Crystalline forms of heterocyclic alkyl-containing aryl amidines, salts, and preparation, compositions, and uses thereof

Abstract

The application provides a crystal form of an aryl amidine compound containing a heterocyclic alkyl group, a salt, preparation, composition and application of the aryl amidine compound.The crystal form has better chemical stability, is beneficial to preparation of a medicine that can be stored for a long time, is more stable, is not prone to crystal transformation, and makes the absorption of different batches of the compound in a human body more stable and consistent, and is not prone to large fluctuation.The structure of the compound is shown as follows: (I).

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, and more specifically, to the crystal form, salts, preparation, composition, and application of a heterocyclic alkyl arylamidine compound. Background Technology

[0002] Pain originates from nociceptors in the peripheral nervous system. These are free nerve endings, widely distributed throughout the skin, muscles, joints, and internal organs. They convert perceived thermal, mechanical, or chemical stimuli into nerve impulses (action potentials), which are then transmitted via afferent nerve fibers to the cell body of the dorsal root ganglion (DRG), ultimately reaching higher nerve centers and causing pain. The generation and conduction of action potentials in neurons depend on voltage-gated sodium channels (VGSCs / Nav) on the cell membrane. Navs are key mediators for transmembrane information transmission along neurons.

[0003] Statistics show that approximately one-fifth of the world's population suffers from moderate to severe chronic pain. The global analgesic market was worth approximately US$36 billion in 2018 and is projected to reach US$56 billion by 2023. Acute moderate to severe pain is expected to grow steadily at a CAGR of 2.5%, while the chronic pain market is projected to grow at a CAGR of around 18%. Chronic pain is the main driver of continued growth in the global pain market over the next decade.

[0004] The secondary structure of voltage-gated sodium channels (VGSC / Nav) comprises four domains (DI-DIV) forming a pore, each with six transmembrane α-helices (S1-S6). S4 is a voltage sensor containing positively charged ions. The intracellular loop between DIII and DIV is considered a rapid inactivation gate. Nav exists in three distinct states, with the inactivated closed state exhibiting different kinetics of rapid inactivation (within milliseconds) or slow inactivation (within seconds). When the cell membrane depolarizes, the sodium channel is activated, opening and causing an influx of sodium ions, further depolarizing the cell membrane and leading to the generation of an action potential. Therefore, inhibiting aberrant sodium channel activity may contribute to the treatment and relief of pain, making Nav a potential peripheral target for pain therapy.

[0005] There are nine main subtypes of human nav toxins (NAVs), namely Nav1.1-Nav1.9. Based on their ability to be effectively inhibited by tetrodotoxin (TX), Navs are classified into TTX-sensitive (TTX-S) and TTX-insensitive (TTX-R) types, and the tissue expression of different subtypes varies significantly. Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.6, and Nav1.7 are TTX-S types. Among them, Nav1.1, Nav1.2, and Nav1.3 are highly expressed in the central nervous system (CNS), Nav1.4 is abundant in skeletal muscle, and Nav1.6 and Nav1.7 are mainly abundant in the central nervous system. Nav1.5, Nav1.8, and Nav1.9 are TTX-R type, with Nav1.5 mainly found in cardiomyocytes, and Nav1.8 and Nav1.9 found in the dorsal root ganglia of the peripheral nervous system (PNS-DRG).

[0006] Studies have shown that alterations in ion channels are the molecular basis for peripheral sensitization, central sensitization, and disinhibition following inflammation or neuropathological injury, and are also important molecular mechanisms in the development of pain. Currently, Nav inhibitors have proven effective; for example, the local anesthetic lidocaine relieves pain by inhibiting Nav, and non-selective Nav inhibitors such as lamotrigine, lacosamide, and mexiletine have been successfully used to treat chronic pain. However, existing clinically used Nav inhibitors lack subtype selectivity, inhibiting sodium ion channels expressed in the heart and central nervous system, resulting in a narrow therapeutic window and limited application. Nav1.8 is an important ion channel involved in chronic pain, atrial fibrillation, and Budd-Chiari syndrome. Highly selective Nav1.8 inhibitors are ideal targets for pain management, producing analgesic effects with relatively few side effects.

[0007] In models of neuropathic pain, nerve damage increases the expression levels of Nav1.8 in axons and neuronal cell bodies. Using Nav1.8 antisense oligonucleotides to reduce Nav1.8 expression significantly alleviates pain. Nav1.8 knockout mice do not exhibit normal visceral inflammatory pain. Functionally gain mutations in the human Nav1.8 gene lead to peripheral neuropathic pain. Based on a series of animal studies and human genetic evidence, selective inhibition of Nav1.8 has the potential to become a novel analgesic therapy for treating various pain types, including inflammatory pain, neuropathic pain, postoperative pain, and cancer pain.

[0008] Highly selective Nav inhibitors are a key area of ​​research for voltage-gated sodium ion channels. Nav1.8, primarily distributed in the peripheral nervous system and limited to pain-sensing neurons, is a highly selective target for pain management. Therefore, selective inhibition of Nav1.8 shows promise in reducing potential toxic side effects. However, clinically used Nav inhibitors lack subtype selectivity, inhibiting sodium ion channels expressed in the heart and central nervous system, resulting in a narrow therapeutic window and limited application. Therefore, it is necessary to develop Nav1.8 inhibitors with higher activity, better selectivity, improved pharmacokinetic properties, and fewer side effects to meet clinical needs.

[0009] PCT / CN2024 / 133203 discloses a series of arylamidine compounds containing heterocyclic alkyl groups. In subsequent research and development, in order to facilitate the handling, filtration and drying of the products, and to seek suitable crystals that are easy to store and have long-term product stability, this invention has conducted a comprehensive study on the crystal forms of the above-mentioned compounds.

[0010] The crystal form of a pharmaceutical active ingredient often affects its chemical stability. Different crystallization and storage conditions can lead to changes in the crystal structure of the compound, sometimes even resulting in other crystal forms. Finding a stable, readily available, and easily stored crystal form is often essential. Generally, amorphous drug products lack regular crystal structures and often have defects, such as poor product stability, fine crystals, difficulty in filtration, easy agglomeration, and poor flowability, which are detrimental to the production of pharmaceutical formulations. Different crystal forms of drugs have different requirements for product storage, production, and scale-up. Therefore, in-depth research on the crystal forms of the aforementioned compounds and improvement of their various properties is crucial. Summary of the Invention

[0011] One object of the present invention is to provide a crystal form; Another object of the present invention is to provide an acid salt; Another object of the present invention is to provide a method for preparing the crystal form; Another object of the present invention is to provide a pharmaceutical composition; Another object of the present invention is to provide uses for the said crystal form.

[0012] To achieve the above objectives, in one aspect, the present invention provides a crystal form of the compound shown in formula (I).

[0013] (I)

[0014] The compound of formula (I) can be drawn either according to formula (I-1) or according to formula (I-2) as follows:

[0015] (I-1) (I-2).

[0016] In this invention, formulas (I-1) and (I-2) represent the same substance; that is, both can be used to represent the compound of formula (I). Formulas (I-1) and (I-2) differ in the way the functional groups are drawn as follows: "and" The difference between them lies in the position of the double bonds. These two drawing methods have appeared in multiple documents and patents (WO2024217557, WO2024041613, WO2025021115, WO2025092901), and their relationship is similar to the "keto-enol tautomerism" relationship; they represent the same substance. Therefore, the crystal forms of the two structures of formula (I-1) and formula (I-2) are both within the scope of protection of this invention. Similarly, formulas (II-1) and (II-2) below represent the same substance, and formulas (III-1) and (III-2) also represent the same substance. It is understood that for the above structures, if only one drawing method appears in this invention (for example, in the embodiments), it should also include the two drawing methods described above, and it does not mean that the structure is limited to a specific drawing method.

[0017] According to some specific embodiments of the present invention, the crystal form is crystal form C, and crystal form C has characteristic peaks at the following 2θ angle positions in the XRPD diagram: 11.3078°±0.2°, 13.5683°±0.2°, and 18.9765°±0.2°.

[0018] According to some specific embodiments of the present invention, the crystal form C also has characteristic peaks at the following 2θ angle positions in the XRPD diagram: 6.8408°±0.2°, 15.0308°±0.2°, and 18.0179°±0.2°.

[0019] According to some specific embodiments of the present invention, the crystal form C has characteristic peaks at the following 2θ angle positions in the XRPD image: 5.4226°±0.2°, 6.8408°±0.2°, 9.6352°±0.2°, 10.9387°±0.2°, 11.3078°±0.2°, 13.5683°±0.2°, 14.1007°±0.2°, 15.0308°±0.2°, 15.2073°±0.2°, 16.1526°±0.2°, and 16.4110°. ±0.2°, 17.1085°±0.2°, 17.4268°±0.2°, 18.0179°±0.2°, 18.9765°±0.2°, 19.3190°±0.2°, 19.8048°±0.2°, 20.4612°±0.2°, 21.1703°±0.2°, 21.9341°±0.2°, 22.4615°±0.2°, 23.2838°±0.2°, 25.7433°±0.2°, 27.8761°±0.2°.

[0020] According to some specific embodiments of the present invention, the XRPD diffraction peak data of crystal form C are as follows:

[0021] According to some specific embodiments of the present invention, the XRPD pattern of the crystal form C is as follows: Figure 7 As shown.

[0022] According to some specific embodiments of the present invention, the TGA chart of the crystal form C loses 0.90% of its weight in the temperature range of 30.0℃±2℃ to 150.0℃±2℃.

[0023] According to some specific embodiments of the present invention, the TGA pattern of the crystal form C is as follows: Figure 8 As shown.

[0024] According to some specific embodiments of the present invention, the DSC diagram of the crystal form C has an exothermic peak at 109.8℃±2℃.

[0025] According to some specific embodiments of the present invention, the DSC diagram of the crystal form C is as follows: Figure 9 As shown.

[0026] According to some specific embodiments of the present invention, the crystal form is crystal form D, and crystal form D has characteristic peaks at the following 2θ angle positions in the XRPD diagram: 4.9961°±0.2°, 6.5244°±0.2°, 9.9843°±0.2°, and 11.5765°±0.2°.

[0027] According to some specific embodiments of the present invention, the crystal form D also has characteristic peaks at the following 2θ angle positions in the XRPD diagram: 16.1881°±0.2°, 17.9848°±0.2°, and 19.5063°±0.2°.

