Nav1.8 inhibitor compound, salt thereof, polymorph thereof, and use thereof

Abstract

The present invention relates to a Nav1.8 inhibitor compound, a salt thereof, a polymorph thereof, and the use thereof. The present invention provides a salt of a compound of formula (I), a compound of formula (I) and a crystal form of a salt thereof, which have good medicinal properties. The structure of the formula (I) is as follows:

Description

A Nav1.8 inhibitor compound and its salt, polymorph and use

[0001] This application requires the applicant to:

[0002] The priority benefit of the prior application, patent application number 202311723384.5, filed with the State Intellectual Property Office of China on December 13, 2023, entitled “A Nav1.8 inhibitor compound, its salt, polymorphic form and use”;

[0003] The priority benefit of the prior application, patent application number 202411777862.5, filed with the State Intellectual Property Office of China on December 4, 2024, entitled “A Nav1.8 inhibitor compound, its salt, polymorphic form and use”;

[0004] The entire contents of said prior application are incorporated into the present application by reference. Technical Field

[0005] The present invention belongs to the field of medicine and relates to a Nav1.8 inhibitor compound and its salt, polymorph, and their preparation methods and applications. Background Art

[0006] Pain is "an unpleasant sensory and emotional feeling, accompanied by actual or potential tissue damage, and it is a subjective feeling." Pain can serve as a warning signal, alerting the body to potential dangers, and plays an indispensable protective role in the body's normal life activities. At the same time, pain is also a common clinical symptom. After the external stimulus that causes pain disappears, intense or persistent pain can cause physiological dysfunction and seriously affect the quality of life of the living organism. According to statistics, about one-fifth of the world's people suffer from moderate to severe chronic pain. In 2018, the global analgesic market was approximately US$36 billion and is expected to reach US$56 billion in 2023. Among them, acute, moderate and severe pain will grow steadily at a compound annual growth rate of 2.5% in the future, and the chronic pain market will grow at a compound annual growth rate of about 18%. Chronic pain is the main driving force for the continued growth of the global pain market in the next decade.

[0007] Pain originates from nociceptors in the peripheral nervous system. These are free nerve endings widely distributed throughout the skin, muscles, joints, and visceral tissues of the body. They convert perceived thermal, mechanical, or chemical stimuli into nerve impulses (action potentials) and transmit them via afferent nerve fibers to their cell bodies in the dorsal root ganglia (DRG), ultimately reaching higher nerve centers, causing pain sensation. The generation and conduction of action potentials in neurons, in turn, rely on voltage-gated sodium channels (NaV) on the cell membrane. When the cell membrane depolarizes, sodium channels activate and open, causing an influx of sodium ions, further depolarizing the cell membrane and leading to the generation of action potentials. Therefore, inhibiting abnormal sodium channel activity can help treat and relieve pain.

[0008] Human sodium channels are transmembrane ion channels composed of a 260kD α subunit and a 30-40kD β subunit. They are classified into nine subtypes based on the α subunits: Nav1.1 to Nav1.9. Nav1.5, Nav1.8, and Nav1.9 are tetrodotoxin (TTX)-insensitive sodium channels. Nav1.5 is primarily found in cardiomyocytes, while Nav1.8 and Nav1.9 are found in the peripheral nervous system. Nav1.8 is a key ion channel involved in chronic pain, atrial fibrillation, and Budd-Chiari syndrome, making it a highly selective target for pain treatment.

[0009] The gene encoding Nav1.8, SCN10A, is located in the human chromosome 3p21-22 region and primarily encodes the α subunit. Studies have found that the human and rat Nav1.8 genes share up to 93% homology. Nav1.8 is primarily present in trigeminal ganglion neurons and DRG neurons, exhibiting electrophysiological characteristics of slow inactivation and rapid recovery. In Nav1.8-expressing neurons, the rise of the action potential is primarily composed of Nav1.8 currents. In models of neuropathic pain, nerve injury increases Nav1.8 expression in axons and neuronal cell bodies. Nav1.8 antisense oligonucleotides significantly alleviate pain while simultaneously reducing Nav1.8 expression. Intra-paw injection of carrageenan in rats increases Nav1.8 expression in DRG neurons. Nav1.8 knockout mice fail to exhibit normal visceral inflammatory pain. Gain-of-function mutations in the human Nav1.8 gene cause peripheral neuropathic pain. Based on a series of animal experiments and human genetic evidence, selective inhibition of Nav1.8 has the potential to become a new analgesic therapy that can be used to treat various types of pain, including inflammatory pain, neuralgia, postoperative pain, and cancer pain.

[0010] The main disadvantage of some known Nav's inhibitors is their poor therapeutic window, which may be the result of their lack of isotype selectivity. Since Nav1.8 is mainly limited to neurons that perceive pain, selective Nav1.8 blockers are unlikely to induce adverse reactions common to non-selective Nav's blockers. Therefore, there is still a need to develop new Nav1.8 selective inhibitors in this area, preferably Nav channel inhibitors with better selectivity for Nav1.8, more effectiveness, increased metabolic stability, increased solubility and fewer side effects.

[0011] Chinese patent application CN202310743287.6 discloses the structure of the compound of formula I:

[0012] The compound of formula I can effectively antagonize the activity of Nav1.8 receptors and has broad application prospects in the preparation of drugs for treating Nav1.8-related diseases. Therefore, further research on the compound of formula I and its salt form and crystal form is of great significance for the development of effective therapeutic drugs. Summary of the Invention

[0013] To solve the problems existing in the prior art, the present invention provides a crystalline form of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the structure of the compound of formula I is shown below:

[0014] In some embodiments, the present invention provides a free crystalline form A of the compound of formula I, wherein the free crystalline form A has an X-ray powder diffraction spectrum expressed at a diffraction angle of 2θ±0.2° and has diffraction peaks at 17.79°, 18.13°, 20.52°, 21.63°, and 25.97°; further, the free crystalline form A has an X-ray powder diffraction spectrum expressed at a diffraction angle of 2θ±0.2° and has diffraction peaks at one or more of the following: 12.85°, 16.20°, 24.46°, and 25.00°; further, the free crystalline form A has an X-ray powder diffraction spectrum expressed at a diffraction angle of 2θ±0.2° and has diffraction peaks at 12.85°, 16.20°, 17.79°, 18.13°, 20.52°, 21.63°, and 25.97°. , 27.77°, 28.83°, 29.03°, 30.33°, 30.62°, 34.25°, and 34.64°; further, the X-ray powder diffraction spectrum of the free crystalline form A expressed at a diffraction angle of 2θ±0.2° has diffraction peaks at 5.78°, 11.56°, 12.85°, 16.20°, 17.39°, 17.79°, 18.13°, 20.52°, 21.63°, 24.46°, 25.00°, 25.97°, 27.33°, 27.77°, 28.83°, 29.03°, 30.33°, 30.62°, 34.25°, and 34.64°; further, the X-ray powder diffraction spectrum of the free crystalline form A expressed at a diffraction angle of 2θ±0.2° has diffraction peaks at 5.78°, 11.56°, 12.85°, 16.20°, The X-ray powder diffraction spectrum has diffraction peaks at 5.78°, 10.77°, 11.56°, 12.85°, 16.20°, 17.39°, 17.79°, 18.13°, 20.52°, 21.63°, 22.01°, 24.46°, 25.00°, 25.56°, 25.97°, 27.33°, 27.77°, 28.83°, 29.03°, 30.33°, 30.62°, 31.77°, 33.33°, 34.25°, 34.64°, 35.19°, 36.01°, and 38.66°; furthermore, the X-ray powder diffraction spectrum of the free form A expressed at a diffraction angle of 2θ±0.2° has a diffraction peak at 5 .78°, 8.10°, 9.06°, 10.77°, 11.56°, 12.85°, 16.20°, 17.39°, 17.79°, 18.13°, 18.45°, 18.93°, 19.55°, 20.52°, 21.63°, 22.01°, 23.20°, 23.89°, 24. 46°, 25.00°, 25.56°, 25.97°, 26.39°, 27.33°, 27.77°, 28.83°, 29.03°, 29.60°, 30.33°, 30.62°, 31.14°, 31.77°, 32.23°, 33.33°, 33.77°, 34.25°, 34.There are diffraction peaks at 64°, 35.19°, 36.01°, 38.66°, and 32.86°; further, the free crystalline form A has an XRPD spectrum substantially as shown in Figure 1-1.

[0015] In some embodiments, the free crystalline Form A has one, two, or three of the following characteristics:

[0016] (1) The TGA curve of free form A shows a weight loss of approximately 0.38±1% at 150.0±3°C;

[0017] (2) The DSC curve of the free form A has an endothermic peak starting point at 169.5±3℃;

[0018] (3) The DSC curve of free form A has an endothermic peak at 171.0±3℃.

[0019] In some embodiments, the DSC graph of the free crystalline Form A is shown in Figure 1-2; the TGA graph of the free crystalline Form A is shown in Figure 1-3.

[0020] According to an embodiment of the present invention, the free-state crystalline form A is an anhydrous crystalline form.

[0021] In some embodiments, the present invention provides a free crystalline form B of the compound of formula I, wherein the free crystalline form B has an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ±0.2° at 11.64°, 12.60°, 17.46°, 20.93°, 25.16°, and 26.56°; further, the free crystalline form B has an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ±0.2° at 11.64°, 12.60°, 17.46°, 20.93°, 25.16°, and 26.56°. The X-ray powder diffraction spectrum of the free form B also has diffraction peaks at one or more of the following positions: 5.80°, 29.25°, 28.22°, 28.51°, and 35.32°; further, the X-ray powder diffraction spectrum of the free form B expressed at a diffraction angle of 2θ±0.2° has diffraction peaks at 5.80°, 11.64°, 12.60°, 17.46°, 20.93°, 22.19°, 25.16 The diffraction peaks are at 5.80°, 11.64°, 12.60°, 16.09°, 17.46°, 18.37°, 20.9°, 33.23°, 35.32°, and 38.52°; further, the X-ray powder diffraction spectrum of the free crystalline form B expressed at a diffraction angle of 2θ±0.2° is 5.80°, 11.64°, 12.60°, 16.09°, 17.46°, 18.37°, 20.9°, 33.23°, 35.32°, and 38.52°. There are diffraction peaks at 3°, 22.19°, 23.03°, 23.82°, 25.16°, 26.56°, 28.22°, 28.51°, 29.25°, 29.79°, 32.20°, 33.23°, 34.42°, 35.32°, and 38.52°; further, the free form B has an XRPD spectrum basically as shown in Figure 2-1.

