Crystal forms of aromatic fused-ring nav1.8 inhibitor and salt thereof, pharmaceutical composition, and use

Abstract

The present invention relates to the field of pharmaceutical crystal forms, and specifically relates to crystal forms of 2-(4,4-difluoroazepin-1-yl)-N-(2-sulfamoylpyridin-4-yl)quinoline-3-carboxamide and a salt thereof, a pharmaceutical composition, and a use. The crystal forms of a compound of formula (I) and a salt thereof which are obtained in the present invention have excellent physical stability and chemical stability, and compared with free base crystal form K1 of the compound of formula (I), have significantly improved solubility, hygroscopicity and bioavailability, and are more conducive to clinical applications. Also disclosed in the present invention is a use of the crystal forms of the compound of formula (I) and the salt thereof as sodium ion channel Nav1.8 inhibitors for treating a wide range of pain.

Description

Crystal forms, pharmaceutical compositions and uses of an aromatic cyclocyclic Nav1.8 inhibitor and its salts Technical Field

[0001] This application relates to the field of biomedicine, specifically to compound 2-(4,4-difluoroaza). Different crystal forms of 1-yl)-N-(2-aminosulfonylpyridin-4-yl)quinoline-3-carboxamide and its salts are also involved, as well as pharmaceutical compositions comprising such crystal forms and their medicinal uses. Background Technology

[0002] Pain is a complex physiological and psychological activity and one of the most common symptoms in clinical practice. Originally intended as a protective mechanism to alert people to potential dangers, abnormal pain can cause physiological dysfunction, especially chronic pain, which severely impacts people's quality of life. According to a 2019 report (http: / / news.medlive.cn / anes / info-progress / show-153086_201.html), the global prevalence of chronic pain is 12%–30%. In the United States, the number of people suffering from pain has surpassed the number suffering from diabetes, heart disease, and cancer, with annual economic losses due to pain reaching $560 billion–635 billion (https: / / www.physio-pedia.com / Epidemiology_of_Pain); while statistics from China in 2015 show that the pain market reached 20.8 billion RMB (https: / / paindoctor.com / resources / chronic-pain-statistics / ). Currently used analgesics, such as opioid receptor agonists, cyclooxygenase inhibitors, and GABA receptor agonists, either have addictive properties, respiratory depression, gastrointestinal side effects, or cause adverse cardiovascular reactions and central nervous system depression, leaving clinical needs far from being met. Therefore, the pain management market has enormous potential. (Nora D. Volkow, A. Thomas McLellan. Opioid Abuse in Chronic Pain-Misconceptions and Mitigation Strategies. N Engl J Med, 2016, 374(13): 1253-63. Sheng HG, Shao JY, Kir Kland SC, et al. Inhibition of human colon Cancer cell growth by selective inhibition of cyclooxygenase-2. J Chm Invest,1997,99:2254.Janette Brohan,Basavana G.Goudra.The Role of GABA Receptor Agonists in Anesthesia and Sedation.CNSDrugs,2017.)

[0003] Pain encompasses various types. Based on the nature of the stimulus, it can be classified as mechanical pain, thermal pain, and chemical pain; based on the inflammatory cause, it can be classified as inflammatory pain and non-inflammatory pain; based on the nerve location, it can be classified as central nervous system pain, peripheral nervous system pain, and autonomic nervous system pain; and based on the duration of the illness, it can be classified as acute pain and chronic pain. Regardless of the form of pain, sodium ion channels (Navs) are involved.

[0004] Human pain originates from pain receptors located in the peripheral nerve endings throughout the body. These receptors convert mechanical, thermal, cold, and chemical stimuli into nerve impulses, which are then transmitted via afferent nerves to the dorsal root ganglion (DRG), and then via efferent nerves to the central nervous system, thus allowing the perception of pain (Bennett DL, Clark AJ, Huang J, et al. The Role of Voltage-Gated Sodium Channels in Pain Signaling. Physiol Rev, 2019, 99: 1079-1151.). The role of the nerve impulse receptors (NAVs) is to trigger and transmit signals during this process, acting as the primary mediator of the rising limb of the action potential (i.e., nerve impulse) (Mark D. Baker, John N. Wood. Involvement of NAVs). + Channels in pain pathways. TRENDS in Pharmacological Sciences, 2001, 22(1):27-31. Alan L Goldin. RESURGENCE OF SODIUM CHANNEL RESEARCH. Annu. Rev. Physiol. 2001. 63:871-894.). Therefore, inhibiting NaVs can help relieve and treat pain. However, existing NaVs inhibitors such as lidocaine, carbamazepine, and lamotrigine all have drawbacks such as narrow therapeutic window and large side effects due to their lack of selectivity for NaVs. Therefore, research has turned to selective NaV inhibitors.

[0005] Navs are a class of transmembrane ion channel proteins composed of an α subunit with a molecular weight of 260 kD and a β subunit with a molecular weight of 30–40 kD (Bennett DL, Clark AJ, Huang J, et al. The Role of Voltage-Gated Sodium Channels in Pain Signaling. Physiol Rev, 2019, 99: 1079-1151.). Based on the strength of their inhibitory activity against tetrodotoxin (TTX), Navs subtypes can be divided into two categories: TTX-sensitive (TTX-S), including Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.6, and Nav1.7; and TTX-resistant (TTX-R), including Nav1.5, Nav1.8, and Nav1.9. Based on existing physiological and pharmacological studies (Bennett DL, Clark AJ, Huang J, et al. The Role of Voltage-Gated Sodium Channels in Pain Signaling. Physiol Rev, 2019, 99: 1079-1151. Alan L Goldin. RESURGENCE OF SODIUM CHANNEL RESEARCH. Annu. Rev. Physiol. 2001. 63: 871-94. Laura Solé, Michael M. Tamkun. Trafficking mechanisms underlying Nav channel subcellular localization in neurons. Channels, 2020, 14(1), 1-17. Manuel de Lera Ruiz, Richard L. Kraus. Voltage-Gated Sodium Channels: Structure, Function, Pharmacology and Clinical As shown in Table 1, Nav1.1, Nav1.2, and Nav1.3 are mainly distributed in the CNS area and are associated with CNS diseases such as epilepsy and local anesthesia; Nav1.4 is mainly distributed in skeletal muscle, and its inhibitors are used as local anesthetics for myotonia; Nav1.5 is mainly distributed in cardiomyocytes, and its inhibitors are used to treat arrhythmias; Nav1.6 is involved in movement disorders; currently, the main targets related to pain are Nav1.7, Nav1.8, and Nav1.9.Among them, Nav1.7 inhibitors have been most widely studied in the field of pain, but no related clinical trials have been successful to date; there are fewer studies on Nav1.9, and its mechanism of action in pain is not yet fully understood, nor has any evidence of pain efficacy models for related inhibitors been reported; regarding the mechanism of action of Nav1.8, Dib-Hajj et al. (Bennett DL, Clark AJ, Huang J, et al. The Role of Voltage-Gated Sodium Channels in Pain Signaling. Physiol Rev, 2019, 99:1079-1151.) summarized existing research in a 2019 review, believing that Nav1.8 is the main contributor to the rising branch of the action potential, its rapid initiation supports high-frequency discharge, it has a high activation threshold, a slow kinetic process, and blocking Nav1.8 can block the generation of action potential and the transmission of electrical signals; Blair and Bean's research (Blair NT, Bean BP. Roles of tetrodotoxin (TTX)-sensitive Na) + current, TTX-resistant Na + current, and Ca 2+(Currently in the action potentials of nociceptive sensory neurons. J Neurosci 2002,22:10277-10290.) suggests that although both Nav1.8 and Nav1.9 are expressed in DRG, Nav1.8 contributes the most to TTX-R current. In the acute phase of nerve injury, Nav1.8 is downregulated in damaged neurons but upregulated in neighboring undamaged neurons, thereby increasing spontaneous firing. In the chronic phase, crosstalk occurs between damaged and undamaged neurons, leading to upregulation of Nav1.8 in damaged neurons, which further increases and maintains idiopathic firing.In addition to mechanistic studies, the efficacy of Nav1.8 inhibitors in animal models of pain has also been validated: for example, Abbott's A-803467 showed an analgesic effect of more than 50% compared to the model groups in carrageenan, complete Freund's adjuvant (CFA), chronic sciatic nerve compression pain (CCI), spinal nerve ligation pain (SNL), and acute mechanical pain models (Michael F. Jarvis, Prisca Honore, et al. A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. PNAS, 2007, 104(20):8520-8525.); and A-803467 showed better efficacy than lidocaine when administered systemically in a streptozotocin (STZ)-induced diabetic neuropathic thermal pain model, while the two were comparable when administered via local plantar injection, but A-803467 maintained its efficacy for a longer period (Mert). T, Gunes Y. Antinociceptive activities of lidocaine and the nav1.8 blocker a803467 in diabetic rats. J Am Assoc Lab Anim Sci. 2012; 51(5):579-585.); Pfizer's PF-01247324 also showed significant pain relief in CFA and SNL models (Payne CE, Brown AR, Theile JW, et al. A novel selective and orally bioavailable Nav 1.8 channel blocker, PF-01247324, attenuates nociception and sensory neuron excitability. Br J Pharmacol. 2015; 172(10):2654-2670.). Most importantly, Vertex's highly selective Nav1.8 inhibitor VX150 has been successful in three pain-related phase II clinical trials. In conclusion, Nav1.8 is a very promising target for treating pain or pain-related diseases.