[0028] According to some specific embodiments of the present invention, the crystal form D has characteristic peaks at the following 2θ angle positions in the XRPD diagram: 4.9961°±0.2°, 6.5244°±0.2°, 9.9843°±0.2°, 11.5765°±0.2°, 13.6111°±0.2°, 16.1881°±0.2°, 17.9848°±0.2°, 19.5063°±0.2°, 22.1287°±0.2°, and 27.3802°±0.2°.

[0029] According to some specific embodiments of the present invention, the XRPD diffraction peak data of the crystal form D are as follows:

[0030] According to some specific embodiments of the present invention, the XRPD pattern of the crystal form D is as follows: Figure 11 As shown.

[0031] According to some specific embodiments of the present invention, the TGA chart of the crystal form D shows a weight loss of 2.12% in the temperature range of 27.9℃±2℃ to 80.0℃±2℃.

[0032] According to some specific embodiments of the present invention, the TGA pattern of the crystal form D is as follows: Figure 12 As shown.

[0033] According to some specific embodiments of the present invention, the DSC diagram of the crystal form D has an exothermic peak at 90.7℃±2℃.

[0034] According to some specific embodiments of the present invention, the DSC diagram of the crystal form D is as follows: Figure 13 As shown.

[0035] According to some specific embodiments of the present invention, the crystal form is crystal form E, which has characteristic peaks at the following 2θ angle positions in the XRPD diagram: 5.1853°±0.2°, 9.3646°±0.2°, 10.3873°±0.2°, 10.7555°±0.2°, 14.0365°±0.2°, and 14.7965°±0.2°.

[0036] According to some specific embodiments of the present invention, the crystal form E also has characteristic peaks at the following 2θ angle positions in the XRPD diagram: 15.0927°±0.2°, 15.4613°±0.2°, 15.8772°±0.2°, 17.1506°±0.2°, 17.4054°±0.2°, 17.6948°±0.2°, and 18.0469°±0.2°.

[0037] According to some specific embodiments of the present invention, the crystal form E has characteristic peaks at the following 2θ angle positions in the XRPD image: 5.1853°±0.2°, 6.0828°±0.2°, 9.3646°±0.2°, 10.3873°±0.2°, 10.7555°±0.2°, 12.7780°±0.2°, 14.0365°±0.2°, 14.7965°±0.2°, 15.0927°±0.2°, 15.4613°±0.2°, 15.8772°±0.2°, and 17.1506°. ±0.2°, 17.4054°±0.2°, 17.6948°±0.2°, 18.0469°±0.2°, 18.3516°±0.2°, 18.5642°±0.2°, 18.9047°±0.2°, 19.2088°±0.2°, 20.5545°±0.2°, 20.8551°±0.2°, 21.1069°±0.2°, 21.7004°±0.2°, 22.3494°±0.2°, 23.6318°±0.2°, 28.3153°±0.2°.

[0038] According to some specific embodiments of the present invention, the XRPD diffraction peak data of the crystal form E are as follows:

[0039] According to some specific embodiments of the present invention, the XRPD pattern of the crystal form E is as follows: Figure 14 As shown.

[0040] According to some specific embodiments of the present invention, the TGA chart of the crystal form E shows a weight loss of 2.11% in the temperature range of 27.3℃±2℃ to 90.0℃±2℃.

[0041] According to some specific embodiments of the present invention, the TGA pattern of the crystal form E is as follows: Figure 15 As shown.

[0042] According to some specific embodiments of the present invention, the DSC spectrum of the crystal form E has an exothermic peak at 103.4℃±2℃.

[0043] According to some specific embodiments of the present invention, the DSC diagram of the crystal form E is as follows: Figure 16 As shown.

[0044] According to some specific embodiments of the present invention, the crystal form is crystal form F, which has characteristic peaks at the following 2θ angle positions in the XRPD diagram: 5.0855°±0.2°, 6.8375°±0.2°, 7.0967°±0.2°, 9.2777°±0.2°, 9.6246°±0.2°, and 11.3242°±0.2°.

[0045] According to some specific embodiments of the present invention, the crystal form F also has characteristic peaks at the following 2θ angle positions in the XRPD diagram: 13.5847°±0.2°, 14.0768°±0.2°, 15.0685°±0.2°, 16.4020°±0.2°, and 17.0812°±0.2°.

[0046] According to some specific embodiments of the present invention, the crystal form F has characteristic peaks at the following 2θ angle positions in the XRPD diagram: 5.0855°±0.2°, 6.8375°±0.2°, 7.0967°±0.2°, 9.2777°±0.2°, 9.6246°±0.2°, 11.3242°±0.2°, 13.5847°±0.2°, 14.0768°±0.2°, 15.0685°±0.2°, 16.4020°±0.2°, 17.0812°±0.2°, 18.0482°±0.2°, 19.0023°±0.2°, 19.7967°±0.2°, 21.2159°±0.2°, and 23.2456°±0.2°.

[0047] According to some specific embodiments of the present invention, the XRPD diffraction peak data of the crystal form F are as follows:

[0048] According to some specific embodiments of the present invention, the XRPD pattern of the crystal form F is as follows: Figure 17 As shown.

[0049] According to some specific embodiments of the present invention, the TGA chart of the crystal form F loses 4.67% of its weight in the temperature range of 27.3℃±2℃ to 150.0℃±2℃.

[0050] According to some specific embodiments of the present invention, the TGA pattern of the crystal form F is as follows: Figure 18 As shown.

[0051] According to some specific embodiments of the present invention, the DSC diagram of the crystal form F has an exothermic peak at 85.9℃±2℃.

[0052] According to some specific embodiments of the present invention, the DSC pattern of the crystal form F is as follows: Figure 19 As shown.

[0053] On the other hand, the present invention provides an acid salt of the compound shown in formula (I) (formula (I-1) or formula (I-2)), the structure of which is shown below:

[0054] (I).

[0055] According to some specific embodiments of the present invention, the acid salt is selected from inorganic or organic acid salts of compounds of formula (I-1) or (I-2); the inorganic acid salt is selected from hydrochloride, sulfate, phosphate or hydrobromide; the organic acid salt is selected from 1,5-naphthalenedisulfonate, methanesulfonate, ethylsulfonate, p-toluenesulfonate, benzenesulfonate, hydroxyethylsulfonate, acetate, maleate, fumarate, citrate, oxalate, malonate, tartrate, malate, adipate, hippurate, succinate or camphorate; preferably, the acid salt is selected from phosphate, maleate or fumarate; more preferably, the acid salt is selected from phosphate and fumarate.

[0056] According to some specific embodiments of the present invention, in each molecule of the acid salt, the number of acids is 0.2-3, with each molecule of the acid salt representing one compound of formula (I-1) or (I-2).

[0057] According to some specific embodiments of the present invention, the number of acids is 0.2, 0.5, 1, 1.5, 1.2, 2, 2.5 or 3.

[0058] According to some specific embodiments of the present invention, the number of acids is 0.5, 1, 2 or 3.

[0059] According to some specific embodiments of the present invention, the number of acids is 0.5 or 1.

[0060] It is understood that the structure of the acid salt is as shown in formula (II):

[0061] (II)

[0062] Wherein A is an inorganic acid salt or an organic acid salt; the inorganic acid salt is selected from hydrochloride, sulfate, phosphate, or hydrobromide; the organic acid salt is selected from 1,5-naphthalenedisulfonate, methanesulfonate, ethylsulfonate, p-toluenesulfonate, benzenesulfonate, hydroxyethylsulfonate, acetate, maleate, fumarate, citrate, oxalate, malonate, tartrate, malate, adipate, hippurate, succinate, or camphorate; preferably, the acid salt is selected from phosphate, maleate, or fumarate; more preferably, the acid salt is selected from phosphate and fumarate; n is 0.2, 0.5, 1, 1.5, 1.2, 2, 2.5 or 3; preferably 0.5, 1, 2 or 3; more preferably 0.5 or 1.

[0063] The compounds of formula (II) above can also be drawn according to formula (II-1) or formula (II-2) below:

[0064] (II-1) (II-2).

[0065] According to some specific embodiments of the present invention, the acid salt is a hydrate or anhydrous; when the acid salt is a hydrate, each molecule of the acid salt contains 0.2-3 water molecules, with the compound shown in formula (I-1) or (I-2) as 1.

[0066] According to some specific embodiments of the present invention, the number of water particles is 0.2, 0.5, 1, 1.5, 2, 2.5 or 3.

[0067] According to some specific embodiments of the present invention, the number of water particles is 0.5, 1, 2 or 3.

[0068] It is understood that the structure of the hydrate of the acid salt is as shown in formula (III):

[0069] (III)

[0070] Where m is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 0.5, 1, 2 or 3.

[0071] The compounds of formula (III) above can also be drawn according to formula (III-1) or formula (III-2) below:

[0072] (III-1) (III-2).

[0073] According to some specific embodiments of the present invention, the acid salt of the compound shown in formula (I-1) or (I-2) is in crystalline form.

[0074] According to some specific embodiments of the present invention, the crystal form is crystal form A of the phosphate of the compound shown in formula (I-1) or (I-2), wherein crystal form A of the phosphate has characteristic peaks at the following 2θ positions in the XRPD diagram: 19.7338°±0.2°, 14.7733°±0.2°, and 4.9234°±0.2°.

[0075] According to some specific embodiments of the present invention, the crystal form is crystal form A of the phosphate of the compound shown in formula (I-1) or (I-2), and the crystal form A of the phosphate also has characteristic peaks at the following 2θ positions: 28.4729°±0.2° and 24.7285°±0.2°.

[0076] According to some specific embodiments of the present invention, the crystal form is crystal form B of the fumarate of the compound shown in formula (I-1) or (I-2), wherein crystal form B of the fumarate has characteristic peaks at the following 2θ positions in the XRPD plot: 4.6311°±0.2°, 6.3918°±0.2°, and 9.2234°±0.2°.

[0077] According to some specific embodiments of the present invention, the crystal form is crystal form B of the fumarate of the compound shown in formula (I-1) or (I-2), wherein the crystal form B of the fumarate also has characteristic peaks at the following 2θ positions: 12.7622°±0.2°, 20.1741°±0.2°, 23.8110°±0.2°, and 27.0322°±0.2°.

