Selective sodium channel modulators and preparation and application thereof

Abstract

The invention belongs to the field of medicinal chemistry. The invention discloses a heterocyclic compound as well as a preparation method and application thereof, and particularly relates to a series of blockers of sodium ion channels with novel structures as well as a preparation method and application thereof. The structure of the compound is shown as a general formula (I). The compounds or stereoisomers, racemes, geometric isomers, tautomers, prodrugs, hydrates, solvates or pharmaceutically acceptable salts and pharmaceutical compositions thereof can be used for treating or / and preventing sodium ion channel (Nav)-mediated related diseases.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry. Specifically, this invention relates to novel compounds or their stereoisomers, racemates, geometric isomers, tautomers, prodrugs, hydrates, solvates or pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them, which are voltage-gated sodium channel (Nav) blockers with novel structures. Background Technology

[0002] Pain is a protective mechanism that allows healthy animals to avoid tissue damage and prevents further harm to damaged tissue. Nevertheless, there are many cases where pain persists beyond its usefulness, or where patients would benefit from suppressing pain.

[0003] Neuropathic pain is a form of chronic pain caused by damage to sensory nerves. It can be divided into two categories: pain caused by nerve metabolic damage and pain caused by damage to nerve continuity. Indications for metabolic pain include postherpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Indications for pain caused by damage to nerve continuity include post-amputation pain, postoperative nerve injury pain, and nerve entrapment injuries such as neuropathic back pain.

[0004] Voltage-gated sodium channels (Nav) are involved in pain signal transduction.

[0005] Sodium channels (NAVs) are biological mediators of electrical signal transduction because they mediate the rapid ascent of action potentials in many excitable cell types, such as neurons, skeletal muscle cells, and cardiomyocytes. The roles of these channels in normal physiology, pathological states caused by mutations in sodium channel genes, preclinical work in animal models, and clinical pharmacological evidence from known sodium channel modulators all point to a central role for NAVs in pain perception. Because NAVs mediate the rapid ascent of action potentials in many excitable cell types (e.g., neurons, skeletal muscle cells, and cardiomyocytes), they are involved in the initiation of signal transduction in these cells. Due to the role of NAVs in the initiation and propagation of neuronal signals, antagonists that reduce NAV currents can prevent or reduce neural signals, and NAVs are considered a potential target for pain relief in cases of observed hyperexcitability. Several clinically useful analgesics have been identified as NAV inhibitors. Local anesthetics such as lidocaine block pain by inhibiting NAV channels, and other compounds, such as carbamazepine, lamotrigine, and tricyclic antidepressants, have been shown to effectively reduce pain through sodium channel inhibition.

[0006] Nav forms a subfamily of the voltage-gated ion channel superfamily and contains nine isoforms, named Nav1.1 and Nav1.9. The tissue localization of these nine isoforms differs. Nav1.4 is the main sodium channel in skeletal muscle, and Nav1.5 is the main sodium channel in cardiomyocytes. Navs 1.7, 1.8, and 1.9 are primarily located in the peripheral nervous system, while Navs 1.1, 1.2, 1.3, and 1.6 are neural channels found in both the central and peripheral nervous systems. The nine isoforms exhibit similar functional behaviors but differ in specific aspects of voltage dependence and kinetic behavior.

[0007] Nav1.8 channels have been identified as potential targets for analgesia, demonstrating their role as carriers of sodium currents, maintaining action potential firing in neurons of the small dorsal root ganglion, and participating in the spontaneous emission of electrical signals in damaged neurons, such as driving neuropathic pain. A major drawback of some known Nav inhibitors is their poor therapeutic window, likely due to their lack of allotype selectivity. Since Nav1.8 is primarily confined to pain-sensing neurons, selective Nav1.8 blockers are unlikely to induce the adverse effects common with non-selective Nav blockers. Therefore, the development of novel selective Nav1.8 inhibitors remains crucial in this field. Summary of the Invention

[0008] The purpose of this invention is to provide a selective inhibitor that has inhibitory activity against sodium ion channels, particularly Nav1.8 sodium ion channels.

[0009] A first aspect of the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof:

[0010]

[0011] Among them, R a1 R a2 R a3 Each of the following groups is independently selected: hydrogen, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic, -ZC(O)NR a R b -ZC(O)-OR c -ZC(O)-R c -Z-OC(O)-R c -C(O)-Z-OR c -OZC(O)-R c -ZP(O)-R c -ZP(O)OR c -Z-OP(O)-R c -Z-OP(O)ORc -ZS(O)-R c -ZS(O)2-R c -ZS(O)2-OR c -ZOS(O)2-R c -ZOS(O)2-OR c Z is selected from: chemical bond, -O-, -S-, -NH-, C1-C12 alkylene; and the alkyl, alkoxy, cycloalkyl, heterocyclic, and alkylene groups are optionally substituted by one or more (e.g., 2, 3, 4, 5, etc.) substituents selected from the group consisting of: halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, amino, and C3-C8 cycloalkyl.

[0012] R a R b R c Each is independently selected from: H, halogen, hydroxyl, cyano, amino, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C1-C6 alkenyl, substituted or unsubstituted C1-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl; the substitution refers to optional substitution by one or more substituents selected from the group consisting of: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy;

[0013] R b1 R b2 R b3 R b4 Each is independently selected from hydrogen, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, and the alkyl or alkoxy group is optionally substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, and amino.

[0014] Or any two R a1 R a2 R a3 R b1 R b2 The ring atoms spaced apart from it connect together to form a 5-7 membered ring, which can be a saturated or unsaturated carbon ring or a heterocycle; the heterocycle may optionally contain one or more N, O, or S (=O). m Heteroatoms; the 5-7 membered ring may optionally be substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, and amino.

[0015] M1 and M2 are each independently selected from C, O, and S (=O). m NR n , where R nSelected from: hydrogen, C1-C6 alkyl; preferably, R n Selected from: hydrogen, methyl, or ethyl, with R being the most preferred. n Selected from hydrogen;

[0016] X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 Each is independently selected from bond, C, N, O, C=O, S (=O). m ;

[0017] R c1 R c2 R c3 Each element is independently selected from hydrogen, halogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)NR c4 R c5 -C(=S)NR c4 R c5 -N(R) c4 R c5 -C(=N)-NR c4 R c5 ;

[0018] R c4 R c5 Each is independently selected from hydrogen, hydroxyl, amino, C1-C6 alkyl, and C1-C6 alkoxy.

[0019] m and n are each independently 0, 1 or 2;

[0020] In formula (I), Indicates a single bond or a double bond.

