 .

[0080] In a certain embodiment, the p-toluenesulfonate crystalline form E is obtained by the following parameters: TGA and / or DSC pattern of the crystalline form;

[0081] In a certain embodiment, the p-toluenesulfonate crystalline form E is an anhydrous crystalline form of a single salt.

[0082] The present invention also provides a pharmaceutical composition comprising the above-mentioned mesylate crystalline form A, p-toluenesulfonate crystalline form A or p-toluenesulfonate crystalline form B, p-toluenesulfonate crystalline form E and pharmaceutical excipients.

[0083] The present invention also provides the use of the above-mentioned mesylate salt form A, p-toluenesulfonate salt form A, p-toluenesulfonate salt form B, p-toluenesulfonate salt form E or the above-mentioned pharmaceutical composition in the preparation of a drug, wherein the drug is used to treat and / or prevent diseases or conditions affected by voltage-gated potassium channels.

[0084] The present invention also provides the use of the above-mentioned mesylate crystalline form A, p-toluenesulfonate crystalline form A, p-toluenesulfonate crystalline form B, p-toluenesulfonate crystalline form E or the above-mentioned pharmaceutical composition in the preparation of a drug, wherein the drug is used to treat and / or prevent epilepsy.

[0085] The present invention also provides the use of the above-mentioned mesylate salt form A, p-toluenesulfonate salt form A, p-toluenesulfonate salt form B, p-toluenesulfonate salt form E or the above-mentioned pharmaceutical composition in the preparation of a drug, wherein the drug is used to treat and / or prevent amyotrophic lateral sclerosis.

[0086] The present invention also provides the use of the above-mentioned mesylate crystalline form A, p-toluenesulfonate crystalline form A, p-toluenesulfonate crystalline form B, p-toluenesulfonate crystalline form E or the above-mentioned pharmaceutical composition in the preparation of a drug, wherein the drug is used to treat and / or prevent depression.

[0087] The present invention also provides the use of the above-mentioned mesylate crystalline form A, p-toluenesulfonate crystalline form A, p-toluenesulfonate crystalline form B, p-toluenesulfonate crystalline form E or the above-mentioned pharmaceutical composition in the preparation of a drug, wherein the drug is used to treat and / or prevent pain.

[0088] The positive progress effect of the present invention is:

[0089] (1) The crystal form of the present invention has the advantages of high purity, strong stability, high solubility, repeatable preparation and excellent performance.

[0090] (2) The solubility of the crystalline form of the present invention in water, simulated intestinal fluid in the fasting state, and simulated gastric fluid is significantly higher than that of the free base.

[0091] (3) In the pharmacokinetic study in rats, the systemic exposure of the crystalline form of the present invention was significantly better than that of the free base, and the overall pharmacokinetic properties were unexpectedly improved.

[0092] In summary, the salt form and crystal form of the present invention have better solubility and better in vivo exposure, which significantly improves the drugability. BRIEF DESCRIPTION OF THE DRAWINGS

[0093] Figure 1 is a hydrogen nuclear magnetic spectrum (deuterated DMSO, 400 MHz) of the mesylate salt form A of the compound of formula I;

[0094] FIG2 is a TGA / DSC diagram of Form A of the mesylate salt of the compound of Formula I;

[0095] FIG3 is an XRPD pattern of the mesylate salt form A of the compound of formula I;

[0096] FIG4 is a hydrogen NMR spectrum (deuterated DMSO, 400 MHz) of the p-toluenesulfonate salt of the compound of Formula I, Form A;

[0097] FIG5 is a TGA / DSC diagram of the p-toluenesulfonate crystalline form A of the compound of Formula I;

[0098] FIG6 is an XRPD pattern of the p-toluenesulfonate salt of the compound of Formula I, Form A;

[0099] FIG7 is a hydrogen NMR spectrum (deuterated DMSO, 400 MHz) of the p-toluenesulfonate salt of the compound of Formula I, Form B;

[0100] FIG8 is a TGA / DSC diagram of the p-toluenesulfonate crystalline form B of the compound of Formula I;

[0101] FIG9 is an XRPD pattern of the p-toluenesulfonate salt of the compound of Formula I, Form B;

[0102] Figure 10 is an XRPD pattern of the p-toluenesulfonate salt of the compound of Formula I, Form E;

[0103] FIG11 is a TGA / DSC diagram of the p-toluenesulfonate salt of the compound of Formula I, Form E;

[0104] FIG12 is a H NMR spectrum (deuterated DMSO, 400 MHz) of the p-toluenesulfonate salt of the compound of Formula I, Form E;

[0105] FIG13 is a hydrogen NMR spectrum (deuterated DMSO, 400 MHz) of the p-toluenesulfonate salt of the compound of Formula I, Form C;

[0106] FIG14 is a TGA / DSC diagram of the p-toluenesulfonate salt of the compound of Formula I, Form C;

[0107] Figure 15 is an XRPD pattern of the p-toluenesulfonate salt of the compound of Formula I, Form C;

[0108] Figure 16 is a hydrogen NMR spectrum (deuterated DMSO, 400 MHz) of the hydrochloride salt form B of the compound of Formula I;

[0109] Figure 17 is an XRPD pattern of Form B of the hydrochloride salt of the compound of Formula I;

[0110] FIG18 is a TGA / DSC diagram of Form B of the hydrochloride salt of the compound of Formula I;

[0111] FIG19 is a hydrogen NMR spectrum (deuterated DMSO, 400 MHz) of the sulfate salt of Form A of the compound of Formula I;

[0112] Figure 20 is a TGA / DSC diagram of the sulfate salt of the compound of Formula I, Form A;

[0113] Figure 21 is an XRPD spectrum of the sulfate salt of the compound of Formula I, Form A;

[0114] FIG22 is a H NMR spectrum (deuterated DMSO, 400 MHz) of Form A of the benzenesulfonate salt of the compound of Formula I;

[0115] FIG23 is a TGA / DSC diagram of Form A of benzenesulfonate salt of the compound of Formula I;

[0116] FIG24 is an XRPD spectrum of Form A of benzenesulfonate salt of the compound of Formula I;

[0117] FIG25 is a H NMR spectrum (deuterated DMSO, 400 MHz) of Form B benzenesulfonate salt of the compound of Formula I;

[0118] FIG26 is a TGA / DSC diagram of Form B of the benzenesulfonate salt of the compound of Formula I;

[0119] FIG27 is an XRPD spectrum of Form B of the benzenesulfonate salt of the compound of Formula I;

[0120] Figure 28 is an XRPD pattern of benzenesulfonate salt Form B heated to 120°C;

[0121] FIG29 is a TGA / DSC graph of benzenesulfonate Form B heated to 120° C.;

[0122] FIG30 is a H-NMR spectrum of benzenesulfonate salt Form B heated to 120° C.