[0006] Table 1. Overview of Navs subtypes

[0007] Currently, there are not many companies reporting on Nav1.8 inhibitors in development. Internationally, these include Abbott, Pfizer (WO2013114250A1), Gilead (AU2015224425A1), Sumitomo (WO2015008861A1), AbbVie (WO2016149169A1), Raqualia (WO2020138271A1), Merck (WO2020092187A1), Lieber (WO2020014243A1), and Vertex (WO2019014352A1). Domestically, these include Hengrui (WO2020151728A1) and Shanghai Jiyu Pharmaceutical (CN111808019A). Most of the companies' patents did not disclose the specific inhibitory activity of Nav1.8, or the activity was not good. Only Pfizer's PF-04531083 and Vertex's VX-150 and VX-548 entered Phase II clinical trials. PF-04531083 was discontinued because it did not show superior activity to placebo in postoperative toothache. VX-150 was successful in three Phase II clinical trials for inflammatory pain, postoperative acute pain, and neuropathic pain, providing preliminary validation of Nav1.8's role in pain. However, according to Vertex's official report, its development has been discontinued due to unsatisfactory pharmacokinetic (PK) properties, while VX-548 is currently undergoing Phase III clinical trials. Therefore, the development of new Nav1.8 inhibitors remains promising and essential.

[0008] The compound 2-(4,4-difluoroaza) disclosed in patent application WO2023138599A -1-yl)-N-(2-aminosulfonylpyridin-4-yl)quinoline-3-carboxamide is a novel inhibitor of the sodium ion channel Nav1.8, and its chemical structure is shown in formula (I):

[0009] This compound can be used to treat a wide range of pain conditions, such as chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, postoperative pain, visceral pain, multiple sclerosis, Sharma-Tutankhamun syndrome, incontinence, or arrhythmias. Currently, there are no publicly available reports on the crystal form and salt form of this compound. It is well known that the crystal form and salt form of a drug affect the quality of the formulation and the manufacturing process. Different crystal forms or salt forms of the same active molecule may have significant differences in appearance, solubility, melting point, dissolution rate, and pharmacokinetic characteristics, thus affecting the stability, bioavailability, and efficacy of the drug. Therefore, it is necessary to study the crystal form and salt form of the compound of formula (I) and develop one or more crystal forms or salt forms that are simple to prepare, have good solubility, high stability, high purity, are not hygroscopic, have high bioavailability, and are suitable for industrial production. Summary of the Invention

[0010] The purpose of this application is to provide crystal forms, pharmaceutical compositions and uses of compounds of formula (I) and their salts.

[0011] The chemical name of the compound of formula (I) is: 2-(4,4-difluoroaza) -1-yl)-N-(2-aminosulfonylpyridin-4-yl)quinoline-3-carboxamide, its structural formula is as follows:

[0012] In a first aspect, the present invention provides a crystal form K2 of a compound of formula (I).

[0013] In some embodiments, in the PXRD powder diffraction pattern obtained using Cu-Kα radiation and expressed in terms of diffraction angle 2θ, the crystal form K2 of compound (I) exhibits characteristic diffraction peaks at 6.0°±0.2°, 7.2°±0.2°, 9.0°±0.2°, 10.3°±0.2°, 12.0°±0.2°, 13.3°±0.2°, 25.3°±0.2°, and 29.8°±0.2°.

[0014] In some embodiments, in the PXRD powder diffraction patterns obtained using Cu-Kα radiation and expressed as diffraction angles 2θ, the crystal form K2 of compound (I) is at 6.0°±0.2°, 6.7°±0.2°, 7.2°±0.2°, 9.0°±0.2°, 10.3°±0.2°, 10.5°±0.2°, 12.0°±0.2°, 13.3°±0.2°, 16.2°±0.2°, 16.7°±0.2°, 16.8°±0.2°, 17.3°±0.2°, 18.0°±0.2°, 1 Characteristic diffraction peaks are observed at 8.6°±0.2°, 18.8°±0.2°, 19.2°±0.2°, 20.2°±0.2°, 20.4°±0.2°, 20.8°±0.2°, 21.5°±0.2°, 21.6°±0.2°, 22.4°±0.2°, 23.8°±0.2°, 24.2°±0.2°, 25.3°±0.2°, 25.9°±0.2°, 26.3°±0.2°, 26.7°±0.2°, 28.6°±0.2°, and 29.8°±0.2°.

[0015] In some embodiments, the crystal form K2 of compound (I) shows an endothermic peak at a peak value of approximately 164°C ± 3°C in differential scanning calorimetry.

[0016] In some embodiments, the X-ray powder diffraction pattern of the crystal form K2 of compound (I) is substantially the same as that in Figure 3.

[0017] In some embodiments, the DSC spectrum of the crystal form K2 of compound (I) is substantially the same as that in Figure 4.

[0018] In a second aspect, the present invention provides a crystal form K4 of a compound of formula (I).

[0019] In some embodiments, in the PXRD powder diffraction pattern obtained using Cu-Kα radiation and expressed in terms of diffraction angle 2θ, the crystal form K4 of compound (I) exhibits characteristic diffraction peaks at 6.5°±0.2°, 10.1°±0.2°, 11.8°±0.2°, 12.3°±0.2°, 12.9°±0.2°, 14.8°±0.2°, 18.4°±0.2°, and 25.6°±0.2°.

[0020] In some embodiments, in the PXRD powder diffraction patterns obtained using Cu-Kα radiation and expressed as diffraction angles 2θ, the crystal form K4 of compound (I) is at 6.3°±0.2°, 6.5°±0.2°, 6.8°±0.2°, 9.0°±0.2°, 10.1°±0.2°, 11.8°±0.2°, 12.3°±0.2°, 12.9°±0.2°, 13.0°±0.2°, 14.8°±0.2°, 16.1°±0.2°, 16.3°±0.2°, 16.7°±0.2°, and 16.9°±0.2°. Characteristic diffraction peaks are observed at 0.2°, 17.7°±0.2°, 18.0°±0.2°, 18.1°±0.2°, 18.4°±0.2°, 19.1°±0.2°, 19.9°±0.2°, 20.2°±0.2°, 20.4°±0.2°, 20.6°±0.2°, 20.9°±0.2°, 21.4°±0.2°, 21.7°±0.2°, 22.4°±0.2°, 22.5°±0.2°, 24.0°±0.2°, 24.4°±0.2°, and 25.6°±0.2°.

[0021] In some embodiments, the crystal form K4 of compound (I) shows endothermic peaks at peak values ​​of approximately 170℃±3℃ and 177℃±3℃ in differential scanning calorimetry.

[0022] In some embodiments, the X-ray powder diffraction pattern of the crystal form K4 of compound (I) is substantially the same as that in Figure 5.

[0023] In some embodiments, the DSC spectrum of the crystal form K4 of compound (I) is substantially the same as that in Figure 6.

[0024] In a third aspect, the present invention provides a crystal form K16 of the compound of formula (I).

[0025] In some embodiments, in the PXRD powder diffraction pattern obtained using Cu-Kα radiation and expressed in terms of diffraction angle 2θ, the crystal form K16 of compound (I) exhibits characteristic diffraction peaks at 7.8°±0.2°, 11.1°±0.2°, 11.4°±0.2°, 14.1°±0.2°, 15.5°±0.2°, 17.6°±0.2°, 22.0°±0.2°, and 23.7°±0.2°.

[0026] In some embodiments, in the PXRD powder diffraction patterns obtained using Cu-Kα radiation and expressed as diffraction angles 2θ, the crystal form K16 of compound (I) is at 7.0°±0.2°, 7.8°±0.2°, 11.1°±0.2°, 11.4°±0.2°, 12.9°±0.2°, 13.6°±0.2°, 14.1°±0.2°, 14.7°±0.2°, 15.5°±0.2°, 15.7°±0.2°, 16.9°±0.2°, 17.6°±0.2°, and 17.9°±0.2°. Characteristic diffraction peaks are observed at 18.8°±0.2°, 20.1°±0.2°, 20.9°±0.2°, 21.2°±0.2°, 21.7°±0.2°, 22.0°±0.2°, 22.7°±0.2°, 23.1°±0.2°, 23.7°±0.2°, 24.1°±0.2°, 25.2°±0.2°, 26.0°±0.2°, 26.3°±0.2°, 26.6°±0.2°, 27.3°±0.2°, 27.7°±0.2°, and 28.4°±0.2°.

[0027] In some embodiments, the crystal form K16 of compound (I) shows an endothermic peak at a peak value of approximately 128°C ± 3°C in differential scanning calorimetry.

[0028] In some embodiments, the X-ray powder diffraction pattern of the crystal form K16 of compound (I) is substantially the same as that in Figure 9.

[0029] In some embodiments, the DSC spectrum of the crystal form K16 of compound (I) is substantially the same as that in Figure 10.

