Selective sodium channel modulator, and preparation therefor and use thereof

Abstract

The present invention belongs to the field of pharmaceutical chemistry. Disclosed in the present invention are a heterocyclic compound, and a preparation method therefor and the use thereof. Specifically, the present invention relates to a series of sodium ion channel blockers having new structures, and a preparation method therefor and the use thereof. The structure thereof is as shown in the following general formula (I). These compounds or a stereoisomer, racemate, geometric isomer, tautomer, prodrug, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof and a pharmaceutical composition thereof can be used for treating or / and preventing related diseases mediated by a sodium ion channel (Nav).

Description

Selective sodium channel modulators and preparations and uses thereof TECHNICAL FIELD

[0001] The present invention is in the field of medicinal chemistry. In particular, the present invention relates to novel compounds or stereoisomers, racemates, geometric isomers, tautomers, prodrugs, hydrates, solvates thereof, or pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions containing them, which are Voltage-gated sodium channels (Nav) blockers with a completely new structure. BACKGROUND

[0002] Pain is a protective mechanism that can keep healthy animals from tissue damage and prevent further damage to damaged tissue. Nonetheless, there are many instances where pain persists beyond its usefulness, or where patients would benefit from the inhibition of pain.

[0003] Neuropathic pain is a form of chronic pain caused by sensory nerve damage, which can be divided into two categories, pain caused by nerve metabolic damage and pain caused by nerve continuity damage. Metabolic damage pain indications include post-herpetic neuropathy, diabetic neuropathy and drug-induced neuropathy. Pain caused by nerve continuity damage indications include post-amputation pain, postoperative nerve damage pain and nerve compression injury such as neuropathic back pain.

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

[0005] Navs are biological mediators of electrical signaling because they mediate the rapid upstroke of the action potential in many excitable cell types, such as neurons, skeletal muscle cells, and cardiac muscle cells. The role of these channels in normal physiology, pathological conditions caused by mutations in sodium channel genes, preclinical work in animal models, and evidence of the clinical pharmacology of known sodium channel modulators all suggest a central role for Navs in pain perception. Navs mediate the rapid upstroke of the action potential in many excitable cell types, such as neurons, skeletal muscle cells, and cardiac muscle cells, and thus are involved in the initiation of signaling in these cells. Because of the role of Navs in the initiation and propagation of neuronal signals, antagonists that reduce Nav current can prevent or reduce nerve signals, and Navs are considered possible targets for reducing pain in situations where hyperexcitability is observed. Several clinically useful analgesics have been identified as inhibitors of Navs. 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 be effective in reducing pain through sodium channel inhibition.

[0006] Nav forms a subfamily of the voltage-gated ion channel superfamily and comprises nine isoforms, designated Nav1.1-Nav1.9. The nine isoforms have different tissue localizations. Nav1.4 is the main sodium channel of skeletal muscle, and Nav1.5 is the main sodium channel of cardiac muscle cells. Nav1.7, 1.8 and 1.9 are primarily localized to the peripheral nervous system, while Nav1.1, 1.2, 1.3 and 1.6 are neural channels found in both the central and peripheral nervous systems. The nine isoforms have similar functional behavior but differ in specific aspects of voltage dependence and kinetic behavior.

[0007] Nav1.8 channels have been identified as possible targets for analgesia, which have been shown to act as carriers of sodium currents that maintain action potential firing of neurons in the dorsal root ganglion and are also involved in spontaneous electrical signaling of damaged neurons, such as driving neuropathic pain, etc. The main drawback of some known Nav inhibitors is their poor therapeutic window, which can be a result of their lack of isoform selectivity. Since Navl.8 is mainly restricted to pain-sensing neurons, selective Nav1.8 blockers are less likely to induce adverse effects commonly seen with non-selective Nav blockers. Therefore, there is still a need in the art to develop new Nav1.8 selective inhibitors. SUMMARY

[0008] It is an object of the present application to provide selective inhibitors having inhibitory activity against sodium ion channels, in particular Nav1.8 sodium ion channels.

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

[0010] wherein R a1 , R a2 , R a3 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl, 3-8 membered heterocyclyl, -Z-C(O)NR a R b , -Z-C(O)-OR c , -Z-C(O)-R c , -Z-OC(O)-R c , -C(O)-Z-OR c , -O-Z-C(O)-R c , -Z-P(O)-R c , -Z-P(O)O-R c , -Z-OP(O)-R c , -Z-OP(O)O-R c , -Z-S(O)-Rc -Z-S(O)2-R c -Z-S(O)2-O-R c -Z-O-S(O)2-R c -Z-O-S(O)2-O-R c Z is selected from the group consisting of: a bond, -O-, -S-, -NH-, C1-C12 alkylene; and said alkyl, alkoxy, cycloalkyl, heterocyclyl, alkylene is optionally substituted with one or more (e.g. 2, 3, 4, 5, etc.) substituents selected from the group consisting of: halo, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy, amino, C3-C8 cycloalkyl;

[0011] R a R b R c each independently is selected from the group consisting of: H, halo, hydroxy, 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; said substitution means optionally substituted with one or more substituents selected from the group consisting of: halo, hydroxy, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy;