[0078] According to some specific embodiments of the present invention, the crystal form is crystal form A of the phosphate of the compound shown in formula (I-1) or (I-2), wherein crystal form A of the phosphate has characteristic peaks at the following 2θ positions in the XRPD plot: 4.9234°±0.2°, 9.8341°±0.2°, 10.9735°±0.2°, 14.7733°±0.2°, 15.3579°±0.2°, 16.9716°±0.2°, 17.66°±0.2°. 79°±0.2°, 19.0116°±0.2°, 19.7338°±0.2°, 22.4749°±0.2°, 23.7070°±0.2°, 24.7285°±0.2°, 26.4139°±0.2°, 28.4729°±0.2°, 29.7696°±0.2°, 30.6925°±0.2°, 31.8245°±0.2°, 35.9037°±0.2°.

[0079] According to some specific embodiments of the present invention, the crystal form is crystal form B of the fumarate of the compound shown in formula (I-1) or (I-2), wherein crystal form B of the fumarate has characteristic peaks at the following 2θ positions in the XRPD plot: 4.6311°±0.2°, 4.9902°±0.2°, 6.3918°±0.2°, 8.6572°±0.2°, 9.2234°±0.2°, 9.9379°±0.2°, 11.4943°±0.2°, 12.1857°±0.2°, and 12.7622°±0.2°. 13.9053°±0.2°, 14.6249°±0.2°, 16.5238°±0.2°, 17.0319°±0.2°, 18.4858°±0.2°, 20.1741°±0.2°, 20.9944°±0.2°, 21.6205°±0.2°, 22.6734°±0.2°, 23.8110°±0.2°, 25.2138°±0.2°, 26.5898°±0.2°, 27.0322°±0.2°, 27.9024°±0.2°.

[0080] According to some specific embodiments of the present invention, wherein the crystal form is crystal form A of the phosphate of the compound shown in formula (I-1) or (I-2), and the XRPD diffraction peak data of crystal form A of the phosphate are shown below:

[0081] According to some specific embodiments of the present invention, wherein the crystal form is crystal form B of the fumarate of the compound shown in formula (I-1) or (I-2), and the XRPD diffraction peak data of crystal form B of the fumarate are shown below:

[0082] According to some specific embodiments of the present invention, wherein the crystal form is crystal form A of the phosphate of the compound shown in formula (I-1) or (I-2), and the XRPD diffraction peak data of crystal form A of the phosphate are as follows: Figure 1 As shown.

[0083] According to some specific embodiments of the present invention, wherein the crystal form is crystal form B of the fumarate of the compound shown in formula (I-1) or (I-2), and the XRPD diffraction peak data of crystal form B of the fumarate are as follows: Figure 4 As shown.

[0084] According to some specific embodiments of the present invention, wherein the crystal form is crystal form A of the phosphate of the compound shown in formula (I-1) or (I-2), and the TGA chart of crystal form A of the phosphate shows a weight loss of 1.18% in the temperature range of 29.0℃±2℃ to 150.0℃±2℃.

[0085] According to some specific embodiments of the present invention, wherein the crystal form is crystal form B of the fumarate of the compound shown in formula (I-1) or (I-2), and the TGA chart of crystal form B of the fumarate shows a weight loss of 1.09% in the temperature range of 30.3℃±2℃ to 100.0℃±2℃.

[0086] According to some specific embodiments of the present invention, wherein the crystal form is crystal form A of the phosphate of the compound shown in formula (I-1) or (I-2), and the TGA diagram of crystal form A of the phosphate is as follows. Figure 2 As shown.

[0087] According to some specific embodiments of the present invention, wherein the crystal form is crystal form B of the fumarate of the compound shown in formula (I-1) or (I-2), and the TGA image of crystal form B of the fumarate is as follows. Figure 5 As shown.

[0088] According to some specific embodiments of the present invention, the crystal form is crystal form A of the phosphate of the compound shown in formula (I-1) or (I-2), and the DSC spectrum of crystal form A of the phosphate has an exothermic peak at 178.8℃±2℃.

[0089] According to some specific embodiments of the present invention, the crystal form is crystal form B of the fumarate of the compound shown in formula (I-1) or (I-2), and the DSC spectrum of crystal form B of the fumarate has an exothermic peak at 141.0℃±2℃.

[0090] According to some specific embodiments of the present invention, wherein the crystal form is crystal form A of the phosphate of the compound shown in formula (I-1) or (I-2), and the DSC diagram of crystal form A of the phosphate is as follows. Figure 3 As shown.

[0091] According to some specific embodiments of the present invention, wherein the crystal form is crystal form B of the fumarate of the compound shown in formula (I-1) or (I-2), and the DSC diagram of crystal form B of the fumarate is as follows. Figure 6 As shown.

[0092] On the other hand, the present invention also provides a method for preparing the crystal form described in the present invention, wherein the method includes recrystallizing the compound of formula (I-1) or (I-2) or its acid salt in an organic solvent to obtain the crystal form.

[0093] According to some specific embodiments of the present invention, the organic solvent is isopropylbenzene, m-xylene, or a mixture of solvent A and solvent B in a volume ratio of 1:(1-10); solvent A is selected from one or more of methanol, ethanol, n-propanol, ethyl formate, cyclopentyl methyl ether, and ethyl acetate, and solvent B is selected from one or more of n-heptane, n-pentane, n-hexane, and n-octane.

[0094] According to some specific embodiments of the present invention, the organic solvent is a mixture of solvent A and solvent B in a volume ratio of 1:(2-9).

[0095] According to some specific embodiments of the present invention, wherein the crystal form is the crystal form of an acid salt of a compound represented by formula (I-1) or (I-2), and the method comprises recrystallizing the acid salt of a compound represented by formula (I-1) or (I-2) in an organic solvent to obtain the crystal form; wherein the organic solvent is a mixture of solvent A and solvent B in a volume ratio of 1:(4-6); solvent A is selected from methanol and / or ethanol, and solvent B is selected from one or more of n-heptane, n-pentane, n-hexane and n-octane.

[0096] According to some specific embodiments of the present invention, the crystal form is the crystal form of an acid salt of the compound shown in formula (I-1) or (I-2), and the organic solvent is a mixed solvent of solvent A and solvent B in a volume ratio of 1:5.

[0097] According to some specific embodiments of the present invention, wherein the crystal form is the crystal form of the compound shown in formula (I-1) or (I-2) (i.e., crystal form C of the free base), and the method comprises recrystallizing the compound shown in formula (I-1) or (I-2) in an organic solvent to obtain the crystal form; the organic solvent is a mixture of solvent A and solvent B in a volume ratio of 1:(8-10); solvent A is selected from ethyl formate and / or ethyl acetate, and solvent B is selected from one or more of n-heptane, n-pentane, n-hexane and n-octane.

[0098] According to some specific embodiments of the present invention, the crystal form is the crystal form of the compound shown in formula (I) or (I-2), and the organic solvent is a mixture of solvent A and solvent B in a volume ratio of 1:9.

[0099] According to some specific embodiments of the present invention, the method includes dissolving the compound shown in formula (I) or (I-2) in an organic solvent at 45-55°C, stirring and cooling down to 0-5°C, then heating up to 45-55°C while stirring, repeating this cycle twice, and then centrifuging to obtain the crystal form (i.e., crystal form C of the free base) of the compound shown in formula (I-1) or (I-2).

[0100] According to some specific embodiments of the present invention, the method includes dissolving the compound shown in formula (I) or (I-2) in an organic solvent at 50°C, stirring and cooling to 5°C, then heating to 50°C while stirring, repeating this cycle twice, and then centrifuging to obtain the crystal form of the compound shown in formula (I-1) or (I-2).

[0101] According to some specific embodiments of the present invention, the cooling rate is 0.1-0.3 °C / min; preferably 0.1 °C / min.

[0102] According to some specific embodiments of the present invention, the heating rate is 0.1-0.3 °C / min; preferably 0.1 °C / min.

[0103] According to some specific embodiments of the present invention, after each heating or cooling to the target temperature, the temperature is equilibrated for 60-180 minutes.

[0104] According to some specific embodiments of the present invention, the method includes dissolving the compound of formula (I-1) or (I-2) in solvent A at room temperature, and then adding solvent B under stirring to crystallize and obtain the crystal form of the compound of formula (I-1) or (I-2). Preferably, the volume ratio of solvent A to solvent B is 1:1-1.5; more preferably, it is 1:1.

[0105] According to some specific embodiments of the present invention, the method includes dissolving the compound of formula (I-1) or (I-2) in solvent A at room temperature, adding seed crystals, and then adding solvent B under stirring to crystallize and obtain the crystal form of the compound of formula (I-1) or (I-2). Preferably, the mass of the seed crystals added is 1 / 8 to 1 / 10 of the mass of the compound of formula (I-1) or (I-2); more preferably, it is 1 / 9 to 1 / 10.

[0106] According to some specific embodiments of the present invention, after adding solvent B, the steps of adding seed crystals and solvent B are repeated 2, 3 or 4 times; the mass of seed crystals added each time is 1 / 8 to 1 / 10 of the compound shown in formula (I-1) or (I-2); preferably 1 / 9 to 1 / 10; the volume of solvent B added each time is 1 / 3 to 2 / 3 of the volume of solvent B added for the first time; preferably 1 / 2.

[0107] According to some specific embodiments of the present invention, the mixture is stirred for 20-40 minutes, preferably 30 minutes, after each addition of seed crystals.

[0108] According to some specific embodiments of the present invention, wherein the crystal form is crystal form D of the compound shown in formula (I-1) or (I-2), and the method includes dissolving crystal form C in a mixed solution of solvent A and solvent B with a volume ratio of 1:(2-3) at room temperature, and evaporating the solvent to obtain crystal form D.

[0109] According to some specific embodiments of the present invention, solvent A is selected from one or more of methanol, ethanol, n-propanol, ethyl formate, cyclopentyl methyl ether and ethyl acetate, and solvent B is selected from one or more of n-heptane, n-pentane, n-hexane and n-octane; preferably solvent A is cyclopentyl methyl ether and solvent B is n-heptane.

[0110] According to some specific embodiments of the present invention, the method includes dissolving crystal form C in a mixed solution of solvent A and solvent B with a volume ratio of 1:(2-3) at room temperature, stirring at room temperature for 5 days, and then allowing the solvent to evaporate naturally to obtain crystal form D.

[0111] According to some specific embodiments of the present invention, wherein the crystal form is crystal form F of the compound shown in formula (I-1) or (I-2), and the method includes dissolving crystal form C in a mixed solution of solvent A and solvent B with a volume ratio of 1:(2-3) at room temperature, and evaporating the solvent to obtain crystal form F.

[0112] According to some specific embodiments of the present invention, solvent A is selected from one or more of methanol, ethanol, n-propanol, ethyl formate, cyclopentyl methyl ether and ethyl acetate, and solvent B is selected from one or more of n-heptane, n-pentane, n-hexane and n-octane; preferably solvent A is n-propane and solvent B is n-hexane.