[0030] In a fourth aspect, the present invention provides a hydrochloride salt of the compound of formula (I).

[0031] In some embodiments, the hydrochloride salt of the compound of formula (I) is a salt formed by the compound of formula (I) and hydrochloric acid in a molar ratio of 1:(1 to 2).

[0032] In some embodiments, the hydrochloride salt of the compound of formula (I) is a salt formed by the compound of formula (I) and hydrochloric acid in a 1:1 molar ratio.

[0033] In some embodiments, the hydrochloride salt of the compound of formula (I) is a salt formed by the compound of formula (I) and hydrochloric acid in a molar ratio of 1:2.

[0034] In a fifth aspect, the present invention provides a hydrochloride crystal form A of a compound of formula (I).

[0035] In some embodiments, in the PXRD powder diffraction pattern obtained using Cu-Kα radiation and expressed in terms of diffraction angle 2θ, the hydrochloride crystal form A of compound (I) shows characteristic diffraction peaks at 9.4°±0.2°, 10.4°±0.2°, 15.3°±0.2°, 19.2°±0.2°, 21.3°±0.2°, and 22.8°±0.2°.

[0036] In some embodiments, in the PXRD powder diffraction pattern obtained using Cu-Kα radiation and expressed in terms of diffraction angle 2θ, the hydrochloride crystal form A of compound (I) exhibits characteristic diffraction peaks at 9.4°±0.2°, 10.4°±0.2°, 13.2°±0.2°, 15.3°±0.2°, 19.2°±0.2°, 20.9°±0.2°, 21.3°±0.2°, 22.1°±0.2°, 22.8°±0.2°, 23.3°±0.2°, 23.9°±0.2°, and 25.5°±0.2°.

[0037] In some embodiments, the hydrochloride crystal form A of compound (I) shows endothermic peaks at peak values ​​of approximately 168℃±3℃ and 265℃±3℃ in differential scanning calorimetry.

[0038] In some embodiments, the X-ray powder diffraction pattern of the hydrochloride crystal form A of compound (I) is substantially the same as that in Figure 11.

[0039] In some embodiments, the DSC spectrum of the hydrochloride crystal form A of compound (I) is substantially the same as that in Figure 12.

[0040] In one embodiment, the crystal form A of the hydrochloride salt of the compound of formula (I) is a hydrate.

[0041] In one embodiment, the crystal form A of the hydrochloride salt of the compound of formula (I) is a hydrate, and the hydrate is selected from hemihydrate, monohydrate, dihydrate, trihydrate and tetrahydrate.

[0042] In one embodiment, the crystal form A of the hydrochloride salt of the compound of formula (I) is a dihydrate.

[0043] In a sixth aspect, the present invention provides a hydrochloride crystal form B of a compound of formula (I).

[0044] In some embodiments, in the PXRD powder diffraction pattern obtained using Cu-Kα radiation and expressed in terms of diffraction angle 2θ, the hydrochloride crystal form B of compound (I) exhibits characteristic diffraction peaks at 11.2°±0.2°, 12.2°±0.2°, 14.5°±0.2°, 16.1°±0.2°, 18.3°±0.2°, 19.9°±0.2°, and 24.5°±0.2°.

[0045] In some embodiments, in the PXRD powder diffraction patterns obtained using Cu-Kα radiation and expressed in terms of diffraction angle 2θ, the crystal form B of the hydrochloride of compound (I) is at 11.2°±0.2°, 12.2°±0.2°, 13.3°±0.2°, 14.2°±0.2°, 14.5°±0.2°, 16.1°±0.2°, 18.3°±0.2°, 18.8°±0.2°, and 19. Characteristic diffraction peaks are observed at 4°±0.2°, 19.9°±0.2°, 20.1°±0.2°, 21.0°±0.2°, 21.1°±0.2°, 22.0°±0.2°, 23.2°±0.2°, 23.7°±0.2°, 24.5°±0.2°, 25.4°±0.2°, 25.7°±0.2°, 26.9°±0.2°, and 34.2°±0.2°.

[0046] In some embodiments, the hydrochloride crystal form B of compound (I) shows an endothermic peak at a peak value of approximately 269°C ± 3°C in differential scanning calorimetry.

[0047] In some embodiments, the X-ray powder diffraction pattern of the hydrochloride crystal form B of compound (I) is substantially the same as that in Figure 13.

[0048] In some embodiments, the DSC spectrum of the hydrochloride crystal form B of compound (I) is substantially the same as that in Figure 14.

[0049] In one embodiment, the hydrochloride salt of the compound of formula (I) is in anhydrous form B.

[0050] In a seventh aspect, the present invention provides a hydrobromide crystal form A of a compound of formula (I).

[0051] In some embodiments, in the PXRD powder diffraction pattern obtained using Cu-Kα radiation and expressed in terms of diffraction angle 2θ, the hydrobromide crystal form A of compound (I) exhibits characteristic diffraction peaks at 7.2°±0.2°, 10.1°±0.2°, 19.0°±0.2°, 20.4°±0.2°, 22.7°±0.2°, 23.7°±0.2°, 25.0°±0.2°, and 28.7°±0.2°.

[0052] In some embodiments, in the PXRD powder diffraction pattern obtained using Cu-Kα radiation and expressed in terms of diffraction angle 2θ, the hydrobromide crystal form A of compound (I) exhibits characteristic diffraction peaks at 7.2°±0.2°, 10.1°±0.2°, 14.2°±0.2°, 18.2°±0.2°, 19.0°±0.2°, 19.9°±0.2°, 20.4°±0.2°, 21.1°±0.2°, 22.1°±0.2°, 22.7°±0.2°, 23.7°±0.2°, 24.5°±0.2°, 25.0°±0.2°, 27.5°±0.2°, and 28.7°±0.2°.

[0053] In some embodiments, the hydrobromide crystal form A of compound (I) shows endothermic peaks at approximately 134℃±3℃ and 203℃±3℃ in differential scanning calorimetry.

[0054] In some embodiments, the X-ray powder diffraction pattern of the hydrobromide crystal form A of compound (I) is substantially the same as that in Figure 17.

[0055] In some embodiments, the DSC spectrum of the hydrobromide crystal form A of compound (I) is substantially the same as that in Figure 18.

[0056] In an eighth aspect, the present invention provides a methanesulfonate crystal form A of a compound of formula (I).

[0057] In some embodiments, in the PXRD powder diffraction pattern obtained using Cu-Kα radiation and expressed in terms of diffraction angle 2θ, the methanesulfonate crystal form A of compound (I) exhibits characteristic diffraction peaks at 6.5°±0.2°, 8.6°±0.2°, 11.6°±0.2°, 13.1°±0.2°, 18.1°±0.2°, 20.5°±0.2°, 21.7°±0.2°, and 30.2°±0.2°.

[0058] In some embodiments, in the PXRD powder diffraction patterns obtained using Cu-Kα radiation and expressed as diffraction angles 2θ, the methanesulfonate crystal form A of compound (I) is at diffraction angles of 6.5°±0.2°, 8.6°±0.2°, 10.2°±0.2°, 11.6°±0.2°, 12.4°±0.2°, 13.1°±0.2°, 14.3°±0.2°, 16.0°±0.2°, 18.1°±0.2°, and 19.0°. Characteristic diffraction peaks are observed at 0.2°, 19.2°±0.2°, 19.7°±0.2°, 20.0°±0.2°, 20.1°±0.2°, 20.5°±0.2°, 21.7°±0.2°, 23.2°±0.2°, 24.6°±0.2°, 25.4°±0.2°, 25.6°±0.2°, 25.9°±0.2°, 26.8°±0.2°, and 30.2°±0.2°.

[0059] In some embodiments, the methanesulfonate crystal form A of compound (I) shows an endothermic peak at a Peak value of approximately 113 °C ± 3 °C in differential scanning calorimetry.

[0060] In some embodiments, the X-ray powder diffraction pattern of the methanesulfonate crystal form A of compound (I) is substantially the same as that in Figure 19.

[0061] In some embodiments, the DSC spectrum of the methanesulfonate crystal form A of compound (I) is substantially the same as that in Figure 20.

[0062] In a ninth aspect, the present invention provides a methanesulfonate crystal form B of a compound of formula (I).

[0063] In some embodiments, in the PXRD powder diffraction pattern obtained using Cu-Kα radiation and expressed in terms of diffraction angle 2θ, the methanesulfonate crystal form B of compound (I) exhibits characteristic diffraction peaks at 4.2°±0.2°, 11.0°±0.2°, 12.5°±0.2°, 16.3°±0.2°, 17.0°±0.2°, 17.9°±0.2°, 21.2°±0.2°, and 25.9°±0.2°.

[0064] In some embodiments, in the PXRD powder diffraction patterns obtained using Cu-Kα radiation and expressed as diffraction angles 2θ, the methanesulfonate crystal form B of compound (I) is at 4.2°±0.2°, 8.4°±0.2°, 11.0°±0.2°, 11.2°±0.2°, 12.5°±0.2°, 13.2°±0.2°, 15.1°±0.2°, 15.3°±0.2°, 16.3°±0.2°, 17.0°±0.2°, and 17.9°. Characteristic diffraction peaks are observed at 18.4°±0.2°, 19.5°±0.2°, 19.8°±0.2°, 20.8°±0.2°, 21.2°±0.2°, 21.6°±0.2°, 22.0°±0.2°, 23.3°±0.2°, 23.6°±0.2°, 24.0°±0.2°, 24.8°±0.2°, 25.9°±0.2°, 27.6°±0.2°, and 28.0°±0.2°.