[0012] R b1 R b2 R b3 R b4 each independently is selected from the group consisting of: hydrogen, halo, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, and said alkyl, alkoxy is optionally substituted with one or more substituents selected from the group consisting of: halo, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy, amino;

[0013] or any two R a1 R a2 R a3 R b1 R b2 together with the intervening ring atoms to which they are attached form a 5-7 membered ring, which can be a saturated or unsaturated carbocyclic or heterocyclic ring; said heterocyclic ring optionally containing one or more N, O, S(=O) m heteroatoms; said 5-7 membered ring can be optionally substituted with one or more substituents selected from the group consisting of: halo, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy, amino;

[0014] M1, M2 are each independently selected from the group consisting of: C, O, S(=O) m N-R n wherein R n is selected from the group consisting of: hydrogen, C1-C6 alkyl; preferably, Rn selected from the group consisting of hydrogen, methyl or ethyl, most preferred R n is selected from the group consisting of hydrogen;

[0015] X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 are each independently selected from the group consisting of a bond, C, N, O, C=O, S(=O) m ;

[0016] R c1 , R c2 , R c3 are each independently selected from the group consisting of 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 ;

[0017] R c4 , R c5 are each independently selected from the group consisting of hydrogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy;

[0018] m, n are each independently 0, 1 or 2;

[0019] in formula (I), denotes a single or double bond.

[0020] In another preferred embodiment, said R a1 is selected from the group consisting of -Z-C(O)NR a R b , -Z-C(O)-OR c , -Z-C(O)-R c , -Z-OC(O)-R c , -C(O)-Z-OR c , -O-Z-C(O)-R c , -Z-P(O)-R c , -Z-P(O)O-R c , -Z-OP(O)-R c , -Z-OP(O)O-R c , -Z-S(O)-R c , -Z-S(O)2-R c , -Z-S(O)2-O-R c , -Z-O-S(O)2-R c , -Z-O-S(O)2-O-Rc .

[0021] In another preferred embodiment, the R a2 is C1-C6 alkoxy.

[0022] In another preferred embodiment, the compound has the structure shown in formula (I-A):

[0023] wherein 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, L1, as defined above.

[0024] In another preferred embodiment, the compound has the structure shown in formula (I-A):

[0025] wherein 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, the compound has the structure shown in formula (I-A):

[0027] wherein 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.

[0028] In another preferred embodiment, R a1 , R a2 , R a3 are each independently selected from the group consisting of fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, amino, ethyl ester, isopropyl ester, tert-butyl ester, phosphate, dimethyl carbamate.

[0029] In another preferred embodiment, R b1 , R b2 , R b3 , R b4 are each independently selected from the group consisting of hydrogen, methyl, trifluoromethyl, ethyl, methoxy, ethoxy.

[0030] In another preferred embodiment, R b1 , R b2 are each independently selected from the group consisting of hydrogen, methyl, trifluoromethyl.

[0031] In another preferred embodiment, R b3 , R b4 are each independently selected from the group consisting of hydrogen, methyl, trifluoromethyl.

[0032] In another preferred embodiment, any two adjacent R a1 , R a2 , R a3 , R b1 , R b2 are linked to form a 5- or 6-membered carbocyclic or heterocyclic ring.

[0033] In another preferred embodiment, the 5- or 6-membered heterocyclic ring contains one or two N, O, S(=O) m heteroatoms.

[0034] In another preferred embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 are each independently selected from the group consisting of a bond, C, N, O, C=O, S(=O)2.

[0035] In another preferred embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 are all selected from C atoms.

[0036] In another preferred embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 any of them contains one or two N atoms.

[0037] In another preferred embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10 It contains any one C=O.

[0038] In another preferred embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 It contains any one S(=O)2.

[0039] 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.

[0040] 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;

[0041] 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.

[0042] In another preferred embodiment, R a1 R a2 R a3 Each is independently selected from fluorine, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, amino, ethyl ester, isopropyl ester, tert-butyl ester, phosphate ester, and dimethyl carbamate.

[0043] In another preferred embodiment, R a1 R a2 R a3 Selected from fluorine, methoxy, isopropoxy, ethyl ester, and dimethyl carbamate groups.

[0044] In another preferred embodiment, R a1 With R b1 or R b2 They connect to form 5- to 8-membered carbon rings or 5- to 8-membered heterocycles.

[0045] In another preferred embodiment, the 5- to 8-membered heterocycle contains one or two O heteroatoms.

[0046] In another preferred embodiment, R b1 R b2 R b3 R b4 Each is independently selected from hydrogen, methyl, trifluoromethyl, ethyl, methoxy, and ethoxy.

[0047] In another preferred embodiment, R b1 , R b2 , R b3 , R b4 are each independently selected from the group consisting of hydrogen, methyl, trifluoromethyl.

[0048] In another preferred embodiment, M1, M2 are independently selected from O, -NH-.

[0049] In another preferred embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 are each independently selected from the group consisting of a bond, C, N, O, C=O, S(=O)2.

[0050] In another preferred embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 are all selected from C atoms or any contain one N atom.