[0021] In another preferred embodiment, the R a1 Selected from the following group: -ZC(O)NR a R b -ZC(O)-OR c -ZC(O)-R c -Z-OC(O)-R c -C(O)-Z-OR c -OZC(O)-R c -ZP(O)-R c -ZP(O)OR c -Z-OP(O)-R c -Z-OP(O)OR c -ZS(O)-R c -ZS(O)2-R c -ZS(O)2-OR c -ZOS(O)2-R c-ZOS(O)2-OR c .

[0022] In another preferred embodiment, the R a2 It is a C1-C6 alkoxy group.

[0023] In another preferred embodiment, the compound has the structure shown in formula (IA):

[0024]

[0025] Among them, R a1 R a2 R a3 R b1 R b2 R b3 R b4 ,M1,M2,X1,X2,X3,X4,X5,X6,X7,X8,X9,X 10 R c1 R c2 R c3 m, n As defined above.

[0026] In another preferred embodiment, R a1 R a2 R a3 Each is independently selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, amino, ethyl ester, isopropyl ester, tert-butyl ester, phosphate ester, and dimethyl carbamate.

[0027] In another preferred embodiment, R b1 R b2 R b3 R b4 Each is independently selected from hydrogen, methyl, trifluoromethyl, ethyl, methoxy, and ethoxy.

[0028] In another preferred embodiment, R b1 R b2 Each is independently selected from hydrogen, methyl, and trifluoromethyl.

[0029] In another preferred embodiment, R b3 R b4 Each is independently selected from hydrogen, methyl, and trifluoromethyl.

[0030] In another preferred embodiment, any two adjacent R a1 R a2 R a3 R b1 R b2 They connect to form 5- or 6-membered carbon rings or heterocycles.

[0031] In another preferred embodiment, the 5- or 6-membered heterocycle contains one or two N, O, or S (=O). m heteroatoms.

[0032] In another preferred embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 Each is independently selected from bond, C, N, O, C=O, S(=O)2.

[0033] In another preferred embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 All are selected from C atoms.

[0034] In another preferred embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 It contains one or two N atoms.

[0035] In another preferred embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 It contains any one C=O.

[0036] In another preferred embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 It contains any one S(=O)2.

[0037] In another preferred embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 The elements can be arbitrarily selected from the bonds C, S, and O.

[0038] In another preferred embodiment, R c1 R c2 R c3 Each is independently selected from hydrogen, hydroxyl, amino, fluorine, cyano, oxo, methyl, -C(=O)NH2, -C(=O)NHCH3, -C(=O)NHC2H5;

[0039] In another preferred embodiment, R c1 R c2 R c3 Each group is independently selected from hydrogen, hydroxyl, amino, fluorine, cyano, and -C(=O)NH2.

[0040] In another preferred embodiment, R a1 R a2 R a3Each is independently selected from fluorine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, amino, ethyl ester, isopropyl ester, tert-butyl ester, phosphate ester, and dimethyl carbamate.

[0041] In another preferred embodiment, R a1 R a2 R a3 Selected from fluorine, methoxy, isopropoxy, ethyl ester, and dimethyl carbamate groups.

[0042] In another preferred embodiment, R a1 With R b1 Or R b2 They connect to form 5-membered carbon rings or 5-membered heterocycles.

[0043] In another preferred embodiment, the 5-membered heterocycle contains an O heteroatom.

[0044] In another preferred embodiment, R b1 R b2 R b3 R b4 Each is independently selected from hydrogen, methyl, trifluoromethyl, ethyl, methoxy, and ethoxy.

[0045] In another preferred embodiment, R b1 R b2 R b3 R b4 Each is independently selected from hydrogen, methyl, and trifluoromethyl.

[0046] In another preferred embodiment, M1 and M2 are independently selected from O and -NH-.

[0047] In another preferred embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 Each is independently selected from bond, C, N, O, C=O, S(=O)2.

[0048] In another preferred embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 All are selected from C atoms or any atom containing one N atom.

[0049] In another preferred embodiment, the compound has a structure selected from the following formula:

[0050]

[0051]

[0052]

[0053] Among them, R b1 Rb2 R b3 R b4 ,M1,M2,X6,X7,X8,X9,X 10 R c1 R c2 R c3 m, n As defined above;

[0054] R1, R2, R3, R4, and R5 are each independently selected from: H, halogen, hydroxyl group, C1-C6 alkyl group, C1-C6 alkoxy group, C3-C8 cycloalkyl group, 3-8 membered heterocyclic group, and -ZC(O)NR group each time they appear. a R b -ZC(O)-OR c -ZC(O)-R c -Z-OC(O)-R c -C(O)-Z-OR c -OZC(O)-R c -ZP(O)-R c -ZP(O)OR c -Z-OP(O)-R c -Z-OP(O)OR c -ZS(O)-R c -ZS(O)2-R c -ZS(O)2-OR c -ZOS(O)2-R c -ZOS(O)2-OR c Z is selected from: chemical bonds, -O-, -S-, -NH-, C1-C12 alkylene groups; and the alkyl, alkoxy, cycloalkyl, heterocyclic, or alkylene group is optionally substituted by one or more (e.g., 2, 3, 4, 5, etc.) substituents selected from the group consisting of: halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, amino, C3-C8 cycloalkyl; R a R b R c Each is independently selected from: H, halogen, hydroxyl, cyano, amino, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C1-C6 alkenyl, substituted or unsubstituted C1-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl; the substitution refers to optional substitution by one or more substituents selected from the group consisting of: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy.

[0055] In another preferred embodiment, R2 and R3 are each independently selected from the following groups each time they appear: F, Cl, Br, I, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, amino, ethyl ester, isopropyl ester, tert-butyl ester, phosphate ester, dimethyl carbamate.

[0056] In another preferred embodiment, R1 is selected each time it appears from: substituted or unsubstituted hydroxyl groups, substituted or unsubstituted C1-C6 alkoxy groups, -ZC(O)NR groups. a R b -ZC(O)-OR c -ZC(O)-R c -Z-OC(O)-R c -C(O)-Z-OR c -OZC(O)-R c -ZP(O)-R c -ZP(O)OR c -Z-OP(O)-R c -Z-OP(O)OR c -ZS(O)-R c -ZS(O)2-R c -ZS(O)2-OR c -ZOS(O)2-R c -ZOS(O)2-OR c ;R a R b R c Each is independently selected from: H, halogen, hydroxyl, cyano, amino, substituted or unsubstituted C1-C6 alkyl; Z is selected from: chemical bond, -O-, -NH-, C1-C6 alkylene; the substitution refers to being optionally substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl; preferably, the substitution refers to being optionally substituted by one or more substituents selected from the group consisting of: F, Cl, Br, cyclopropyl.