[0123] FIG31 is an XRPD spectrum of the crystalline form B of the naphthoate salt of the compound of Formula I;

[0124] FIG32 is a H NMR spectrum (deuterated DMSO, 400 MHz) of the maleate salt Form A of the compound of Formula I;

[0125] Figure 33 is a TGA / DSC diagram of maleate salt Form A of the compound of Formula I;

[0126] Figure 34 is an XRPD spectrum of maleate salt Form A of the compound of Formula I. DETAILED DESCRIPTION

[0127] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0128] Instruments and analytical methods

[0129] X-ray powder diffraction (XRPD)

[0130] The X-ray powder diffraction (XRPD) method involved in the present invention is as follows:

[0131] X-ray powder diffraction data of the sample were collected under ambient conditions using a Bruker D2 X-ray powder diffractometer. Approximately 2 mg of sample was spread flat on a high-purity silicon sample table, flattened with a glass slide through a weighing paper, and then sampled for detection. The X-ray tube used a Cu target (Kα) with a Kα2 / Kα1 intensity ratio of 0.50. The X-ray emitter power was 300 W, the voltage was 30 kV, and the current was 10 mA. The divergence slit was 0.6 mm, and the Soller slit was 4.0°. The step rate was 0.15 s / step, the step size was 0.02° (2θ), and the total number of steps was 1837.

[0132] X-ray powder diffraction data were collected using a Rigaku Smartlab SE model X-ray powder diffractometer under ambient conditions. A sample of approximately 2 mg was spread flat on a high-purity silicon sample stage, flattened with a glass slide through a weighing paper, and then injected for testing. The X-ray tube used a Cu target (Kα) with a Kα2 / Kα1 intensity ratio of 0.50. The X-ray transmitter power was 1600kW, the voltage was 40kV, and the current was 40mA. The entrance slit was 0.5°, and the receiving slit was 20.0mm. The measurement range was 3-40° (2θ), with a step rate of 8° / min and a step size of 0.01° (2θ).

[0133] X-ray powder diffraction data were collected using a Malvern Panalytical Aeris X-ray powder diffractometer under ambient conditions. Several milligrams of sample were spread flat on a zero-background silicon sample pan, flattened with a glass slide through a weighing paper, and then examined. The X-ray tube used a Cu target (Kα) with a Kα2 / Kα1 intensity ratio of 0.50. The X-ray emitter power was 300 W, the voltage was 40 kV, and the current was 7.5 mA. The test range was 3 to 40° (2θ), the scanning speed was 0.14° / s, and the step size was 0.02° (2θ).

[0134] Thermogravimetric Analyzer (TGA)

[0135] The thermogravimetric analysis (TGA) curve involved in the present invention is the thermogravimetric data of the sample collected using the TA Discovery series thermogravimetric instrument TGA550, as follows:

[0136] A few milligrams of sample were placed in a Tzero aluminum pan (automatically weighed by the instrument during the test) and heated from room temperature to the target temperature under N2 protection with an N2 flow rate of 60 mL / min and a heating rate of 10°C / min.

[0137] Differential Scanning Calorimetry (DSC)

[0138] The differential scanning calorimetry (DSC) curve involved in the present invention is the thermal data of the sample collected using a TA Discovery series differential scanning calorimeter DSC2500, as follows:

[0139] Weigh a few milligrams of sample into a Tzero aluminum pan, seal it with a Tzero seal cap, and heat it to the target temperature (before decomposition temperature) under N2 protection with an N2 flow rate of 50 mL / min and a heating rate of 10°C / min.

[0140] Nuclear magnetic resonance (1HNMR)

[0141] The nuclear magnetic resonance (NMR) spectra involved in the present invention were collected using a Bruker AVANCE NEO 400 MHz NMR spectrometer, and DMSO-d6 was used as the NMR test solvent.

[0142] High-performance liquid chromatography (HPLC)

[0143] The purity / content of the samples involved in the present invention are collected by high performance liquid chromatography on an Agilent 1260II model or equivalent high performance liquid chromatograph. The specific instrument and test parameters are as follows:

[0144] Ion chromatography test (IC)

[0145] The contents of chloride ions and sulfate ions involved in the present invention were tested using ion chromatography (IC). The specific instrument and test parameters of the test method are as follows:

[0146] Chloride ion content test method:

[0147] Sulfate content test method:

[0148] The English / Chinese abbreviation comparison table of the solvents involved in the present invention is as follows:

[0149] Raw material preparation example

[0150] The free base 1 of the compound of formula I was synthesized by referring to the preparation method of compound A crystal form 1 in Example 6.2.1A of patent CN 115190874A.

[0151] The free base 4 of compound I was synthesized by referring to the preparation method of compound A crystal form 4 in Example 6.2.4D of patent CN 115190874A.

[0152] In the following examples, effect examples and comparative examples, except for Example 4, the remaining "free base" refers to free base 1.

[0153] Salt Form Preparation Example

[0154] Example 1 Preparation and Characterization of Form A of the Methanesulfonate Salt of Formula I

[0155] 602.46 mg of the free base of the compound of Formula I was weighed into a 20 mL glass bottle and 7 mL of MTBE was added to obtain a suspension. 151.55 mg of methanesulfonic acid was diluted with 2.5 mL of MTBE and slowly added to the suspension of the free base. The residual liquid acid solution was rinsed with 4 mL of MTBE and then added to the suspension. The reaction molar ratio was 1 / 1 (ligand / free base). The mixture was wrapped in aluminum foil and magnetically stirred at 5 ° C to avoid light.

[0156] After magnetic stirring for 2 days, the sample was separated and the solid was vacuum dried at 30°C. The dried sample was transferred to a 20 mL glass bottle and slurried with 5 mL of Toluene. After being wrapped in aluminum foil and slurried in the dark at room temperature for 1 hour, the solid was centrifuged and vacuum dried at 30°C for 7 hours to obtain 550.88 mg of the mesylate salt Form A of the compound of Formula I as an off-white solid with a yield of 71% and a purity of 97.7%.

[0157] The methanesulfonate crystal form A of the compound of formula I is 1 The products were characterized by H NMR, XRPD, DSC and TGA. 1 Please see Figure 1 for H NMR; see Figure 2 for DSC / TGA; and see Figure 3 for XRPD.

[0158] Formula I compound mesylate salt crystal form A 1H NMR results indicated an acid-base molar ratio of 1.0. Its TGA / DSC spectrum revealed minimal weight loss before 180°C, at 0.85%. A slight endothermic peak was observed at approximately 174.14°C (peak), and a sharp endothermic peak at 213.85°C (peak), with a thermal enthalpy of 66.99 J / g. Characterization data indicated that Form A of the mesylate salt was a monosalt, anhydrous crystalline form.

[0159] The characteristic peak data of XRPD (Malvern Panalytical Aeris type) are shown in the following table:

[0160] Example 2 Preparation and Characterization of Form A of the p-Toluenesulfonate Salt of Formula I

[0161] Weigh 20 mg of the free base of the compound of Formula I into an HPLC vial, add 0.3 mL of EtOAc and an equimolar ratio of p-toluenesulfonic acid, and stir magnetically at room temperature. After stirring magnetically at room temperature (approximately 20°C) for 2-3 days, centrifuge. Dry under vacuum at 30°C for 5 hours to obtain the p-toluenesulfonic acid salt of the compound of Formula I, Form A, with an HPLC purity of 92.7%.