[0065] In some embodiments, the methanesulfonate crystal form B of compound (I) shows endothermic peaks at approximately 69°C ± 3°C and 260°C ± 3°C in differential scanning calorimetry.

[0066] In some embodiments, the X-ray powder diffraction pattern of the methanesulfonate crystal form B of the compound of formula (I) is substantially the same as that in Figure 21.

[0067] In some embodiments, the DSC spectrum of the methanesulfonate crystal form B of compound (I) is substantially the same as that in Figure 22.

[0068] In a tenth aspect of the present invention, a phosphate crystal form A of a compound of formula (I) is provided.

[0069] In some embodiments, in the PXRD powder diffraction pattern obtained using Cu-Kα radiation and expressed in terms of diffraction angle 2θ, the phosphate crystal form A of compound (I) exhibits characteristic diffraction peaks at 6.8°±0.2°, 13.9°±0.2°, 19.6°±0.2°, 21.5°±0.2°, 21.8°±0.2°, 22.0°±0.2°, 24.3°±0.2°, and 28.0°±0.2°.

[0070] In some embodiments, in the PXRD powder diffraction patterns obtained using Cu-Kα radiation and expressed as diffraction angles 2θ, the phosphate crystal form A of compound (I) is at 6.8°±0.2°, 7.1°±0.2°, 10.2°±0.2°, 11.6°±0.2°, 13.7°±0.2°, 13.9°±0.2°, 14.3°±0.2°, 17.7°±0.2°, 18.0°±0.2°, 18.7°±0.2°, and 19.6°±0.2°. Characteristic diffraction peaks are observed at 19.9°±0.2°, 20.1°±0.2°, 20.3°±0.2°, 20.6°±0.2°, 20.7°±0.2°, 21.3°±0.2°, 21.5°±0.2°, 21.8°±0.2°, 22.0°±0.2°, 23.5°±0.2°, 23.6°±0.2°, 24.3°±0.2°, 24.6°±0.2°, 26.4°±0.2°, and 28.0°±0.2°.

[0071] In some embodiments, the phosphate crystal form A of compound (I) shows endothermic peaks at approximately 79℃±3℃ and 191℃±3℃ in differential scanning calorimetry.

[0072] In some embodiments, the X-ray powder diffraction pattern of phosphate crystal form A of compound (I) is substantially the same as that of 24.

[0073] In some embodiments, the DSC spectrum of phosphate crystal form A of compound (I) is substantially the same as that in Figure 25.

[0074] In an eleventh aspect, the present invention provides a pharmaceutical composition comprising at least one of the following: a free base crystal form of a compound of formula (I) (e.g., crystal form K2, crystal form K4, crystal form K16 described above), a salt and crystal form (e.g., crystal form A of hydrochloride, crystal form B of hydrochloride, crystal form A of hydrobromide, crystal form A of methanesulfonate, crystal form B of methanesulfonate, crystal form A of phosphate), and one or more pharmaceutically acceptable carriers.

[0075] In a twelfth aspect of the present invention, the use of a compound of formula (I) crystal form (e.g., crystal form K2, crystal form K4, crystal form K16 above), salt and crystal form (e.g., crystal form A of hydrochloride, crystal form B of hydrochloride, crystal form A of hydrobromide, crystal form A of methanesulfonate, crystal form B of methanesulfonate, crystal form A of phosphate) or a pharmaceutical composition thereof as a Nav1.8 inhibitor, said Nav1.8 inhibitor being used for the prevention and / or treatment of diseases or conditions at least partially mediated by Nav1.8.

[0076] In some implementations, the disease or condition mediated by Nav1.8 is pain.

[0077] In some embodiments, the pain is chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, postoperative pain, visceral pain, multiple sclerosis, Sharma-Tutankhamun syndrome, incontinence, or arrhythmia.

[0078] The effects of the invention

[0079] The compounds of formula (I) of the present invention exhibit good inhibitory activity against Nav1.8 and possess favorable pharmacokinetic, safety, and other properties. Furthermore, it has been found that crystalline forms of compounds of formula (I) or their salts are produced using certain solvents and / or methods. These crystalline forms, including substantially pure forms and mixtures of substantially pure forms, exhibit one or more advantageous characteristics. For example, they offer advantages in bioavailability and stability, making them suitable for use as active ingredients in pharmaceutical formulations. In particular, crystal forms K2, K4, and K16 of compounds of formula (I), hydrochloride salts of compounds of formula (I) and their various crystalline forms (e.g., hydrochloride crystal forms A and B), methanesulfonates and their various crystalline forms (e.g., methanesulfonate crystal forms A and B), and hydrobromide and phosphate crystal forms offer one or more advantages such as: improved manufacturing processes of compounds of formula (I), improved bioavailability and / or stability of compounds of formula (I), improved solubility of compounds of formula (I), improved hygroscopicity of compounds, and / or improved stability of pharmaceutical formulations containing compounds of formula (I) and extended shelf life. Attached Figure Description

[0080] Figure 1 shows the XRPD pattern of the free alkali crystal form K1 obtained in Example 1;

[0081] Figure 2 shows the DSC spectrum of the free alkali crystal form K1 obtained in Example 1;

[0082] Figure 3 shows the XRPD pattern of the free alkali crystal form K2 obtained in Example 2;

[0083] Figure 4 shows the DSC spectrum of the free alkali crystal form K2 obtained in Example 2;

[0084] Figure 5 shows the XRPD pattern of the free alkali crystal form K4 obtained in Example 3;

[0085] Figure 6 shows the DSC spectrum of the free alkali crystal form K4 obtained in Example 3;

[0086] Figure 7 shows the DSC spectrum of the free alkali crystal form K13 obtained in Example 4;

[0087] Figure 8 shows the DSC spectrum of the free alkali crystal form K14 obtained in Example 5;

[0088] Figure 9 shows the XRPD pattern of the free alkali crystal form K16 obtained in Example 6;

[0089] Figure 10 shows the DSC spectrum of the free alkali crystal form K16 obtained in Example 6;

[0090] Figure 11 shows the XRPD pattern of hydrochloride crystal form A obtained in Example 7;

[0091] Figure 12 shows the DSC spectrum of hydrochloride crystal form A obtained in Example 7;

[0092] Figure 13 shows the XRPD pattern of hydrochloride crystal form B obtained in Example 8;

[0093] Figure 14 shows the DSC spectrum of hydrochloride crystal form B obtained in Example 8;

[0094] Figure 15 shows the XRPD pattern of trifluoroacetate crystal form A obtained in Example 9;

[0095] Figure 16 shows the DSC spectrum of trifluoroacetate crystal form A obtained in Example 9;

[0096] Figure 17 shows the XRPD pattern of hydrobromide crystal form A obtained in Example 11;

[0097] Figure 18 shows the DSC spectrum of hydrobromide crystal form A obtained in Example 11;

[0098] Figure 19 shows the XRPD pattern of methanesulfonate crystal form A obtained in Example 12;

[0099] Figure 20 shows the DSC spectrum of methanesulfonate crystal form A obtained in Example 12;

[0100] Figure 21 shows the XRPD pattern of methanesulfonate crystal form B obtained in Example 13;

[0101] Figure 22 shows the DSC spectrum of methanesulfonate crystal form B obtained in Example 13;

[0102] Figure 23 shows the DSC spectrum of sulfate crystal form A obtained in Example 14;

[0103] Figure 24 shows the XRPD pattern of phosphate crystal form A obtained in Example 15.

[0104] Figure 25 shows the DSC spectrum of phosphate crystal form A obtained in Example 15;

[0105] Figure 26 is a superimposed XRPD result of the one-month stability study of hydrochloride crystal form B in Experiment Example 4;

[0106] Figure 27 is a superimposed XRPD result of the one-month stability study of hydrochloride crystal form A in Experiment Example 4;

[0107] Figure 28 is a superimposed XRPD result of the one-month stability study of free alkali crystal K4 in Experiment Example 4;

[0108] Figure 29 is a superimposed XRPD result of the one-month stability study of free alkali crystal K2 in Experiment Example 4;

[0109] Figure 30 shows the mean blood drug concentration-time curves of rats after oral administration of different free alkali crystal forms in Experiment Example 5;

[0110] Figure 31 shows the mean blood drug concentration-time curves after oral administration of different salt crystal forms to rats in Experiment 5. Detailed Implementation

[0111] The following specific embodiments illustrate the implementation of the invention. Those skilled in the art can easily understand other advantages and effects of the invention from the content disclosed in this specification. It should be understood that the terminology used is descriptive and not intended to limit the invention.

[0112] Terminology Definition

[0113] The terms “polymorph,” “polymorphic product,” “crystal variation,” “crystal form,” “crystal variation,” “polymorphic form,” and “crystal form” as used in this application are to be understood as synonymous and refer to the solid crystalline form of a compound or complex, including, but not limited to, single-component or multi-component crystals, and / or polymorphs of compounds, solvates, hydrates, inclusion compounds, eutectics, salts, solvates of salts, and hydrates of salts.