[0057] In another preferred embodiment, R4 is selected each time it appears from: substituted or unsubstituted hydroxyl groups, substituted or unsubstituted C1-C6 alkoxy groups, -ZC(O)NR groups. a R b -ZC(O)-OR c -ZC(O)-R c -Z-OC(O)-R c -C(O)-Z-OR c -OZC(O)-R c-ZP(O)-R c -ZP(O)OR c -Z-OP(O)-R c -Z-OP(O)OR c -ZS(O)-R c -ZS(O)2-R c -ZS(O)2-OR c -ZOS(O)2-R c -ZOS(O)2-OR c ;R a R b R c Each is independently selected from: H, halogen, hydroxyl, cyano, amino, substituted or unsubstituted C1-C6 alkyl; Z is selected from: chemical bond, -O-, -NH-, C1-C6 alkylene; the substitution refers to being optionally substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl; preferably, the substitution refers to being optionally substituted by one or more substituents selected from the group consisting of: F, Cl, Br, cyclopropyl.

[0058] In another preferred embodiment, R1 is selected each time it appears from: substituted or unsubstituted hydroxyl groups, substituted or unsubstituted C1-C6 alkoxy groups, -ZC(O)NR groups. a R b -ZC(O)-OR c -ZC(O)-R c -Z-OC(O)-R c -C(O)-Z-OR c -OZC(O)-R c ;R a R b R c Each is independently selected from: H, halogen, hydroxyl, cyano, amino, substituted or unsubstituted C1-C6 alkyl; Z is selected from: chemical bond, -O-, -NH-, C1-C6 alkylene; the substitution refers to being optionally substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl; preferably, the substitution refers to being optionally substituted by one or more substituents selected from the group consisting of: F, Cl, Br, cyclopropyl.

[0059] In another preferred embodiment, R4 is selected from: C1-C6 alkoxy, -ZC(O)NR each time it appears. a R b -ZC(O)-OR c -Z-OC(O)-Rc ;R a R b R c Each is independently selected from: H, halogen, hydroxyl, cyano, amino, C1-C6 alkyl; Z is selected from: chemical bond, -O-, -NH-, C1-C6 alkylene.

[0060] In another preferred embodiment, R4 is selected from the following groups each time it appears: fluorine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, amino, ethyl ester, isopropyl ester, tert-butyl ester, phosphate ester, and dimethyl carbamate.

[0061] In another preferred embodiment, the compound has a structure selected from the following formula:

[0062]

[0063] Among them, R b2 R b3 R b4 ,M1,M2,X6,X7,X8,X9,X 10 R c1 R c2 R c3 m, n As defined above;

[0064] M3 is selected from: O, -NH-;

[0065] R2, R3, R4, and R5 are each independently selected from: H, halogen, hydroxyl group, C1-C6 alkyl group, C1-C6 alkoxy group, C3-C8 cycloalkyl group, 3-8 membered heterocyclic group, and -ZC(O)NR group each time they appear. a R b -ZC(O)-OR c -ZC(O)-R c -Z-OC(O)-R c -C(O)-Z-OR c -OZC(O)-R c -ZP(O)-R c -ZP(O)OR c -Z-OP(O)-R c -Z-OP(O)OR c -ZS(O)-R c -ZS(O)2-R c -ZS(O)2-OR c -ZOS(O)2-R c -ZOS(O)2-OR cZ is selected from: chemical bonds, -O-, -S-, -NH-, C1-C12 alkylene groups; and the alkyl, alkoxy, cycloalkyl, heterocyclic, or alkylene group is optionally substituted by one or more (e.g., 2, 3, 4, 5, etc.) substituents selected from the group consisting of: halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, amino, C3-C8 cycloalkyl; R a R b R c Each is independently selected from: H, halogen, hydroxyl, cyano, amino, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C1-C6 alkenyl, substituted or unsubstituted C1-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl; the substitution refers to optional substitution by one or more substituents selected from the group consisting of: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy.

[0066] In another preferred embodiment, Selected from R b1 R b2 R b3 R b4 Each is independently selected from hydrogen, methyl, trifluoromethyl, ethyl, methoxy, and ethoxy.

[0067] In another preferred embodiment, Selected from

[0068] In another preferred embodiment, R c1 R c2 R c3 Each is independently selected from hydrogen, hydroxyl, amino, fluorine, cyano, oxo, methyl, -C(=O)NH2, -C(=O)NHCH3, -C(=O)NHC2H5.

[0069] In another preferred embodiment, R c1 R c2 R c3 Each is independently selected from hydrogen and -C(=O)NH2.

[0070] In another preferred embodiment, Selected from: Rc is selected from hydrogen, hydroxyl, amino, fluorine, cyano, oxo, methyl, -C(=O)NR c4 R c5 In another preferred embodiment, Selected from:

[0071]

[0072] In another preferred embodiment, the compound is selected from the group consisting of:

[0073]

[0074]

[0075]

[0076] A second aspect of the invention provides a compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof for use in the preparation of a medicament for inhibiting a voltage-gated sodium channel; wherein the voltage-gated sodium channel is Nav1.8.

[0077] A third aspect of the invention provides the use of a compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof in the preparation of a medicament for inhibiting voltage-gated sodium channel-related diseases, including but not limited to: pain, multiple sclerosis, peroneal muscular dystrophy, incontinence, pathological cough, or arrhythmia.

[0078] In another preferred embodiment, the pain includes: chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, etc.

[0079] A fourth aspect of the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound, isomer thereof, solvate thereof, or pharmaceutically acceptable salt or hydrate thereof described in the first aspect of the present invention.

[0080] In another preferred embodiment, pharmaceutically acceptable carriers include fillers, disintegrants, surfactants, and solubilizers.

[0081] The fifth aspect of the present invention provides the use of a pharmaceutical composition of a compound of formula I, an isomer, a solvate, or a pharmaceutically acceptable salt or hydrate thereof in the preparation of a medicament for treating, preventing, or alleviating voltage-gated sodium channel-related diseases, including but not limited to: pain, multiple sclerosis, peroneal muscular dystrophy, incontinence, pathological cough, or arrhythmia.

[0082] In another preferred embodiment, the pain includes: chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, etc.

[0083] The sixth aspect of the present invention provides a method for preparing the compound described in the first aspect of the present invention, which is simple, efficient and easy to automate.