[0162] The p-toluenesulfonate salt form A of the compound of formula I is 1 The products were characterized by H NMR, XRPD, DSC and TGA. 1 Please see Figure 4 for H NMR, Figure 5 for DSC / TGA, and Figure 6 for XRPD.

[0163] The TGA results showed that the sample had no significant weight loss before decomposition. The DSC results showed that the sample had small endothermic peaks at 113.26℃ and 178.05℃ (peak), and an endothermic peak at 223.99℃ (peak), with a melting heat of 68.20 J / g. 1 H NMR results showed that the product contained 1.0 equivalent of p-toluenesulfonic acid. The p-toluenesulfonate crystalline form A is an anhydrous form of a mono-p-toluenesulfonate salt.

[0164] The characteristic peak data of XRPD (Rigaku Smartlab SE model) are shown in the following table:

[0165] Example 3 Preparation and Characterization of Form B of the p-Toluenesulfonate Salt of Formula I

[0166] Weigh 500.3 mg of the free base of the compound of Formula I into a 20-mL glass bottle and add 7.5 mL of toluene to obtain a suspension. Weigh 253.71 mg of p-toluenesulfonic acid monohydrate and add it to the suspension at a molar ratio of 1 / 1 (ligand / free base). A small amount of seed crystals is added and magnetic stirring is performed at room temperature. After stirring for a period of time, 1 mL of toluene is added. The system continues to be magnetically stirred at room temperature for 2 days, resulting in a light yellow suspension. Centrifuge to obtain a solid. The resulting solid is vacuum dried overnight at 30°C to yield 601.8 mg of sample, with a yield of approximately 79.3%.

[0167] A 100 mg sample dried at 30°C in vacuum was slurried in 2 mL of 2-MeTHF at room temperature in the dark. After overnight drying, a small sample was filtered to obtain a filter cake. The filter cake was dried in vacuum overnight at room temperature and then further dried in an oven at room temperature overnight to yield 437.3 mg of crystalline p-toluenesulfonate Form B with an HPLC purity of 96.8%.

[0168] Seed crystal preparation method: 100.57 mg of the free base of the compound of Formula I was weighed into an HPLC vial, 1.5 mL of Toluene was added to obtain a suspension, and then 50.69 mg of p-toluenesulfonic acid monohydrate was added (the acid-base ratio was 1 / 1). The suspension was stirred magnetically at room temperature in the dark overnight, and the solid was separated by centrifugation and dried in vacuo at 30°C overnight to obtain seed crystals.

[0169] The p-toluenesulfonate salt form B of the compound of formula I is 1 The products were characterized by H NMR, XRPD and TGA. 1 Please see Figure 7 for H NMR, Figure 8 for TGA / DSC, and Figure 9 for XRPD.

[0170] 1 H NMR results showed that the p-toluenesulfonate salt Form B of the compound of Formula I contained 1.0 equivalent of p-toluenesulfonic acid. TGA results showed no significant weight loss before decomposition. DSC results revealed endothermic peaks at 180.9°C and 223.0°C (peaks), with the heat of fusion at the 223.0°C endothermic peak being 54.52 J / g. Characterization data indicate that the p-toluenesulfonate salt Form B is an anhydrous form of a mono-p-toluenesulfonate salt.

[0171] The characteristic peak data of XRPD of p-toluenesulfonate salt form B (Bruker D2 model) are shown in the following table:

[0172] Example 4 Preparation and Characterization of Form E of the p-Toluenesulfonate Salt of Formula I

[0173] Preparation: 499.94 mg of the free base of Formula I (Form 4) was weighed into a 20 mL vial. 7.5 mL of ethyl acetate and 254.19 mg of p-toluenesulfonic acid monohydrate (1 / 1 ratio) were added. The mixture was stirred magnetically overnight at room temperature in the dark. After overnight stirring, the solid was centrifuged and dried under vacuum at 30°C for 4 hours to obtain Form E of the p-toluenesulfonate salt of Formula I with a purity of 98.6%.

[0174] The p-toluenesulfonate crystalline form E of the compound of formula I is used 1 The results were characterized by H NMR, XRPD, DSC and TGA. Please see Figure 10 for XRPD and Figure 11 for TGA / DSC. 1 Please see Figure 12 for H NMR.

[0175] The TGA results showed that there was no significant weight loss before the sample decomposed. The DSC results showed that the sample had an endothermic peak at 180.26℃ with a melting heat of 26.13 J / g and an endothermic peak at 224.05℃ (peak) with a melting heat of 59.89 J / g. 1 H NMR results indicated the presence of 1.0 equivalent of p-toluenesulfonic acid. Characterization data indicated that p-toluenesulfonate Form E is an anhydrous form of a mono-p-toluenesulfonate salt. XRPD (Malvern Panalytical Aeris model) characteristic peak data are shown in the following table:

[0176] Example 5 Preparation and Characterization of Form C of the p-Toluenesulfonate Salt of Formula I

[0177] Weigh 20 mg of the free base of the compound of Formula I into an HPLC vial, add 0.3 mL of MTBE and an equimolar ratio of p-toluenesulfonic acid, and stir magnetically at room temperature. After stirring magnetically at room temperature (approximately 20°C) for 2-3 days, centrifuge. Dry under vacuum at 30°C for 5 hours to obtain the p-toluenesulfonic acid salt of the compound of Formula I, Form C, with an HPLC purity of 95.9%.

[0178] The p-toluenesulfonate salt form C of the compound of formula I is used 1 The products were characterized by H NMR, XRPD, DSC and TGA. 1 Please see Figure 13 for H NMR, Figure 14 for TGA / DSC, and Figure 15 for XRPD.

[0179] TGA results showed that the sample lost 4.973% of its weight before 150°C. DSC results showed that the sample had endothermic peaks at 128.1 and 224.2°C (peaks), with the enthalpy of the endothermic peak at 224.2°C being 60.17 J / g, and an exothermic peak at 143.0°C (peak). 1H NMR results showed that the product contained 1.0 equivalent of p-toluenesulfonic acid. The p-toluenesulfonate salt form C was a hydrate of a mono-p-toluenesulfonate salt.

[0180] The characteristic peak data of XRPD (Rigaku Smartlab SE model) are shown in the following table:

[0181] Example 6 Preparation and Characterization of Form B of Hydrochloride Salt of Compound of Formula I

[0182] 19.99 mg of the starting free base was weighed into an HPLC vial, and 0.3 mL of MTBE was added to obtain a suspension. 4.4 μL of hydrochloric acid (acid-base ratio of 1 / 1) was added to the free base suspension, and magnetic stirring was performed at room temperature (17-21°C). At the beginning of the reaction, 0.2 mL of MTBE was added. After continuing magnetic stirring at room temperature for 2 days, the system became a white suspension. The solid was separated by centrifugation and dried in vacuo at 30°C for 5 h to obtain the hydrochloride salt Form B of the compound of Formula I with an HPLC purity of 93.6%.

[0183] The hydrochloric acid form B of the compound of formula I is used 1 The products were characterized by H NMR, XRPD, DSC and TGA. 1 Please see Figure 16 for H NMR, Figure 17 for XRPD, and Figure 18 for TGA / DSC.