[0022] In some embodiments, the free crystalline Form B has one, two, or three of the following characteristics:

[0023] (1) The TGA curve of the free form B shows a weight loss of approximately 0.23±1% at 150.0±3°C;

[0024] (2) The DSC curve of the free form B has an endothermic peak starting point at 165.8±3℃;

[0025] (3) The DSC curve of free form B has an endothermic peak at 168.47±3℃.

[0026] In some embodiments, the DSC graph of the free crystalline Form B is shown in Figure 2-2; the TGA graph of the free crystalline Form B is shown in Figure 2-3.

[0027] According to an embodiment of the present invention, the free-state crystalline form B is an anhydrous crystalline form.

[0028] On the other hand, the present invention provides a method for preparing the free crystalline form A of the compound of formula I, which includes the following methods:

[0029] Method 1: Place the first sample bottle containing the compound of formula I in an open position into a second sample bottle containing a solvent, seal the second sample bottle, and let it stand at room temperature; the solvent does not cover the mouth of the first sample bottle;

[0030] The solvent is selected from one or more of ethanol, acetone, methyl tert-butyl ether, ethyl acetate, dichloromethane, tetrahydrofuran, acetonitrile, n-heptane, and toluene;

[0031] Method 2: Place the first sample bottle containing the solution of the compound of Formula I in an open position into a second sample bottle containing an anti-solvent, seal the second sample bottle, and let it stand at room temperature; the anti-solvent does not cover the top of the first sample bottle;

[0032] The solvent in the solution of the compound of formula I is selected from one or more of dichloromethane, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, and N,N-dimethylformamide;

[0033] The anti-solvent is selected from one or more of n-heptane, methyl tert-butyl ether, and water;

[0034] Method 3: Add a solvent to the compound of formula I at room temperature, stir magnetically, and collect the solid;

[0035] The solvent is selected from one or more of water, ethanol, isopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, acetone, methyl ethyl ketone, dimethyl sulfoxide, acetonitrile, toluene, N,N-dimethylformamide, and N-methylpyrrolidone;

[0036] Method 4: Add solvent to the compound of formula I at 50°C, stir magnetically, and collect the solid;

[0037] The solvent is selected from one or more of water, ethanol, isopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, acetone, methyl ethyl ketone, dimethyl sulfoxide, acetonitrile, toluene, N,N-dimethylformamide, and N-methylpyrrolidone;

[0038] Method 5: Add the compound of formula I into organic solvent I, dissolve it, filter it, and evaporate it at room temperature:

[0039] Preferably, the organic solvent I is selected from one or more of methanol, ethanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, acetone, methyl ethyl ketone, dichloromethane, and acetonitrile;

[0040] Method 6: Completely dissolve the compound of formula I in a good solvent, filter, and add an antisolvent dropwise to the clear solution until solid precipitates;

[0041] The good solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, dichloromethane, tetrahydrofuran, methyl ethyl ketone, N-methylpyrrolidone, N,N-dimethylacetamide, ethanol, and isopropyl acetate;

[0042] The anti-solvent is selected from one or more of water, toluene, methyl tert-butyl ether, and n-heptane;

[0043] In some embodiments, when the anti-solvent is selected from water, the good solvent is selected from one of dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, N-methylpyrrolidone, and N,N-dimethylacetamide; when the anti-solvent is selected from methyl tert-butyl ether, the good solvent is selected from dichloromethane; when the anti-solvent is selected from n-heptane, the good solvent is selected from methyl ethyl ketone or ethanol.

[0044] Method 7: Dissolve the compound of formula I completely in a good solvent, filter, and add the clear solution to an antisolvent;

[0045] The good solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, dichloromethane, ethyl acetate, 1,4-dioxane, methyl ethyl ketone, and tetrahydrofuran;

[0046] The anti-solvent is selected from one or more of water, n-heptane, methyl tert-butyl ether, and toluene;

[0047] In some embodiments, when the anti-solvent is selected from water, the good solvent is selected from dimethyl sulfoxide or N,N-dimethylformamide; when the anti-solvent is selected from methyl tert-butyl ether, the good solvent is selected from 1,4-dioxane or methyl ethyl ketone; when the anti-solvent is selected from n-heptane, the good solvent is selected from ethyl acetate; when the anti-solvent is selected from toluene, the good solvent is selected from methyl ethyl ketone or tetrahydrofuran.

[0048] Method 8: Add the compound of formula I to organic solvent I at 50°C, dissolve, filter, stir magnetically, and cool to room temperature;

[0049] Preferably, the organic solvent I is selected from one or more of methanol, ethanol, isopropyl acetate, acetonitrile, ethyl acetate, and acetone;

[0050] Method 9: Add the compound of formula I into a mortar or add the compound of formula I and a solvent into a mortar and grind;

[0051] Preferably, the solvent is selected from one or more of water, methyl tert-butyl ether, and n-heptane.

[0052] On the other hand, the present invention provides a method for preparing the free crystalline Form B of the compound of Formula I, which includes the following methods:

[0053] Method 1: Completely dissolve the compound of formula I in a good solvent, filter, and add an antisolvent dropwise to the clear solution until solid precipitates;

[0054] The good solvent is selected from one or two of tetrahydrofuran and N,N-dimethylacetamide, and the anti-solvent is selected from n-heptane.

[0055] The anti-solvent is selected from one or more of water, toluene, methyl tert-butyl ether, and n-heptane.

[0056] Method 2: Completely dissolve the compound of formula I in a good solvent, filter, and add the clarified solution to an antisolvent;

[0057] The good solvent is selected from one or two of dichloromethane and 1,4-dioxane; and the anti-solvent is selected from n-heptane.

[0058] Method 3: Add the compound of formula I to isopropanol at 40-60°C (e.g. 50°C), dissolve, filter, stir, and cool to room temperature.

[0059] Method 4: Completely dissolve the compound of formula I in tetrahydrofuran, filter, and add n-heptane to the clear solution with stirring until solid precipitates, then add free-state Form B seed crystals and stir.

[0060] According to an embodiment of the present invention, the free-state Form B seed crystals can be prepared by one of the methods one, two, three, and four.

[0061] On the other hand, the present invention provides a pharmaceutically acceptable salt of the compound of formula I, wherein the pharmaceutically acceptable salt is selected from the salts formed by the compound of formula I and an acid or base. In some embodiments, the pharmaceutically acceptable salt of the compound of formula I is selected from the salts formed by the compound of formula I and the following acids or bases: hydrochloric acid, sulfuric acid, maleic acid, phosphoric acid, fumaric acid, tartaric acid, citric acid, L-malic acid, succinic acid, p-toluenesulfonic acid, methanesulfonic acid, sodium hydroxide, and arginine.

[0062] When the compound of formula I forms a salt with an acid or a base, the molar ratio of the acid or base to the compound of formula I can be 5:1 to 1:5, for example, 5:1, 4.5:1, 4:1, 3.5:1, 3:1, 2.5:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, and 1:5.

[0063] In some embodiments, the pharmaceutically acceptable salt of the compound of formula I is selected from the maleate salt of the compound of formula I; in some embodiments, in the maleate salt, the molar ratio of the compound of formula I to maleic acid is 1:1.

[0064] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula I is selected from the sodium salt of the compound of Formula I; in some embodiments, in the sodium salt, the molar ratio of the compound of Formula I to sodium is 1:1.

[0065] In another aspect, the present invention provides a crystalline form of a pharmaceutically acceptable salt of the compound of formula I.

[0066] In some embodiments, the present invention provides a maleate salt form A of the compound of formula I, wherein the maleate salt form A has an X-ray powder diffraction spectrum expressed at a diffraction angle of 2θ±0.2° and has diffraction peaks at 8.39°, 13.78°, 16.31°, 17.07°, and 18.44°; further, the maleate salt form A has an X-ray powder diffraction spectrum expressed at a diffraction angle of 2θ±0.2° and has diffraction peaks at 8.39°, 13.78°, 16.31°, 17.07°, 18.44°, 20.96°, 25.62°, and 26.78°; further, the maleate salt form A has an X-ray powder diffraction spectrum expressed at a diffraction angle of 2θ±0.2° and has diffraction peaks at 2θ±0.2°. The maleate salt form A has a diffraction peak at 8.39°, 13.78°, 16.31°, 17.07°, 18.44°, 20.96°, 21.61°, 25.29°, 25.62°, and 26.78°; further, the maleate salt form A has an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ±0.2° at 8.39°, 13.78°, 16.31°, 17.07°, 18.44°, 20.45°, 20.96°, 21.61°, 25.29°, 25.62°, 26.19°, and 26.78°; further, the maleate salt form A has an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ±0.2° at 8.39°, 13.78°, 16.31°, 17.07°, 18.44°, 20.45°, 20.96°, 21.61°, 25.29°, 25.62°, 26.19°, and 26.78°. The X-ray powder diffraction spectrum has diffraction peaks at 8.39°, 13.78°, 16.31°, 17.07°, 18.44°, 19.01°, 20.45°, 20.96°, 21.61°, 22.65°, 23.19°, 24.62°, 25.29°, 25.62°, 26.19°, 26.78°, 27.03°, 27.41°, 28.47°, 28.96°, 30.05°, 31.25°, 31.61°, and 33.91°; further, the maleate salt form A has an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ±0.2° at 8.39°, 10.65°, 13.78°, 16.31°, 17.07°, 18.44°, 19.01°, 20.45°, 20.96°, 21.61°, 22.65°, 23.19°, 24.62°, .31°, 17.07°, 18.44°, 19.01°, 20.45°, 20.96°, 21.61°, 22.65°, 23.19°, 24.62°, 25.29°, 25.62°, 26.19°, 26.78°, 27.03°, 27.41°, 28.47°, 28.96°, 30.05, 30.74°, 31.25°, 31.61°, 32.70°, 33.13°, 33.91°, 34.49°, 35.22°, 36.21°, and 38.48°; further, the maleate salt form A has an XRPD spectrum substantially as shown in Figure 3-1;

[0067] In some embodiments, the maleate salt Form A has one or both of the following characteristics:

[0068] (1) The TGA curve of the maleate salt form A shows a weight loss of 0.5-3% at 120±3°C, preferably 0.5, 1.0, 1.5, 2.0, 2.5, 3.0%, for example 1.41%;

[0069] (2) The maleate salt form A has an endothermic peak at 139.1±3°C.