[0051] In another preferred embodiment, the compound has a structure selected from the group consisting of:

[0052] wherein R b1 , R b2 , R b3 , R b4 , M1, M2, X6, X7, X8, X9, X 10 , R c1 , R c2 , R c3 , m, n, L1, are as defined above;

[0053] R1, R2, R3, R4, R5are each independently at each occurrence selected from the group consisting of H, halogen, hydroxyl, C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl, 3-8 membered heterocyclyl, -Z-C(O)NR a R b , -Z-C(O)-OR c , -Z-C(O)-R c , -Z-OC(O)-R c , -C(O)-Z-OR c , -O-Z-C(O)-R c , -Z-P(O)-R c , -Z-P(O)O-R c , -Z-OP(O)-R c , -Z-OP(O)O-R c , -Z-S(O)-R c , -Z-S(O)2-R c-Z-S(O)2-O-R c -Z-O-S(O)2-R c -Z-O-S(O)2-O-R c Z is selected from the group consisting of: a bond, -O-, -S-, -NH-, C1-C12 alkylene; and said alkyl, alkoxy, cycloalkyl, heterocyclyl, alkylene is optionally substituted with one or more (e.g. 2, 3, 4, 5, etc.) substituents selected from the group consisting of: halo, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy, amino, C3-C8 cycloalkyl; R a R b R c each independently is selected from the group consisting of: H, halo, hydroxy, 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; said substitution means optionally substituted with one or more substituents selected from the group consisting of: halo, hydroxy, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy.

[0054] In another preferred embodiment, the compound has a structure selected from the group consisting of:

[0055] wherein, R b1 R b2 R b3 R b4 M1, M2, X6, X7, X8, X9, X 10 R c1 R c2 R c3 m, n, R1, R2, R3, R4, R5, as defined above.

[0056] In another preferred embodiment, R2, R3are each independently at each occurrence selected from the group consisting of: F, Cl, Br, I, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, amino, ethyl ester, isopropyl ester, t-butyl ester, phosphate ester, dimethyl carbamate.

[0057] In another preferred embodiment, R1is selected at each occurrence from the group consisting of: substituted or unsubstituted hydroxy, substituted or unsubstituted C1-C6 alkoxy, -Z-C(O)NR a R b -Z-C(O)-OR c -Z-C(O)-R c -Z-OC(O)-R c-C(O)-Z-OR c -O-Z-C(O)-R c -Z-P(O)-R c -Z-P(O)O-R c -Z-OP(O)-R c -Z-OP(O)O-R c -Z-S(O)-R c -Z-S(O)2-R c -Z-S(O)2-O-R c -Z-O-S(O)2-R c -Z-O-S(O)2-O-R c ; R a R b R c each independently selected from the group consisting of: H, halogen, hydroxyl, cyano, amino, substituted or unsubstituted C1-C6 alkyl; Z is selected from the group consisting of: a bond, -O-, -NH-, C1-C6 alkylene; said substitution means optionally substituted with one or more substituents selected from the group consisting of: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl; preferably, said substitution means optionally substituted with one or more substituents selected from the group consisting of: F, Cl, Br, cyclopropyl.

[0058] In another preferred embodiment, R4is, at each occurrence, selected from the group consisting of: substituted or unsubstituted hydroxyl, substituted or unsubstituted C1-C6 alkoxy, -Z-C(O)NR a R b -Z-C(O)-OR c -Z-C(O)-R c -Z-OC(O)-R c -C(O)-Z-OR c -O-Z-C(O)-R c -Z-P(O)-R c -Z-P(O)O-R c -Z-OP(O)-R c -Z-OP(O)O-R c -Z-S(O)-R c -Z-S(O)2-R c -Z-S(O)2-O-R c -Z-O-S(O)2-R c -Z-O-S(O)2-O-R c ; R a R b R ceach independently selected from the group consisting of: H, halogen, hydroxyl, cyano, amino, substituted or unsubstituted C1-C6alkyl; Z is selected from the group consisting of: a bond, -O-, -NH-, C1-C6alkylene; said substitution means optionally substituted with one or more substituents selected from the group consisting of: halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl; preferably, said substitution means optionally substituted with one or more substituents selected from the group consisting of: F, Cl, Br, cyclopropyl.

[0059] In another preferred embodiment, R1at each occurrence is selected from the group consisting of: substituted or unsubstituted hydroxyl, substituted or unsubstituted C1-C6alkoxy, -Z-C(O)NR a R b , -Z-C(O)-OR c , -Z-OC(O)-R c , -Z-OC(O)-R c , -C(O)-Z-OR c , -O-Z-C(O)-R c ; R a , R b , R c each independently selected from the group consisting of: H, halogen, hydroxyl, cyano, amino, substituted or unsubstituted C1-C6alkyl; Z is selected from the group consisting of: a bond, -O-, -NH-, C1-C6alkylene; said substitution means optionally substituted with one or more substituents selected from the group consisting of: halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl; preferably, said substitution means optionally substituted with one or more substituents selected from the group consisting of: F, Cl, Br, cyclopropyl.

[0060] In another preferred embodiment, R4at each occurrence is selected from the group consisting of: C1-C6alkoxy, -Z-C(O)NR a R b , -Z-C(O)-OR c , -Z-OC(O)-R c ; R a , R b , R c each independently selected from the group consisting of: H, halogen, hydroxyl, cyano, amino, C1-C6alkyl; Z is selected from the group consisting of: a bond, -O-, -NH-, C1-C6alkylene.