[0114] Polymorphs can be detected, identified, classified, and characterized using techniques well known to those skilled in the art, including, but not limited to: differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD), single-crystal X-ray diffraction (SXRD), vibrational spectroscopy, solution calorimetry, solid-state nuclear magnetic resonance (SSNMR), Fourier transform-infrared spectroscopy (FT-IR), Raman spectroscopy, hot-stage optical microscopy, scanning electron microscopy (SEM), electron crystallography, as well as quantitative analysis, particle size analysis (PSA), surface area analysis, solubility, and dissolution rate. A polymorph can be described as the ability of a specific compound to crystallize in different crystalline forms while maintaining the same chemical structure. Polymorphs of a given substance are chemically equivalent, containing the same atoms bonded together in the same manner, but differing in their crystalline forms. The graphical representation of such data can vary slightly (e.g., relative peak intensities and peak positions) due to factors such as variations in instrument response and sample concentration and purity, as is known to those skilled in the art. Nevertheless, those skilled in the art can compare the graphic data in the figures of this application with the graphic data generated for an unknown crystal form, and can confirm whether the two sets of graphic data represent the same crystal form.

[0115] Unless otherwise stated, when this application refers to spectra or data presented in graphical form (e.g., XRPD, IR, Raman, and NMR spectra), the term "peak" refers to a peak or other special feature that is not caused by background noise and can be recognized by a person skilled in the art.

[0116] As is well known in the field of X-ray powder diffraction (XRPD), for any given crystal form, the apparatus used to obtain the X-ray powder diffraction pattern, humidity, temperature, powder crystal orientation, and other parameters can all cause some variability in the appearance, intensity, and position of peaks in the diffraction pattern. In the present case, a variability of ±0.2°2θ peak positions takes into account these possible variations without hindering the clear identification of the indicated crystal form. Crystal form identification can be based on any unique difference peaks (in °2θ units) or combinations thereof, typically more prominent peaks. Therefore, in some embodiments, the crystalline compounds of this application are characterized by XRPD patterns with certain peak positions that have substantially the same characteristics as the XRPD patterns provided in the accompanying drawings. Depending on the instrumentation used in this application, there may be an error tolerance of ±0.2° for the diffraction peak positions. For example, an X-ray powder diffraction pattern “substantially consistent” with Figure 1 provided in this application may be identical to the XRPD pattern in the accompanying drawings, or more likely it may be slightly different. Such XRPD patterns may not necessarily show every peak in the diffraction pattern presented in this application, and / or may show slight variations in the appearance, intensity, or shift of the peaks due to differences in the conditions involved in obtaining the data. Those skilled in the art can determine whether a sample of the crystalline compound has the same or different crystal form as disclosed in this application by comparing their XRPD patterns. Similarly, those skilled in the art can determine whether the given diffraction peak positions (expressed in °2θ) derived from the XRPD pattern are at approximately the same positions as the values ​​presented in this application. In the context of this application, 2θ values ​​in X-ray powder diffraction patterns are in degrees (°).

[0117] Similarly, as is well known in the field of differential scanning calorimetry (DSC), the melting peak height of a DSC curve depends on many related factors, such as sample preparation and instrument conditions, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystalline compounds of this application are characterized by DSC plots with characteristic peak positions, possessing substantially the same properties as the DSC plots provided in the accompanying drawings. Depending on the instrument used in this experiment, the melting temperature has an error tolerance of ±3°C, ±4°C, or ±5°C.

[0118] X-ray powder diffraction patterns, DSC curves, TGA curves, and the terms "substantially identical" or "essentially identical" generally refer to X-ray powder diffraction patterns or DSC curves where at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about 95%, or at least about 99% of the peaks are displayed in the figure.

[0119] The term "substantially pure" generally refers to chemical purity and crystal form purity. More specifically, a crystal form is substantially free of one or more other crystal forms, meaning that the purity of the crystal form is at least about 60%, or at least about 70%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 93%, or at least about 95%, or at least about 98%, or at least about 99%, or at least about 99.5%, or at least about 99.6%, or at least about 99.7%, or at least about 99.8%, or at least about 99.9%, or the crystal form contains other crystal forms that constitute less than about 30%, or less than about 20%, or less than about 10%, or less than about 5%, or less than about 3%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, or less than about 0.01% of the total volume or total weight of the crystal form.

[0120] The purity of the crystals in this application can be determined by, for example, known methods such as X-ray powder diffraction, thermal analysis, etc. The purity of the crystals or mixed crystals in this application does not need to be 100%, but can be no less than about 70%, or no less than about 80%, or no less than about 90%, or no less than about 95%, or no less than about 98%, and the purity within this range can guarantee quality.

[0121] As used herein, the terms “about” and “approximately” generally mean within ±10%, appropriately within ±5%, and particularly within ±1%, of a given value or range. Alternatively, to those skilled in the art, the terms “about” and “approximately” mean within an acceptable standard error of the average value.

[0122] As used in this application, the term "solution" generally refers to a mixture containing at least one solvent and at least one compound, which is at least partially dissolved in the solvent.

[0123] Hygroscopicity is an important physical property of active pharmaceutical ingredients (APIs), directly affecting their storage stability, processability, and manufacturing process. Dynamic water adsorption (DVS) was used to investigate the adsorption and desorption of moisture by samples at 25°C and relative humidity ranging from 0% to 95% RH, in order to determine the hygroscopic properties of various crystal forms.

[0124] The term "pharmaceutical composition" generally refers to a mixture of one or more compounds described in this application, or their physiologically / pharmaceutical acceptable salts or prodrugs, with other chemical components, such as physiologically / pharmaceutical acceptable excipients, excipients, diluents, adjuvants, carriers, and additional therapeutic agents. The purpose of a pharmaceutical composition is to facilitate the administration of the compound to a living organism.

[0125] As described in this application, pharmaceutically acceptable compositions of this application may also contain pharmaceutically acceptable excipients, such as those used in this application, including any solvent, solid excipient, diluent, binder, disintegrant, or other liquid excipient, dispersant, flavoring agent or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for the specific target dosage form. The use of any conventional excipients, except for those incompatible with the compounds of this application, such as any adverse biological effects or interactions with any other component of the pharmaceutically acceptable composition in a harmful manner, is also within the scope of this application.

[0126] As described in this application, pharmaceutically acceptable compositions of this application may also contain pharmaceutically acceptable excipients, such as those used in this application, including any solvent, solid excipient, diluent, binder, disintegrant, or other liquid excipient, dispersant, flavoring agent or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for the specific target dosage form. The use of any conventional excipients, except for those incompatible with the compounds of this application, such as any adverse biological effects or interactions with any other component of the pharmaceutically acceptable composition in a harmful manner, is also within the scope of this application.

[0127] The pharmaceutical compositions of this application can be administered orally, by injection, topically, sublingually, or via an implantable cartridge. The term "injection" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial (cavity), intrasternal, intramembranous, intraocular, intrahepatic, intralesional, and intracranial injection or infusion techniques. For example, the pharmaceutical compositions of this application can be administered orally in any acceptable oral dosage form, including, but not limited to, capsules, tablets, aqueous suspensions, or solutions. As another example, the aseptic injection method of the pharmaceutical compositions of this application can be an aqueous or oily suspension, which can be formulated according to known techniques using suitable dispersants, wetting agents, and suspending agents.

[0128] The compounds of formula (I) of this application exhibit inhibitory effects and are capable of preventing or treating diseases related to the inhibitory effects of sodium ion channel Nav1.8, such as for treating a wide range of pain, including chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, postoperative pain, visceral pain, multiple sclerosis, Sharma-Tutan syndrome, incontinence, or arrhythmias.

[0129] The term "application" refers to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with an animal, human, subject, cell, tissue, organ, or biological fluid when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid. "Application" can refer to therapeutic, pharmacokinetic, diagnostic, research, and experimental methods. Cellular application includes contact between a reagent and a cell, as well as contact between a reagent and a fluid, wherein the fluid is in contact with the cell. "Application" also means by means of a reagent, diagnostic agent, conjugate composition, or by means of another cell in vitro and ex vivo treatment, such as cells. When applied to a human, veterinary, or research subject, "application" refers to a therapeutic treatment, preventative or prophylactic measure, research, and diagnostic application.

[0130] As used in this application, the term "treatment" refers to any disease or condition, and in some embodiments, it means improving the disease or condition (i.e., slowing down, stopping, or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" means mitigating and / or improving at least one bodily parameter, including bodily parameters that may not be perceptible to the patient. In still other embodiments, "treatment" means regulating the disease or condition from a physical (e.g., stabilizing perceptible symptoms), physiological (e.g., stabilizing bodily parameters), or both. In still other embodiments, "treatment" means preventing or delaying the onset, occurrence, or worsening of the disease or condition.

[0131] The term "subject" refers to an animal. In some embodiments, the animal is a mammal. For example, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In a non-limiting example, the subject is a human.