[0084] Specifically (taking 3DMSD01-04 as an example), the preparation of 3DMSD01-04 can use starting material 1 as the starting material and includes 5 steps:

[0085] Step 1: The starting material compound 1 undergoes a demethylation reaction to synthesize intermediate 2 solution;

[0086] Step 2: Intermediate 2 undergoes iodination to obtain intermediate 3;

[0087] Step 3: Etherification of intermediate 3 with phenolic hydroxyl groups to obtain intermediate 4;

[0088] Step 4: Intermediate 4 iodine is replaced by a hydroxyl group to obtain intermediate 5;

[0089] Step 5: The intermediate 5-phenol hydroxymethyl etherification yields 3DMSD01-04;

[0090] The specific synthetic route information is as follows:

[0091]

[0092] Based on the method described above, various compounds of the present invention can be prepared by using other starting materials.

[0093] The present invention also relates to pharmaceutically acceptable salts of compounds of general formula (I). The present invention also relates to solvates of compounds, including their salts and active metabolites, and, suitably, tautomers of these compounds according to general formula (I), comprising prodrug formulations.

[0094] "Pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt of an organic or inorganic acid or base of the compound of the present invention. Representative pharmaceutically acceptable salts include, for example, alkali metal salts, alkaline earth salts, ammonium salts, and water-soluble and water-insoluble salts such as acetates, carbonates, chlorides, gluconates, glutamates, lactates, laurates, malates, or tartrates.

[0095] "Prodrug" refers to a drug precursor, which is a compound that must undergo a chemical transformation by a metabolic process before becoming an active pharmacological agent when administered to a patient. Exemplary prodrugs according to formula (I) are esters and amides, preferably alkyl esters of fatty acid esters. The prodrug formulation herein comprises all substances formed by simple transformation by enzymes, metabolism, or any other means, including hydrolysis, oxidation, or reduction. Suitable prodrugs contain, for example, substances of general formula (I) bound to a solubility-improving substance (e.g., tetraethylene glycol, sugars, formic acid, or glucuronic acid, etc.) via an enzymatically cleavable linker (e.g., carbamate, phosphate, N-glucosidate, or sulfhydryl group). Such prodrugs of compounds according to the invention can be administered to a patient, and the prodrug can be converted into a substance of general formula (I) to achieve the desired pharmacological effect.

[0096] Some compounds of formula (I) may be contained in the form of racemates, their enantiomers, and optionally in the form of their non-corresponding isomers and all possible mixtures thereof.

[0097] According to the present invention, all chiral C atoms should have D- and / or L- configurations: combinations within a compound should also be possible, i.e., some chiral C atoms can be D- and others can be L- configurations.

[0098] The compounds according to the invention can be suitably formulated together with other active substances and excipients and carriers commonly used in pharmaceutical compositions, such as (depending on the formulation to be produced) talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous and non-aqueous carriers, fat bodies of animal or plant origin, paraffin derivatives, ethylene glycol (especially polyethylene glycol), various plasticizers, dispersants or emulsifiers, pharmaceutically compatible gases (e.g., air, oxygen, carbon monoxide, etc.), and preservatives.

[0099] To produce liquid formulations, additives such as sodium chloride solution, ethanol, sorbitol, glycerol, olive oil, almond oil, propylene glycol, or ethylene glycol can be used.

[0100] When solutions are used for infusion or injection, they are preferably aqueous solutions or suspensions that can be produced prior to use, for example, from lyophilized formulations containing such active substances or along with carriers, such as mannitol, lactose, glucose, albumin, etc. The sterilization is achieved by mixing the prepared solution with excipients, such as preservatives, stabilizers, emulsifiers, solubilizers, buffers, and / or salts for adjusting osmotic pressure. Sterilization can be achieved by aseptic filtration using a filter. Small amounts of antibiotics may also be added to ensure sterility is maintained.

[0101] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here.

[0102] The positive and progressive effects of the present invention after adopting the above technical solution are as follows:

[0103] (1) The sodium channel small molecule regulator provided by the present invention is stable, has excellent activity and good selectivity, and can be used to prevent and / or treat (stabilize, alleviate or cure) sodium channel-related diseases or symptoms, and has broad application prospects.

[0104] (2) The selective sodium channel small molecule regulator described in this invention has a simple and efficient preparation process that is easy to automate.

[0105] The specific embodiments of the present invention will now be described in further detail with reference to the accompanying drawings. Attached Figure Description

[0106] Figure 1 This is the HPLC chromatogram of 3DMSD01-04 in Example 1 of the present invention.

[0107] Figure 2 This is the HPLC chromatogram of 3DMSD01-06 in Example 2 of the present invention.

[0108] Figure 3 This is the HPLC chromatogram of 3DMSD01-07 in Example 3 of the present invention.

[0109] Figure 4 This is the HPLC chromatogram of 3DMSD01-08 in Example 4 of the present invention.

[0110] It should be noted that these accompanying drawings and textual descriptions are not intended to limit the scope of the invention in any way, but rather to illustrate the concept of the invention to those skilled in the art by referring to specific embodiments. Detailed Implementation

[0111] Through long-term and in-depth research, the inventors discovered a compound as shown in formula (I). This compound exhibits unexpected activity in regulating cytokines and / or interferons, and can be used to treat diseases mediated by cytokines and / or interferons. The compound also exhibits unexpected activity against Nav 1.8 and excellent selectivity for other Nav subtypes, and can be used for the treatment, relief, or prevention of Nav 1.8-related diseases. Based on the above findings, the inventors completed this invention.

[0112] the term

[0113] In this document, unless otherwise specified, all abbreviations have their conventional meanings as understood by those skilled in the art.

[0114] "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group. For example, "C1-12 alkyl" refers to straight-chain alkyl and branched alkyl groups comprising 1 to 12 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, etc.

[0115] "Alkenyl" is a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds that can occur at stable sites on the chain. Non-limiting examples include C2-C8 alkenyl groups (such as C2, C3, C4, C5, C6, C7, C8), C2-C6 alkenyl groups, and C2-C4 alkenyl groups. The specified ranges used herein represent alkenyl groups that can be considered as independent categories, having each value of the range as described herein, such as the alkyl portion. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, and butadienyl groups (including 1,2-butadienyl and 1,3-butadienyl). In one embodiment, the alkenyl group is optionally substituted, as described herein.

[0116] "Cycloalkyl" refers to a saturated or partially unsaturated cycloalkyl group having a monocyclic or polycyclic structure, including fused ring, bridged ring, and spirocyclic systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclogroups having at least one double bond). As used herein, C 3-8 Cycloalkyl groups have 3 to 8 ring carbon atoms (e.g., 3, 4, 5, 6, 7, or 8 ring carbon atoms). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and partially unsaturated groups such as cyclopentenyl and cyclohexenyl.