[0070] In some embodiments, the TGA / DSC diagram of the maleate salt form A is substantially as shown in FIG3-2; 1 The H NMR spectrum is basically as shown in Figure 3-3.

[0071] In some embodiments, the present invention provides a sodium salt crystalline form A of the compound of formula I, wherein the sodium salt crystalline form A has an X-ray powder diffraction spectrum expressed at a diffraction angle of 2θ±0.2° at 16.70°, 17.02°, 21.23°, 22.33°, 24.39°, 25.50°, and 25.89°. Further, the sodium salt crystalline form A has an X-ray powder diffraction spectrum expressed at a diffraction angle of 2θ±0.2° at 16.70°, 17.02°, 17.67°, 18.51°, 21.23°, 22.33°, 24.39°, 25.50°, 25.89°, and 29.73°. Further, the sodium salt crystalline form A has an X-ray powder diffraction spectrum expressed at a diffraction angle of 2θ±0.2° at 16.70°, 17.02°, 17.67°, 18.51°, 21.23°, 22.33°, 24.39°, 25.50°, 25.89°, and 29.73°. The X-ray powder diffraction spectrum of the sodium salt form A has diffraction peaks at 16.70°, 17.02°, 17.67°, 18.51°, 21.23°, 22.33°, 24.39°, 25.50°, 25.89°, 29.73°, and 30.76°; further, the X-ray powder diffraction spectrum of the sodium salt form A expressed at a diffraction angle of 2θ±0.2° has diffraction peaks at 4.85°, 9.70°, 12.13°, 13.55°, 14.20°, 14.55, 1670°, 17.02°, 17.67°, 18.51°, 21.23°, 22.33°, 24.39°, 25.50°, 25.89°, 26.72°, 27.74°, 28. The X-ray powder diffraction spectrum of the sodium salt form A expressed at a diffraction angle of 2θ±0.2° has diffraction peaks at 4.85°, 9.70°, 12.13°, 13.55°, 14.20°, 14.55, 16.70°, 17.02°, 17.67°, 18.51°, 20.27°, 21.23°, 22.33°, 23.35°, 24.39°, 25.50°, 25.89°, 26.72°, 27.74°, 28.44°, 29.73°, 30.76°, 31.43°, 31.88°, 32.46°, and 39.71°; further, The X-ray powder diffraction spectrum of the sodium salt crystal form A expressed at a diffraction angle of 2θ±0.2° is 4.85°, 9.70°, 12.13°, 13.55°, 14.20°, 14.55°, 16.70°, 17.02°, 17.67°, 18.51°, 20.27°, 21.23°, 22.33°, 23.3 5°, 24.39°, 25.50°, 25.89°, 26.72°, 27.74°, 28.44°, 28.87°, 29.73°, 30.76°, 31.43°, 31.88°, 32.46°, 32.98°, 34.06°, 35.13°, 35.68°, 36.33°, 38.There are diffraction peaks at 30° and 39.71°; further, the sodium salt crystal form A has an XRPD spectrum substantially as shown in Figure 4-1.

[0072] In some embodiments, the sodium salt Form A has one or two of the following characteristics:

[0073] (1) The TGA curve of the sodium salt form A shows a weight loss of 1.0-5.0% at 150±3°C, preferably 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0%, for example 2.75%;

[0074] (2) The sodium salt crystal form A has two endothermic peaks at 191.0±3°C and 215.0±3°C.

[0075] In some embodiments, the TGA / DSC diagram of the sodium salt crystal form A is substantially as shown in FIG4-2; 1 The H NMR spectrum is basically as shown in Figure 4-3.

[0076] In another aspect, the present invention provides a method for preparing a pharmaceutically acceptable salt (including a crystalline form of the salt) of the compound of formula I, comprising mixing the compound of formula I with a suitable acid or base to obtain the pharmaceutically acceptable salt.

[0077] In some embodiments, when the pharmaceutically acceptable salt of the compound of Formula I is a maleate or sodium salt, the preparation method comprises the following steps: mixing the compound of Formula I with an equimolar amount of maleic acid or sodium hydroxide, stirring in an organic solvent A, and isolating to obtain a solid. In some embodiments, the stirring time is 1-5 days, for example, 3 days, and the stirring temperature is room temperature; the organic solvent A is selected from one or more of isopropanol, ethyl acetate, and 2-methyltetrahydrofuran. In some embodiments, the compound of Formula I is mixed with maleic acid or sodium hydroxide to obtain a suspension in an organic solvent A, which is then suspended and stirred;

[0078] In some embodiments, when the pharmaceutically acceptable salt of the compound of Formula I is maleate salt Form A, the preparation method comprises the following steps: mixing the compound of Formula I with an equimolar amount of maleic acid to obtain a suspension in an organic solvent A, suspending and stirring the suspension, and isolating the suspension to obtain a solid. In some embodiments, the suspension and stirring time is 1-5 days, for example, 3 days, and the suspension and stirring temperature is room temperature; the organic solvent A is selected from ethyl acetate.

[0079] In some embodiments, when the pharmaceutically acceptable salt of the compound of Formula I is sodium salt Form A, the preparation method comprises the following steps: mixing the compound of Formula I with an equimolar amount of sodium hydroxide, obtaining a suspension in an organic solvent A, suspending and stirring the suspension, and isolating to obtain a solid. In some embodiments, the suspension and stirring time is 1-5 days, for example, 3 days, and the suspension and stirring temperature is room temperature; the organic solvent A is selected from one or more of isopropyl alcohol, ethyl acetate, and 2-methyltetrahydrofuran.

[0080] In another aspect, the present invention provides a pharmaceutical composition comprising one or more of the free crystalline forms of the compound of Formula I as described above (e.g., free crystalline form A, free crystalline form B), and pharmaceutically acceptable salts of the compound of Formula I as described above (including crystalline forms thereof).

[0081] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient or carrier.

[0082] In another aspect, the present invention provides a pharmaceutical composition comprising substance A and a pharmaceutically acceptable carrier, wherein substance A is a free crystalline form of the compound of formula I or a crystalline form of a pharmaceutically acceptable salt of the compound of formula I as described in any one of the above items; preferably, substance A is a free crystalline form A of the compound of formula I, a free crystalline form B of the compound of formula I, a maleate salt crystalline form A, or a sodium salt crystalline form A.

[0083] In another aspect, the present invention provides the use of a free crystalline form of the compound of Formula I (e.g., free crystalline form A, free crystalline form B), a pharmaceutically acceptable salt of the compound of Formula I (including its crystalline form), or the pharmaceutical composition in the preparation of a drug for treating and / or preventing diseases related to voltage-gated sodium ion channels.

[0084] According to an embodiment of the present invention, the voltage-gated sodium ion channel-related disease is a Nav1.8-related disease.

[0085] According to an embodiment of the present invention, the free crystalline form of the compound of Formula I (e.g., free crystalline form A, free crystalline form B), the pharmaceutically acceptable salt of the compound of Formula I (including its crystalline form) or the pharmaceutical composition described in the present invention can provide patients in need with better and more effective clinical treatment drugs or regimens.

[0086] The present invention also provides a method for treating and / or preventing diseases related to Nav1.8, which comprises administering to a patient a therapeutically effective dose of a crystalline form of the compound of Formula I as described above, a pharmaceutically acceptable salt of the compound of Formula I as described above, a crystalline form of the salt as described above, or a pharmaceutical composition as described above; preferably, a pharmaceutical preparation comprising a free crystalline form of the compound of Formula I as described above (e.g., free crystalline form A, free acid crystalline form B), a pharmaceutically acceptable salt of the compound of Formula I (including its crystalline form, such as maleate crystalline form A, sodium salt crystalline form A) or the pharmaceutical composition.

[0087] According to an embodiment of the present invention, the Nav1.8-related diseases include: pain.

[0088] Preferably, the pain includes acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.

[0089] Definitions and Explanations of Terms

[0090] The various terms and phrases used in the present invention have general meanings known to those skilled in the art. Even so, the present invention still hopes to provide a more detailed description and explanation of these terms and phrases herein. If the mentioned terms and phrases are inconsistent with the known meanings, the meanings expressed in the present invention shall prevail.

[0091] Unless otherwise indicated, the numerical ranges described in this specification and claims are equivalent to describing at least each specific integer value therein. For example, two or more represent 2, 3, 4, 5, 6, 7, 8, 9, 10 or more. When certain numerical ranges are defined or understood as "numbers", they should be understood as describing the two endpoints of the range, each integer within the range, and each decimal within the range. For example, "a number from 0 to 10" should be understood as describing not only each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also at least the sum of each of these integers with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9, respectively.

[0092] When the word "about" a numerical value is recorded in this specification and claims, it includes the numerical value itself, as well as numerical values ​​within a range around the numerical value that is acceptable in the art, such as numerical values ​​within a range of ±15% of the numerical value, numerical values ​​within a range of ±10% of the numerical value, numerical values ​​within a range of ±5% of the numerical value, etc. For example, about 10 represents: numerical values ​​within the range of 10±1.5, that is, values ​​within the range of 8.5 to 11.5; numerical values ​​within the range of 10±1.0, that is, values ​​within the range of 9.0 to 11.0; and numerical values ​​within the range of 10±0.5, that is, values ​​within the range of 9.5 to 10.5.

[0093] The "2θ or 2θ angle" mentioned in the present disclosure refers to the diffraction angle, θ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2θ is ±0.20 (preferably ±0.10) (including the case where the numbers exceeding 2 decimal places are rounded off).

[0094] The salts and polymorphs of the compound of formula I of the present invention may be used in combination with other active ingredients as long as it does not cause other adverse effects such as allergic reactions.

[0095] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0096] The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0097] The term "therapeutically effective dose" refers to the amount of an active compound or drug that will elicit the biological or medical response that a researcher, veterinarian, physician, or other clinician is seeking in a tissue, system, animal, individual, or human, and includes one or more of the following: (1) preventing disease, e.g., preventing a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but has not yet experienced or developed the pathology or symptoms of the disease; (2) inhibiting disease, e.g., inhibiting the disease, disorder, or condition (i.e., preventing further development of the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition; (3) alleviating disease, e.g., alleviating the disease, disorder, or condition (i.e., reversing the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition.