[0113] According to some specific embodiments of the present invention, the method includes dissolving crystal form C in a mixed solution of solvent A and solvent B with a volume ratio of 1:(2-3) at room temperature, stirring at room temperature for 1 day, and then allowing the solvent to evaporate naturally to obtain crystal form F.

[0114] According to some specific embodiments of the present invention, wherein the crystal form is crystal form E of the compound shown in formula (I-1) or (I-2), and the method includes recrystallizing crystal form C in isopropylbenzene or m-xylene to obtain crystal form E.

[0115] According to some specific embodiments of the present invention, wherein the crystal form is crystal form E of the compound shown in formula (I-1) or (I-2), and the method includes dissolving crystal form C in isopropylbenzene or m-xylene at 45-55°C (preferably 50-55°C), and obtaining crystal form E after the isopropylbenzene or m-xylene volatilizes.

[0116] According to some specific embodiments of the present invention, wherein the crystal form is crystal form E of the compound shown in formula (I-1) or (I-2), and the method comprises suspending and stirring crystal form C in isopropylbenzene at 50 °C for 5 days and then drying it. Alternatively, the free base crystal form E is obtained by stirring free base crystal form C in m-xylene at a temperature cycle (50 °C~5 °C, 0.1 °C / min) for 5 days and then drying it.

[0117] In another aspect, the present invention also provides a pharmaceutical composition comprising the crystalline or acidic salt of any one of the present invention, as well as a pharmaceutically acceptable carrier, diluent, and / or excipient.

[0118] In another aspect, the present invention also provides the use of the crystal form or acid salt of the present invention or the pharmaceutical composition thereof in the preparation of a medicament for treating diseases caused by abnormal activation of voltage-gated sodium channels or for treating diseases by inhibiting voltage-gated sodium channels.

[0119] According to some specific embodiments of the present invention, the voltage-gated sodium channel is Na V 1.8 channels.

[0120] According to some specific embodiments of the present invention, the disease is pain, pain-related diseases, multiple sclerosis, incontinence, or arrhythmia.

[0121] According to some specific embodiments of the present invention, the pain is one or more of the following: acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain, and idiopathic pain.

[0122] In summary, this invention provides a crystal form, salt, preparation, composition, and application of arylamidine compounds containing heterocyclic alkyl groups. The crystal form of this invention has the following advantages: (1) higher melting point and better chemical stability, which is beneficial for making pharmaceuticals that can be stored for a long time; (2) better solid properties, more uniform particle size distribution, and better flowability, which is beneficial for making tablets or capsules; (3) more stable crystal form, less prone to crystal transformation, making the absorption of different batches of the compound in the human body more stable and consistent, and less prone to large fluctuations. Attached Figure Description

[0123] Figure 1 The image shown is the XRPD diagram of phosphate crystal form A in Example 2. Figure 2 This is a TGA image of phosphate crystal form A in Example 2; Figure 3 The DSC diagram of phosphate crystal form A in Example 2; Figure 4 XRPD image of fumarate crystal form B in Example 3; Figure 5 This is a TGA image of fumarate crystal form B from Example 3; Figure 6 The image shows the DSC diagram of fumarate crystal form B in Example 3. Figure 7 The image shown is the XRPD diagram of the free alkali crystal form C in Example 4. Figure 8 This is a TGA image of the free alkali crystal form C in Example 4; Figure 9 The image shows the DSC diagram of the free alkali crystal form C in Example 4; Figure 10XRPD image of the amorphous solid in Example 1; Figure 11 The image shown is the XRPD diagram of the free alkali crystal form D in Example 5. Figure 12 The image shown is a TGA image of the free alkali crystal form D in Example 5. Figure 13 The image shows the DSC diagram of the free alkali crystal form D in Example 5; Figure 14 The image shown is the XRPD diagram of the free alkali crystal form E in Example 6. Figure 15 The image shown is a TGA image of the free alkali crystal form E in Example 6; Figure 16 The image shows the DSC diagram of the free alkali crystal form E in Example 6; Figure 17 The image shown is the XRPD diagram of the free alkali crystal form F in Example 7. Figure 18 The image shown is a TGA image of the free alkali crystal form F in Example 7. Figure 19 The image shown is a DSC diagram of the free alkali crystal form F in Example 7. Figure 20 XRPD overlay image of the sample for evaluating the stability of the free alkali crystalline C solid in Test Example 1; Figure 21 The DVS diagram of phosphate crystal form A in test example 2; Figure 22 XRPD overlay images of phosphate crystal form A in Test Example 2 before and after DVS testing; Figure 23 DVS diagram of fumarate crystal form B in test example 2; Figure 24 XRPD overlay images of fumarate crystal form B in Test Example 2 before and after DVS testing; Figure 25 DVS diagram of free alkali crystal form C in test example 2; Figure 26 XRPD overlay images of free alkali crystal form C in test example 2 before and after DVS testing; Figure 27 , Figure 28 , Figure 29 and Figure 30 The graph shows the solubility test results for Test Example 3. Detailed Implementation

[0124] The following detailed embodiments illustrate the implementation process and beneficial effects of the present invention, aiming to help readers better understand the essence and characteristics of the present invention, and are not intended to limit the scope of implementation of this case.

[0125] The XRPD images of this invention were acquired using an X-ray powder diffractometer manufactured by PANalytical, and the scanning parameters are shown in Table 1.

[0126] Table 1 XRPD Test Parameters

[0127] The TGA data of this invention were acquired using a Discovery TA5500 / TA550 thermogravimetric analyzer, and the DSC / mDSC data were acquired using a Discovery TA2500 / TA250 differential scanning calorimeter. Tables 2 and 3 list the test parameters.

[0128] Table 2 TGA and DSC Test Parameters

[0129] Table 3 mDSC Scan Parameters

[0130] The freeze-drying of the samples of this invention was completed using a SCIENTZ-30FG / A freeze dryer from Ningbo Xinzhi Biotechnology Co., Ltd.

[0131] The liquid NMR spectra of this invention were acquired on a Bruker 400M NMR spectrometer, DMSO- d 6. As a solvent.

[0132] The purity and solid stability of the samples in this invention were tested using a Waters H-Class high-performance liquid chromatograph, the dynamic solubility of the samples was tested using an Agilent 1260 high-performance liquid chromatograph, and the salt molar ratio was tested using a Thermo AQ RFIC ion chromatograph. The analytical conditions are shown in Tables 4 to 5.

[0133] Table 4 High Performance Liquid Chromatography Test Conditions

[0134] Table 5 Ion Chromatography Test Conditions

[0135] Example 1: Preparation of compound BX20-9-PCC2

[0136] Step 1: Synthesis of intermediate S3

[0137] The synthesis route is shown in the following formula:

[0138] Methods: Compound A3 (5.90 g, 29.20 mmol) was dissolved in MeCN (210 mL), cooled in an ice-water bath, and CDI (7.00 g, 30.70 mmol) was added to replace N2. The mixture was stirred at below 10 °C for 1.5 h. S2 (4.68 g, 30 mmol) and K2CO3 (5.00 g, 36.50 mmol) were then added, and the reaction mixture was stirred at 35 °C for 12 h. After the reaction was complete, water and dilute hydrochloric acid were added to the reaction mixture and stirred until clear. The mixture was extracted with EA, washed with concentrated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA = 20:1 to 10:1) to give a white solid S3 (7.40 g, 78.7%).

[0139] MS (ESI, m / z) 323 [M+H] + .

[0140] Step 2: S4 Synthesis

[0141] The synthesis route is shown in the following formula:

[0142] Method: Compound S3 (9.00 g, 28.0 mmol) was dissolved in anhydrous methanol (800 mL) and anhydrous tetrahydrofuran (160 mL). The solution was cooled to -40 °C, and the first batch of NiCl2·6H2O (6.80 g, 28.6 mmol) and NaBH4 (5.60 g, 148.4 mmol) and the second batch of NiCl2·6H2O (6.80 g, 28.6 mmol) and NaBH4 (5.60 g, 148.4 mmol) were added separately. The reaction was complete after the addition was finished. After the reaction was complete, saturated ammonium chloride was slowly added dropwise to the reaction solution at -40 °C and stirred for 30 min. The solution was allowed to rise naturally to room temperature, filtered through diatomaceous earth, extracted with DCM / MeOH, washed with concentrated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain a colorless oily compound S4 (3.57 g, 39.3%).

[0143] MS (ESI, m / z) 325 [M+H] + .

[0144] The NMR spectrum is as follows: 1 H NMR (400 MHz, CDCl3) δ = 6.96-6.83 (m, 2H), 4.47 (d, J = 9.6 Hz, 1H), 4.02 (d, J= 2.8 Hz, 1H), 2.92-2.84 (m, 1H), 1.70 (s, 3H), 0.81-0.78 (m,3H). Step 3: S5 Synthesis The synthesis route is shown in the following formula:

[0145] Method: Compound S4 (3.57 g, 11.0 mmol) was dissolved in toluene (30 mL), N2 was substituted, the temperature was lowered to -30°C, and DiBAL-H (1.5 M, 7.7 mL, 11.6 mmol) was slowly added dropwise. The reaction mixture was stirred at -25 to -30°C for 2 h. After the reaction was complete, the reaction solution was quenched in saturated ammonium chloride, filtered through diatomaceous earth, extracted with EA, washed with concentrated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a colorless oily compound S5 (3.53 g, crude product).

[0146] MS (ESI, m / z) 327 [M+H] + .

[0147] Step 4: S6 Synthesis

[0148] The synthesis route is shown in the following formula:

[0149] Method: Compound S5 (3.53 g, 10.8 mmol) was dissolved in anhydrous DCM (30 mL) and stirred until dissolved. Et3N (2.18 g, 21.6 mmol) was added, and the mixture was cooled to 0–10 °C in an ice-water bath. AcCl (1.70 g, 21.6 mmol) was slowly added dropwise. After the addition was complete, the mixture was brought to room temperature and stirred for 1 h. After the reaction was complete, saturated ammonium chloride was added to quench the reaction mixture, and the mixture was extracted with DCM, washed with concentrated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a colorless oily compound S6 (4.36 g, crude product).

[0150] MS (ESI, m / z) 369 [M+H] + .