[0184] TGA results showed that the sample lost 0.2099% of its weight before 120° C. and lost 8.859% of its weight between 120° C. and 190° C. DSC results showed that the sample had endothermic peaks at 173.0° C. and 197.7° C. (peak).

[0185] A sample with 94.6% HPLC purity was obtained after re-preparation using the above method in the dark and vacuum drying at 40°C for 4 hours. This sample was used to collect molar ratio data. The free base content was 85.5% by HPLC, and the Cl- content was 5.8% by IC, corresponding to a calculated acid-base molar ratio of 0.7. The hydrochloride salt Form B is an anhydrous crystalline form.

[0186] The characteristic peak data of XRPD (Bruker D2 model) are shown in the following table:

[0187] Example 7 Preparation and Characterization of Sulfate Form A of Compound I

[0188] Weigh 20 mg of the free base of the compound of Formula I into an HPLC vial, add 0.3 mL of IPA and an equimolar ratio of sulfuric acid, and stir magnetically at room temperature. After stirring magnetically at room temperature (approximately 20°C) for 2-3 days, centrifuge. Dry under vacuum at 30°C for 5 hours to obtain the sulfate salt of the compound of Formula I, Form A, with an HPLC purity of 98.2%.

[0189] The sulfuric acid crystal form A of the compound of formula I is used 1 The products were characterized by H NMR, XRPD, DSC and TGA. 1 Please see Figure 19 for H NMR, Figure 20 for TGA / DSC, and Figure 21 for XRPD.

[0190] TGA results showed that the sample lost 10.82% of its weight before 170° C. DSC results showed that the sample had an endothermic peak at 139.0° C. (peak) with a thermal enthalpy of 114.9 J / g.

[0191] A sample with 98.4% HPLC purity was obtained after re-preparation using the above method in the dark and vacuum drying at 40°C for 4 hours. This sample was used to collect molar ratio data. The free base content was 85.5% by HPLC, and the sulfate content was 17.0% by IC, corresponding to a calculated acid-base molar ratio of 1.0. Sulfate Form A is a hydrated form of the monosulfate salt.

[0192] The characteristic peak data of XRPD (Rigaku Smartlab SE model) are shown in the following table:

[0193] Example 8 Preparation and Characterization of Form A of the Benzenesulfonate Salt of the Compound of Formula I

[0194] Into an HPLC vial, 29.91 mg of the starting free base and 12.39 mg of benzenesulfonic acid (acid-base ratio of 1 / 1) were weighed, 0.65 mL of MTBE was added, and the mixture was magnetically stirred at room temperature (14-23°C) in the dark. The system solidified at the beginning of the reaction. After adding 0.2 mL of MTBE and continuing magnetic stirring at room temperature overnight, the system became a white suspension. After 3 days of reaction, the solid was separated by centrifugation and dried in vacuo at 40°C for 4 h to obtain Form A of the benzenesulfonate salt of the compound of Formula I with an HPLC purity of 96.0%.

[0195] The benzenesulfonate salt form A of the compound of formula I was characterized by 1H NMR, XRPD, DSC and TGA. 1 Please see Figure 22 for H NMR, Figure 23 for TGA / DSC, and Figure 24 for XRPD.

[0196] The TGA results showed that the sample had no weight loss before decomposition, and the DSC results showed that the sample had an endothermic peak at 207.7°C (peak) with a thermal enthalpy of 58.34 J / g. 1 H NMR results showed that the benzenesulfonate salt contained 1.0 equivalent of benzenesulfonic acid. The benzenesulfonate salt form A is an anhydrous crystalline form of the monobenzenesulfonate salt.

[0197] The characteristic peak data of XRPD (Bruker D2 model) are shown in the following table:

[0198] Example 9 Preparation and Characterization of Form B of the Benzenesulfonate Salt of Formula I

[0199] In a 4 mL glass bottle, 100.32 mg of the starting free base and 62.14 mg of benzenesulfonic acid (acid-base ratio of 1 / 1) were weighed, 2 mL of MTBE was added, and the mixture was stirred magnetically in the dark at room temperature (approximately 15°C). At the beginning of the reaction, 2 mg of benzenesulfonate Form A seed crystals were added. After reacting at room temperature for 2 days, the solid was separated by centrifugation and dried in vacuo at 30°C overnight to obtain the benzenesulfonate Form B of the compound of Formula I with an HPLC purity of 97.7%.

[0200] The seed crystal preparation method is as follows: 29.91 mg of the free base of the compound of Formula I was weighed into an HPLC vial and 0.65 mL of MTBE was added to obtain a suspension. 12.39 mg of benzenesulfonic acid (acid-base ratio of 1 / 1) was added to solidify the system. 0.2 mL of solvent was added to obtain a white suspension. The suspension was magnetically stirred at room temperature in the dark for 3 days, and then the solid was centrifuged and dried in vacuo at 40°C for 4 hours.

[0201] The benzoate crystal form B of the compound of formula I is used 1 The products were characterized by H NMR, XRPD, DSC and TGA. 1 Please see Figure 25 for H NMR, Figure 26 for TGA / DSC, and Figure 27 for XRPD.

[0202] The TGA results showed that the sample lost 1.3% of its weight before 120°C, and the DSC results showed that the sample had endothermic peaks at 86.0 and 200.7°C (peak). 1 H NMR results showed the presence of 1.2 equivalents of benzenesulfonic acid.

[0203] The sample was heated to 120°C and returned to room temperature. XRPD showed that the sample's crystal form remained unchanged, but some peaks shifted (Figure 28). TGA / DSC results showed that the sample lost 0.4% of its weight before 120°C. DSC results showed that the sample had endothermic peaks at 71.0 and 204.3°C (peaks) (Figure 29). 1 H NMR results showed that it contained 1.2 equivalents of benzenesulfonic acid (Figure 30). The above data indicate that benzenesulfonate salt form B is a hydrate of monobenzenesulfonate.

[0204] The characteristic peak data of XRPD (Bruker D2 model) (before heating) are shown in the following table:

[0205] Example 10 Preparation and Characterization of Form B of Naphthoate Salt of Formula I

[0206] In an HPLC vial, 29.75 mg of the starting free base and 21.29 mg of 2-naphthalenesulfonic acid (acid-base ratio of 1.3 / 1) were weighed, 0.45 mL of EtOAc was added, and the mixture was stirred magnetically in the dark at room temperature (14-23°C). After reacting for 3 days, the solid was separated by centrifugation and dried in vacuo at 40°C for 4 h to obtain the naphthalene salt Form B of the compound of Formula I with an HPLC purity of 80.0%.

[0207] XRPD was used to characterize the naphthoic acid crystal form B of the compound of formula I. The XRPD spectrum is shown in Figure 31.

[0208] The characteristic peak data of XRPD (Bruker D2 model) are shown in the following table:

[0209] Example 11 Preparation and Characterization of Form A of the Maleate Salt of the Compound of Formula I

[0210] Into an HPLC vial, 29.99 mg of the starting free base and 9.14 mg of maleic acid (acid-base ratio 1 / 1) were weighed, 0.65 mL of MTBE was added, and the mixture was magnetically stirred at room temperature (14-23°C) in the dark. The system solidified at the beginning of the reaction. 0.2 mL of MTBE was added, and magnetic stirring was continued at room temperature overnight to form a white suspension. The solid was separated by centrifugation and dried in vacuo at 30°C overnight to obtain the maleate salt Form A of the compound of Formula I with an HPLC purity of 96.9%.