[0098] The term "pharmaceutically acceptable" means that the formulation ingredients or active ingredients have no undue adverse effect on health and well-being for the general purpose of treatment.

[0099] The term "pharmaceutically acceptable excipient or carrier" refers to one or more compatible solid or liquid fillers or gels suitable for human use, which must be of sufficient purity and sufficiently low toxicity. "Compatibility" as used herein refers to the ability of the components of the composition to blend with the compound of the invention, and with each other, without significantly reducing the compound's efficacy. Some examples of pharmacologically acceptable excipients or carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers, wetting agents (e.g., sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc. The pharmaceutical composition can be specifically formulated for oral administration, parenteral injection, or rectal administration in solid or liquid form. The pharmaceutical composition can be formulated into a variety of dosage forms for easy administration, for example, oral preparations (such as tablets, capsules, solutions or suspensions), injectable preparations (such as injectable solutions or suspensions, or injectable dry powders that can be used immediately after adding a pharmaceutical solvent before injection).

[0100] When used for the above-mentioned therapeutic and / or prophylactic purposes, the total daily dosage of the salts, polymorphs, and pharmaceutical compositions of the compound of formula I of the present invention must be determined by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dosage level must be determined based on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound being used; the specific composition being used; the patient's age, weight, general health, sex, and diet; the administration time, route of administration, and excretion rate of the specific compound being used; the duration of treatment; drugs used in combination with or concurrently with the specific compound being used; and similar factors well known in the medical field. For example, it is common practice in the art to start the dose of the compound at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

[0101] The term "free state" refers to the form of a compound that has not been further salted, such as the compound of Formula I itself. Those skilled in the art will appreciate that when a "free state" forms a salt with an acid, the "free state" can be understood as the "free base" of the corresponding salt formed with the acid. That is, "free base" and "free state" have equivalent meanings, and similarly, "free acid" can also have equivalent meanings to "free state" (when the free state forms a salt with a base). Beneficial effects

[0102] The present invention provides salts of the compound of formula I and crystal forms of the compound of formula I and its salts, which have good pharmaceutical properties. BRIEF DESCRIPTION OF THE DRAWINGS

[0103] Figure 1-1 is an XRPD pattern of the free form A of the compound of formula I;

[0104] Figure 1-2 is a DSC diagram of the free form A of the compound of formula I;

[0105] Figure 1-3 is a TGA diagram of the free form A of the compound of formula I;

[0106] Figure 2-1 is an XRPD pattern of the free form B of the compound of formula I;

[0107] Figure 2-2 is a DSC diagram of the free form B of the compound of formula I;

[0108] Figure 2-3 is a TGA diagram of the free form B of the compound of formula I;

[0109] Figure 3-1 XRPD pattern of maleate salt form A

[0110] Figure 3-2 TGA / DSC diagram of maleate crystal form A

[0111] Figure 3-3 Maleate Crystalline Form A 1 H NMR spectra

[0112] Figure 4-1 XRPD pattern of sodium salt form A

[0113] Figure 4-2 TGA / DSC diagram of sodium salt form A

[0114] Figure 4-3 Sodium salt crystal form A 1 H NMR spectra

[0115] Figure 5 Dynamic solubility curve at 37℃

[0116] Figure 6-1 XRPD overlay of solubility samples of free form A in H2O

[0117] Figure 6-2 XRPD overlay of solubility samples of free form A in SGF

[0118] Figure 6-3 XRPD overlay of solubility samples of free form A in FaSSIF

[0119] Figure 6 XRPD overlay of solubility samples of free form A in FeSSIF

[0120] Figure 7-1 DVS diagram of free crystal form A

[0121] Figure 7-2 XRPD overlay of free form A before and after DVS test

[0122] Figure 7-3 DVS diagram of maleate crystal form A

[0123] Figure 7-4 XRPD overlay of maleate crystal form A before and after DVS test

[0124] Figure 8-1 XRPD overlay of the stability evaluation sample of free form A

[0125] Figure 8-2 XRPD overlay of maleate salt form A stability evaluation sample DETAILED DESCRIPTION

[0126] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0127] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0128] The instruments and detection methods used in the present invention are as follows:

[0129] 1. X-ray powder diffraction (XRPD)

[0130] The XRPD patterns were collected on X-ray powder diffraction analyzers manufactured by Bruker and PANalytacal, and the scanning parameters are shown in Tables A-1a and A-1b below, respectively.

[0131] Table A-1a XRPD test parameters

[0132] Table A-1b XRPD test parameters

[0133] 2. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)

[0134] 2.1 TGA and DSC patterns were acquired on a TA Q500 thermogravimetric analyzer and a TA Q2000 differential scanning calorimeter, respectively. The test parameters are listed in Table A-2a below.

[0135] Table A-2a DSC and TGA test parameters

[0136] 2.2 TGA and DSC patterns were collected on a TA 5500 thermogravimetric analyzer and a TA 2500 differential scanning calorimeter, respectively. The test parameters are listed in Table A-2b below.

[0137] Table A-2b TGA and DSC test parameters

[0138] 3. Dynamic Water Sorption (DVS)

[0139] Dynamic moisture sorption (DVS) curves were collected on a DVS IntrInsic from SMS (Surface Measurement Systems). Relative humidity at 25°C was calibrated using the deliquescent temperatures of LiCl, Mg(NO₃)₂, and KCl. DVS test parameters are listed in Table A-3.

[0140] Table A-3 DVS test parameters

[0141] 4. Liquid NMR ( 1 H NMR)

[0142] Liquid-state NMR spectra were collected on a Bruker 400M NMR spectrometer using DMSO-d6 as the solvent.

[0143] 5. Ultra-Performance Liquid Chromatography and Ion Chromatography (UPLC / IC)

[0144] In the experiment, the purity test, dynamic solubility and stability test were performed by Waters H-Class ultra-high performance liquid chromatograph, and the ion salt formation molar ratio test was performed by ion chromatography. The analysis conditions are shown in Table A-4 and Table A-5.

[0145] Table A-4 HPLC test conditions

[0146] Table A-5 Ion chromatography test conditions

[0147] 6. Preparation of Biosolvent

[0148] Preparation of simulated gastric fluid (SGF)

[0149] Weigh 100 mg of NaCl and 50 mg of Trinaton X-100 into a 50-mL volumetric flask and dissolve in purified water. Add 816 μL of 1 M hydrochloric acid and adjust the pH to 1.8 with 1 M hydrochloric acid or 1 M NaOH solution. Bring to volume with purified water.

[0150] Preparation of simulated fasting intestinal fluid (FaSSIF)

[0151] Weigh 340 mg of anhydrous NaH2PO4 and 620 mg of NaCl into a 100-mL volumetric flask. Dissolve with purified water, then add 55.44 μL of 50% NaOH solution. Adjust the pH to 6.5 with 1 M hydrochloric acid or 1 M NaOH solution. Bring to volume with purified water. Next, weigh 110 mg of SIF powder into a 50-mL volumetric flask and dissolve with the above solution to bring to volume.

[0152] Preparation of simulated fed state intestinal fluid (FeSSIF)

[0153] Add 0.82 mL of glacial acetic acid and 1.18 g of NaCl to a 100 mL volumetric flask and dissolve in purified water. Add 528 μL of 50% NaOH solution. Adjust the pH to 5.0 with 1 M hydrochloric acid or 1 M NaOH solution, and bring to volume with purified water. Then, weigh 560 mg of SIF powder into a 50 mL volumetric flask and dissolve in the above solution to bring to volume.

[0154] VII. The reagents used in the present invention are shown in Table A-6 below.

[0155] Table A-6 Comparison table of Chinese and English names of solvents used in the experiment

[0156] Example 1: Preparation of compound of formula I

[0157] 5-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyrimidine 1-oxide

[0158] The synthetic route of the compound of formula I is as follows:

[0159] Step 1: Synthesis of 4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzoic acid

[0160] At room temperature, 4,5-dichloro-2-fluorobenzoic acid (1.0 g, 4.78 mmol), cesium carbonate (4.68 g, 14.35 mmol) and 4-(trifluoromethoxy)phenol (8 mL) were added to a 20 mL microwave tube, sealed, and reacted at 150°C for 1 hour. After cooling to room temperature, water (10 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (20 mL × 3). The organic phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and dried. The crude product was purified by column chromatography (SiO2; PE:EA = 10:1) to obtain 4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzoic acid (3) (1.0 g; yield 56.9%).

[0161] Step 2: Synthesis of 4,5-dichloro-N-(pyrimidin-5-yl)-2-(4-(trifluoromethoxy)phenoxy)benzamide

[0162] 4,5-Dichloro-2-(4-(trifluoromethoxy)phenoxy)benzoic acid (1.0 g, 2.72 mmol), 5-aminopyrimidine (310.88 mg, 3.27 mmol), and HATU (2.07 g, 5.45 mmol) were added to DMF (10 mL), followed by DIPEA (1.06 g, 8.17 mmol). After complete addition, the reaction mixture was allowed to react at room temperature for 16 hours. LC-MS indicated the reaction was complete. NH4Cl solution (15 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (20 mL × 3). The organic phases were combined and washed with water (20 mL × 2) and saturated brine (10 mL), respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried. The crude product was separated by normal phase silica gel column chromatography (SiO2; EtOAc / PE = 1:1) to give 4,5-dichloro-N-(pyrimidin-5-yl)-2-(4-(trifluoromethoxy)phenoxy)benzamide (1.10 g; yield 90.9%).

[0163] Step 3: 5-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyrimidine 1-oxide (compound of formula I)

[0164] At room temperature, 4,5-dichloro-N-(pyrimidin-5-yl)-2-(4-(trifluoromethoxy)phenoxy)benzamide (1.0 g, 2.09 mmol) was weighed into DCM (10 mL), and m-CPBA (849.89 mg, 4.19 mmol; 85%) was slowly added. The reaction mixture was allowed to react at room temperature for 16 hours. After completion, the reaction mixture was diluted with dichloromethane (20 mL) and washed with saturated aqueous sodium bicarbonate (15 mL x 2). The organic phase was dried over Na2SO4, concentrated, and subjected to preparative high-pressure liquid chromatography (ammonia-acetonitrile) to afford 5-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyrimidine 1-oxide (86.6 mg, 8.38% yield).

[0165] 1 H NMR (400MHz, DMSO): δ8.85-8.84(m,2H),8.43-8.42(m,1H),8.04(s,1H),7.45(s,1H),7.40-7.37(m,2H),7.20-7.18(m,2H).