[0151] Step 5: S7 Synthesis

[0152] The synthesis route is shown in the following formula:

[0153] Methods: Compound S6 (4.36 g, 11.8 mmol) was dissolved in anhydrous DCM (40 mL), N2 was replaced, and the temperature was lowered to -60 °C. TMSCN (3.52 g, 35.5 mmol) and BF3OEt2 (5.04 g, 35.5 mmol) were added dropwise. After the addition was complete, the mixture was stirred at -60 °C for 1 h, then allowed to rise naturally to room temperature and stirred for 12 h. After the reaction was complete, the reaction solution was quenched with saturated sodium carbonate solution, filtered through diatomaceous earth, extracted with DCM, washed with concentrated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain a colorless oily compound S7 (2.25 g, 56.9%).

[0154] MS (ESI, m / z) 336 [M+H] + .

[0155] Step 6: Synthesis of intermediate S8

[0156] The synthesis route is shown in the following formula:

[0157] Method: S7 (1.1 g, 3.28 mmol) was dissolved in DCM (15 mL), substituted with N2, and cooled to -78 °C. BBr3 (2.1 mL, 21.32 mmol) was slowly added dropwise. After the addition was complete, the temperature was raised to 0 °C and the reaction was stirred for 3 hours. After the reaction was complete, the reaction solution was slowly added dropwise to ice water, extracted with DCM, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a yellow oily compound S8 (1.0 g, crude product).

[0158] MS (ESI, m / z) 322 [M+H] + .

[0159] Step 7: Synthesis of intermediate S9

[0160] The synthesis route is shown in the following formula:

[0161] Method: S8 (500 mg, crude, 1.55 mmol) was dissolved in DMF (5 mL), and Cs2CO3 (2.1 mL, 21.32 mmol) and 3-iodooxetine (1.14 g, 6.2 mmol) were added. The mixture was heated to 70 °C and stirred for 16 hours. After the reaction was complete, the mixture was quenched with water, extracted with EA, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a yellow oily compound S9 (565 mg, crude).

[0162] MS (ESI, m / z) 378 [M+H] + .

[0163] Step 8: Synthesis of intermediate S10

[0164] The synthesis route is shown in the following formula:

[0165] Method: S9 (565 mg, crude, 1.5 mmol) was dissolved in MeOH (7.5 mL), and an aqueous solution of KOH (587 mg, 10.5 mmol, dissolved in 1.5 mL water) was added. The mixture was heated to 60 °C and stirred for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, diluted with water, extracted with MTBE, and the aqueous phase was adjusted to pH < 3 with 1 N HCl. The solution was extracted with EA, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oily compound S10 (330 mg, crude).

[0166] MS (ESI, m / z) 397 [M+H] + .

[0167] Step 9: Synthesis of intermediate S11

[0168] The synthesis route is shown in the following formula:

[0169] Methods: S10 (330 mg, crude, 0.83 mmol) was dissolved in DMF (6 mL), and EDCI (318 mg, 1.66 mmol), HOBT (135 mg, 1.0 mmol), and DIEA (321 mg, 2.4 mmol) were added. After stirring at room temperature for 10 minutes, 5-amino-2-fluorobenzonitrile (79 mg, 0.58 mmol) was added, and the reaction was continued at room temperature with stirring for 4 hours. After the reaction was complete, the mixture was quenched with water, extracted with EA, washed once with water and once with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a yellow oily compound S11 (400 mg, crude).

[0170] MS (ESI, m / z) 515 [M+H] + .

[0171] Step 10: Synthesis of BX20-9-PCC2

[0172] The synthesis route is shown in the following formula:

[0173] Method: Compound S11 (400 mg, crude, 0.78 mmol) was dissolved in EtOH (5 mL), and NH2OH (0.2 mL, 3.12 mmol, 50% in H2O) was added. The mixture was heated to 80 °C and stirred for 1 hour. After the reaction was complete, the solution was concentrated under reduced pressure and purified by preparative chromatography (formic acid system). The purified solution was then lyophilized to obtain a white amorphous solid, BX20-9-PCC2 (45 mg, 11%). The XRPD plot is shown below. Figure 10 As shown.

[0174] MS (ESI, m / z) 548 [M+H] + .

[0175] 1 H NMR (400 MHz, DMSO- d 6) δ 10.34 (s, 1H), 9.65 (s, 1H), 7.76 (d,1H), 7.69-7.62 (m, 1H), 7.22-7.14 (m, 3H), 5.33-5.25 (m, 1H), 5.07 (d, 3H),4.90-4.82 (m, 2H), 4.73-4.66 (m, 2H), 4.29-4.22 (m, 1H), 2.81-2.73 (m, 1H),1.60 (s, 3H), 0.72 (d, 3H).

[0176] Example 2 Preparation of phosphate crystal form A

[0177] Weigh 300.4 mg of the amorphous sample obtained in Example 1 into a 20 mL vial at room temperature, add 3.0 mL of ethanol / n-heptane (1:5, v / v), and stir magnetically at room temperature. Weigh 69.6 mg of 15 M H3PO4 aqueous solution into a 3 mL vial, add 1.0 mL of ethanol / n-heptane (1:5, v / v), and obtain a dilute phosphoric acid solution. Slowly add the dilute phosphoric acid solution to the 20 mL vial, rinse the 3 mL vial with 2.0 mL of ethanol / n-heptane (1:5, v / v), and transfer the rinsing solution to the 20 mL vial. Stir at room temperature for about 1 day, centrifuge, and vacuum dry the solid at room temperature for about 1 day. Collect the solid; the obtained solid is the phosphate crystal form A of BX20-9-PCC2. The XRPD plot is shown below. Figure 1 As shown, the TGA diagram is as follows: Figure 2 As shown, the DSC diagram is as follows Figure 3 As shown.

[0178] NMR data: 1 H NMR (400 MHz, DMSO- d 6) δ 10.34 (s, 1H), 9.62 (s, 1H), 7.75 (dd, J =6.5, 2.8 Hz, 1H), 7.67 – 7.63 (m, 1H), 7.23 – 7.12 (m, 3H), 5.80 (s, 2H),5.37 – 5.25 (m, 1H), 5.07 (d, J = 10.5 Hz, 1H), 4.90 – 4.83 (m, 2H), 4.71 -4.67 (m, 2H), 4.26 (dd, J = 10.5, 7.3 Hz, 1H), 2.81 – 2.73 (m, 1H), 1.61 (s, 3H), 0.73 – 0.71 (m, 3H).

[0179] Example 3 Preparation of fumarate crystal form B

[0180] Weigh 300.3 mg of the amorphous sample obtained in Example 1 and 32.1 mg of fumaric acid into a 20 mL vial at room temperature. Add 5.0 mL of ethanol / n-heptane (1:5, v / v) and stir magnetically for about 1 day at room temperature, then centrifuge. Dry the solid under vacuum at room temperature for about 32 hours, then under vacuum at 50 °C for about 1 hour. Collect the solid; the resulting solid is fumarate form B of BX20-9-PCC2, with a free base to acid ratio of 1:0.5. The XRPD plot is shown below. Figure 4 As shown, the TGA diagram is as follows: Figure 5 As shown, the DSC diagram is as follows Figure 6 As shown.

[0181] NMR data: 1 H NMR (400 MHz, DMSO- d 6) δ 13.11 (s, 0.5H), 10.34 (s, 1H), 9.63 (s, 1H), 7.75 (dd, J= 6.5, 2.8 Hz, 1H), 7.67 – 7.63 (m, 1H), 7.21 –7.10 (m, 3H), 6.63 (s, 1H), 5.79 (s, 2H), 5.33 – 5.26 (m, 1H), 5.07 (d, J =10.5 Hz, 1H), 4.90 – 4.83 (m, 2H), 4.72 – 4.67 (m, 2H), 4.26 (dd, J = 10.4,7.4 Hz, 1H), 2.81 – 2.73 (mz, 1H), 1.61 (s, 3H), 0.73 – 0.71 (m, 3H).

[0182] Example 4 Preparation of free alkali crystal form C

[0183] Method 1: Weigh 20.5 mg of the amorphous sample obtained in Example 1 at room temperature into a 5 mL vial, add 0.5 mL of ethyl formate / n-pentane (1:9, v / v) solvent to obtain a suspension. This suspension is first stirred at 50 °C and equilibrated for a period of time (approximately 2 hours). Then, while stirring, the temperature is lowered to 5 °C at a rate of 0.1 °C / min. After equilibration at 5 °C for another period of time (approximately 2 hours), the temperature is raised to 50 °C while stirring at a rate of 0.1 °C / min. This process is repeated twice. The solid is then separated by centrifugation. After air-drying at room temperature for approximately 4 hours, the solid is collected. The obtained solid is the free basal crystalline form C of BX20-9-PCC2. The XRPD diagram of the free basal crystalline form C is shown below. Figure 7 As shown, the TGA diagram is as follows: Figure 8 As shown, the DSC diagram is as follows Figure 9 As shown.

[0184] Temperature-dependent XRPD testing was performed on the free alkali crystalline form C. The results showed that after purging with nitrogen for 20 minutes, heating to 80 °C under nitrogen protection, and then cooling to 25 °C, the crystal form of the free alkali crystalline form C remained unchanged. Humidity-dependent XRPD testing was also performed on the free alkali crystalline form C. The results showed that at an initial humidity of 50%RH, the crystal form remained unchanged after purging with wet nitrogen for 1 hour under conditions of 50%RH to 90%RH. Furthermore, at conditions of 10%RH to 90%RH, the crystal form remained unchanged after purging with wet nitrogen for 1 hour. Based on sample characterization and the results of temperature-dependent and humidity-dependent XRPD tests, it is presumed that the free alkali crystalline form C is an amorphous form.

[0185] NMR data: 1H NMR (400 MHz, DMSO- d 6) δ 10.34 (s, 1H), 9.63 (s, 1H), 7.75 (dd, J =6.5, 2.8 Hz, 1H), 7.67 – 7.63 (m, 1H), 7.21 – 7.12 (m, 3H), 5.80 (s, 2H), 5.33 – 5.26 (m, 1H), 5.07 (d, J = 10.4 Hz, 1H), 4.89 – 4.83(m, 2H), 4.72 –4.67 (m, 2H), 4.26 (dd, J = 10.5, 7.4 Hz, 1H), 2.81 – 2.73 (m, 1H), 1.61 (s,3H), 0.77 – 0.68 (m, 3H). Method 2: Weigh 101.8 mg of the amorphous sample obtained in Example 1, add 1.0 mL of ethyl formate, and the sample dissolves completely. Add 1.0 mL of n-pentane while stirring at room temperature; no solid precipitates. Add 10.8 mg of seed crystals (free base crystal form C), and stir at room temperature for 30 minutes; the seed crystals dissolve completely. Add 0.5 mL of n-pentane while stirring at room temperature; no solid precipitates. Add 10.2 mg of seed crystals (free base crystal form C), and stir at room temperature for approximately 30 minutes; the seed crystals do not dissolve completely. Add 0.5 mL of n-pentane every 10 minutes while stirring at room temperature, repeating the above steps three times (a total of 1.5 mL of n-pentane is added), and the sample becomes a suspension. Stir at room temperature for 10 minutes, centrifuge, and air-dry at room temperature. The dry sample mass is 95.9 mg, which is the free base crystal form C.