[0211] The maleate salt form A of the compound of formula I is 1 The products were characterized by H NMR, XRPD, DSC and TGA. 1 Please see Figure 32 for H NMR, Figure 33 for TGA / DSC, and Figure 34 for XRPD.

[0212] TGA results showed that the sample lost 0.5% of its weight before 120°C. DSC results showed that the sample had an endothermic peak at 127.8°C (peak), with a thermal enthalpy of 73.43 J / g. 1 H NMR results showed that the maleate salt contained 1.0 equivalent of maleic acid. Maleate salt Form A is an anhydrous crystalline form of the monomaleate salt.

[0213] The characteristic peak data of XRPD (Bruker D2 model) are shown in the following table:

[0214] Effect Example 1 Solubility Test of Higher Purity Salt Sample of Formula I Compound

[0215] Samples of the following 4 salt forms were tested for solubility in biologic solvent and water, namely: p-toluenesulfonate crystal forms A / B / E, and methanesulfonate crystal form A. The specific steps were as follows: Water and biologic solvent were respectively added to the samples (the feeding concentration was 1 mg / mL, calculated based on the free base of the compound of formula I). After shaking or ultrasonic treatment for about 2 mins, the turbid samples were transferred to a shaker (37 °C, 100 rpm / min). After shaking for the corresponding time, the samples were filtered through a filter membrane (nylon membrane, membrane pore size 0.22 μm), and the solubility of the filtrate was measured. Among them, the SGF system was shaken for 1 h, and the water / FaSSIF system was shaken for 4 h.

[0216] The results showed that compared with the free base, the solubility (mg / mL) of all salt forms in water / FaSSIF / SGF was increased to a certain extent, specifically 0.008 - 0.05 vs. <LOQ, 0.002 - 0.004 vs. 0.001, 0.22 - 0.24 vs. 0.11. The solubility in simulated gastric fluid (SGF) was 2 - 2.18 times that of the free base, the solubility in simulated intestinal fluid in the fasting state (FaSSIF) was 2 - 4 times that of the free base, and the solubility in water was more than 100 - 800 times that of the free base.

[0217] Table 1 Summary of solubility of 4 salt forms and free base Solubility unit (calculated based on the free base): mg / mL; LOD = 0.06 μg / mL, LOQ = 0.18 μg / mL.

[0218] Effect Example 2 Evaluation of solid state stability of higher purity salt form samples of the compound of formula I

[0219] The following six samples were evaluated: sulfate crystal form A, p-toluenesulfonate crystal form B, p-toluenesulfonate crystal form E, methanesulfonate crystal form A, benzenesulfonate crystal form B, and maleate crystal form A. Specifically, 4 - 11 mg of the samples were weighed and placed in brown HPLC vials, and were left open under the following three conditions: 1) 25 °C / 60% RH, 2) 40 °C / 75% RH, 3) 60 °C. Purity tests (HPLC) and crystal form detection (XRPD) were performed on the starting samples and the samples stored for 1 / 2 week.

[0220] The experimental results are shown in the following table. 1) In terms of crystal form: The crystal forms of p-toluenesulfonate crystal form B / methanesulfonate crystal form A / p-toluenesulfonate crystal form E remained unchanged after being placed under various conditions for two weeks; the other salt forms showed deliquescence or a decrease in crystallinity after being placed; 2) In terms of purity: After being placed for 2 weeks, the purity of methanesulfonate crystal form A under the conditions of 25 °C / 60% RH and 60 °C and the purity of p-toluenesulfonate crystal form B under the condition of 25 °C / 60% RH were basically unchanged or slightly decreased; the purity of p-toluenesulfonate crystal form E was basically unchanged or slightly decreased under the three investigated conditions. The purity of other samples decreased significantly under different conditions.

[0221] Table 2 Summary of 2-week solid-state stability study data for six salt forms and free base Form A All samples were prepared and delivered fresh. NA: Sample deliquescence not analyzed; ^: Samples marked with this label were sampled and tested 6 days later, while others were sampled and tested 1 week later; *: Samples marked with this label were sampled and tested 13 days later, while others were sampled and tested 2 weeks later.

[0222] Effect Example 3 Comparison of Pharmacokinetic Properties of Methanesulfonate Crystal Form A, P-Toluenesulfonate Crystal Form B, P-Toluenesulfonate Crystal Form E and Free Base of Formula I in Rats

[0223] 1) Study Objective: To determine the pharmacokinetic characteristics of the free base, p-toluene salt form B, p-toluenesulfonate form E, and methanesulfonate form A of the compound of Formula I in male SD rats

[0224] 2) Experimental content

[0225] Healthy male SD rats (3 per group) were fasted for at least 12 hours and dosed at 10 mg / kg body weight. Blood was collected via the jugular vein at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after dosing. Approximately 0.2 mL of whole blood was collected into EDTA-K2 anticoagulant tubes. Plasma was centrifuged within 1 hour of collection and frozen at -80°C until further use. Plasma samples were analyzed for drug concentrations using LC-MS / MS.

[0226] Experimental results: According to the obtained blood drug concentration data, The pharmacokinetic parameters after drug administration were calculated using the non-compartmental model using Pharsight 7.0 software (Pharsight, USA).

[0227] Table 3 PK parameters of the free base, p-toluene salt crystal form B, p-toluenesulfonate crystal form E and methanesulfonate crystal form A of the compound of formula I in male SD rats after single administration (10 mg / kg)

[0228] As can be seen from the above table, the p-toluene salt crystalline form B, p-toluenesulfonate salt crystalline form E and methanesulfonate salt crystalline form A involved in the present invention have significantly improved PK properties compared to the free base.

[0229] C of p-toluenesulfonate crystal form B max and AUC (0-t) (0-24 hours) were 647.78ng / mL and 7543.52h*ng / ml respectively. Compared with the free base of 331.25ng / mL and 3500.00h*ng / ml, both indicators have increased by nearly 100%, and the performance has been significantly improved.

[0230] C of p-toluenesulfonate Form E max and AUC(0-t) (0-24 hours) were 835.77 ng / mL and 10296.17 h*ng / ml, respectively, relative to the free base C max There is a nearly 2.5 times improvement in AUC (0-t) (0-24 hours) has a 2.9-fold improvement, with excellent performance.

[0231] Methanesulfonate Form A C max and AUC (0-t) (0-24 hours) were 938.72 ng / mL and 8569.96 h*ng / ml, respectively, relative to the free base C max There is a nearly 2.8-fold improvement in AUC (0-t) (0-24 hours) has a 2.4-fold improvement, and the performance is also excellent.