[0166] LC-MS, M / Z (ESI): 458.1 [MH] - .

[0167] Example 2: Preparation of crystal form by gas-solid diffusion method

[0168] Approximately 40 mg of the compound of Formula I was weighed and placed into 2 mL transparent sample vials. Separately, 3 mL of the solvent system listed in Table 1-1 was added to separate 20 mL vials. The 2 mL transparent sample vials were then placed into the 20 mL sample vials. The 20 mL sample vials were sealed and allowed to stand at room temperature. Solid samples were then filtered to obtain solid samples. After vacuum drying at room temperature, the samples were subjected to XRPD analysis. The results showed that free-state Form A was obtained in all the solvent systems listed in Table 1-1.

[0169] Table 1-1: Crystal form screening results by gas-solid diffusion method

[0170] Example 3: Preparation of crystal form by gas-liquid diffusion method

[0171] Approximately 40 mg of the compound of Formula I was weighed and placed in 2 mL transparent sample bottles. A small amount of the good solvent listed in Table 2 was added to each 2 mL sample bottle at room temperature, and the sample was shaken to fully dissolve. The resulting solution was filtered with a 0.22 μm filter membrane into another 2 mL transparent sample bottle. Another 20 mL sample bottle was taken and 4 mL of the corresponding anti-solvent listed in Table 2 was added thereto. The 2 mL transparent sample bottle containing the filtered clear solution was placed open in the 20 mL sample bottle. The 20 mL sample bottle was sealed and allowed to stand at room temperature to precipitate solids. After vacuum drying at room temperature, the sample was subjected to XRPD analysis. The results showed that free crystalline Form A was obtained in all solvent systems listed in Tables 1-2. When DMSO was the good solvent and H2O was the anti-solvent, a mixture of free crystalline Forms A and B was obtained.

[0172] Table 1-2: Crystal form screening results by gas-liquid diffusion method

[0173] Example 4: Preparation of crystal form by room temperature suspension method

[0174] Weigh approximately 50 mg of the compound of formula I and place them in 2 mL transparent sample bottles. Add 0.1-0.5 mL of the solvent in Table 3 to each sample bottle at room temperature, stir magnetically for about two weeks, and filter to obtain a solid sample. After vacuum drying at room temperature, the solid sample was subjected to XRPD testing. The results showed that free crystalline Form A was obtained under the solvent systems in Table 1-3. The free crystalline Form A obtained in the solvent EtOH was selected for XRPD, TGA, and DSC testing. Its XRPD spectrum is shown in Figure 1-1, and the XRPD diffraction peak data are shown in Table 1-4; the DSC graph is shown in Figure 1-2, and the TGA graph is shown in Figure 1-3.

[0175] Table 1-3: Room temperature suspension method crystal screening results

[0176] Table 1-4: XRPD diffraction peak data of free form A

[0177] Example 5: Preparation of crystal form by 50°C suspension method

[0178] Approximately 50 mg of the compound of Formula I was weighed into a 2 mL transparent sample vial. 0.1-0.5 mL of each solvent listed in Tables 1-5 was added to the vial at 50°C. The mixture was magnetically stirred for approximately one week and filtered to obtain a solid sample. After vacuum drying at room temperature, the sample was subjected to XRPD analysis. The results showed that free-state Form A was obtained in all solvent systems listed in Tables 1-5.

[0179] Table 1-5: Screening results of 50℃ suspension crystals

[0180] Example 6: Preparation of crystal form by slow evaporation method

[0181] Approximately 40 mg of the compound of Formula I was weighed into 2 mL transparent sample vials. 2-7 mL of the solvent listed in Tables 1-6 were added to the sample vials. The resulting solution was filtered through a 0.22 μm filter membrane. The clarified solution was allowed to slowly evaporate at room temperature to obtain a solid. After vacuum drying at room temperature, the sample was subjected to XRPD analysis. The results showed that free crystalline Form A was obtained in all solvent systems listed in Tables 1-6. When the solvent was 1,4-dioxane, a mixture of free crystalline Form B and a small amount of free crystalline Form A was obtained.

[0182] Table 1-6: Slow evaporation method crystal form screening results

[0183] Example 7: Preparation of Crystalline Forms by Antisolvent Method

[0184] Approximately 40 mg of the compound of Formula I was weighed into a 2 mL transparent sample bottle, dissolved in a small amount of a good solvent at room temperature, and the resulting solution was filtered through a 0.22 μm filter membrane. 2-4 times the amount of antisolvent was then slowly added to the filtered clear solution until solid precipitated, and a solid sample was obtained by filtration. After vacuum drying at room temperature, the sample was subjected to XRPD analysis. The results showed that free crystalline Form A and free crystalline Form B were obtained under the solvent systems listed in Tables 1-7.

[0185] Table 1-7: Anti-solvent method crystal screening results

[0186] Example 8: Preparation of Crystalline Forms by Anti-Anti-Solvent Method

[0187] Approximately 40 mg of the compound of formula I was weighed into a 2 mL transparent sample bottle, and the sample was dissolved in a small amount of a good solvent at room temperature. The resulting solution was filtered with a 0.22 μm filter membrane. The filtered clear solution was then quickly added to 2-4 times the anti-solvent to precipitate the solid, which was filtered to obtain a solid sample. After vacuum drying at room temperature, the sample was subjected to XRPD testing. The results showed that under the solvent system of Table 1-8, free crystalline form A and free crystalline form B were obtained. When the good solvent was 1,4-dioxane and the anti-solvent was H2O, a mixture of free crystalline form B and a small amount of free crystalline form A was obtained.

[0188] Table 1-8: Anti-antisolvent method crystal screening results

[0189] Example 9: Preparation of crystal form by cooling method

[0190] Approximately 40 mg of the compound of Formula I was weighed into a 2 mL transparent sample vial. The sample was dissolved in a small amount of solvent at 50°C, and the resulting solution was filtered through a 0.22 μm filter membrane. The filtered clear solution was allowed to slowly cool at room temperature under magnetic stirring to precipitate a solid. The solid sample was filtered and dried under vacuum at room temperature. The sample was then subjected to XRPD analysis. The results showed that free crystalline Form A and free crystalline Form B were obtained in the solvent systems listed in Tables 1-9.

[0191] Table 1-9: Cooling method crystal screening results

[0192] Example 10: Preparation of crystal form by grinding method

[0193] Approximately 40 mg of the compound of Formula I was weighed into a mortar and ground for approximately 10 minutes under various conditions. The ground solids were dried under vacuum at room temperature, and then XRPD analysis was performed on the samples. The results showed that the free-state Form A, containing a large amount of amorphous form, was obtained under the solvent systems listed in Tables 1-10.

[0194] Table 1-10: Crystal form screening results by grinding method

[0195] Example 11: Preparation of Free Form B

[0196] The preparation process of free crystal form B is as follows:

[0197] Weigh 500 mg of the compound of Formula I into a round-bottom flask. Add 6.25 mL of THF to the round-bottom flask at room temperature. Dissolve the sample by sonication. Filter the resulting solution through a 0.22 μm filter membrane and transfer it to another 100 mL round-bottom flask. Slowly add 18.75 mL of heptane to the filtered, clarified solution under magnetic stirring. A white solid precipitates. Approximately 5 mg of seed crystals of free-state Form B (obtained by the THF / heptane antisolvent method in Example 7) are then added, and stirring is continued. After stirring at room temperature for approximately three hours, a white solid is obtained by filtration. After vacuum drying at room temperature, XRPD, TGA, and DSC analysis are performed. The XRPD pattern of free-state Form B is shown in Figure 2-1, and the XRPD diffraction peak data are shown in Table 1-12. The DSC pattern is shown in Figure 2-2, and the TGA pattern is shown in Figure 2-3.

[0198] Table 1-11: Characterization of free form B

[0199] Table 1-12: XRPD diffraction peak data of free form B of Example 11

[0200] Example 12 Salt type screening

[0201] Starting with the free form A sample, 13 ligands (acid-base feed ratio of 1:1) and 3 solvents were selected to set up a total of 39 salt type screening tests. The specific steps of the screening test are as follows: weigh about 20 mg of the free form A sample and an equimolar amount of the corresponding ligand into an HPLC vial, add 0.5 mL of solvent and mix to obtain a suspension, and the liquid acid is first diluted with the corresponding solvent and then mixed with the starting sample. After suspension and stirring at room temperature for about 3 days, the solid is separated by centrifugation and dried in vacuo at 50°C. The XRPD characterization results of the obtained solid show (Table 2-1) that a total of 2 salt type crystal samples were obtained in the salt type screening test, namely maleate crystal form A and sodium salt crystal form A. The salt samples obtained by screening were characterized by TGA / DSC, and the results were analyzed by XRPD. 1 The molar ratio of the salt was determined by H NMR and HPLC / IC, and the salt characterization results are summarized in Table 2-2.

[0202] Table 2-1 Summary of salt type screening test results *: The molar ratio of ligand to free state is 1:1; # : The sample was observed to turn orange-red. a : The sample was stirred at room temperature and clarified, then stirred at 5°C; b The sample was stirred at 5°C and clarified, and then 1.0 mL of n-heptane was added to induce crystallization; c : After adding n-heptane to induce crystallization, the sample formed a gel and then cycled between 50°C and 5°C;d : After adding n-heptane to induce crystallization, the sample was clarified and then stirred at 5℃; e : The sample remained clear after stirring at 5℃ and then evaporated at room temperature.

[0203] Table 2-2 Summary of the characterization results of the salt types obtained by screening # :Depend on 1 Calculated by H NMR or HPLC / IC; ND: not detected.

[0204] 12.1 Maleate Salt Form A

[0205] Form A maleate salt was obtained by slurrying a sample of free Form A and an equimolar amount of maleic acid in EtOAc at room temperature for three days, separating the solid sample by centrifugation, and drying it in vacuo at 50°C. XRPD and TGA / DSC results of the Form A maleate salt are shown in Figures 3-1 and 3-2, respectively. TGA results show a 1.41% weight loss upon heating the sample to 120°C, while DSC results reveal an endothermic signal observed at 139.1°C (onset temperature). 1 The H NMR results are shown in Figure 3-3. The molar ratio of maleic acid to compound of Formula I in the sample was 1:1, and no residual EtOAc solvent was found. The XRPD diffraction peak data for maleate salt Form A are shown in Table 2-3.