[0117] "Carbocyclic group," "carbocyclic group," "carbocyclic," or "cycloalkyl" is a saturated or partially unsaturated (i.e., non-aromatic) group containing all carbon ring atoms. A carbocyclic group typically comprises one ring of 3 to 7 carbon atoms or two fused rings each containing 3, 4, 5, 6, or 7 carbon atoms. A cycloalkyl substituent may have a substituted nitrogen or carbon atom as a side chain, or the substituted carbon atom of two substituents may have a cycloalkyl group linked as a spiroyl group. Examples of carbocyclic groups include cyclohexenyl, cyclohexyl, cyclopentenyl, cyclopentyl, cyclobutenyl, cyclobutyl, and cyclopropyl rings. In one embodiment, the carbocyclic group is optionally substituted as described herein. In one embodiment, a cycloalkyl group is a partially unsaturated (i.e., non-aromatic) group containing all carbon ring atoms. In another embodiment, a cycloalkyl group is a saturated group containing all carbon ring atoms.

[0118] A "heterocyclic group" is a saturated cyclic group. For example, it can have 1, 2, 3, or 4 heteroatoms independently selected from N, S, and O, with the remaining ring atoms being carbon atoms. In a representative embodiment, the heteroatom is nitrogen. In a representative embodiment, the heteroatom is oxygen. Monocyclic heterocyclic alkyl groups typically have 3 to about 8 ring atoms or 4 to 6 ring atoms. Examples of heterocyclic alkyl groups include morpholino, piperazino, piperidino, and pyrrololino.

[0119] "Aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring that shares adjacent carbon atom pairs) group, a polycyclic (i.e., a ring with adjacent carbon atom pairs) group with a conjugated π-electron system, including but not limited to phenyl and naphthyl.

[0120] "Heteroaryl" refers to a heteroaryl system containing 1 to 4 heteroatoms, including nitrogen, oxygen and S. For example, 5-7-membered heteroaryl refers to a heteroaryl system containing 5-7 ring atoms, and 5-10-membered heteroaryl refers to a heteroaryl system containing 5-10 ring atoms, including but not limited to furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc.

[0121] "Alkoxy" is an alkyl group as defined above, consisting of a specified number of carbon atoms covalently bonded together by an oxygen bridge (-O-). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-butoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexyloxy, 2-hexyloxy, 3-hexyloxy, and 3-methylpentoxy. Similarly, "alkylthio" or "thioalkyl" groups are alkyl groups as defined above, consisting of a specified number of carbon atoms covalently bonded together by a sulfur bridge (-S-). In one embodiment, the alkoxy group may optionally be substituted, as described herein.

[0122] "Substitution" refers to the replacement of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is the substituent described accordingly above, or the substituent appearing in the various examples. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are stable or chemically feasible combinations. Such substituents include, but are not limited to: halogens, hydroxyl groups, carboxyl groups (-COOH), C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C8 cycloalkyl groups, 3- to 12-membered heterocyclic groups, aryl groups, heteroaryl groups, C1-C8 aldehyde groups, C2-C10 acyl groups, C2-C10 ester groups, amino groups, C1-C6 alkoxy groups, C1-C10 sulfonyl groups, etc.

[0123] As used in this article, unless otherwise specified, solvents or solutions are added by pouring directly or adding at a constant rate.

[0124] As used in this article, the term "room temperature" generally refers to 4-30°C, preferably 20±5°C.

[0125] As used in this article, the "slow addition" method includes, but is not limited to: adding drop by drop, adding slowly along the container wall, etc.

[0126] The term "pharmaceutical excipients" refers to the excipients and additives used in the production of pharmaceuticals and the dispensing of prescriptions. It includes all substances contained in pharmaceutical preparations, excluding the active ingredient. See the Pharmacopoeia of the People's Republic of China (2020 edition) or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009) for details.

[0127] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0128] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to one skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the inventive methods. The preferred embodiments and materials described herein are for illustrative purposes only.

[0129] General methods and reagents

[0130] All solvents used in this invention are of analytical grade and contain approximately 0.1% water.

[0131] All test methods in this invention are general methods, and the test parameters are as follows:

[0132] The high-performance liquid chromatography (HPLC) method of this invention:

[0133] Test method:

[0134] Column: SunFire C18 5µm 4.6x150mm

[0135] Column temperature: 25℃

[0136] Flow rate: 1.000 ml / min

[0137] Mobile phase:

[0138] A: 0.03% TFA in H2O

[0139] B: 0.03% TFA in ACN

[0140] gradient:

[0141] Time (min) Mobile phase A (%V / V) Mobile phase B (% V / V) 0.01 90 10 13.00 5 95 16.00 5 95

[0142] The present invention provides a liquid chromatography-mass spectrometry (LCMS) method:

[0143] Chromatographic column: Sunfire C18 150*4.6mm 5um 1.00ml / min

[0144] Column temperature: 40℃

[0145] Gradient: 10% B hold for 1.8min, increase to 95% B within 10.2min, hold at 95% B for 3.0min, then back to 10% B within 0.01min

[0146] A: 0.03% TFA in H2O

[0147] B: 0.03% TFA in ACN

[0148] The present invention provides a method for nuclear magnetic resonance (H-NMR) analysis:

[0149] Test method:

[0150] Spectrometer: Avance

[0151] Solvent: DMSO-d6

[0152] Number of scans: 8

[0153] Spectral frequency: 400MHz

[0154] Scan time: 50s

[0155] The F-NMR method of this invention:

[0156] Test method:

[0157] Spectrometer: Avance

[0158] Solvent: DMSO-d6

[0159] Number of scans: 32

[0160] Spectral frequency: 377MHz

[0161] Scan time: 70s

[0162] Example 1: Preparation of 3DMSD01-04

[0163] 1500 mg of starting material 1 was dissolved in 45 mL of DCM, and then 2.38 g of BBr3 was added at 0 °C. The mixture was stirred at 0 °C for 1 h under nitrogen protection, poured into ice water, and extracted three times with EA, 50 mL each time. The EA layers were combined, dried with Na2SO4, filtered, concentrated, and purified by column chromatography with a 1:1 PE / EA as the mobile phase to obtain 995 mg of white solid intermediate 2. 955 mg of intermediate 2 was dissolved in 30.4 mg of DMSO and 15 mL of MeOH, and then 585 mg of NIS was added. The mixture was stirred at room temperature for 0.5 h until homogeneous. The reaction solution was concentrated and purified by column chromatography with a 1:1 PE / EA as the mobile phase to obtain 1.27 g of yellow solid intermediate 3. 170 mg of intermediate 3 was dissolved in 8 mL of DMF, and then 80.2 mg of K2CO3 and 74.1 mg of 2-iodopropane were added at room temperature. The mixture was then stirred at 60 °C for 16 h to reach the reaction endpoint. The reaction solution was diluted with 30 mL of water and extracted three times with EA (20 mL each time). The organic layers were combined, dried with Na2SO4, filtered, concentrated, and purified by column chromatography using a 1:1 PE / EA mobile phase to obtain 145 mg of yellow solid intermediate 4. 145 mg of intermediate 4 was dissolved in 11.6 mL of DMSO and 2.9 mL of H2O, stirred thoroughly, and then 58 mg of Cu(acac)2, 58 mg of BHMPO, and 29 mg of LiOH·H2O were added. The mixture was stirred at 80 °C under nitrogen protection for 16 h to reach the reaction endpoint. The reaction solution was diluted with 30 mL of water and extracted three times with EA (20 mL each time). The organic layers were combined, concentrated, and purified to obtain 85 mg of white solid intermediate 5. 131 mg of intermediate 5 was dissolved in 7 mL of DMF, and then 34.9 mg of K2CO3 and 76.9 mg of iodomethane were added at room temperature. The mixture was stirred at room temperature for 16 h to reach the reaction endpoint. The reaction solution was diluted with 30 mL of water and extracted three times with EA, 20 mL each time. The organic layers were combined, dried with Na2SO4, filtered, concentrated, and purified by HPLC to obtain 51 mg of white solid final product 3DMSD01-04 with a purity of 96.40% (254 nm). Its HPLC chromatogram is shown in [Figure number missing]. Figure 1shown. LCMS (ESI): RT 1.958min; m / z 532.7[M+H]+. 1H NMR (400MHz, DMSO-d6) δ10.76(s,1H),8.49(d,J=5.6Hz,1H),8.27(d,J=2.0Hz,1H),8.07( d,J=2.0Hz,1H),7.80(dd,J=5.6,2.4Hz,1H),7.63(d,J=2.0Hz,1H),6.88(dd,J=7.6,1.2Hz ,1H),5.17(d,J=10.4Hz,1H),4.38-4.35(m,1H),4.32-4.27(m,1H),3.86(s,3H),2.74-2.6 9(m,1H),1.62(s,3H),1.31(d,J=6.0Hz,3H),1.18(d,J=6.0Hz,3H),0.75(d,J=6.0Hz,3H). 19 F NMR (377MHz, DMSO-d6) δ -73.448 (1CF3), -151.26 (1F), -158.63 (1F), the reaction process is as follows:

[0164]

[0165] Example 2: Preparation of regulator 3DMSD01-06

[0166] 500 mg of starting material 1 was dissolved in 10 mL of DMF, and then 118 mg of K2CO3 and 242.6 mg of mgiodomethane were added at room temperature. The mixture was stirred at room temperature for 16 h to reach the reaction endpoint. The reaction solution was diluted with 30 mL of water and extracted three times with EA (extractant extractant), 50 mL each time. The organic layers were combined, dried over Na2SO4 to remove water, filtered, concentrated, and purified by column chromatography to obtain 440 mg of yellow solid intermediate 2. 440 mg of intermediate 2 was dissolved in 35.2 mL of DMSO and 8.8 mL of H2O and stirred until homogeneous. Then 176 mg of Cu(acac)2, 176 mg of BHMPO, and 88 mg of LiOH·H2O were added, and the mixture was stirred under nitrogen protection at 80 °C for 16 h to reach the reaction endpoint. The reaction solution was diluted with 100 mL of water and extracted three times with EA (extractant extractant), 40 mL each time. The organic layers were combined, concentrated, and purified to obtain 170 mg of a white solid intermediate 3. 140 mg of intermediate 3 was dissolved in 15 mL of DCM, and then 346.9 mg of Et3N and 306 mg of dimethylcarbamic chloride were added at room temperature. The reaction mixture was stirred at room temperature for 48 h until the reaction endpoint was reached. The reaction mixture was concentrated and purified to obtain the white final product 3DMSD01-06. Purity was 96.49% (254 nm), and its HPLC chromatogram is shown below. Figure 2 As shown. LCMS(ESI): RT 1.815 min; m / z 561.7 [M+H] + 1H NMR (400MHz, DMSO-d6) δ10.66(s,1H),8.49(d,J=5.6Hz,1H),8.28(d,J=2.0Hz,1H ),8.06(s,1H),7.85(dd,J=5.6,2.1Hz,1H),7.61(d,J=2.0Hz,1H),7.16(d,J=8.0H z,1H),5.09(d,J=10.4Hz,1H),4.25(dd,J=10.4,8.0Hz,1H),3.93(d,J=1.2Hz,3H) ,3.07(s,3H),2.92(s,3H),2.81-2.70(m,1H),1.61(s,3H),0.75(d,J=6.4Hz,3H).

[0167] 19F NMR (377MHz, DMSO-d6) δ -73.368 (1CF3), -151.24 (1F), -152.67 (1F). The reaction process is as follows:

[0168]

[0169] Example 3: Preparation of regulator 3DMSD01-07

[0170] 140 mg of starting material 1 was dissolved in 5 mL of pyridine, and then 72.9 mg of Ac₂O was added at room temperature. After shaking well, the mixture was stirred at room temperature for 16 h to reach the reaction endpoint. The reaction solution was concentrated and purified by preparative HPLC to obtain 50.57 mg of white solid final product 3DMSD01-07. The purity was 95.32% (254 nm), and its HPLC chromatogram is shown in [Figure number missing]. Figure 3 As shown. LCMS(ESI): RT 1.824 min; m / z 532.2 [M+H] +. 1H NMR (400MHz, DMSO-d6) δ10.68(s,1H),8.49(d,J=5.6Hz,1H),8.30(d,J=2.0Hz,1H ),8.06(d,J=2.0Hz,1H),7.84(dd,J=5.6,2.4Hz,1H),7.62(d,J=2.4Hz,1H),7.19 (d,J=8.4Hz,1H),5.09(d,J=10.0Hz,1H),4.26(dd,J=10.0,7.6Hz,1H),3.94(d,J =2.0Hz,3H),2.78-2.75(m,1H),2.35(s,3H),1.61(s,3H),0.75(d,J=6.0Hz,3H).