[0186] Method 3: Weigh 2.04 g of the amorphous sample obtained in Example 1, and add 40.0 mL of ethyl formate / n-pentane (1:9, v / v) to obtain a suspension. Stir the sample magnetically at 50 °C for 2 hours, then cool to 5 °C at a rate of 0.1 °C / min. After stirring overnight at 5 °C, centrifuge. The solid is then vacuum-dried overnight at room temperature. Collect the solid and test XRPD; this indicates the free alkali crystal form C.

[0187] Example 5 Preparation of free alkali crystal form D

[0188] Free base crystal form D was obtained by suspending and stirring free base crystal form C in cyclopentyl methyl ether / n-heptane (1:2, v / v) at room temperature for 5 days, followed by air-drying at room temperature. XRPD results showed that the crystal form of the sample remained unchanged after heating to 76 °C and cooling to room temperature. Heating to 110 °C and cooling to room temperature resulted in the sample transforming into an amorphous form. The measured XRPD pattern is shown below. Figure 11 As shown, the TGA diagram is as follows: Figure 12 As shown, the DSC diagram is as follows Figure 13 As shown.

[0189] Example 6 Preparation of free alkali crystal form E

[0190] Free base crystal form E (829163-32-A1) was obtained by suspending and stirring free base crystal form C in isopropylbenzene at 50 °C for 5 days, followed by air drying. Alternatively, free base crystal form E was obtained by stirring free base crystal form C in m-xylene under temperature cycling (50 °C~5 °C, 0.1 °C / min) for 5 days, followed by air drying. XRPD results showed that the crystal form remained unchanged after heating the sample to 85 °C and cooling to room temperature and humidity. After heating to 115 °C and cooling to room temperature and humidity, it transformed into an amorphous form. The measured XRPD pattern is shown below. Figure 14 As shown, the TGA diagram is as follows: Figure 15 As shown, the DSC diagram is as follows Figure 16 As shown.

[0191] Example 7 Preparation of free alkali crystal form F

[0192] Free alkali crystal form F (829163-47-A1) was obtained by suspending and stirring free alkali crystal form C (829163-29-A) in n-propanol / n-hexane (1:2, v / v) at room temperature for 1 day, followed by washing with n-hexane and air-drying at room temperature. XRPD results showed that the crystal form of the sample remained essentially unchanged after heating to 70 °C and cooling to room temperature. Heating to 125 °C and cooling to room temperature transformed it into an amorphous form. The measured XRPD pattern is shown below. Figure 17 As shown, the TGA diagram is as follows: Figure 18 As shown, the DSC diagram is as follows Figure 19 As shown.

[0193] Physicochemical property tests: Test Example 1: Solid Stability Test Phosphate form A, fumarate form B, and free base form C were subjected to stability testing under ICH illumination conditions (VIS ≥1200000 Lux·hrs + UV ≥200 W·hrs / m2). Simultaneously, each salt form and the free base were placed at 25 °C / 60%RH, 40 °C / 75%RH, 60 °C, and 25 °C / 92.5%RH for one week. Physicochemical stability was evaluated by XRPD and HPLC. The results are shown in Tables 6 and 7.

[0194] Table 6 Summary of Solid Stability Assessment (I)

[0195] Table 7 Summary of Solid Stability Assessment (II)

[0196] The results are as follows: 1) Phosphate crystal form A showed a decrease in purity after being placed at 60 °C for one week. Phosphate crystal form A showed no significant changes in purity or crystal form after being placed at 25 °C / 60%RH, 40 °C / 75%RH, and 25 °C / 92.5%RH for one week, or under light irradiation (VIS ≥ 1200000 Lux·hrs + UV ≥ 200 W·hrs / m²). 2) Fumarate crystal form B and free base crystal form C showed no significant changes in purity or crystal form after being placed at 25 °C / 60%RH, 40 °C / 75%RH, 60 °C, and 25 °C / 92.5%RH for one week, or under light irradiation (VIS ≥ 1200000 Lux·hrs + UV ≥ 200 W·hrs / m²). 1) No significant changes in purity and crystal form after placement; 2) Experiments show that the solid stability of fumarate crystal form B and free alkali crystal form C is very good.

[0197] The free alkali crystalline form C was placed at 80 °C for 24 hours, and its physical and chemical stability was tested by XRPD and HPLC, respectively. The results are summarized in Table 8, and the specific characterization results are listed below. Figure 20 See Table 9. The results show that no significant changes in crystal form and purity were observed in the free alkali crystal form C after the solid stability assessment. The data further demonstrate the solid stability of the free alkali crystal form C.

[0198] Table 8 Summary of Solid Stability Assessment

[0199] Table 9 Summary of HPLC impurities in the solid stability sample of free alkali crystal form C (829163-29-A)

[0200] Test Example 2: Hygroscopicity Test of the Crystal Form of the Invention

[0201] The hygroscopicity of phosphate crystal form A, fumarate crystal form B, and free base crystal form C was evaluated using a dynamic moisture adsorption (DVS) instrument. Starting at 0% relative humidity (0% / RH), the percentage change in sample mass was collected at a constant temperature of 25 °C as humidity varied (0%RH-95%RH-0%RH). The DVS evaluation results are summarized in Table 10, and the DVS test results and subsequent XRPD results are listed below. Figures 21 to 26 The results showed that phosphate crystal form A ( Figure 21 and Figure 22 ), fumarate crystal form B ( Figure 23 and Figure 24 ) and free alkali crystal form C ( Figure 25 and Figure 26 The water adsorption rates at 25 °C / 80%RH were 0.5068%, 0.1994%, and 0.6186%, respectively. No significant changes in crystal form were observed in any of the salt forms and the free base after DVS testing.

[0202] Table 10 Hygroscopicity Assessment Results

[0203] Test Example 3: Solubility Test of the Crystal Form of the Invention

[0204] The dynamic solubility of phosphate crystal form A, fumarate crystal form B, and free base crystal form C in pure water and three biological solvents was evaluated. The dynamic solubility of each sample in pure water, SGF, FaSSIF, and FeSSIF solvents (1, 2, 4, and 24 hours) was determined by rotary mixing at a feed concentration of 2 mg / mL (calculated as free base) at 37 °C. Samples at each time point were centrifuged and filtered (using a 0.45 μm PTFE filter), and the HPLC concentration and pH of the filtrate were measured. The XRPD of the centrifuged solid samples was tested. The solubility test results are summarized in Table 11, and the dynamic solubility curves are shown in [Table data missing]. Figures 27 to 30 Dynamic solubility results showed no significant differences in the solubility of phosphate crystal form A, fumarate crystal form B, and free base crystal form C in various biological solvents. In pure water, phosphate crystal form A had the highest solubility, followed by fumarate crystal form B, while free base crystal form C had the lowest solubility. No significant changes in crystal form were observed for any salt form or free base after the solubility test.

[0205] Table 11 Summary of Dynamic Solubility Test Results

[0206] S: Solubility (mg / mL). FC: Crystal form change. -: Sample dissolved, not tested. No: Crystal form unchanged.

[0207] Biological experimental data: The invention is further described and explained below with reference to test examples.

[0208] Experimental Example 1: The blocking activity of the compound of the present invention on sodium ion channel 1.8 (Nav1.8)

[0209] 1. Research Objective

[0210] Manual patch-clamp technique was used to evaluate whether the test compound had a potential inhibitory effect on the voltage-gated sodium ion channel hNav1.8. This experiment was conducted by examining the effect of the compound at five concentrations, or at single or two concentration points, on the hNav1.8 channel current.

[0211] 2. Test Methods

[0212] 2.1 Test Materials

[0213] 1) Cells: The HEK293 cell line stably expressing the hNav1.8 / β3 ion channel was prepared by the Biology Department of Kanglong Pharmaceutical (Beijing) Co., Ltd. (the lentiviral vectors expressing human Nav1.8 and β3 were transduced into HEK293 cells, and the cells were screened. For details, please refer to: Proc Natl Acad Sci US A. 2022 Jul 26;119(30):e2208211119. doi: 10.1073 / pnas.2208211119. and Cell Lines / BSYS CHONaV1.8 / β3 Cell Line manual). The cell line was cultured in a medium containing 90% DMEM, 10% fetal bovine serum, 100 U / mL penicillin-streptomycin solution, 0.75 μg / mL puromycin and 100 μg / mL hygromycin. When the cell density reaches 40%–80% of the bottom area of ​​the culture dish, the cells are digested with trypsin and passaged three times a week. Before the experiment, the cells are cultured in 6 cm culture dishes at a total number of 5 × 10⁵ and seeded on glass slides for subsequent manual patch-clamp experiments.

[0214] 2) Compounds: The test compounds were dissolved in DMSO to prepare stock solutions with final concentrations of 10 or 30 mM. The stock solutions were then diluted with DMSO to prepare the required intermediate solutions. Before the experiment, the intermediate solutions of the test compounds were diluted again with extracellular fluid at a ratio of 1:1000 to prepare a series of working solutions. The concentration of DMSO in the working solutions was 0.1% (volume ratio). The potential inhibitory effect of the compounds on the hNav1.8 channel was determined.

[0215] 2.2 Test Procedure

[0216] 1) Place the small glass slide containing HEK293 cells in the culture dish into the perfusion tank of the micromanipulation table.

[0217] 2) Using an Olympus IX71 or IX73 inverted microscope, position the appropriate cells in the center of the field of view. Use a ×10 objective lens to locate the tip of the glass electrode and center it in the field of view. Then, use the micromanipulator to move the electrode down while adjusting the coarse focus knob to slowly bring the electrode closer to the cells.

[0218] 3) When you get close to the cell, switch to a 40x objective lens for observation. Use the micromanipulator to fine-tune the setting so that the electrode gradually gets closer to the cell surface.

[0219] 4) Apply negative pressure to form a seal with a resistance higher than 1 GΩ between the electrode tip and the cell membrane.