[0206] Table 2-3 XRPD diffraction peak data of maleate salt form A

[0207] 12.2 Preparation of Sodium Salt Form A

[0208] Sodium salt Form A was obtained by slurrying a free Form A sample with an equimolar amount of sodium hydroxide in 2-MeTHF at room temperature for three days, separating the solid sample by centrifugation, and drying it in vacuo at 50°C. XRPD and TGA / DSC results of the sodium salt Form A sample are shown in Figures 4-1 and 4-2, respectively. TGA results show a 2.75% weight loss when heated to 150°C, while DSC results reveal two endothermic peaks at 191.0°C and 215.0°C (peak temperatures). 1 The H NMR results are shown in Figure 4-3. No 2-MeTHF solvent residue was found in the sample. The HPLC / IC results showed that the Na + The molar ratio with the compound of formula I is 1:1. The XRPD diffraction peak data of sodium salt form A are shown in Table 2-4 below.

[0209] Table 2-4 XRPD diffraction peak data of sodium salt form A

[0210] Example 13 Evaluation Test

[0211] 13.1 Dynamic Solubility

[0212] Solids were mixed by rotation at 37°C at a solid feed concentration of 10 mg / mL (in free form), and the solubility of each sample in H2O, SGF, FaSSIF, and FeSSIF was measured at different time points (1, 2, 4, and 24 hours). Samples were taken at each time point, centrifuged (10,000 rpm), and filtered (0.45 μm PTFE). The HPLC concentration and pH value of the filtrate were measured, and the solid sample after centrifugation was tested by XRPD. The solubility test results are summarized in Tables 2-5, and the solubility curves are shown in Figure 5. The XRPD results show that the free form A crystalline form remains unchanged after the dynamic solubility test (Figures 6-1 to 6-4).

[0213] Table 2-5 Summary of 37℃ dynamic solubility test results S: solubility (mg / mL).

[0214] 13.2. Hygroscopicity

[0215] The hygroscopicity of free Form A and maleate Form A was evaluated using a dynamic moisture sorption instrument (DVS). The percentage change in mass of the samples was recorded as the humidity varied (0% RH-95% RH) at a constant temperature of 25°C. The DVS test results and the XRPD results of the samples before and after the DVS test are shown in Figures 7-1 to 7-4. The results showed that the moisture adsorption of free Form A and maleate Form A at 25°C / 80% RH was 0.1698% and 0.224%, respectively. The crystal forms of all samples remained unchanged after the DVS test, and in particular, the free Form A had almost no hygroscopicity.

[0216] 13.3 Solid-state stability

[0217] The free form Form A and the maleate salt Form A were stored at 80°C / closed for one day, and at 25°C / 60% RH and 40°C / 75% RH, respectively, for one week. The physical and chemical stability of the samples was tested by XRPD and HPLC. Purity data is listed in Table 2-6, and the XRPD results are shown in Figures 8-1 and 8-2. The results showed that no significant change in purity was observed for all samples, and the crystal form remained unchanged.

[0218] Table 2-6 Summary of solid-state stability evaluation

[0219] Test Example 1: Detection of the inhibitory activity of compounds on Nav1.8 ion channels

[0220] All reagents, except NaOH and KOH for acid-base titration, were purchased from Sigma (St. Louis, MO). Final concentrations of test compounds were prepared on the day of the experiment and dissolved in extracellular fluid. The extracellular fluid (mM) consisted of: NaCl, 137 mM; KCl, 4 mM; CaCl₂, 1.8 mM; MgCl₂, 1 mM; HEPES, 10 mM; and glucose, 10 mM; pH 7.4 (NaOH titration). All test and control compound solutions contained 1 μM TTX. The intracellular fluid (mM) consisted of: aspartic acid, 140 mM; magnesium chloride, 2 mM; ethylene glycol tetraacetic acid (EGTA), 11 mM; and N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), 10 mM. The pH was adjusted to 7.4 with cesium hydroxide.

[0221] The test compound was dissolved in dimethyl sulfoxide (DMSO) at a concentration of 9 mM. On the day of the test, it was dissolved in the extracellular fluid to the required concentration. Electrophysiological experimental steps:

[0222] Transfer the cells to a perfusion tank and perfuse with extracellular solution. Thaw the intracellular solution on the day of the experiment. Electrodes were pulled using PC-10 (Narishige, Japan). Whole-cell patch clamp recordings were performed, with noise filtered at one-fifth the sampling frequency. Fill the electrode with intracellular solution to a quarter of the length of the electrode tube and install the electrode on the probe. Set the desired protocol, adjust the interface to Membrane test, and the Stage to Bath. Apply positive pressure to the electrode, touch the electrode tip to the cell, adjust the three-way valve of the aspirator to the three-way position, and then apply negative pressure to the electrode to form a high-resistance seal between the electrode and the cell. Adjust the Stage to Patch, control the leak to -200pA, and continue to apply negative pressure to rupture the cell membrane, establishing a current path. Open the aspirator and extracellular solution valves to allow perfusion, observe the cell current, and begin drug addition after the cell current stabilizes (at least three sweeps of overlapping current curves). Add drug from low to high concentrations, with each dose lasting at least 2 minutes. Wait until the current stabilizes before changing concentrations.

[0223] The test article is administered using a gravity-fed perfusion system. During the initial recording period, the peak current amplitude is observed for at least 1 minute until it stabilizes. During this period, the CV% of all peak current amplitudes should be less than 10% to exclude fluctuations in the initial current. The average of the peak current amplitudes recorded during the last 10 recordings during the initial recording period is used as the peak current of the negative control. After the initial current stabilizes, the test article is administered starting at a low concentration until the peak currents of the 10 recordings stabilize again or, after 5 minutes of continuous administration, the peak current remains unchanged after administration. "Stable" or "unchanged" is defined as follows: 1) if the absolute average of the peak current for 10 consecutive scans exceeds 200pA with a CV value of less than 10%, or 2) if the average of the peak current for 10 consecutive scans is between 200pA and 50pA with a CV value of less than 30%. The next higher concentration is then administered.

[0224] The average peak current of the last 10 scans for each concentration was used as the peak current for that concentration and was used for data analysis. If steady state was not achieved within 5 minutes, the average peak current of the last 10 scans at that time was used as the peak current for that concentration and was used for data analysis. The cell was discarded and not used for testing at higher concentrations. At least two cells were tested for each compound concentration.

[0225] Voltage pulse program:

[0226] The cell is clamped at –80 mV and then depolarized to 10 mV with a 10-ms square wave to elicit a NaV1.8 current. This procedure is repeated every 5 seconds. The maximum current evoked by the square wave is measured and, after stabilization, the test compound is perfused. Once the response stabilizes, the magnitude of the blockade is calculated.

[0227] Data processing and fitting

[0228] Data acquisition and analysis will be performed using pCLAMP 10 (Molecular Devices, Union City, CA). Current stability refers to the ability of the current to vary within a limited range over time. The inhibitory activity (IC) of the drug against the Nav1.8 channel is calculated by plotting the dose-response relationship between the drug's concentration series and the stable current values ​​generated by its action on HEK293 / Nav1.8 cells. 50 ).

[0229] Table B-1: Inhibitory activity of compounds on Nav1.8 ion channels

[0230] The test results show that the compound of the present invention has strong inhibitory activity on Nav1.8 ion channel.

[0231] Test Example 2: Pharmacokinetics test in mice

[0232] For a pharmacokinetic study in mice, three male ICR mice were fasted overnight and administered 10 mg / kg orally by gavage. Blood was collected before dosing and at 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours after dosing. Blood samples were centrifuged at 8000 rpm for 6 minutes at 4°C, and plasma was collected and stored at -20°C. Plasma was collected at each time point and mixed with 3-5 times the volume of acetonitrile containing the internal standard. The mixture was vortexed for 1 minute and centrifuged at 13000 rpm for 10 minutes at 4°C. The supernatant was then mixed with 3 times the volume of water, and an appropriate amount of the mixture was analyzed by LC-MS / MS. Key pharmacokinetic parameters were analyzed using a non-compartmental model using WinNonlin 7.0 software.

[0233] Table B-2: Pharmacokinetic test results of the compounds in mice

[0234] The test results show that the compound of the present invention has good pharmacokinetic characteristics.

[0235] Test Example 3: Rat Spinal Nerve Ligation Neuropathic Pain Model

[0236] Male SD rats weighing 180-220 g were anesthetized and placed in a prone position on the operating table. An opening was made along the spine near the hip bone of the animal to separate the fascia and muscles. The L5 transverse process was carefully bitten off with forceps, the L5 nerve was separated with a glass needle, and the L5 nerve was ligated with a 5-0 ligature. The muscles and skin were sutured and disinfected with iodine. 14 days after modeling, the animals were divided into different groups, with 10 rats in each group. Different compounds were orally administered, and the mechanical pain threshold of the animals was tested with Von-Frey fibers at different time points after administration. For specific dosage and detection time, please see Table B-3 below.

[0237] Mechanical pain threshold test method: The test animal is continuously stimulated with Von-Frey fiber to bend the fiber, and the animal's paw withdrawal reaction is observed. The test animals are stimulated one by one in the order of fiber weight from small to large, and each fiber weight is stimulated continuously for 5 times. If a positive reaction occurs less than 3 times, the above operation is repeated with a larger fiber. When 3 or more positive reactions occur for the first time, the fiber is the pain threshold of the animal (each animal is tested 3 times and the average value is taken). Fiber weight: 0.6, 1.0, 1.4, 2.0, 4.0, 6.0, 8.0, 10.0, 15.0; the cut-off value is 15.0g.

[0238] Table B-3: Effects of compounds on pain threshold in rats with spinal nerve ligation One-way ANOVA, ***P<0.001, **P<0.01, *P<0.05 NA: No test was scheduled at this time point

[0239] The test results show that the compound of the present invention can significantly improve the reduction of the mechanical pain threshold of animals caused by spinal nerve ligation modeling in rats and has excellent analgesic effect.