[0171] 19 F NMR (377MHz, DMSO-d6) δ -73.350 (1CF3), -150.347 (1F), -152.345 (1F). The reaction process is as follows:

[0172]

[0173] Example 4: Preparation of regulator 3DMSD01-08

[0174] 500 mg of starting material 1 was dissolved in 15 mL of DCM. Then, 862 mg of Et3N and 750 mg of dimethylcarbamic chloride were added at room temperature. After mixing thoroughly, the mixture was stirred at room temperature for 48 h to reach the reaction endpoint. The reaction solution was concentrated and purified by column chromatography to obtain 430 mg of yellow solid intermediate 2. 430 mg of intermediate 2 was dissolved in a mixed solvent of DMSO / H2O (30 mL / 7.5 mL). After mixing thoroughly, 160 mg of Cu(acac)2, 160 mg of BHMPO, and 80 mg of LiOH·H2O were added. After mixing thoroughly, the mixture was stirred at 80 °C for 16 h under nitrogen protection to reach the reaction endpoint. The reaction solution was diluted with 100 mL of water and then extracted three times with EA, 40 mL each time. The organic layers were combined, concentrated, and purified by column chromatography to obtain 100 mg of white solid intermediate 3. 90 mg of intermediate 3 was dissolved in 10 mL of DMF, and then 22.7 mg of K2CO3 and 23.2 mg of iodomethane were added at room temperature. After thorough mixing, the mixture was stirred at room temperature for 16 h to reach the reaction endpoint. The reaction solution was concentrated and purified by preparative chromatography to obtain 53.37 mg of white solid final product 3DMSD01-08. The purity was 99.04% (254 nm), and its HPLC chromatogram is shown below. Figure 4 As shown. LCMS(ESI): RT 1.778 min; m / z 561.4 [M+H]+ . 1 H NMR (400MHz, DMSO-d6) δ10.86(s,1H),8.50(d,J=5.6Hz,1H),8.31(d,J=2.0Hz,1H),8.07(s,1H),7.83(dd,J=5.6,2.0Hz,1H),7.63(s,1H),7.01(d,J= 8.0Hz,1H),5.27(d,J=10.0Hz,1H),4.21-4.06(m,1H),3.91(s,3H),3.11( s,3H),2.94(s,3H),2.58-2.57(m,1H),1.60(s,3H),0.78(d,J=6.0Hz,3H).

[0175] 19 F NMR (377MHz, DMSO-d6) δ -73.466 (1CF3), -149.894 (1F), -159.128 (1F). The reaction process is as follows:

[0176]

[0177] Example 5: In vitro inhibitory effect of the compound on Nav 1.8 (IC50) 50 )

[0178] Patch-clamp technique is considered the "gold standard" for studying ion channels. It utilizes glass microelectrodes sealed to the cell membrane to measure various membrane channel currents. Navs are a class of transmembrane proteins that exist in three different states: resting, activated, and inactive. Patch-clamp technique assesses the inhibitory effect of different compounds on different Navs states by measuring changes in membrane channel currents after different compounds bind to them in these states.

[0179] The representative compounds of this invention were transfected into stable CHO cell lines with specific ion channels. The effects of the compounds on Nav1.8 current were determined by manual patch-clamp assays, and their inhibitory strength was then evaluated.

[0180] The manual patch-clamp experimental protocol is as follows:

[0181] 1) Cell Culture

[0182] Maintenance medium: CHO cells were cultured in Ham's F-12 medium containing 10% fetal bovine serum, 10 μg / mL Blasticidin S, 200 μg / mL Hygromycin B, 0.8 mg / mL G418, and 100 μg / mL Zeocin at 37°C and 5% carbon dioxide.

[0183] Cell passage: Remove the old culture medium and wash once with PBS, then add 1 mL of 0.25% Trypsin-EDTA solution and incubate at 37°C for approximately 1.5 min. When the cells detach from the bottom of the dish, add approximately 5 mL of preheated (37°C) complete culture medium. Gently pipette the cell suspension to separate aggregated cells. Transfer the cell suspension to sterile centrifuge tubes and centrifuge at 1000 rpm for 5 min to collect the cells. For expansion or maintenance culture, seed the cells in 6 cm cell culture dishes at a density of 2.5 × 10⁶ cells per dish. 5 100 cells (final volume: 5 mL).

[0184] To maintain the electrophysiological activity of cells, the cell density must not exceed 80%.

[0185] Patch-clamp assay was performed. Cells were separated using 0.25% Trypsin-EDTA prior to the assay, and 6.5 × 10⁶ cells were used. 3 The cells were seeded onto coverslips and cultured in 24-well plates (final volume: 500 μL). After induction with tetracycline for 24-72 hours, the cells were tested.

[0186] 2) Preparation of compound samples

[0187] Weigh an appropriate amount of the test sample. Calculate the required DMSO volume using the formula: DMSO volume = actual compound mass × purity / (molecular weight × theoretical concentration). Take the corresponding volume of DMSO, dissolve the test sample, and simultaneously weigh the DMSO. Calculate the volume using the solvent density to ensure the accuracy of the dosage. Calculate the actual stock solution concentration based on the final amount of DMSO used.

[0188] For the highest detectable concentration of the test substance, the stock solution is directly diluted with extracellular fluid or further diluted with DMSO. Other concentrations are first diluted sequentially with DMSO from high to low concentration to create intermediate dilutions, which are then further diluted with extracellular fluid to the working solution concentration. The concentration of DMSO in each working solution does not exceed 0.3%. All extracellular fluids used in the assay contain 100 nM TTX to block endogenous TTX-S (tetrodotoxin-sensitive) sodium channels present in cells. The working solution of the test substance is sonicated for 20 min before patch-clamp assay.

[0189] 3) Medium-level sodium ion channel blocking effect in patch-clamp

[0190] The voltage stimulation protocol for whole-cell patch-clamp recording of hNav1.8 sodium channel currents is as follows: After whole-cell sealing, the cell voltage is clamped at -120 mV. The voltage is first stepped from -130 mV to -10 mV in 10 mV increments and held for 5 s, followed by a 0 mV depolarization pulse to obtain the half-inactivated voltage (Vhalf). The resting state and half-inactivated state of sodium currents are detected using a two-pulse mode. First, a depolarization pulse (TP1) to 0 mV is applied for 50 ms to detect the resting sodium current. Then, the voltage is adjusted to Vhalf and held for 5 s, followed by restoring the voltage to -120 mV and holding for 20 ms to restore the unbound and inactivated channel. A second depolarization pulse (TP2) to 0 mV is then applied for 50 ms to detect the half-inactivated sodium current. Finally, the voltage was restored to the clamping voltage of -120mV, and data was repeatedly acquired at 20-second intervals to observe the effect of the drug on the peak sodium current in two different states. Experimental data were acquired using an EPC 10 amplifier (HEKA) or an IPA amplifier (Sutter Instrument) and stored in PatchMaster (HEKA) or SutterPatch (within Igor) software.