[0220] 5) Compensate for the transient capacitive current Cfast in voltage clamp mode. Then, repeatedly apply short negative voltages to rupture the membrane, eventually forming a whole-cell recording mode.

[0221] 6) Under the condition of membrane potential clamped at -60mV, the slow capacitive current Cslow, cell membrane capacitance (Cm) and input membrane resistance (Ra) are compensated respectively.

[0222] 7) After the cells stabilize, change the clamping voltage to -80mV, set the sampling frequency to 20kHz, and the filtering frequency to 10kHz. The leakage current detection conditions are: clamping voltage changed to -80mV, time duration 200ms.

[0223] 8) The hNav1.8 current testing method is as follows: A 20-millisecond depolarization command voltage is applied to depolarize the membrane potential from -80mV to -10mV, and then the membrane potential is repolarized to -80mV to close the channel. Stimulation is performed every 15 seconds. The instantaneous peak current under the depolarization voltage is the magnitude of the Nav1.8 sodium channel current.

[0224] 9) The hNav1.8 current used to detect the test compound was continuously recorded for 120 seconds before drug administration to assess the stability of the hNav1.8 current generated by the test cells. Only stable cells within the acceptable range of the evaluation criteria were allowed to proceed to the subsequent compound detection.

[0225] 10) Testing the inhibitory effect of the test compound on hNav1.8 current: First, the hNav1.8 current measured in extracellular fluid containing 0.1% DMSO is used as the baseline. After the hNav1.8 current has stabilized for at least 5 minutes, the solution containing the test compound is sequentially perfused around the cells from low to high concentration. After each perfusion, wait approximately 5 minutes to allow the compound to fully act on the cells while simultaneously recording the hNav1.8 current. After the recorded current tends to stabilize, the last 5 hNav1.8 current values ​​are recorded, and their average is taken as the final current value at the specific concentration. After testing the compound, 5 nM of the reference compound is added to the same cell to completely inhibit its current, serving as a positive control for that cell. Simultaneously, the positive and reference compounds are detected synchronously using the same patch-clamp system before and after the test drug experiment to ensure the reliability and sensitivity of the entire detection system. The above test steps are repeated on two separate test cells (n=2).

[0226] 2.3 Data Analysis

[0227] 1) The data must meet the following standards: initial sealing resistance greater than 1GΩ; film breaking resistance Ra less than 15MΩ; leakage current under detection voltage less than 50% of the current value under that condition; Nav1.8 peak current magnitude at least greater than 200pA; 2) The data will be analyzed according to the following steps (data output by PatchMaster software): After injecting blank solvent or a compound gradient solution, five consecutive current values ​​were obtained and stabilized. The average value was then used as the "current magnitude". 空白 "and "current magnitude" 化合物 The current suppression percentage is calculated using the following formula.

[0228]

[0229] 3. Experimental Results and Analysis

[0230] Table 12. Restrictive activity (IC50) of compound BX20-9-PCC2 against Nav1.8 50 (nM)

[0231] Conclusion: Table 12 shows that compound BX20-9-PCC2 has a significant inhibitory effect on the activity of Nav1.8 channel.

[0232] Experimental Example 2: Pharmacokinetic determination of the compound of the present invention in SD rats

[0233] 1. Experimental Objective

[0234] Using SD rats as test animals, the pharmacokinetic behavior of the example compounds at a dose of 10 mg / kg by intragastric administration / 1 mg / kg

[0235] by intravenous administration in rat plasma was studied.

[0236] 2. Test Methods

[0237] SPF-grade SD rats with a body weight of (200±20) g were purchased from Beijing Sibeifu Biotechnology Co., Ltd., with the animal production license number SCXK (Beijing) 2022-0030. The test was carried out after 3-4 days of acclimation feeding.

[0238] Intragastric administration group: The example compound was formulated into a suspension with a drug concentration of 1 mg / mL, using Tween 80 + 0.5% methyl cellulose (MC, CAS: 9004-67-5) (1:99, v / v) as the formulation solvent. The acclimated rats were administered intragastrically at a dose of 10 mg / kg with an administration volume of 10 mL / kg. Blood was collected via jugular vein puncture before administration (0 h) and at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration.

[0239] Intravenous administration group: The example compound was formulated into a solution with a drug concentration of 0.2 mg / mL, using 5% DMA + 5% Solutol HS-15 + 90% normal saline as the formulation solvent. The acclimated rats were administered via tail vein injection at a dose of 1 mg / kg with an administration volume of 5 mL / kg. Blood was collected via jugular vein puncture before administration (0 h) and at 5, 15, 30 min, 1, 2, 4, 6, 8, and 24 h after administration.

[0240] The collected blood volume was approximately 0.2 mL, which was placed in a labeled EDTA-K2 anticoagulant test tube. Immediately after blood collection, the blood collection tube was gently and completely inverted 3 times to mix with the anticoagulant, then immediately placed in an ice water bath, centrifuged at 1700 g for 10 min at 4°C. After the centrifugation operation, the plasma was promptly aliquoted into correspondingly labeled EP tubes and stored in a -80°C refrigerator.

[0241] A briefly validated LC-MS / MS method was used to determine the concentration of the example compound in plasma after administration.

[0242] 3. Test Results and Analysis

[0243] The main pharmacokinetic parameters were calculated using WinNonlin 8.3. The results are shown in Table 13.

[0244] Table 13 Results of rat pharmacokinetic test

[0245] Conclusion: Compound BX20-9-PCC2 exhibits good pharmacokinetic absorption in rats and has favorable pharmacokinetic properties.

[0246] Experimental Example 3 Determination of Pharmacokinetics of the Compound of the Present Invention in Beagle Dogs

[0247] 1. Test Objective

[0248] Using Beagle dogs as test animals, the pharmacokinetic behavior of the example compounds in dog plasma after intragastric administration at a dose of 3 mg / kg / intravenous injection at a dose of 0.5 mg / kg was studied.

[0249] 2. Test Method

[0250] Beagle dogs with a body weight of 9 to 12 kg were purchased from Hubei Yizhicheng Biotechnology Co., Ltd., with the animal production license number SCXK (E) 2021-0020. The test was carried out after 3-4 days of feeding.

[0251] Intragastric administration group: The example compound was formulated into a suspension with a drug concentration of 3 mg / mL, using a solvent of Tween 80 + 0.5% methyl cellulose (MC, CAS: 9004-67-5) (1:99, v / v). Adaptively fed dogs were administered intragastrically at a dose of 3 mg / kg and a administration volume of 1 mL / kg. Blood was collected via forelimb venipuncture before administration (0 h) and at 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, and 24 h after administration.

[0252] Intravenous administration group: The example compound was formulated into a solution with a drug concentration of 0.5 mg / mL, using a solvent of 5% DMA + 5% Solutol HS-15 + 90% normal saline. Adaptively fed dogs were administered via tail vein injection at a dose of 0.5 mg / kg and a administration volume of 1 mL / kg. Blood was collected via forelimb venipuncture before administration (0 h) and at 5, 15, 30 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 24 h after administration.

[0253] The collected blood volume was approximately 1 mL, which was placed in a labeled EDTA-K2 anticoagulant test tube. Immediately after blood collection, the blood collection tube was gently and completely inverted 3 times to mix with the anticoagulant, and then immediately centrifuged at 1700 g for 10 min at 4°C in an ice water bath. After the centrifugation operation, the plasma was promptly aliquoted into correspondingly labeled EP tubes and stored in a -80°C refrigerator.

[0254] The concentration of the example compound in plasma after administration was determined using a briefly validated LC-MS / MS method.

[0255] 3. Test Results and Analysis

[0256] The main pharmacokinetic parameters were calculated using WinNonlin 8.3. The results are shown in Table 14.

[0257] Table 14 Results of canine pharmacokinetic studies

[0258] Conclusion: Compound BX20-9-PCC2 is well absorbed in dogs and exhibits good pharmacokinetic characteristics.

Claims

1. A crystal form of the compound shown in formula (I), the structure of which is shown below: （I）。 2. The crystal form according to claim 1, wherein, The crystal form is crystal form C, which has characteristic peaks at the following 2θ angle positions in the XRPD diagram: 11.3078°±0.2°, 13.5683°±0.2°, 18.9765°±0.2°; preferably, it has characteristic peaks at the following 2θ angle positions: 6.8408°±0.2°, 15.0308°±0.2°, 18.0179°±0.2°; more preferably, crystal form C has characteristic peaks at the following 2θ angle positions in the XRPD diagram: 5.4226°±0.2°, 6.8408°±0.2°, 9.6352°±0.2°, 10.9387°±0.2°, 11.3078°±0.2°, 13.5683°±0.2°, 14.1007°±0.2°, 1 5.0308°±0.2°, 15.2073°±0.2°, 16.1526°±0.2°, 16.4110°±0.2°, 17.1085°±0.2°, 17.4268°±0.2°, 18.0179°±0.2°, 18.9765°±0.2°, 19.3190°±0.2°, 19. The preferred crystal forms are 8048°±0.2°, 20.4612°±0.2°, 21.1703°±0.2°, 21.9341°±0.2°, 22.4615°±0.2°, 23.2838°±0.2°, 25.7433°±0.2°, and 27.8761°±0.2°. The XRPD diagram of the preferred crystal form C is shown in Figure 7.

3. The crystal form according to claim 2, wherein, The TGA chart of the crystal form C shows a weight loss of 0.90% in the temperature range of 30.0℃±2℃ to 150.0℃±2℃; preferably, the TGA chart of the crystal form C is shown in Figure 8.

4. The crystal form according to any one of claims 2 to 3, wherein, The DSC pattern of the crystal form C shows an exothermic peak at 109.8℃±2℃; preferably, the DSC pattern of the crystal form C is shown in Figure 9.