[0240] Test Example 4: Rat Incisional Pain Model

[0241] Male SD rats weighing 200-250g were anesthetized and fixed in a prone position. The soles of their hind limbs were flattened upwards, the toes were fixed with surgical tape, and then disinfected. A longitudinal incision of about 1cm was made by cutting the skin fascia with a scalpel at 0.5cm from the heel of the animal to the toe tip. After lifting the flexor digitorum brevis with surgical curved forceps, a longitudinal incision was made on the belly of the muscle with a scalpel without completely cutting the muscle. The skin was sutured and disinfected. On the second day of modeling, the animals were divided into different groups, with 8 rats in each group. Different compounds were orally administered, and the mechanical pain threshold of the animals was tested with Von-Frey fibers at different time points after administration. For details of the specific grouping dosage and detection time, please see Table B-4 below.

[0242] Mechanical pain threshold test method: The test animal is continuously stimulated with Von-Frey fiber to bend the fiber, and the animal's paw withdrawal reaction is observed. The test animals are stimulated one by one in the order of fiber weight from small to large, and each fiber weight is stimulated continuously for 5 times. If a positive reaction occurs less than 3 times, the above operation is repeated with a larger fiber. When 3 or more positive reactions occur for the first time, the fiber is the pain threshold of the animal (each animal is tested 3 times and the average value is taken). Fiber weight: 0.6, 1.0, 1.4, 2.0, 4.0, 6.0, 8.0, 10.0, 15.0; the cut-off value is 15.0g.

[0243] Table B-4: Effects of compounds on pain threshold in rats with incisional pain model One-way ANOVA, vs Vehicle group, ***P<0.001

[0244] The test results show that the compound of the present invention can significantly improve the reduction of the mechanical pain threshold of animals caused by the incisional pain model in rats and has excellent analgesic effect.

Claims

1. A crystalline form of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein: The structure of the compound of formula I is shown below:

2. The crystal form according to claim 1, wherein The crystal form is the free crystal form A of the compound of formula I, and the free crystal form A has diffraction peaks at 17.79°, 18.13°, 20.52°, 21.63°, and 25.97° in an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ±0.2°; Preferably, the X-ray powder diffraction spectrum of the free crystalline form A expressed at a diffraction angle of 2θ±0.2° also has diffraction peaks at one or more of the following locations: 12.85°, 16.20°, 24.46°, 25.00°; Preferably, the X-ray powder diffraction spectrum of the free crystalline form A represented by a diffraction angle of 2θ±0.2° has diffraction peaks at 12.85°, 16.20°, 17.79°, 18.13°, 20.52°, 21.63°, 24.46°, 25.00°, and 25.97°; Preferably, the free crystalline form A has an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ±0.2° at 5.78°, 11.56°, 12.85°, 16.20°, 17.39°, 17.79°, 18.13°, 20.52°, 21.63°, 24.46°, 25.00°, 25.97°, 27.33°, 27.77°, 28.83°, 29.03°, 30.33°, 30.62°, 34.25°, and 34.64°; Preferably, the free crystalline form A has an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ±0.2° at 5.78°, 10.77°, 11.56°, 12.85°, 16.20°, 17.39°, 17.79°, 18.13°, 20.52°, 21.63°, 22.01°, 24.46°, 25.00°, 25.56°, 25.97°, 27.33°, 27.77°, 28.83°, 29.03°, 30.33°, 30.62°, 31.77°, 33.33°, 34.25°, 34.64°, 35.19°, 36.01°, and 38.66°; Preferably, the X-ray powder diffraction spectrum of the free crystalline form A represented by a diffraction angle of 2θ±0.2° is 5.78°, 8.10°, 9.06°, 10.77°, 11.56°, 12.85°, 16.20°, 17.39°, 17.79°, 18.13°, 18.45°, 18.93°, 19.55°, 20.52°, 21.63°, 22.01°, 23.20°, 23.89°, 24. There are diffraction peaks at 46°, 25.00°, 25.56°, 25.97°, 26.39°, 27.33°, 27.77°, 28.83°, 29.03°, 29.60°, 30.33°, 30.62°, 31.14°, 31.77°, 32.23°, 33.33°, 33.77°, 34.25°, 34.64°, 35.19°, 36.01°, 38.66°, and 32.86°; Preferably, the free crystalline form A has an XRPD spectrum substantially as shown in FIG1-1; Preferably, the free crystalline form A is anhydrous crystalline form; Preferably, the free crystalline form A has one, two or three of the following characteristics: (1) The TGA curve of free form A shows a weight loss of approximately 0.38±1% at 150.0±3°C; (2) The DSC curve of the free form A has an endothermic peak starting point at 169.5±3℃; (3) The DSC curve of free form A has an endothermic peak at 171.0±3℃; Preferably, the DSC graph of the free crystalline form A is substantially as shown in Figure 1-2; Preferably, the TGA graph of the free crystalline form A is substantially as shown in Figures 1-3.

3. The crystal form according to claim 1, wherein The crystal form is a free crystal form B of the compound of formula I, and the free crystal form B has diffraction peaks at 11.64°, 12.60°, 17.46°, 20.93°, 25.16°, and 26.56° in an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ±0.2°; Preferably, the X-ray powder diffraction spectrum of the free crystalline form B expressed at a diffraction angle of 2θ±0.2° also has diffraction peaks at one or more of the following locations: 5.80°, 29.25°, 28.22°, 28.51°, 35.32°; Preferably, the free crystalline form B has an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ±0.2° at 5.80°, 11.64°, 12.60°, 17.46°, 20.93°, 22.19°, 25.16°, 26.56°, 28.22°, 28.51°, 29.25°, 33.23°, 35.32°, and 38.52°; Preferably, the free crystalline form B has an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ±0.2° at 5.80°, 11.64°, 12.60°, 16.09°, 17.46°, 18.37°, 20.93°, 22.19°, 23.03°, 23.82°, 25.16°, 26.56°, 28.22°, 28.51°, 29.25°, 29.79°, 32.20°, 33.23°, 34.42°, 35.32°, and 38.52°; Preferably, the free crystalline Form B has an XRPD spectrum substantially as shown in FIG2-1; Preferably, the free crystalline form B is an anhydrous crystalline form; Preferably, the free crystalline form B has one, two or three of the following characteristics: (1) The TGA curve of free form B shows a weight loss of approximately 0.23±1% at 150.0±3°C; (2) The DSC curve of the free form B has an endothermic peak starting point at 165.8±3℃; (3) The DSC curve of free form B has an endothermic peak at 168.47±3℃; Preferably, the DSC graph of the free crystalline form B is substantially as shown in Figure 2-2; Preferably, the TGA graph of the free crystalline form B is substantially as shown in Figure 2-3.

4. A method for preparing the free crystalline form A of the compound of formula I according to claim 2, wherein: Choose one of the following methods: Method 1: Place the first sample bottle containing the compound of formula I in a second sample bottle containing a solvent, seal the second sample bottle, and let it stand at room temperature; the solvent does not cover the mouth of the first sample bottle; The solvent is selected from one or more of ethanol, acetone, methyl tert-butyl ether, ethyl acetate, dichloromethane, tetrahydrofuran, acetonitrile, n-heptane, and toluene; Method 2: Place the first sample bottle containing the solution of the compound of formula I in the second sample bottle containing the anti-solvent, seal the second sample bottle, and let it stand at room temperature; the anti-solvent does not cover the mouth of the first sample bottle; The solvent in the solution of the compound of formula I is selected from one or more of dichloromethane, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, and N,N-dimethylformamide; The anti-solvent is selected from one or more of n-heptane, methyl tert-butyl ether, and water; Method 3: Add a solvent to the compound of formula I at room temperature, stir magnetically, and collect the solid; The solvent is selected from one or more of water, ethanol, isopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, acetone, methyl ethyl ketone, dimethyl sulfoxide, acetonitrile, toluene, N,N-dimethylformamide, and N-methylpyrrolidone; Method 4: Add solvent to the compound of formula I at 50°C, stir magnetically, and collect the solid; The solvent is selected from one or more of water, ethanol, isopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, acetone, methyl ethyl ketone, dimethyl sulfoxide, acetonitrile, toluene, N,N-dimethylformamide, and N-methylpyrrolidone; Method 5: Add the compound of formula I into organic solvent I, filter after dissolving, and evaporate at room temperature: Preferably, the organic solvent I is selected from one or more of methanol, ethanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, acetone, methyl ethyl ketone, dichloromethane and acetonitrile; Method 6: Dissolve the compound of formula I completely in a good solvent, filter, and dropwise add an antisolvent to the clear solution until solid precipitates; The good solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, dichloromethane, tetrahydrofuran, methyl ethyl ketone, N-methylpyrrolidone, N,N-dimethylacetamide, ethanol, and isopropyl acetate; The anti-solvent is selected from one or more of water, toluene, methyl tert-butyl ether, and n-heptane; Preferably, when the anti-solvent is selected from water, the good solvent is selected from one of dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, N-methylpyrrolidone, and N,N-dimethylacetamide; when the anti-solvent is selected from methyl tert-butyl ether, the good solvent is selected from dichloromethane; when the anti-solvent is selected from n-heptane, the good solvent is selected from methyl ethyl ketone or ethanol; Method 7: Completely dissolve the compound of formula I in a good solvent, filter, and add the clear solution to an anti-solvent; The good solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, dichloromethane, ethyl acetate, 1,4-dioxane, methyl ethyl ketone, and tetrahydrofuran; The anti-solvent is selected from one or more of water, n-heptane, methyl tert-butyl ether, and toluene; Method 8: Add the compound of formula I into organic solvent I at 50°C, filter after dissolving, stir magnetically, and cool at room temperature; Preferably, the organic solvent I is selected from one or more of methanol, ethanol, isopropyl acetate, acetonitrile, ethyl acetate, and acetone; Method 9: adding the compound of formula I into a mortar or adding the compound of formula I and a solvent into a mortar and grinding; Preferably, the solvent is selected from one or more of water, methyl tert-butyl ether and n-heptane.

5. A method for preparing the free crystalline form B of the compound of formula I according to claim 3, comprising the following methods: Method 1: Dissolve the compound of formula I completely in a good solvent, filter, and add an anti-solvent dropwise to the clear solution until solid precipitates; The good solvent is selected from one or two of tetrahydrofuran and N,N-dimethylacetamide, and the anti-solvent is selected from n-heptane; The anti-solvent is selected from one or more of water, toluene, methyl tert-butyl ether, and n-heptane; Method 2: completely dissolve the compound of formula I in a good solvent, filter, and add the clear solution into an anti-solvent; The good solvent is selected from one or two of dichloromethane and 1,4-dioxane; the anti-solvent is selected from n-heptane; Method 3: Add the compound of formula I to isopropanol at 40-60°C (e.g. 50°C), filter after dissolving, stir, and cool at room temperature; Method 4: Completely dissolve the compound of formula I in tetrahydrofuran, filter, add n-heptane to the clear solution with stirring until solid precipitates, then add free form B seed crystals and stir.