[0191] The patch-clamp procedure begins by using a microelectrode puller to draw a glass capillary into a recording electrode. The electrode, filled with intracellular fluid, is then placed into a microelectrode holder. Next, a coverslip containing cells is placed in a recording bath under an inverted microscope. Under the microscope, the microelectrode manipulator is manipulated to immerse the electrode in the extracellular fluid, and the electrode resistance (Rpip) is recorded. The electrode is then slowly brought into contact with the cell surface, and negative pressure is applied to create a GΩ high-resistance seal. Fast capacitance compensation is then performed, and negative pressure is continued to rupture the cell membrane, establishing a whole-cell recording mode. Finally, slow capacitance compensation is performed, and experimental parameters such as series resistance (Rs) are recorded. No leakage compensation is applied.

[0192] Once the current amplitude stabilized in the control extracellular solution, drug administration began. After each drug concentration reached equilibrium (approximately 5 minutes), the next concentration was measured. Blank control extracellular solution and the working solution of the test compound were administered sequentially from low to high concentration through the recording bath using gravity perfusion, while a peristaltic pump was used for fluid replacement during recording. The current detected in the extracellular solution without the compound served as a control for each cell. Each concentration was measured independently twice. All electrophysiological experiments were performed at room temperature.

[0193] First, the peak sodium current after each drug concentration was applied was recorded. compound) and peak current (contrast current) control Normalize, and then calculate the inhibition rate corresponding to each drug concentration under different states, i.e. For each concentration inhibition rate, the mean (Mean), standard deviation (SD), and standard error (SE) were calculated, and the data are expressed as Mean ± SE.

[0194] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0195] Calculate the IC of the compound using the above equation. 50 The value was calculated, and a nonlinear fit was performed on the concentration-effect curve, where IC50 was the concentration-effect value. 50 This is the half-inhibitory concentration (IC50). 50 The calculations and curve fitting were performed using GraphPad Prism software.

[0196] The calculated inhibitory activity of some of the compounds in the examples against hNav1.8 is shown in Table 1 below.

[0197] Table 1

[0198] serial number <![CDATA[IC 50 (nM) - Resting state]]> <![CDATA[IC 50 (nM)-Semi-inactivated state]]> Example 1 11.6 14.2 Example 2 30.5 37.8 Example 3 2.2 2.4 Example 4 95.6 149.5

[0199] It is evident that the compounds disclosed herein have a significant inhibitory effect on the activity of NaV1.8 channels.

[0200] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some changes or modifications to the above-described technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes, and modifications made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof: in, R a1 R a2 R a3 Each of the following groups is independently selected: hydrogen, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic, -ZC(O)NR a R b -ZC(O)-OR c -ZC(O)-R c -Z-OC(O)-R c -C(O)-Z-OR c -OZC(O)-R c -ZP(O)-R c -ZP(O)OR c -Z-OP(O)-R c -Z-OP(O)OR c -ZS(O)-R c -ZS(O)2-R c -ZS(O)2-OR c -ZOS(O)2-R c -ZOS(O)2-OR c Z is selected from: chemical bond, -O-, -S-, -NH-, C1-C12 alkylene; and the alkyl, alkoxy, cycloalkyl, heterocyclic, and alkylene groups are optionally substituted by one or more (e.g., 2, 3, 4, 5, etc.) substituents selected from the group consisting of: halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, amino, and C3-C8 cycloalkyl. R a R b R c Each is independently selected from: H, halogen, hydroxyl, cyano, amino, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C1-C6 alkenyl, substituted or unsubstituted C1-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl; the substitution refers to optional substitution by one or more substituents selected from the group consisting of: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy; R b1 R b2 R b3 R b4 Each is independently selected from hydrogen, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, and the alkyl or alkoxy group is optionally substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, and amino. Or any two R a1 R a2 R a3 R b1 R b2 The ring atoms spaced apart from it connect together to form a 5-7 membered ring, which can be a saturated or unsaturated carbon ring or a heterocycle; the heterocycle may optionally contain one or more N, O, or S (=O). m Heteroatoms; the 5-7 membered ring may optionally be substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, and amino. M1 and M2 are each independently selected from C, O, and S (=O). m NR n , where R n Selected from: hydrogen, C1-C6 alkyl; preferably, R n Selected from: hydrogen, methyl, or ethyl, with R being the most preferred. n Selected from hydrogen; X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 Each is independently selected from bond, C, N, O, C=O, S (=O). m ; R c1 R c2 R c3 Each element is independently selected from hydrogen, halogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)NR c4 R c5 -C(=S)NR c4 R c5 -N(R) c4 R c5 -C(=N)-NR c4 R c5 ; R c4 R c5 Each is independently selected from hydrogen, hydroxyl, amino, C1-C6 alkyl, and C1-C6 alkoxy. m and n are each independently 0, 1 or 2; In formula (I), Indicates a single bond or a double bond.

2. The compound according to claim 1, characterized in that, The compound has the structure shown in formula (IA): Among them, R a1 R a2 R a3 R b1 R b2 R b3 R b4 ,M1,M2,X1,X2,X3,X4,X5,X6,X7,X8,X9,X 10 R c1 R c2 R c3 m, n As defined in claim 1.

3. The compound according to claim 1, characterized in that, R a1 With R b1 Or R b2 They connect to form 5-membered carbon rings or 5-membered heterocycles.

4. The compound according to claim 1, characterized in that, R b1 R b2 R b3 R b4 Each is independently selected from hydrogen, methyl, trifluoromethyl, ethyl, methoxy, and ethoxy.

5. The compound according to claim 1, characterized in that, M1 and M2 are independently selected from O and -NH-.

6. The compound according to claim 1, characterized in that, X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 Each is independently selected from bond, C, N, O, C=O, S(=O)2.

7. The compound according to claim 1, characterized in that, R c1 R c2 R c3 Each is independently selected from hydrogen, hydroxyl, amino, fluorine, cyano, oxo, methyl, -C(=O)NH2, -C(=O)NHCH3, -C(=O)NHC2H5.

8. The compound according to any one of claims 1 to 7, characterized in that, The compounds are selected from the group consisting of:

9. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a pharmaceutically acceptable carrier and a compound, or an isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, as described in any one of claims 1-8.

10. The pharmaceutical composition according to claim 9, characterized in that, The pharmaceutical composition is used for the treatment, relief, or prevention of diseases or conditions related to sodium channel regulation; preferably, the disease or condition is pain.

11. The use of the compound according to any one of claims 1-8, or a pharmaceutically acceptable salt or hydrate thereof, characterized in that, This is used to prepare a pharmaceutical composition for treating, alleviating, or preventing diseases related to sodium channel regulation; preferably, the disease or symptom is pain.

12. The use as described in claim 11, characterized in that, The pain or disease described is selected from the following group: chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, peroneal muscular atrophy, incontinence, pathological cough, or arrhythmia.

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