[0061] In another preferred embodiment, R4at each occurrence is selected from the group consisting of: fluoro, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, amino, ethyl ester, isopropyl ester, t-butyl ester, phosphate ester, dimethyl carbamate.

[0062] In another preferred embodiment, the compound has a structure selected from the group consisting of:

[0063] wherein R b2 , R b3 , R b4 , M1, M2, X6, X7, X8, X 10 , R c1 , R c2 , R c3 , m, n, L1, as defined above;

[0064] M3is selected from: O, -NH-;

[0065] R2, R3, R4, R5are each independently at each occurrence selected from: H, halogen, hydroxyl, C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl, 3-8 membered heterocyclyl, -Z-C(O)NR a R b , -Z-C(O)-OR c , -Z-C(O)-R c , -Z-OC(O)-R c , -C(O)-Z-OR c , -O-Z-C(O)-R c , -Z-P(O)-R c , -Z-P(O)O-R c , -Z-OP(O)-R c , -Z-OP(O)O-R c , -Z-S(O)-R c , -Z-S(O)2-R c , -Z-S(O)2-O-R c , -Z-O-S(O)2-R c , -Z-O-S(O)2-O-R c , Z is selected from: a bond, -O-, -S-, -NH-, C1-C12alkylene; and said alkyl, alkoxy, cycloalkyl, heterocyclyl, alkylene is optionally substituted with one or more (e.g. 2, 3, 4, 5, etc.) substituents selected from the group consisting of: halogen, hydroxyl, cyano, C1-C6alkyl, C1-C6alkoxy, amino, C3-C8cycloalkyl; R a , R b , R ceach independently selected from the group consisting of: 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; said substitution means optionally substituted with 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, the compound has a structure selected from the group consisting of:

[0067] wherein R b2 , R b3 , R b4 , M1, M2, X6, X7, X8, X 10 , R c1 , R c2 , R c3 , m, n, M3, R2, R3, R4, R5, as defined above.

[0068] In another preferred embodiment, is selected from the group consisting of: R b1 , R b2 , R b3 , R b4 each independently selected from the group consisting of: hydrogen, methyl, trifluoromethyl, ethyl, methoxy, ethoxy.

[0069] In another preferred embodiment, is selected from the group consisting of:

[0070] In another preferred embodiment, R c1 , R c2 , R c3 each independently selected from the group consisting of: hydrogen, hydroxyl, amino, fluorine, cyano, oxo, methyl, -C(=O)NH2, -C(=O)NHCH3, -C(=O)NHC2H5.

[0071] In another preferred embodiment, R c1 , R c2 , R c3 each independently selected from the group consisting of: hydrogen, -C(=O)NH2.

[0072] In another preferred embodiment, is selected from the group consisting of: Rc is selected from the group consisting of: hydrogen, hydroxyl, amino, fluorine, cyano, oxo, methyl, -C(=O)NR c4 R c5 .

[0073] In another preferred embodiment, selected from the group consisting of:

[0074] In another preferred embodiment, the compound is selected from the group consisting of:

[0075] A second aspect of the present application provides a use of a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer thereof, in the manufacture of a medicament for inhibiting voltage-gated sodium channels; the voltage-gated sodium channels are Navl.8.

[0076] A third aspect of the present application provides a use of a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer thereof, in the manufacture of a medicament for inhibiting a disease associated with voltage-gated sodium channels, including but not limited to: pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or arrhythmia, etc.

[0077] 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.

[0078] A fourth aspect of the present application provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the first aspect of the present application, isomers, solvates or pharmaceutically acceptable salts or hydrates thereof.

[0079] In another preferred embodiment, the pharmaceutically acceptable carrier includes a filler, a disintegrant, a surfactant, a solubilizer.

[0080] A fifth aspect of the present application provides a use of a pharmaceutical composition of a compound of Formula I, isomers, solvates or pharmaceutically acceptable salts or hydrates thereof, in the manufacture of a medicament for treating, preventing or alleviating a disease associated with voltage-gated sodium channels, including but not limited to: pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or arrhythmia, etc.

[0081] 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.

[0082] The sixth aspect of the present application provides a preparation method of the compound of the first aspect of the present application, which is simple and efficient in preparation process and easy to realize automation.

[0083] Specifically (taking 3DMSD01-04 as an example), the preparation of 3DMSD01-04 can start from starting material 1, including 5 steps:

[0084] Step 1: demethylation of starting material compound 1 to synthesize intermediate 2 solution;

[0085] Step 2: iodization of intermediate 2 to obtain intermediate 3;

[0086] Step 3: phenolic hydroxyl etherification of intermediate 3 to obtain intermediate 4;

[0087] Step 4: iodine of intermediate 4 is replaced by hydroxyl to obtain intermediate 5;

[0088] Step 5: phenolic hydroxyl methyl etherification of intermediate 5 to obtain 3DMSD01-04;

[0089] The specific synthesis route information is as follows:

[0090] Based on the method, by using other starting materials, each compound of the present application can be prepared.