6. A pharmaceutically acceptable salt of a compound of formula I, wherein The structure of the compound of formula I is shown below: The pharmaceutically acceptable salt is selected from the salts of the compound of formula I and acid or base; Preferably, the pharmaceutically acceptable salt of the compound of formula I is selected from the salts formed by the compound of formula I and the following acids or bases: hydrochloric acid, sulfuric acid, maleic acid, phosphoric acid, fumaric acid, tartaric acid, citric acid, L-malic acid, succinic acid, p-toluenesulfonic acid, methanesulfonic acid, sodium hydroxide, arginine; Preferably, the pharmaceutically acceptable salt of the compound of formula I is selected from the maleate salt of the compound of formula I; in the maleate salt, the molar ratio of the compound of formula I to maleic acid is 1:1; Preferably, the pharmaceutically acceptable salt of the compound of formula I is selected from the sodium salt of the compound of formula I; in the sodium salt, the molar ratio of the compound of formula I to sodium is 1:

1.

7. A pharmaceutically acceptable salt of the compound of formula I according to claim 6, wherein the salt is a crystalline form; Preferably, the crystalline form is maleate crystalline form A, and the X-ray powder diffraction spectrum of the maleate crystalline form A represented by a diffraction angle of 2θ±0.2° has diffraction peaks at 8.39°, 13.78°, 16.31°, 17.07°, and 18.44°; further, the X-ray powder diffraction spectrum of the maleate crystalline form A represented by a diffraction angle of 2θ±0.2° has diffraction peaks at 8.39°, 13.78°, 16.31°, 17.07°, 18.44°, 20.96°, 25.62°, and 26.78°; further, the X-ray powder diffraction spectrum of the maleate crystalline form A represented by a diffraction angle of 2θ±0.2° has diffraction peaks at 8.39°, 13.78°, 16.31°, 17.07°, 18.44°, 20.96°, 25.62°, and 26.78°. 3.78°, 16.31°, 17.07°, 18.44°, 20.96°, 21.61°, 25.29°, 25.62°, and 26.78°; further, the maleate salt form A has a diffraction peak at 8.39°, 13.78°, 16.31°, 17.07°, 18.44°, 20.45°, 20.96°, 21.61°, 25.29°, 25.62°, 26.19°, and 26.78° in an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ±0.2°; further, the maleate salt form A has a diffraction peak at 8. The maleate salt form A has diffraction peaks at 8.39°, 10.65°, 13.78°, 16.31°, 17.07°, 18.44°, 19.01°, 20.45°, 20.96°, 21.61°, 22.65°, 23.19°, 24.62°, 25.29°, 25.62°, 26.19°, 26.78°, 27.03°, 27.41°, 28.47°, 28.96°, 30.05°, 31.25°, 31.61°, and 33.91°; further, the maleate salt form A has an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ±0.2° at 8.39°, 10.65°, 13.78°, 16.31°, 17.07°, 18.44°, 19.01°, 20.45°, 20.96°, 21.61°, 22.65°, 23.19°, 24.62°, 25.29°, 25.62°, 26.19°, 26.78°, 27.03°, , 17.07°, 18.44°, 19.01°, 20.45°, 20.96°, 21.61°, 22.65°, 23.19°, 24.62°, 25.29°, 25.62°, 26.19°, 26.78°, 27.03°, 27.41°, 28.47°, 28.96°, 30.05, 30.74°, 31.25°, 31.61°, 32.70°, 33.13°, 33.91°, 34.49°, 35.22°, 36.21°, and 38.48°; further, the maleate salt form A has an XRPD spectrum substantially as shown in FIG. 3-1; Preferably, the maleate salt form A has one or two of the following characteristics: (1) The TGA curve of the maleate salt form A shows a weight loss of 0.5-3% at 120±3°C, preferably 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, for example 1.41%; (2) The maleate salt form A has an endothermic peak at 139.1±3°C; Preferably, the TGA / DSC graph of the maleate salt form A is substantially as shown in FIG3-2; 1 The H NMR pattern is basically as shown in Figure 3-3; Or the crystal form is sodium salt crystal form A of the compound of formula I, and the X-ray powder diffraction spectrum of the sodium salt crystal form A represented by a diffraction angle of 2θ±0.2° has diffraction peaks at 16.70°, 17.02°, 21.23°, 22.33°, 24.39°, 25.50°, and 25.89°; further, the X-ray powder diffraction spectrum of the sodium salt crystal form A represented by a diffraction angle of 2θ±0.2° has diffraction peaks at 16.70°, 17.02°, 17.67°, 18.51°, 21.23°, 22.33°, 24.39°, 25.50°, 25.89°, and 29.73°; ​​further, the X-ray powder diffraction spectrum of the sodium salt crystal form A represented by a diffraction angle of 2θ±0.2° has diffraction peaks at 16.70°, 17.02°, 17.67°, 18.51°, 21.23°, 22.33°, 24.39°, 25.50°, 25.89°, and 29.73°. The X-ray powder diffraction spectrum has diffraction peaks at 16.70°, 17.02°, 17.67°, 18.51°, 21.23°, 22.33°, 24.39°, 25.50°, 25.89°, 29.73°, and 30.76°; further, the X-ray powder diffraction spectrum of the sodium salt form A represented by a diffraction angle of 2θ±0.2° is at 4.85°, 9.70°, 12.13°, 13.55°, 14.20°, 14.55, 1670°, 17.02°, 17.67°, 18.51°, 21.23°, 22.33°, 24.39°, 25.50°, 25.89°, 26.72°, 27.74°, 28.44°, 29.7 3°, 30.76°; further, the X-ray powder diffraction spectrum of the sodium salt form A represented by a diffraction angle of 2θ±0.2° is 4.85°, 9.70°, 12.13°, 13.55°, 14.20°, 14.55, 16.70°, 17.02°, 17.67°, 18.51°, 20.27°, 21.23°, 22.33°, 23.35°, 24.39°, 25.50°, 25.89°, 26.72°, 27.74°, 28.44°, 29.73°, 30.76°, 31.43°, 31.88°, 32.46°, and 39.71°; further, the sodium salt form A is represented by a X-ray powder diffraction spectrum represented by a diffraction angle of 2θ±0.2°. The X-ray powder diffraction pattern represented by the diffraction angle of 2θ±0.2° is 4.85°, 9.70°, 12.13°, 13.55°, 14.20°, 14.55°, 16.70°, 17.02°, 17.67°, 18.51°, 20.27°, 21.23°, 22.33°, 23.35°, 24.3 9°, 25.50°, 25.89°, 26.72°, 27.74°, 28.44°, 28.87°, 29.73°, 30.76°, 31.43°, 31.88°, 32.46°, 32.98°, 34.06°, 35.13°, 35.68°, 36.33°, 38.30°, 39.There is a diffraction peak at 71°; further, the sodium salt form A has an XRPD spectrum substantially as shown in FIG4-1;. Preferably, the sodium salt crystalline form A has one or two of the following characteristics: (1) The TGA curve of the sodium salt form A shows a weight loss of 1.0-5.0% at 150±3°C, preferably 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, for example 2.75%; (2) The sodium salt form A has two endothermic peaks at 191.0±3°C and 215.0±3°C; Preferably, the TGA / DSC diagram of the sodium salt crystal form A is substantially as shown in FIG4-2; 1 The H NMR graph is basically as shown in Figure 4-3.

8. A method for preparing a pharmaceutically acceptable salt of a compound of formula I according to claim 6, comprising mixing a compound of formula I with a suitable acid or base to obtain the pharmaceutically acceptable salt; Preferably, when the pharmaceutically acceptable salt of the compound of formula I is a maleate or sodium salt, the preparation method comprises the following steps: mixing the compound of formula I and maleic acid or sodium hydroxide, stirring in an organic solvent A, and separating to obtain a solid; preferably, the stirring time is 1-5 days, and the stirring temperature is room temperature; the organic solvent A is selected from one or more of isopropanol, ethyl acetate, and 2-methyltetrahydrofuran; preferably, mixing the compound of formula I and maleic acid or sodium hydroxide, obtaining a suspension in an organic solvent A, and suspending and stirring; Preferably, when the pharmaceutically acceptable salt of the compound of formula I is maleate crystalline form A, the preparation method comprises the following steps: mixing the compound of formula I and an equimolar amount of maleic acid to obtain a suspension in an organic solvent A, suspending and stirring, and separating to obtain a solid; preferably, the suspension stirring time is 1-5 days, and the suspension stirring temperature is room temperature; the organic solvent A is selected from ethyl acetate; Preferably, when the pharmaceutically acceptable salt of the compound of formula I is sodium salt form A, the preparation method comprises the following steps: mixing the compound of formula I and an equimolar amount of sodium hydroxide to obtain a suspension in an organic solvent A, suspending and stirring, and separating to obtain a solid; in some embodiments, the suspension and stirring time is 1-5 days, for example, 3 days, and the suspension and stirring temperature is room temperature; the organic solvent A is selected from one or more of isopropanol, ethyl acetate, and 2-methyltetrahydrofuran.

9. A pharmaceutical composition, wherein: A pharmaceutical composition comprising a crystalline form of the compound of formula I according to any one of claims 1 to 3, 6 to 7, a pharmaceutically acceptable salt thereof, or one or more crystalline forms of a pharmaceutically acceptable salt thereof; Preferably, the crystalline form of the compound of formula I is a free crystalline form of the compound of formula I; Preferably, the crystalline form of the compound of formula I is the free crystalline form A of the compound of formula I; Preferably, the crystalline form of the compound of formula I is the free crystalline form B of the compound of formula I; Preferably, the crystalline form of the pharmaceutically acceptable salt of the compound of formula I is maleate crystalline form A or sodium salt crystalline form A.

10. Use of a crystalline form of the compound of formula I according to any one of claims 1-3, 6-7, or a pharmaceutically acceptable salt thereof, or a crystalline form of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9 in the preparation of a drug; Preferably, the drug is used to treat and / or prevent voltage-gated sodium channel-related diseases; Preferably, the voltage-gated sodium channel-related disease is a Nav1.8-related disease; Preferably, the Nav1.8-related diseases include: pain; Preferably, the pain includes: acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.

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