[0132] The embodiments described below are not intended to be limited by any theory, but are merely for illustrating the crystal form, preparation method and use of this application, and are not intended to limit the scope of the invention.

[0133] The explanations of the abbreviations used in this invention are shown in Table 2 below.

[0134] Table 2 Abbreviations

[0135] Instruments and methods

[0136] 1. X-ray powder diffraction (XRPD)

[0137] 1.1 Testing conditions

[0138] PXRD was measured at room temperature using an Empyrean X-ray diffractometer with a copper target using Cu Kα rays (IKα1:IKα2=0.5, λ1=1.540598, λ2=1.544426). Specific instrument parameters are shown in Table 3.

[0139] Table 3 Instrument Parameters

[0140] 2. Differential Scanning Calorimetry (DSC)

[0141] 2.1 Testing conditions

[0142] DSC was performed using a Netzsch DSC 214Nevio differential scanning calorimeter. The specific testing conditions were as follows: temperature range: 40℃-300℃; heating rate: 10℃ / min; aluminum crucible; gas atmosphere: N2; gas flow rate: 50mL / min.

[0143] 3. Thermogravimetric analysis (TGA)

[0144] 3.1 Testing conditions

[0145] TGA was determined using Mettler Toledo's TGA2 thermogravimetric analyzer under the following conditions: temperature range: 30℃-500℃; heating rate: 10℃ / min; alumina crucible; gas atmosphere: N2; gas flow rate: 50mL / min.

[0146] 4. Dynamic moisture adsorption analysis (DVS)

[0147] 4.1 Testing conditions

[0148] DVS was measured using the DVS intrinsic of the Surface Measurement System, with the following specific testing conditions: Test range: 0-95%RH; Method stage type: Step dm / dt [% / min]; Cycle: Full cycle.

[0149] Unless otherwise specified in the examples, the room temperature is 20℃~30℃.

[0150] Example 1: Preparation of Free Alkali Crystal Form K1

[0151] Compound of formula (I) was prepared according to Example 14 of patent CN 116462662A and named free alkali crystal form K1 after characterization.

[0152] The X-ray powder diffraction pattern of the free alkali crystal form K1, as determined by XRPD, is shown in Figure 1. The DSC pattern is shown in Figure 2.

[0153] Example 2: Preparation of free alkali crystal form K2

[0154] Weigh 1.0 g of compound (I) into a crystallization container, add 21.0 ml of methanol, heat to dissolve, cool to room temperature and stir for 1.5 h, add 10.0 ml of n-heptane dropwise, stir to precipitate crystals for 2 h after the addition is complete, filter, collect the obtained solid, dry to dryness at 60℃±5℃ to obtain a white solid, which is characterized and named free base crystal form K2.

[0155] The X-ray powder diffraction data of crystal form K2, as determined by XRPD, are shown in Table 4, and its diffraction pattern is shown in Figure 3. Thermal analysis characterization of crystal form K2 was performed, and its DSC pattern is shown in Figure 4.

[0156] Table 4. Diffraction angles, interplanar spacings, and relative intensities of free alkali crystal form K2.

[0157] Example 3: Preparation of free alkali crystal form K4

[0158] Weigh 50 mg of compound (I), add 500 μL of butanone, dissolve at room temperature, and allow to evaporate naturally to obtain a solid.

[0159] XRPD analysis revealed the following X-ray powder diffraction data for the free alkali crystalline form K4, as shown in Table 5 and its diffraction pattern, as shown in Figure 5. Thermal analysis characterization of crystalline form K4 was performed, and its DSC pattern is shown in Figure 6.

[0160] Table 5. Diffraction angles, interplanar spacings, and relative intensities of free alkali crystal form K4.

[0161] Example 4: Preparation of free alkali crystal form K13

[0162] Weigh 30 mg of compound (I), add 300 μL of acetone and heat to dissolve. Add the solution dropwise to 1 mL of n-heptane at room temperature and stir to precipitate. Filter and dry to obtain a solid.

[0163] The DSC spectrum of free alkali crystal K13 is shown in Figure 7, with its endothermic peak starting at 48.7℃.

[0164] Example 5: Preparation of Free Alkali Crystal Form K14

[0165] Weigh 30 mg of compound (I), add 300 μL of tetrahydrofuran and 300 μL of water and heat to dissolve. Let stand at -15℃ to -20℃ to precipitate, filter, and dry to obtain solid.

[0166] The DSC spectrum of free alkali crystal K14 is shown in Figure 8, with its endothermic peak starting at 49.2℃.

[0167] Example 6: Preparation of Free Alkali Crystal Form K16

[0168] Weigh 1.00 g of compound (I), add 10 mL of acetonitrile, heat to dissolve, cool to room temperature and stir for 5 h, filter and dry to obtain solid.

[0169] The X-ray powder diffraction pattern of the free alkali crystalline form K16, as determined by XRPD, is shown in Figure 9. The DSC pattern of the crystalline form K16, obtained through thermal analysis, is shown in Figure 10.

[0170] Example 7 Preparation of hydrochloride crystal form A

[0171] Weigh 10.0 g of compound (I) into a crystallization container, add 100.0 ml of tetrahydrofuran, heat to reflux and stir until dissolved, filter while hot, and add 6.45 ml of concentrated hydrochloric acid dropwise at 60℃±5℃. After the addition is complete, cool to room temperature and stir to induce crystallization for 4 h. Filter and collect the obtained solid to obtain a crystalline white solid. Dry the sample at 60℃±5℃ for 3 h to 5 h to obtain hydrochloride crystal form A.

[0172] The X-ray powder diffraction data of hydrochloride crystal form A, as determined by XRPD, are shown in Table 6, and its diffraction pattern is shown in Figure 11. Thermal analysis characterization of hydrochloride crystal form A was performed, and its DSC pattern is shown in Figure 12.

[0173] Table 6. Diffraction angles, interplanar spacings, and relative intensities of hydrochloride crystal form A.

[0174] Example 8: Preparation of hydrochloride crystal form B

[0175] Weigh 10.0 g of compound (I) into a crystallization container, add 150.0 ml of ethanol, and add 6.45 ml of concentrated hydrochloric acid dropwise while stirring at room temperature. After the addition is complete, heat to 50℃~60℃ and stir to suspend the reaction for 10 min~15 min. Cool to room temperature and stir to allow crystals to precipitate overnight. Filter and collect the obtained solid to obtain a crystalline white solid. Dry the sample at 65℃±5℃ for 5 h~6 h to obtain hydrochloride crystal form B.

[0176] The X-ray powder diffraction data of hydrochloride crystal form B, as determined by XRPD, are shown in Table 7-1, and its diffraction pattern is shown in Figure 13. Thermal analysis characterization of hydrochloride crystal form B was performed, and its DSC pattern is shown in Figure 14.

[0177] Table 7-1 Diffraction angles, interplanar spacings, and relative intensities of hydrochloride crystal form B

[0178] Single-crystal cultivation was performed on hydrochloride crystal form A and hydrochloride crystal form B, both yielding regular single crystals. The structures of the samples were confirmed by single-crystal diffraction analysis (SXRD). Single-crystal data were analyzed using a Bruker D8 VENTURE single-crystal diffractometer (Cu Kα) equipped with a CCD detector. The single crystal data of hydrochloride crystal form A and hydrochloride crystal form B produced on the surface are summarized in Table 7-2.

[0179] Table 7-2 Single crystal data and structures of hydrochloride crystal form A and hydrochloride crystal form B

[0180] Example 9 Preparation of trifluoroacetate

[0181] Weigh 400 mg of compound I into a crystallization container, add 520 μl of trifluoroacetic acid, stir at room temperature to react and crystallize overnight, filter, collect the obtained solid, dry at 65℃±5℃ to dry, and obtain a white solid, which is characterized and named trifluoroacetate crystal form A.

[0182] The X-ray powder diffraction pattern of trifluoroacetate crystal form A, as determined by XRPD, is shown in Figure 15, and its DSC pattern is shown in Figure 16.

[0183] Example 11 Preparation of hydrobromide

[0184] Weigh 100 mg of compound (I) into a crystallization container, add 1.0 ml of ethanol, add 0.5 ml of ethanol dilution solution containing 105 μl of hydrobromic acid while stirring at room temperature, stir and react to crystallize overnight, filter, collect the obtained solid, dry to dryness at 65℃±5℃ to obtain a white solid, which is characterized and named hydrobromide crystal form A.

[0185] The X-ray powder diffraction pattern of hydrobromide crystal form A, as determined by XRPD, is shown in Figure 17. The DSC pattern is shown in Figure 18.

[0186] Example 12 Preparation of Methanesulfonate Crystal Form A

[0187] Weigh 50 mg of compound (I) into a crystallization container, add 0.5 ml of ethanol, add 104 μl of methanesulfonic acid while stirring at room temperature, dissolve and crystallize overnight at room temperature, filter, collect the obtained solid, dry to dryness at 40℃±5℃, and obtain a white solid, which is named methanesulfonate crystal form A after characterization.

[0188] The X-ray powder diffraction pattern of methanesulfonate crystal form A, as determined by XRPD, is shown in Figure 19. The DSC pattern is shown in Figure 20.