[0091] The present application also relates to pharmaceutically acceptable salts of the compounds of general formula (I). The present application also relates to solvates of the compounds, including their salts and active metabolites, and, where appropriate, to tautomers thereof according to general formula (I).

[0092] A "pharmaceutically acceptable salt" is a pharmaceutically acceptable, organic or inorganic acid or base salt of a compound of the present application. Representative pharmaceutically acceptable salts include, for example, alkali metal salts, alkaline earth salts, ammonium salts, water-soluble and water-insoluble salts, such as acetate, carbonate, chloride, gluconate, glutamate, lactate, laurate, malate, or tartrate.

[0093] A "prodrug" means a precursor of a drug which, when administered to a patient, must undergo chemical conversion by metabolic processes before becoming the active pharmacological agent. Exemplary prodrugs of the compounds according to formula (I) are esters and amides, preferably alkyl esters of fatty acid esters. Prodrug formulations herein include all substances formed by enzymatic, metabolic or any other way of simple conversion, including hydrolysis, oxidation or reduction. Suitable prodrugs contain, for example, a substance of general formula (I) bound via an enzymatically cleavable linkage (e.g. a carbamate, phosphate, N-glucoside or sulphur group) to a solubility-improving substance (e.g. tetraethylene glycol, a sugar, formic acid or glucuronic acid etc.). Such prodrugs of the compounds according to the application can be applied to a patient and the prodrug can be converted to the substance of general formula (I) to obtain the desired pharmacological effect.

[0094] Some of the compounds of formula (I) are contained as racemates, as their enantiomers and, optionally, as their non-enantiomeric isomers and all possible mixtures thereof.

[0095] According to the application, all chiral C atoms should have the D- and / or L-configuration: combinations within one compound should also be possible, i.e. some chiral C atoms can be D- and others L-configuration.

[0096] The compounds according to the application can be appropriately formulated together with further active substances as well as with the excipients and carriers customary in pharmaceutical compositions, for example (depending on the preparation to be produced) talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous and non-aqueous carriers, fatty bodies of animal or vegetable origin, paraffin derivatives, ethylene glycol (in particular polyethylene glycol), various plasticizers, dispersants or emulsifiers, pharmaceutically compatible gases (e.g. air, oxygen, carbon monoxide etc.), preservatives.

[0097] For the production of liquid preparations, additives such as sodium chloride solution, ethanol, sorbitol, glycerol, olive oil, almond oil, propylene glycol or ethylene glycol can be used.

[0098] When solutions for infusion or injection are used, they are preferably aqueous solutions or suspensions, which can be produced before use, for example from lyophilized preparations, which contain such active substances or together with carriers, such as mannitol, lactose, glucose, albumin etc. The sterilized solutions have already been produced and are appropriately mixed with excipients, for example with preservatives, stabilizers, emulsifiers, solubilizers, buffers and / or salts for the adjustment of the osmotic pressure. The sterilization can be achieved by sterile filtration using filters. A small amount of antibiotic can also be added to ensure the maintenance of sterility.

[0099] It should be understood that, within the scope of the present application, each of the technical features described above and each of the technical features described in detail below (such as the examples) can be combined with each other to form new or preferred technical solutions. Due to the limited space, they will not be listed one by one here.

[0100] After adopting the above technical solutions, the positive progress effect of the present application is:

[0101] (1) The sodium channel small molecule modulator provided by the present application has stable properties, excellent activity, and good selectivity, and can be used for preventing and / or treating (stabilizing, alleviating or curing) sodium channel related diseases or disorders, and has a wide application prospect.

[0102] (2) The preparation method of the selective sodium channel small molecule modulator is simple, efficient, and easy to realize automation.

[0103] The specific embodiments of the present application will be described in further detail below with reference to the accompanying drawings. BRIEF DESCRIPTION OF DRAWINGS

[0104] Figure 1 is an HPLC spectrum of 3DMSD01-04 in Example 1 of the present application.

[0105] Figure 2 is an HPLC spectrum of 3DMSD01-06 in Example 2 of the present application.

[0106] Figure 3 is an HPLC spectrum of 3DMSD01-07 in Example 3 of the present application.

[0107] Figure 4 is an HPLC spectrum of 3DMSD01-08 in Example 4 of the present application.

[0108] Figure 5 is an HPLC spectrum of 3DMSD01-37 in Example 5 of the present application.

[0109] It should be noted that these drawings and written descriptions are not intended to limit the scope of the concept of the present application in any way, but to illustrate the concept of the present application to those skilled in the art by referring to specific embodiments. DETAILED DESCRIPTION

[0110] The present inventors have found a compound as shown in formula (I) through long-term and in-depth research. The compound has unexpected activity in regulating cytokines and / or interferons, and can be used for treating diseases mediated by cytokines and / or interferons. The compound has unexpected activity on Nav 1.8, and has excellent selectivity on other Nav subtypes, and can be used for treating, alleviating or preventing diseases related to Nav 1.8. Based on the above findings, the present inventors have completed the present application.

[0111] TERMS

[0112] In this document, each of the numerical ranges recited herein are inclusive of the

[0113] "Alkyl" refers to straight-chain or branched-chain saturated aliphatic hydrocarbon groups, e.g., "Ci-12 alkyl" refers to straight-chain and branched-chain alkyl groups including 1-12 (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, t-butyl, sec-butyl, n-pentyl, and the like.