[0232] Summary of the preparation results of various salt types under non-light-shielding conditions in comparative examples

[0233] Based on the pKa of the free base of the compound of formula I (acidity: 14.6 and basicity: 5.6; calculated by ACD Labs software), 50 salt / cocrystal experiments were set up with 10 acids in 5 solvent systems. Conventional experimental procedures were used, no light protection was performed, and the materials were added in an equimolar ratio of acid and base. The specific experimental steps were as follows: approximately 20 mg of the free base synthesized by the raw material preparation example and an equimolar ratio of ligand were weighed into an HPLC vial, and then 0.3 mL of the corresponding solvent was added (the order of adding the liquid ligand was: weigh the free base first, then add the solvent and then the ligand), and magnetically stirred at room temperature. After magnetic stirring at room temperature (about 20°C) for 2-3 days, the clear or solid-free sample was transferred to 5°C for stirring and then to 20°C for storage. If it was still clear, open evaporation at room temperature or anti-solvent addition was tried, centrifuged, and vacuum dried at 30°C for 5 hours before characterization.

[0234] Relevant test results show that relatively stable and high-purity salt forms of the compound of formula I are not easy to obtain.

[0235] Table 4 Summary of preparation results of salt forms of compounds of formula I Glue: react at room temperature for 2 to 3 days to form a gel; according to the XRPD results, if a diffraction peak containing the acid ligand involved in the experiment is detected, it is marked as "free base + ligand", if only the diffraction peak of the free base is observed, it is registered as "free base".

Claims

1. A mesylate crystalline form A of a compound of formula I, characterized in that: The mesylate salt form A uses Cu-Kα radiation, and the X-ray powder diffraction pattern expressed in 2θ has diffraction peaks at the following positions: 5.60°±0.2°, 12.31°±0.2°, and 15.40°±0.2°; 2. The mesylate salt crystalline form A according to claim 1, wherein The X-ray powder diffraction pattern of the mesylate salt form A expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 9.47°±0.2°, 10.99°±0.2°, 17.57°±0.2°, and 19.15°±0.2°; Preferably, there are further diffraction peaks at one or more of the following positions: 14.86°±0.2°, 17.12°±0.2°, 18.33°±0.2°, 22.42°±0.2°, 22.94°±0.2°; More preferably, there are diffraction peaks at one or more of the following positions: 7.35°±0.2°, 11.36°±0.2°, 19.66°±0.2°, 20.10°±0.2°, 21.78°±0.2°, 26.69°±0.2°, and 28.95°±0.2°.

3. The mesylate salt crystalline form A according to claim 1, wherein The X-ray powder diffraction pattern of the mesylate salt form A expressed in 2θ angles has diffraction peaks at the following positions: 5.60°±0.2°, 9.47°±0.2°, 10.99°±0.2°, 12.31°±0.2°, 15.40°±0.2°, 17.57°±0.2°, and 19.15°±0.2°; Preferably, there are diffraction peaks at the following positions: 5.60°±0.2°, 9.47°±0.2°, 10.99°±0.2°, 12.31°±0.2°, 14.86°±0.2°, 15.40°±0.2°, 17.12°±0.2°, 17.57°±0.2°, 18.33°±0.2°, 19.15°±0.2°, 22.42°±0.2°, and 22.94°±0.2°; More preferably, diffraction peaks are present at the following positions: 5.60°±0.2°, 7.35°±0.2°, 9.47°±0.2°, 10.99°±0.2°, 11.36°±0.2°, 12.31°±0.2°, 14.86°±0.2°, 15.40°±0.2°, 17.12°±0.2°, 17.57°±0.2°, 18.33°±0.2°, 19.15°±0.2°, 19.66°±0.2°, 20.10°±0.2°, 21.78°±0.2°, 22.42°±0.2°, 22.94°±0.2°, 26.69°±0.2°, and 28.95°±0.2°; More preferably, there are diffraction peaks at the following positions: 5.60°±0.2°, 7.35°±0.2°, 9.47°±0.2°, 10.99°±0.2°, 11.36°±0.2°, 12.31°±0.2°, 13.48°±0.2°, 14.02°±0.2°, 14.86°±0.2°, 15.40°±0.2°, 16.45°±0.2°, 17.12°±0.2°, 17.57°±0.2 °, 18.33°±0.2°, 19.15°±0.2°, 19.66°±0.2°, 20.10°±0.2°, 20.66°±0.2°, 21.78°±0.2°, 22.42°±0.2°, 22.94°±0.2°, 23.44°±0.2°, 26.69°±0.2°, 27.18°±0.2°, 28.95°±0.2°, 34.31°±0.2°, 36.14°±0.2°.

4. The mesylate salt crystalline form A according to claim 3, wherein The X-ray powder diffraction pattern of the mesylate salt form A expressed at 2θ angles has diffraction peaks as shown in the following table: Preferably, the X-ray powder diffraction pattern of the mesylate salt form A expressed in 2θ angles is substantially as shown in FIG3 .

5. The mesylate crystalline form A according to any one of claims 1 to 4, characterized in that: It meets one or more of the following conditions: (1) The differential scanning calorimetry of the mesylate salt form A has an endothermic peak at 213.85°C ± 3°C; Preferably, the differential scanning calorimetry of the mesylate salt form A has an endothermic peak at 213.85°C ± 3°C, and the heat of fusion is 66.99 J / g; More preferably, the differential scanning calorimetry diagram of the mesylate salt form A is substantially as shown in Figure 2; (2) The thermogravimetric analysis of the mesylate salt Form A showed a weight loss of 0.85% when the temperature was raised to 180°C; Preferably, the thermogravimetric analysis diagram of the mesylate salt form A is substantially as shown in Figure 2; (3) The mesylate crystalline form A is an anhydrous form of the monomethanesulfonate.

6. The mesylate salt crystalline form A according to claim 5, wherein It meets one or more of the following conditions: (1) The mesylate salt form A is obtained by an X-ray powder diffraction pattern using the following parameters: (2) The mesylate salt form A is obtained by TGA and / or DSC pattern of the crystal form using the following parameters:

7. A p-toluenesulfonate crystalline form A of a compound of formula I, characterized in that: The p-toluenesulfonate crystalline form A uses Cu-Kα radiation, and the X-ray powder diffraction pattern expressed in 2θ has diffraction peaks at the following positions: 5.17°±0.2°, 10.40°±0.2°, and 18.34°±0.2°; 8. The p-toluenesulfonate crystalline form A according to claim 7, wherein The X-ray powder diffraction pattern of the p-toluenesulfonate salt form A expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 8.55°±0.2°, 14.19°±0.2°; Preferably, there are further diffraction peaks at one or more of the following positions: 7.04°±0.2°, 17.56°±0.2°; More preferably, there are diffraction peaks at one or more of the following positions: 11.16°±0.2°, 14.61°±0.2°, 15.14°±0.2°, 19.85°±0.2°, 21.01°±0.2°, 22.21°±0.2°, 22.58°±0.2°, and 24.65°±0.2°.