[0189] Example 13 Preparation of Methanesulfonate Crystal Form B

[0190] Weigh 800 mg of compound (I) into a crystallization container, add 8.0 ml of ethanol, add 4.0 ml of ethanol dilution solution containing 252 μl of methanesulfonic acid while stirring at room temperature, heat to 50 °C and stir to dissolve for 10 min to 15 min, cool to room temperature and stir to crystallize overnight, filter, collect the obtained solid, dry at 65 °C ± 5 °C for 4 h to obtain 938 mg of white solid, which was characterized and named methanesulfonate crystal form B.

[0191] The X-ray powder diffraction pattern of methanesulfonate crystal form B, as determined by XRPD, is shown in Figure 21. The DSC pattern is shown in Figure 22.

[0192] Example 14 Preparation of Sulfate

[0193] Weigh 50 mg of compound (I) into a crystallization container, add 0.5 ml of acetonitrile, add 53 μl of concentrated sulfuric acid while stirring at room temperature, dissolve until clear, stir at room temperature to crystallize overnight, filter, collect the obtained solid, dry to dryness at 40℃±5℃, and obtain a white solid, which is characterized and named sulfate crystal form A.

[0194] The DSC spectrum of sulfate crystal form A is shown in Figure 23. Its endothermic peak begins at 55.5℃.

[0195] Example 15 Preparation of Phosphate

[0196] Weigh 50 mg of compound (I) into a crystallization container, add 0.5 ml of ethyl acetate, add 125 μl of phosphoric acid while stirring at room temperature. The solution is not completely dissolved. Stir at room temperature and crystallize overnight. Filter, collect the obtained solid, and dry to dryness at 40℃±5℃ to obtain a white solid. It shows obvious deliquescence when left open at room temperature. After characterization, it is named phosphate crystal form A.

[0197] The X-ray powder diffraction pattern of phosphate crystal form A, as shown in Figure 24, was determined by XRPD. The DSC pattern, shown in Figure 25, shows that the endothermic peak begins at 55.6℃.

[0198] Experimental Example 1: Hygroscopicity Determination

[0199] Weigh 30-50 mg each of the free alkali crystal form, hydrochloride crystal form, hydrobromide crystal form, methanesulfonate crystal form, and phosphate crystal form of the compound of formula (I) prepared in the above examples, and conduct a DVS hygroscopicity test. The relative humidity test range is 0-95%RH, and the change in crystal form of the samples after the DVS test is measured. The test results are shown in Table 8.

[0200] Table 8 Results of DVS Hygroscopicity Study

[0201] Experimental Example 2: Suspension Competition Experiment

[0202] Weigh 20 mg of each of the free base crystal forms of the compound (I) prepared in the above examples, place the two crystal forms in the same 5 mL centrifuge tube, add 1.2 mL of butanone / n-heptane mixed solvent (butanone / n-heptane volume ratio 1:5) and suspend and stir at 40 °C for 24 h, separate the solid and liquid, and test the thermodynamic stability of the crystal forms. The results are shown in Table 9.

[0203] Table 9 Results of the Hybrid Suspension Competition Experiment

[0204] Experimental Example 3: Equilibrium Solubility Test

[0205] Weigh 50 mg each of the free alkali crystal form K1, hydrochloride crystal form A, hydrochloride crystal form B, and trifluoroacetate crystal form A of the compound of formula (I) prepared in the above examples, and determine their 24-hour equilibrium solubility in different pH media. The results are shown in Table 10.

[0206] Table 10 Results of Solubility Investigation in Medium Equilibrium

[0207] Experiment Example 4: Stability Test

[0208] To investigate the stability of the various crystal forms / salt forms prepared in this invention, samples of hydrochloride crystal form A and hydrochloride crystal form B prepared in the above examples were placed under high temperature (60℃) and accelerated (40℃±2℃ / 75%±5%RH) conditions for 1 month, respectively. Samples were taken at 0 days and 1 month, and the crystal form changes of the samples were tested by XRD.

[0209] The free alkali crystal forms K2 and K4 prepared in the above examples were placed under accelerated (40℃±2℃ / 75%±5%RH) and long-term (25℃±2℃ / 65%±5%RH) conditions for one month, respectively. Samples were taken at day 0 and month 1, and the crystal form changes of the samples were tested by XRD. The results are shown in Table 11, and the XRPD spectrum detection results are shown in Figures 26-29.

[0210] Table 11-1 Stability test results

[0211] Table 11-2 Stability test results

[0212] Experimental Example 5: In vivo pharmacokinetic test in rats

[0213] 1. Experimental Objective

[0214] The study investigated the plasma concentration levels and pharmacokinetic characteristics of compound (I) in rats after a single oral administration of different crystal / salt forms at the same dosage.

[0215] 2. Materials and Methods

[0216] 2.1 Test Drug

[0217] Free alkali crystal form K1, obtained from Example 1

[0218] Free alkali crystal form K2, obtained in Example 2;

[0219] Free alkali crystal form K4, obtained in Example 3;

[0220] Hydrochloride crystal form A, obtained in Example 7;

[0221] Hydrochloride crystal form B, obtained in Example 8;

[0222] Trifluoroacetate crystal form A, obtained in Example 9.

[0223] 2.2 Experimental Animals

[0224] Eighteen SD rats were used, with three rats in each group, and their weights ranged from 210 to 240g.

[0225] 2.3 Sampling Method

[0226] The test drug was prepared into a homogeneous suspension with a concentration of 7.00 mg / ml by adding 0.5% MC (4000 cps) + 0.1% Tween 80 aqueous solution. The suspension was immediately administered orally to rats at a dose of 70 mg / kg. Blood samples of 0.1 ml were collected from the jugular vein before administration and at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. The blood samples were placed in EDTA-K2 tubes, centrifuged at 3000 r / min for 10 min, and the plasma was separated and stored frozen at -80℃.

[0227] 2.4 LC / MS / MS Analysis of Biological Samples

[0228] Take 50 μL of plasma and mix it with 5 μL of working solution or blank diluent. Add 150 μL of acetonitrile precipitant containing internal standard, vortex for 2 min, centrifuge at 12000 r / min for 10 min, take 2 μL of supernatant and mix it with 200 μL of pure water:acetonitrile (1:1). Inject the mixture into 3 μL for analysis.

[0229] 2.5 Test Results

[0230] The main pharmacokinetic parameters of different crystal / salt forms after a single oral administration to SD rats are shown in Table 12 below, and the mean plasma concentration-time curves are shown in Figures 30 and 31.

[0231] Table 12-1 Main pharmacokinetic parameters after a single oral administration in rats

[0232] Table 12-2 Main pharmacokinetic parameters after a single oral administration in rats

[0233] It will be apparent to those skilled in the art that various modifications and variations can be made to the compounds and their preparation methods without departing from the spirit or scope of this application. Therefore, the scope of protection of this application covers various modifications and variations made to this application, as long as the modifications or variations are within the scope covered by the claims and their equivalent embodiments.

Claims

1. A crystalline form K2 of a compound of Formula (I), characterized by, having characteristic peaks at 2-theta values of 6.0°±0.2°, 7.2°±0.2°, 9.0°±0.2°, 10.3°±0.2°, 12.0°±0.2°, 13.3°±0.2°, 25.3°±0.2°, 29.8°±0.2°; Preferably, the X-ray powder diffraction pattern of said crystalline Form K2 has characteristic peaks at 2θ values of 6.0°±0.2°, 6.7°±0.2°, 7.2°±0.2°, 9.0°±0.2°, 10.3°±0.2°, 10.5°±0.2°, 12.0°±0.2°, 13.3°±0.2°, 16.2°±0.2°, 16.7°±0.2°, 16.8°±0.2°, 17.3°±0.2°, 18.0°±0.2°, 18.6°±0.2°, 18.8°±0.2°, 19.2°±0.2°, 20.2°±0.2°, 20.4°±0.2°, 20.8°±0.2°, 21.5°±0.2°, 21.6°±0.2°, 22.4°±0.2°, 23.8°±0.2°, 24.2°±0.2°, 25.3°±0.2°, 25.9°±0.2°, 26.3°±0.2°, 26.7°±0.2°, 28.6°±0.2°, 29.8°±0.2°; Preferably, said crystalline Form K2 has an XPRD pattern substantially as set out in Figure 3.

2. A crystalline form K4 of a compound of formula (I) characterized by, having characteristic peaks at 2-theta values of 6.5°±0.2°, 10.1°±0.2°, 11.8°±0.2°, 12.3°±0.2°, 12.9°±0.2°, 14.8°±0.2°, 18.4°±0.2°, 25.6°±0.2°, Preferably, the X-ray powder diffraction pattern of said crystalline Form K4 has characteristic peaks at 2θ values of 6.3°±0.2°, 6.5°±0.2°, 6.8°±0.2°, 9.0°±0.2°, 10.1°±0.2°, 11.8°±0.2°, 12.3°±0.2°, 12.9°±0.2°, 13.0°±0.2°, 14.8°±0.2°, 16.1°±0.2°, 16.3°±0.2°, 16.7°±0.2°, 16.9°±0.2°, 17.7°±0.2°, 18.0°±0.2°, 18.1°±0.2°, 18.4°±0.2°, 19.1°±0.2°, 19.9°±0.2°, 20.2°±0.2°, 20.4°±0.2°, 20.6°±0.2°, 20.9°±0.2°, 21.4°±0.2°, 21.7°±0.2°, 22.4°±0.2°, 22.5°±0.2°, 24.0°±0.2°, 24.4°±0.2°, 25.6°±0.2°; Preferably, said crystalline Form K4 has an XPRD pattern substantially as set out in Figure 5.