[0114] "Alkenyl" is a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds that can occur in any stable point of the chain. Non-limiting examples are C2-C8 alkenyl (such as C2, C3, C4, C5, C6, C7, C8), C2-C6 alkenyl, and C2-C4 alkenyl. The specified ranges as used herein indicate that each value of the range can be taken as an independent category, as do alkyl moieties described herein. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl). In one embodiment, the alkenyl group is optionally substituted as described herein.

[0115] "Cycloalkyl" refers to saturated or partially unsaturated cyclic alkyl groups having a single ring or multiple rings that are fused, bridged, or spiro rings. The term "cycloalkyl" includes cycloalkenyl (i.e., cyclic groups 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.

[0116] "Carbocyclic," "carbocyclic group," "carbocycle," or "cycloalkyl" is a saturated or partially unsaturated (i.e., non-aromatic) group containing all carbon ring atoms. Carbocyclic groups typically comprise a ring of 1 to 3 to 7 carbon atoms or 2 fused rings each comprising 3, 4, 5, 6, or 7 carbon atoms. Cycloalkyl substituents can be pendant from a substituted nitrogen atom or carbon atom, or a substituted carbon atom with two substituents can have a cycloalkyl group attached as a spiro group. Examples of carbocycles include the rings of cyclohexenyl, cyclohexyl, cyclopentenyl, cyclopentyl, cyclobutenyl, cyclobutyl, and cyclopropyl. In one embodiment, the carbocycle is optionally substituted as described herein. In one embodiment, the cycloalkyl is a partially unsaturated (i.e., non-aromatic) group containing all carbon ring atoms. In another embodiment, the cycloalkyl is a saturated group containing all carbon ring atoms.

[0117] "Heterocyclyl" is a saturated ring 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 heteroatoms are nitrogen. In a representative embodiment, the heteroatoms are oxygen. Monocyclic heterocycloalkyl groups typically have 3 to about 8 ring atoms or 4 to 6 ring atoms. Examples of heterocycloalkyl groups include morpholinyl, piperazinyl, piperidinyl, pyrrolinyl.

[0118] "Aryl" means a fully carbon monocyclic or fused polycyclic (that is, rings which share adjacent pairs of carbon atoms) ring group having a conjugated pi electron system, including but not limited to phenyl and naphthyl.

[0119] "Heteroaryl" means a heteroaromatic system containing 1 to 4 heteroatoms, including nitrogen, oxygen, and S, for example, 5-7 membered heteroaryl means a heteroaromatic system containing 5-7 ring atoms, 5-10 membered heteroaryl means a heteroaromatic system containing 5-10 ring atoms, including but not limited to furanyl, thienyl, pyridyl, pyrrolyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.

[0120] "Alkoxy" is an alkyl group as defined above covalently bonded through an oxygen bridge (-O-), of the specified number of carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. Similarly, an "alkylsulfanyl" or "thioalkyl" group is an alkyl group as defined above covalently bonded through a sulfur bridge (-S-), of the specified number of carbon atoms. In one embodiment, the alkoxy group is optionally substituted, as described herein.

[0121] "Substituted" means that one or more hydrogen atoms on a given group are replaced with a particular substituent. The particular substituents are those described in the immediately preceding paragraph, or those appearing in each of the embodiments. Unless otherwise indicated, a substituted group can have, at each substitutable position, one substituent selected from the indicated group, which can be the same or different at different positions on the group. It will be understood by one of ordinary skill in the art that combinations of substituents that are not chemically feasible or that are not stable are not intended within the scope of the application. The substituents include, but are not limited to, halogen, hydroxyl, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehydic, C2-C10 acyl, C2-C10 ester, amino, C1-C6 alkoxy, C1-C10 sulfonyl, and the like.

[0122] As used herein, unless otherwise specified, the manner of adding a solvent or solution is by pouring directly or adding uniformly, etc.

[0123] As used herein, the term "room temperature" generally refers to 4-30°C, preferably 20±5°C.

[0124] As used herein, the manner of "slowly adding" includes, but is not limited to, dropwise addition, slow addition along the wall of the container, etc.

[0125] The term "pharmaceutical excipients" refers to excipients and additives used in the production of pharmaceuticals and the dispensing of prescriptions, and all substances contained in pharmaceutical preparations other than active ingredients. See the People's Republic of China Pharmacopoeia (2020 edition) or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009) for details.

[0126] The present application will be further described in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present application and not to limit the scope of the present application. The experimental methods in the following examples, if not specified, are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are by weight.

[0127] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. In addition, any method and material similar or equivalent to those described herein can be used in the present application. The preferred methods and materials described herein are only for demonstration.

[0128] General methods and reagents

[0129] The solvents used in the present application are all of analytical purity, with a water content of about 0.1%.