9. The p-toluenesulfonate crystalline form A according to claim 7, wherein The X-ray powder diffraction pattern of the p-toluenesulfonate salt form A expressed in 2θ angles has diffraction peaks at the following positions: 5.17°±0.2°, 8.55°±0.2°, 10.40°±0.2°, 14.19°±0.2°, and 18.34°±0.2°; Preferably, there are diffraction peaks at the following positions: 5.17°±0.2°, 7.04°±0.2°, 8.55°±0.2°, 10.40°±0.2°, 14.19°±0.2°, 17.56°±0.2°, and 18.34°±0.2°; More preferably, diffraction peaks are present at the following positions: 5.17°±0.2°, 7.04°±0.2°, 8.55°±0.2°, 10.40°±0.2°, 11.16°±0.2°, 14.19°±0.2°, 14.61°±0.2°, 15.14°±0.2°, 17.56°±0.2°, 18.34°±0.2°, 19.85°±0.2°, 21.01°±0.2°, 22.21°±0.2°, 22.58°±0.2°, and 24.65°±0.2°; More preferably, there are diffraction peaks at the following positions: 5.17°±0.2°, 7.04°±0.2°, 7.98°±0.2°, 8.55°±0.2°, 10.40°±0.2°, 11.16°±0.2°, 11.51°±0.2°, 13.15°±0.2°, 14.19°±0.2°, 14.61°±0.2°, 15.14°±0.2°, 16.15°±0.2°, 17.56°±0.2°, 18.34°±0.2°, 19.52°±0.2° , 19.85°±0.2°, 20.44°±0.2°, 21.01°±0.2°, 21.56°±0.2°, 22.21°±0.2°, 22.58°±0.2°, 23.75°±0.2°, 24.65°±0.2°, 25.38°±0.2°, 26.45°±0.2°, 26.96°±0.2°, 28.82°±0.2°, 30.53°±0.2°, 31.81°±0.2°, 35.27°±0.2°, and 37.51°±0.2°.

10. The p-toluenesulfonate crystalline form A according to claim 9, wherein The X-ray powder diffraction pattern of the p-toluenesulfonate salt form A expressed at 2θ angles has diffraction peaks as shown in the following table: Preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form A expressed at 2θ angles is substantially as shown in FIG6 .

11. The p-toluenesulfonate crystalline form A according to any one of claims 7 to 10, characterized in that: It meets one or more of the following conditions: (1) The differential scanning calorimetry of the p-toluenesulfonate salt form A has an endothermic peak at 223.99°C ± 3°C; Preferably, the differential scanning calorimetry of the p-toluenesulfonate salt form A has an endothermic peak at 223.99°C ± 3°C, and the heat of fusion is 68.20 J / g; Further preferably, the differential scanning calorimetry diagram of the p-toluenesulfonate salt form A is substantially as shown in Figure 5; (2) The thermogravimetric analysis of the p-toluenesulfonate salt Form A is substantially as shown in FIG5 ; (3) The p-toluenesulfonate crystalline form A is an anhydrous form of mono-p-toluenesulfonate.

12. The p-toluenesulfonate crystalline form A according to claim 11, wherein It meets one or more of the following conditions: (1) The p-toluenesulfonate salt form A is obtained by the following parameters to obtain an XRPD pattern of the crystalline form; (2) The p-toluenesulfonate salt form A is obtained by TGA and / or DSC pattern of the crystalline form using the following parameters; 13. A p-toluenesulfonate crystalline form B of a compound of formula I, characterized in that: The p-toluenesulfonate salt form B uses Cu-Kα radiation, and the X-ray powder diffraction pattern expressed in 2θ has diffraction peaks at the following positions: 13.44°±0.2°, 17.28°±0.2°, and 17.38°±0.2°; 14. The p-toluenesulfonate crystalline form B according to claim 13, wherein The X-ray powder diffraction pattern of the p-toluenesulfonate salt form B expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 5.64°±0.2°, 14.49°±0.2°, 15.13°±0.2°, 20.45°±0.2°, 21.15°±0.2°, and 22.15°±0.2°; Preferably, there are further diffraction peaks at one or more of the following positions: 7.84°±0.2°, 10.11°±0.2°, 11.36°±0.2°, 12.03°±0.2°, 13.60°±0.2°, 18.58°±0.2°, 23.97°±0.2°; More preferably, there are diffraction peaks at one or more of the following positions: 5.09°±0.2°, 9.22°±0.2°, 10.87°±0.2°, 16.21°±0.2°, 19.55°±0.2°, 22.89°±0.2°, 25.03°±0.2°, and 27.08°±0.2°.

15. The p-toluenesulfonate crystalline form B according to claim 13, wherein The X-ray powder diffraction pattern of the p-toluenesulfonate salt form B expressed in 2θ angles has diffraction peaks at the following positions: 5.64°±0.2°, 13.44°±0.2°, 14.49°±0.2°, 15.13°±0.2°, 17.28°±0.2°, 17.38°±0.2°, 20.45°±0.2°, 21.15°±0.2°, and 22.15°±0.2°; Preferably, 5.64°±0.2°, 7.84°±0.2°, 10.11°±0.2°, 11.36°±0.2°, 12.03°±0.2°, 13.44°±0.2°, 13.60°±0.2°, 14.49°±0.2°, 15.13°±0.2°, 17.28°±0.2°, 17.38°±0.2°, 18.58°±0.2°, 20.45°±0.2°, 21.15°±0.2°, 22.15°±0.2°, and 23.97°±0.2°; More preferably, there are diffraction peaks at the following positions: 5.09°±0.2°, 5.64°±0.2°, 7.84°±0.2°, 9.22°±0.2°, 10.11°±0.2°, 10.87°±0.2°, 11.36°±0.2°, 12.03°±0.2°, 13.44°±0.2°, 13.60°±0.2°, 14.49°±0.2°, 15.13° ±0.2°, 16.21°±0.2°, 17.28°±0.2°, 17.38°±0.2°, 18.58°±0.2°, 19.55°±0.2°, 20.45°±0.2°, 21.15°±0.2°, 22.15°±0.2°, 22.89°±0.2°, 23.97°±0.2°, 25.03°±0.2°, 27.08°±0.2°; Further preferably, there are diffraction peaks at the following positions: 5.09°±0.2°, 5.64°±0.2°, 7.06°±0.2°, 7.84°±0.2°, 9.22°±0.2°, 10.11°±0.2°, 10.87°±0.2°, 11.36°±0.2°, 12.03°±0.2°, 13.44°±0.2°, 13.60°±0.2°, 14.49°±0.2°, 15.13°±0.2°, 16.21°±0.2°, 17.28°±0.2° , 17.38°±0.2°, 18.58°±0.2°, 19.55°±0.2°, 20.45°±0.2°, 21.15°±0.2°, 22.15°±0.2°, 22.89°±0.2°, 23.97°±0.2°, 25.03°±0.2°, 27.08°±0.2°, 29.19°±0.2°, 30.07°±0.2°, 30.73°±0.2°, 31.60°±0.2°, 35.97°±0.2°, and 37.84°±0.2°.

16. The p-toluenesulfonate crystalline form B according to claim 15, characterized in that The X-ray powder diffraction pattern of the p-toluenesulfonate salt form B expressed at 2θ angles has diffraction peaks as shown in the following table: Preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form B expressed in 2θ angles is substantially as shown in FIG9 .