3. A crystalline form K16 of a compound of Formula (I), characterized by, having characteristic peaks at 2θ values of 7.8°±0.2°, 11.1°±0.2°, 11.4°±0.2°, 14.1°±0.2°, 15.5°±0.2°, 17.6°±0.2°, 22.0°±0.2°, 23.7°±0.2°; Preferably, said crystalline form K16 has an XPRD pattern substantially as set out in Figure 9. Preferably, said crystalline form K16 has an XPRD pattern substantially as set out in Figure 9.

4. A hydrochloride salt of a compound of formula (I), 5. The hydrochloride salt of claim 4, characterized in that, The hydrochloride salt of said compound of formula (I) is a salt formed between said compound of formula (I) and hydrochloric acid in a molar ratio comprised between 1 :1 and 1 :

2.

6. The hydrochloride salt of claim 4, characterized in that, The hydrochloride salt of said compound of formula (I) is a salt formed between said compound of formula (I) and hydrochloric acid in a molar ratio of 1 :

1.

7. The hydrochloride salt of claim 4, characterized in that, The hydrochloride salt of said compound of formula (I) is a salt formed between said compound of formula (I) and hydrochloric acid in a molar ratio of 1 :

2.

8. The hydrochloride salt of claim 4 or 5, characterized in that, The hydrochloride salt is present in the form of a crystalline form A having an X- ray powder diffraction pattern with characteristic peaks at 2Q values of 9.4°±0.2°, 10.4°±0.2°, 15.3°±0.2°, 19.2°±0.2°, 21.3°±0.2°, 22.8°±0.2°; Preferably, said crystalline form K16 has an XPRD pattern substantially as set out in Figure 9. Preferably, said crystalline form K16 has an XPRD pattern substantially as set out in Figure 9.

9. The hydrochloride salt of claim 8, characterized in that, The hydrochloride salt is present in the form of a crystalline form A, said crystalline form A being a hydrate, preferably said hydrate is selected from the group consisting of hemihydrate, monohydrate, dihydrate, trihydrate and tetrahydrate, more preferably said hydrate is a dihydrate.

10. The hydrochloride salt of claim 4 or 5, characterized in that, The hydrochloride salt is present in the form of a crystalline form B having an X- ray powder diffraction pattern with characteristic peaks at 2Q values of 11.2°±0.2°, 12.2°±0.2°, 14.5°±0.2°, 16.1°±0.2°, 18.3°±0.2°, 19.9°±0.2°, 24.5°±0.2°; The hydrochloride salt is present in the form of a crystalline form B having an X- ray powder diffraction pattern with characteristic peaks at 2Q values of 11.2°±0.2°, 12.2°±0.2°, 14.5°±0.2°, 16.1°±0.2°, 18.3°±0.2°, 19.9°±0.2°, 24.5°±0.2°; Preferably, the hydrochloride salt Form B has an XPRD pattern substantially as shown in Figure 13. Preferably, the hydrochloride salt Form B has an XPRD pattern substantially as shown in Figure 13.

11. The hydrochloride salt of claim 10, characterized in that, The hydrochloride salt is present in the form of a crystalline Form B which is an anhydrate.

12. A hydrobromide salt of a compound of formula (I) ###0002### characterized in that, The hydrobromide salt is present in the form of a crystalline Form A which has an X-ray powder diffraction pattern with characteristic peaks at 2-theta values of 7.2°±0.2°, 10.1°±0.2°, 19.0°±0.2°, 20.4°±0.2°, 22.7°±0.2°, 23.7°±0.2°, 25.0°±0.2°, 28.7°±0.2°; Preferably, the hydrobromide salt Form A has an XPRD pattern substantially as shown in Figure 17. The hydrobromide salt is present in the form of a crystalline Form A which has an X-ray powder diffraction pattern with characteristic peaks at 2-theta values of 7.2°±0.2°, 10.1°±0.2°, 19.0°±0.2°, 20.4°±0.2°, 22.7°±0.2°, 23.7°±0.2°, 25.0°±0.2°, 28.7°±0.2°; 13. A mesylate salt of a compound of formula (I) ###0002### characterized in that, Preferably, the hydrobromide salt Form A has an XPRD pattern substantially as shown in Figure 17. The mesylate salt is present in the form of a crystalline Form A which has an X-ray powder diffraction pattern with characteristic peaks at 2-theta values of 6.5°±0.2°, 8.6°±0.2°, 11.6°±0.2°, 13.1°±0.2°, 18.1°±0.2°, 20.5°±0.2°, 21.7°±0.2°, 30.2°±0.2°; Preferably, the mesylate salt Form A has an XPRD pattern substantially as shown in Figure 19. Preferably, the X-ray powder diffraction pattern of said mesylate salt Form A shows characteristic peaks at 2Q values of 6.5°±0.2°, 8.6°±0.2°, 10.2°±0.2°, 11.6°±0.2°, 12.4°±0.2°, 13.1°±0.2°, 14.3°±0.2°, 16.0°±0.2°, 18.1°±0.2°, 19.0°±0.2°, 19.2°±0.2°, 19.7°±0.2°, 20.0°±0.2°, 20.1°±0.2°, 20.5°±0.2°, 21.7°±0.2°, 23.2°±0.2°, 24.6°±0.2°, 25.4°±0.2°, 25.6°±0.2°, 25.9°±0.2°, 26.8°±0.2°, 30.2°±0.2°; Preferably, said mesylate salt Form A has an XPRD pattern substantially as set out in Figure 19.

14. A mesylate salt of a compound of formula (I) ###0002### characterized in that, said mesylate salt exists in a crystalline Form B having an X-ray powder diffraction pattern with characteristic peaks at 2Q values of 4.2°±0.2°, 11.0°±0.2°, 12.5°±0.2°, 16.3°±0.2°, 17.0°±0.2°, 17.9°±0.2°, 21.2°±0.2°, 25.9°±0.2°; Preferably, the X-ray powder diffraction pattern of said mesylate salt Form B shows characteristic peaks at 2Q values of 4.2°±0.2°, 8.4°±0.2°, 11.0°±0.2°, 11.2°±0.2°, 12.5°±0.2°, 13.2°±0.2°, 15.1°±0.2°, 15.3°±0.2°, 16.3°±0.2°, 17.0°±0.2°, 17.9°±0.2°, 18.4°±0.2°, 19.5°±0.2°, 19.8°±0.2°, 20.8°±0.2°, 21.2°±0.2°, 21.6°±0.2°, 22.0°±0.2°, 23.3°±0.2°, 23.6°±0.2°, 24.0°±0.2°, 24.8°±0.2°, 25.9°±0.2°, 27.6°±0.2°, 28.0°±0.2°; Preferably, said mesylate salt Form B has an XPRD pattern substantially as set out in Figure 21.

15. A phosphate salt of a compound of formula (I), ###00006### (I) characterized in that, said phosphate salt exists in a crystalline Form A having an X-ray powder diffraction pattern with characteristic peaks at 2Q values of 6.8°±0.2°, 13.9°±0.2°, 19.6°±0.2°, 21.5°±0.2°, 21.8°±0.2°, 22.0°±0.2°, 24.3°±0.2°, 28.0°±0.2°; Preferably, the X-ray powder diffraction pattern of said phosphate Form A shows characteristic peaks at 2Q values of 6.8°±0.2°, 7.1°±0.2°, 10.2°±0.2°, 11.6°±0.2°, 13.7°±0.2°, 13.9°±0.2°, 14.3°±0.2°, 17.7°±0.2°, 18.0°±0.2°, 18.7°±0.2°, 19.6°±0.2°, 19.9°±0.2°, 20.1°±0.2°, 20.3°±0.2°, 20.6°±0.2°, 20.7°±0.2°, 21.3°±0.2°, 21.5°±0.2°, 21.8°±0.2°, 22.0°±0.2°, 23.5°±0.2°, 23.6°±0.2°, 24.3°±0.2°, 24.6°±0.2°, 26.4°±0.2°, 28.0°±0.2°; Preferably, said phosphate Form A has an XPRD pattern substantially as shown in Figure 24.

16. A pharmaceutical composition comprising, A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 3, or a salt of a compound of formula (I) as defined in any one of claims 4 to 15, and one or more pharmaceutically acceptable carriers.

17. Use of a compound of formula (I) as defined in any one of claims 1 to 3, or a salt of a compound of formula (I) as defined in any one of claims 4 to 15, or a pharmaceutical composition as defined in claim 16, as a Nav1.8 inhibitor for the prevention and / or treatment of a disease or condition mediated at least in part by Nav1.8; Preferably, said disease or condition mediated by Nav1.8 is pain; More preferably, said pain is chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, post-surgical pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence or cardiac arrhythmia.

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