5. The crystal form according to claim 1, wherein, The crystal form is crystal form D, which has characteristic peaks at the following 2θ angle positions in the XRPD diagram: 4.9961°±0.2°, 6.5244°±0.2°, 9.9843°±0.2°, and 11.5765°±0.2°; preferably, it has characteristic peaks at the following 2θ angle positions: 16.1881°±0.2°, 17.9848°±0.2°, and 19.5063°±0.2°; more preferably, the XRPD diagram of crystal form D is shown in Figure 11. The crystal form is crystal form E, which has characteristic peaks at the following 2θ angle positions in the XRPD image: 5.1853°±0.2°, 9.3646°±0.2°, 10.3873°±0.2°, 10.7555°±0.2°, 14.0365°±0.2°, 14.7965°±0.2°; preferably, it has characteristic peaks at the following 2θ angle positions: 15.0927°±0.2°, 15.4613°±0.2°, 15.8772°±0.2°, 17.1506°. 17.4054°±0.2°, 17.6948°±0.2°, 18.0469°±0.2°; more preferably, the crystal form E has characteristic peaks at the following 2θ angle positions in the XRPD diagram: 18.3516°±0.2°, 18.5642°±0.2°, 18.9047°±0.2°, 19.2088°±0.2°, 21.7004°±0.2°, 22.3494°±0.2°; and even more preferably, the XRPD diagram of the crystal form E is shown in Figure 14. The crystal form is crystal form F, which has characteristic peaks at the following 2θ angle positions in the XRPD image: 5.0855°±0.2°, 6.8375°±0.2°, 7.0967°±0.2°, 9.2777°±0.2°, 9.6246°±0.2°, 11.3242°±0.2°; preferably, it has characteristic peaks at the following 2θ angle positions: 13.5847°±0.2°, 14.0768°±0.2°, 15°±0.2°. 0.0685°±0.2°, 16.4020°±0.2°, 17.0812°±0.2°; more preferably, the crystal form F has characteristic peaks at the following 2θ angle positions in the XRPD diagram: 18.0482°±0.2°, 19.0023°±0.2°, 19.7967°±0.2°, 21.2159°±0.2°, 23.2456°±0.2°; even more preferably, the XRPD diagram of the crystal form F is shown in Figure 17.

6. The crystal form according to claim 5, wherein, When the crystal form is crystal form D, the TGA chart of crystal form D shows a weight loss of 2.12% in the temperature range of 27.9℃±2℃ to 80.0℃±2℃; preferably, the TGA chart of crystal form D is shown in Figure 12; When the crystal form is crystal form E, the TGA chart of crystal form E shows a weight loss of 2.11% in the temperature range of 27.3℃±2℃ to 90.0℃±2℃; preferably, the TGA chart of crystal form E is shown in Figure 15; When the crystal form is crystal form F, the TGA chart of crystal form F shows a weight loss of 4.67% in the temperature range of 27.3℃±2℃ to 150.0℃±2℃; preferably, the TGA chart of crystal form F is shown in Figure 18.

7. The crystal form according to any one of claims 5 to 6, wherein, When the crystal form is crystal form D, the DSC diagram of crystal form D has an exothermic peak at 90.7℃±2℃; preferably, the DSC diagram of crystal form D is shown in Figure 13. When the crystal form is crystal form E, the DSC diagram of crystal form E has an exothermic peak at 103.4℃±2℃; preferably, the DSC diagram of crystal form E is shown in Figure 16. When the crystal form is crystal form F, the DSC diagram of crystal form F has an exothermic peak at 85.9℃±2℃; preferably, the DSC diagram of crystal form F is shown in Figure 19.

8. An acid salt of the compound shown in formula (I), the structure of which is shown below: （I）。 9. The acid salt according to claim 8, wherein, The acid salt is selected from inorganic or organic acid salts of compounds of formula (I); the inorganic acid salt is selected from hydrochloride, sulfate, phosphate or hydrobromide; the organic acid salt is selected from 1,5-naphthalenedisulfonate, methanesulfonate, ethylsulfonate, p-toluenesulfonate, benzenesulfonate, hydroxyethylsulfonate, acetate, maleate, fumarate, citrate, oxalate, malonate, tartrate, malate, adipate, hippurate, succinate or camphorate; preferably, the acid salt is selected from phosphate, maleate or fumarate; more preferably, the acid salt is selected from phosphate and fumarate.

10. The acid salt according to claim 8 or 9, wherein, In the molecule of the acid salt, each molecule of the acid salt contains 0.2-3 acids, with the compound shown in formula (I) as 1, preferably 0.2, 0.5, 1, 1.5, 1.2, 2, 2.5 or 3, further preferably 0.5, 1, 2 or 3, and even more preferably 0.5 or 1.

11. The acid salt according to any one of claims 8 to 10, wherein, The acid salt is a hydrate or anhydrous form; when the acid salt is a hydrate, the number of water molecules in each molecule of the acid salt is 0.2-3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3.

12. The acid salt according to any one of claims 8 to 11, wherein the acid salt of the compound shown in formula (I) is a crystal form, said crystal form being selected from phosphate crystal form A or fumarate crystal form B; said phosphate crystal form A has characteristic peaks at the following 2θ angle positions in the XRPD diagram: 19.7338°±0.2°, 14.7733°±0.2°, 4.9234°±0.2°; preferably, it also has characteristic peaks at the following 2θ angle positions: 28.4729°±0.2°, 24°±0.2°. 0.7285°±0.2°; The fumarate crystal form B has characteristic peaks at the following 2θ angle positions in the XRPD image: 4.6311°±0.2°, 6.3918°±0.2°, 9.2234°±0.2°; Preferably, it also has characteristic peaks at the following 2θ angle positions: 12.7622°±0.2°, 13.9053°±0.2°, 20.1741°±0.2°, 23.8110°±0.2°, 27.0322°±0.2°.

13. The acid salt according to claim 12, wherein, When the crystal form is phosphate crystal form A, phosphate crystal form A has characteristic peaks at the following 2θ angle positions in the XRPD diagram: 4.9234°±0.2°, 9.8341°±0.2°, 10.9735°±0.2°, 14.7733°±0.2°, 15.3579°±0.2°, 16.9716°±0.2°, 17.6679°±0.2°, 19.0116°±0.2°, 19.73 38°±0.2°, 22.4749°±0.2°, 23.7070°±0.2°, 24.7285°±0.2°, 26.4139°±0.2°, 28.4729°±0.2°, 29.7696°±0.2°, 30.6925°±0.2°, 31.8245°±0.2°, 35.9037°±0.2°; the preferred XRPD pattern of the phosphate crystal form A is shown in Figure 1; When the crystal form is fumarate crystal form B, fumarate crystal form B has characteristic peaks at the following 2θ angle positions in the XRPD diagram: 4.6311°±0.2°, 4.9902°±0.2°, 6.3918°±0.2°, 8.6572°±0.2°, 9.2234°±0.2°, 9.9379°±0.2°, 11.4943°±0.2°, 12.1857°±0.2°, 12.7622°±0.2°, 13.9053°±0.2°, and 14.6249°±0.2°. The preferred fumarate crystal form B has the following XRPD patterns: 16.5238°±0.2°, 17.0319°±0.2°, 18.4858°±0.2°, 20.1741°±0.2°, 20.9944°±0.2°, 21.6205°±0.2°, 22.6734°±0.2°, 23.8110°±0.2°, 25.2138°±0.2°, 26.5898°±0.2°, 27.0322°±0.2°, and 27.9024°±0.2°. Figure 4 shows the preferred fumarate crystal form B.

14. The acid salt according to claim 12 or 13, wherein, When the crystal form is phosphate crystal form A, the TGA chart of phosphate crystal form A shows a weight loss of 1.18% in the temperature range of 29.0℃±2℃ to 150.0℃±2℃; preferably, the TGA chart of phosphate crystal form A is shown in Figure 2; When the crystal form is fumarate crystal form B, the TGA chart of fumarate crystal form B shows a weight loss of 1.09% in the temperature range of 30.3℃±2℃ to 100.0℃±2℃; preferably, the TGA chart of fumarate crystal form B is shown in Figure 5.

15. The acid salt according to any one of claims 12 to 14, wherein, When the crystal form is phosphate crystal form A, the DSC diagram of phosphate crystal form A has an exothermic peak at 178.8℃±2℃; preferably, the DSC diagram of phosphate crystal form A is shown in Figure 3; When the crystal form is fumarate crystal form B, the DSC diagram of fumarate crystal form B has an exothermic peak at 141.0℃±2℃; preferably, the DSC diagram of fumarate crystal form B is shown in Figure 6.

16. The method for preparing the crystal form according to any one of claims 1-7 or 9-15, wherein, The method includes recrystallizing the compound of formula (I) or its acid salt in an organic solvent to obtain the crystal form.

17. The preparation method according to claim 16, wherein, The organic solvent is isopropylbenzene, m-xylene, or a mixture of solvent A and solvent B in a volume ratio of 1:(1-10), preferably in a volume ratio of 1:(2-9); solvent A is selected from one or more of methanol, ethanol, ethyl formate, ethyl acetate, n-propanol, and cyclopentyl methyl ether, and solvent B is selected from one or more of n-heptane, n-pentane, n-hexane, and n-octane.

18. The preparation method according to claim 17, wherein, When the crystal form is the crystal form of the acid salt of the compound shown in formula (I), the method includes recrystallizing the acid salt of the compound shown in formula (I) in an organic solvent to obtain the crystal form; the organic solvent is a mixture of solvent A and solvent B in a volume ratio of 1:(4-6), preferably 1:5; solvent A is selected from methanol and / or ethanol, and solvent B is selected from one or more of n-heptane, n-pentane, n-hexane and n-octane; When the crystal form is crystal form C, crystal form D or crystal form F of the compound shown in formula (I), the method includes recrystallizing the compound shown in formula (I) in an organic solvent to obtain the crystal form; the organic solvent is a mixture of solvent A and solvent B in a volume ratio of 1:(1-10), preferably in a volume ratio of 1:(1.5-9); solvent A is selected from one or more of ethyl formate, ethyl acetate, cyclopentyl methyl ether and n-propanol, and solvent B is selected from one or more of n-heptane, n-pentane, n-hexane and n-octane; When the crystal form is crystal form E of the compound shown in formula (I), the method includes recrystallizing crystal form C in isopropylbenzene or m-xylene to obtain crystal form E.

19. A pharmaceutical composition comprising the crystal form according to any one of claims 1 to 7 or the acid salt according to any one of claims 8 to 15, and one or more pharmaceutically acceptable carriers, diluents and / or excipients.

20. Use of the crystal form according to any one of claims 1 to 7, or the acid salt according to any one of claims 8 to 15, or the pharmaceutical composition according to claim 19, in the preparation of a medicament for treating diseases caused by abnormal activation of voltage-gated sodium channels or for treating diseases by inhibiting voltage-gated sodium channels.

21. The use according to claim 20, wherein, The voltage-gated sodium channel is Nav1.

8.

22. The use according to claim 20, wherein the disease is pain, pain-related disease, multiple sclerosis, incontinence, or arrhythmia; wherein the pain is preferably one or more of acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain, and idiopathic pain.

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