17. The p-toluenesulfonate crystalline form B according to claim 13, wherein It meets one or more of the following conditions: (1) The differential scanning calorimetry of the p-toluenesulfonate salt form B has an endothermic peak at 222.98°C ± 3°C, and a heat of fusion of 54.52 J / g; Preferably, the differential scanning calorimetry diagram of the p-toluenesulfonate salt Form B is substantially as shown in Figure 8; (2) The thermogravimetric analysis of the p-toluenesulfonate salt Form B is substantially as shown in FIG8 ; (3) The p-toluenesulfonate crystalline form B is an anhydrous crystalline form of a single salt.

18. The p-toluenesulfonate crystalline form B according to claim 17, wherein It meets one or more of the following conditions: (1) The p-toluenesulfonate salt Form B is obtained by the following parameters to obtain an XRPD pattern of the crystalline form; (2) The p-toluenesulfonate salt Form B is obtained by TGA and / or DSC pattern of the crystalline form using the following parameters:

19. A p-toluenesulfonate crystalline form E of a compound of formula I, characterized in that: The p-toluenesulfonate salt form E uses Cu-Kα radiation, and the X-ray powder diffraction pattern expressed in 2θ has diffraction peaks at the following positions: 5.60°±0.2°, 8.15°±0.2°, and 17.33°±0.2°; 20. The p-toluenesulfonate crystalline form E according to claim 19, wherein The X-ray powder diffraction pattern of the p-toluenesulfonate salt form E expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 11.31°±0.2°, 13.89°±0.2°, 19.88°±0.2°; Preferably, there are further diffraction peaks at one or more of the following positions: 9.85°±0.2°, 10.02°±0.2°, 18.83°±0.2°, 20.23°±0.2°; More preferably, there are diffraction peaks at one or more of the following positions: 14.15°±0.2°, 16.12°±0.2°, 17.88°±0.2°, 22.33°±0.2°, 25.51°±0.2°, 27.23°±0.2°; Further preferably, there are diffraction peaks at one or more of the following positions: 3.34°±0.2°, 16.43°±0.2°, 21.72°±0.2°, 22.87°±0.2°, 23.17°±0.2°, 23.99°±0.2°, 24.51°±0.2°, 30.48°±0.2°, 33.75°±0.2°, and 34.38°±0.2°.

21. The p-toluenesulfonate crystalline form E according to claim 19, wherein The X-ray powder diffraction pattern of the p-toluenesulfonate salt form E expressed in 2θ angles has diffraction peaks at the following positions: 5.60°±0.2°, 8.15°±0.2°, 11.31°±0.2°, 13.89°±0.2°, 17.33°±0.2°, and 19.88°±0.2°; Preferably, there are diffraction peaks at the following positions: 5.60°±0.2°, 8.15°±0.2°, 9.85°±0.2°, 10.02°±0.2°, 11.31°±0.2°, 13.89°±0.2°, 17.33°±0.2°, 18.83°±0.2°, 19.88°±0.2°, and 20.23°±0.2°; More preferably, diffraction peaks are present at the following positions: 5.60°±0.2°, 8.15°±0.2°, 9.85°±0.2°, 10.02°±0.2°, 11.31°±0.2°, 13.89°±0.2°, 14.15°±0.2°, 16.12°±0.2°, 17.33°±0.2°, 17.88°±0.2°, 18.83°±0.2°, 19.88°±0.2°, 20.23°±0.2°, 22.33°±0.2°, 25.51°±0.2°, and 27.23°±0.2°; More preferably, the diffraction peaks are at the following positions: 3.34°±0.2°, 5.60°±0.2°, 8.15°±0.2°, 9.85°±0.2°, 10.02°±0.2°, 11.31°±0.2°, 13.89°±0.2°, 14.15°±0.2°, 16.12°±0.2°, 16.43°±0.2°, 17.33°±0.2°, 17.88°±0.2°, 18.83 °±0.2°, 19.88°±0.2°, 20.23°±0.2°, 21.72°±0.2°, 22.33°±0.2°, 22.87°±0.2°, 23.17°±0.2°, 23.99°±0.2°, 24.51°±0.2°, 25.51°±0.2°, 27.23°±0.2°, 30.48°±0.2°, 33.75°±0.2°, 34.38°±0.2°.

22. The p-toluenesulfonate crystalline form E according to claim 21, wherein The X-ray powder diffraction pattern of the p-toluenesulfonate salt form E expressed at 2θ angles has diffraction peaks as shown in the following table: Preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form E expressed at 2θ angles is substantially as shown in FIG10 .

23. The p-toluenesulfonate crystalline form E according to any one of claims 19 to 22, wherein: It meets one or more of the following conditions: (1) The differential scanning calorimetry of the p-toluenesulfonate salt form E shows two endothermic peaks at 180.26°C ± 3°C and 224.05°C ± 3°C, respectively; Preferably, the differential scanning calorimetry diagram of the p-toluenesulfonate salt form E has an endothermic peak at a peak value of 180.26°C±3°C, and a melting heat of 26.13 J / g; and an endothermic peak at a peak value of 224.05°C±3°C, and a melting heat of 59.89 J / g; Further preferably, the differential scanning calorimetry diagram of the p-toluenesulfonate salt form E is substantially as shown in Figure 11; (2) The thermogravimetric analysis of the p-toluenesulfonate salt Form E is substantially as shown in FIG11 ; (3) The p-toluenesulfonate crystalline form E is an anhydrous crystalline form of a single salt.

24. The p-toluenesulfonate crystalline form E according to claim 23, wherein It meets one or more of the following conditions: (1) The p-toluenesulfonate salt form E is obtained by the following parameters to obtain an XRPD pattern of the crystalline form; (2) The p-toluenesulfonate salt Form E is obtained by TGA and / or DSC patterns of the crystalline form using the following parameters:

25. A pharmaceutical composition, characterized in that It comprises the mesylate crystalline form A according to any one of claims 1 to 6, the p-toluenesulfonate crystalline form A according to any one of claims 7 to 12, the p-toluenesulfonate crystalline form B according to any one of claims 13 to 18, or the p-toluenesulfonate crystalline form E according to any one of claims 19 to 24, and pharmaceutical excipients.

26. Use of the mesylate crystalline form A according to any one of claims 1 to 6, the p-toluenesulfonate crystalline form A according to any one of claims 7 to 12, the p-toluenesulfonate crystalline form B according to any one of claims 13 to 18, the p-toluenesulfonate crystalline form E according to any one of claims 19 to 24, or the pharmaceutical composition according to claim 25 in the preparation of a medicament. The medicament is used for treating and / or preventing diseases or conditions affected by voltage-gated potassium channels.

27. Use of the mesylate crystalline form A according to any one of claims 1 to 6, the p-toluenesulfonate crystalline form A according to any one of claims 7 to 12, the p-toluenesulfonate crystalline form B according to any one of claims 13 to 18, the p-toluenesulfonate crystalline form E according to any one of claims 19 to 24, or the pharmaceutical composition according to claim 25 in the preparation of a medicament. The medicament is used to treat and / or prevent one or more of the following diseases or conditions: epilepsy, amyotrophic lateral sclerosis, depression and pain.

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