[0130] All test methods of the present application are general methods, and the test parameters are as follows:

[0131] High performance liquid chromatography (HPLC) method of the present application:

[0132] Test method:

[0133] Chromatographic column: SunFire C18 5um 4.6x150mm

[0134] Column temperature: 25°C

[0135] Flow rate: 1.000 ml / min

[0136] Mobile phase:

[0137] A: 0.03% TFA in H2O

[0138] B: 0.03% TFA in ACN

[0139] Gradient:

[0140] The liquid chromatograph mass spectrometer (LCMS) method of the present application:

[0141] Column: Sunfire C18 150*4.6mm 5um 1.00ml / min

[0142] Column temperature: 40℃

[0143] 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

[0144] A: 0.03% TFA in H2O

[0145] B: 0.03% TFA in ACN

[0146] The nuclear magnetic resonance (H-NMR) method of the present application:

[0147] Test method:

[0148] Spectrometer: Avance

[0149] Solvent: DMSO-d6

[0150] Number of scans: 8

[0151] Spectrum frequency: 400MHz

[0152] Scan time: 50s

[0153] The nuclear magnetic resonance (F-NMR) method of the present application:

[0154] Test method:

[0155] Spectrometer: Avance

[0156] Solvent: DMSO-d6

[0157] Scans: 32

[0158] Spectral frequency: 377 MHz

[0159] Scan time: 70 s

[0160] Example 1 : Preparation of 3D MSD 01-04

[0161] Take 1500 mg of starting material 1, dissolve in 45 mL of DCM, then add 2.38 g of BBr3 at 0°C, then stir at 0°C for 1 h under nitrogen protection, pour into ice water, then extract with EA three times, 50 mL each time. Combine the EA layers, then dry with Na2SO4, filter, concentrate, and purify by column chromatography with 1:1 PE / EA as the mobile phase to obtain 995 mg of white solid intermediate 2; take 955 mg of intermediate 2, dissolve in 30.4 mg of DMSO and 15 mL of MeOH, then add 585 mg of NIS, stir at room temperature for 0.5 h until uniform. Concentrate the reaction solution, then purify by column chromatography with 1:1 PE / EA as the mobile phase to obtain 1.27 g of yellow solid intermediate 3; take 170 mg of intermediate 3, dissolve in 8 mL of DMF, then add 80.2 mg of K2CO3 and 74.1 mg of 2-iodopropane at room temperature. Then control the temperature at 60°C and stir for 16 h to reach the reaction endpoint. Dilute the reaction solution with 30 mL of water, then extract with EA three times, 20 mL each time, combine the organic layers, dry with Na2SO4, filter, and concentrate, then purify by column chromatography with 1:1 PE / EA as the mobile phase to obtain 145 mg of yellow solid intermediate 4; take 145 mg of intermediate 4, dissolve in 11.6 mL of DMSO and 2.9 mL of H2O, stir until uniform, then add 58 mg of Cu(acac)2, 58 mg of BHMPO, and 29 mg of LiOH.H2O, stir at 80°C under nitrogen protection for 16 h to reach the reaction endpoint. Dilute the reaction solution with 30 mL of water, then extract with EA three times, 20 mL each time. Combine the organic layers, concentrate, and purify to obtain 85 mg of white solid intermediate 5; take 131 mg of intermediate 5, dissolve in 7 mL of DMF, then add 34.9 mg of K2CO3 and 76.9 mg of iodomethane at room temperature, then stir at room temperature for 16 h to reach the reaction endpoint. Dilute the reaction solution with 30 mL of water, then extract with EA three times, 20 mL each time. Combine the organic layers, dry with Na2SO4, filter, concentrate, and purify by HPLC to obtain 51 mg of white solid final product 3DMSD01-04 with a purity of 96.40% (254 nm), and its HPLC spectrum is shown in Figure 1. LCMS (ESI): RT 1.958 min; m / z 532.7 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.80 (dd, J = 5.6, 2.4 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 6.88 (dd, J = 7.6, 1.2 Hz, 1H), 5.17 (d, J = 10.4 Hz, 1H), 4.38 - 4.35 (m, 1H), 4.32 - 4.27 (m, 1H), 3.86 (s, 3H), 2.74 - 2.69 (m, 1H), 1.62 (s, 3H), 1.31 (d, J = 6.0 Hz, 3H), 1.18 (d, J = 6.0 Hz, 3H), 0.75 (d, J = 6.0 Hz, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -73.448 (1CF3), -151.26 (1F), -158.63 (1F), the reaction scheme as follows:

[0162] Example 2: Preparation of modulator 3DMSD01-06

[0163] Take 500 mg of starting material 1, dissolve in 10 mL of DMF, then add 118 mg of K2CO3 and 242.6 mg of iodomethane at room temperature, stir at room temperature for 16 h to reach the reaction endpoint. The reaction solution is diluted with 30 mL of water, extracted with EA three times, 50 mL each time, the organic layers are combined, dried with Na2SO4, filtered, concentrated and purified by column chromatography to obtain 440 mg of yellow solid intermediate 2; take 440 mg of intermediate 2, dissolve in 35.2 mL of DMSO and 8.8 mL of H2O, stir evenly, then add 176 mg of Cu(acac)2, 176 mg of BHMPO and 88 mg of LiOH.H2O, stir at 80°C under nitrogen protection for 16 h to reach the reaction endpoint. The reaction solution is diluted with 100 mL of water and extracted with EA three times, 40 mL each time. The organic layers are combined, concentrated and purified to obtain 170 mg of white solid intermediate 3; take 140 mg of intermediate 3, dissolve in 15 mL of DCM, then add 346.9 mg of Et3N and 306 mg of dimethylcarbamic chloride at room temperature. The reaction solution is stirred at room temperature for 48 h to reach the reaction endpoint. The reaction solution is concentrated and purified to obtain the white final product 3DMSD01-06. Purity 96.49% (254 nm), its HPLC spectrum is shown in Figure 2. LCMS (ESI): RT 1.815 min; m / z 561.7 [M+H] +1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.06 (s, 1H), 7.85 (dd, J = 5.6, 2.1 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 5.09 (d, J = 10.4 Hz, 1H), 4.25 (dd, J = 10.4, 8.0 Hz, 1H), 3.93 (d, J = 1.2 Hz, 3H), 3.07 (s, 3H), 2.92 (s, 3H), 2.81 - 2.70 (m, 1H), 1.61 (s, 3H), 0.75 (d, J = 6.4 Hz, 3H).

[0164] 19F NMR (377 MHz, DMSO-d6) δ -73.368 (1CF3), -151.24 (1F), -152.67 (1F). The reaction scheme is as follows:

[0165] Example 3: Preparation of modulator 3DMSD01-07

[0166] Take 140 mg of starting material 1 dissolved in 5 mL of pyridine, then add 72.9 mg of Ac2O at room temperature. After shaking, stir at room temperature for 16 h to reach the end of the reaction. The reaction solution is concentrated and purified by preparative HPLC to obtain 50.57 mg of white solid end product 3DMSD01-07. Purity 95.32% (254 nm), and its HPLC spectrum is shown in Figure 3. LCMS (ESI): RT 1.824 min; m / z 532.2 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 5.6, 2.4 Hz, 1H), 7.62 (d, J = 2.4 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 5.09 (d, J = 10.0 Hz, 1H), 4.26 (dd, J = 10.0, 7.6 Hz, 1H), 3.94 (d, J = 2.0 Hz, 3H), 2.78 - 2.75 (m, 1H), 2.35 (s, 3H), 1.61 (s, 3H), 0.75 (d, J = 6.0 Hz, 3H).

[0167] 19F NMR (377 MHz, DMSO-d6) δ -73.350 (1 CF3), -150.347 (1 F), -152.345 (1 F). The reaction procedure is as follows:

[0168] Example 4: Preparation of modulator 3DMSD01-08

[0169] Take 500 mg of starting material 1 dissolved in 15 mL of DCM, then add 862 mg of Et3N and 750 mg of dimethylcarbamic chloride at room temperature, mix well and then stir at room temperature for 48 h to reach the end of the reaction, concentrate the reaction liquid and then purify by column chromatography to obtain 430 mg of yellow solid intermediate 2. Take 430 mg of intermediate 2 dissolved in a mixed solvent of DMSO / H2O (30 mL / 7.5 mL), mix well and then add 160 mg of Cu(acac)2, 160 mg of BHMPO and 80 mg of LiOH.H2O, mix well and then stir at 80°C under nitrogen protection for 16 h to reach the end of the reaction. Dilute the reaction liquid with 100 mL of water, then extract with EA three times, each time 40 mL, combine the organic layers, then concentrate and purify by column chromatography to obtain 100 mg of white solid intermediate 3. Take 90 mg of intermediate 3, dissolve in 10 mL of DMF, then add 22.7 mg of K2CO3 and 23.2 mg of iodomethane at room temperature. Mix well and stir at room temperature for 16 h to reach the end of the reaction. Concentrate the reaction liquid and purify by preparative chromatography to obtain 53.37 mg of white solid final product 3DMSD01-08. Purity 99.04% (254 nm), its HPLC spectrum is shown in Figure 4. LCMS (ESI): RT 1.778 min; m / z 561.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.50 (d, J = 5.6 Hz, 1H), 8.31 (d, J = 2.0 Hz, 1H), 8.07 (s, 1H), 7.83 (dd, J = 5.6, 2.0 Hz, 1H), 7.63 (s, 1H), 7.01 (d, J = 8.0 Hz, 1H), 5.27 (d, J = 10.0 Hz, 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 = 6.0 Hz, 3H).

[0170] 19F NMR (377 MHz, DMSO-d6) δ -73.466 (1 CF3), -149.894 (1 F), -159.128 (1 F). The reaction scheme is as follows:

[0171] Example 5: Preparation of modulator 3DMSD01-37

[0172] Take 4.5 g of starting material 1 dissolved in 45 mL of DCM, then add 28.5 mL of BBr3 at 0°C, mix well, then stir at 0°C and under nitrogen protection for 1 h. Then add 9.5 mL of BBr3 at 0°C, mix well, then stir at 0°C and under nitrogen protection for 2 h. The resulting mixture is introduced into ice water and extracted with 50 mL of DCM for 3 times. The organic layers are combined and dried with Na2SO4, filtered, concentrated and purified with a chromatographic column to obtain 2.5 g of white solid compound 2. Mix 2.5 g of compound 2 with 85 mg of DMSO and 40 mL of methanol, then add 1.3 g of NIS and stir at room temperature for 1 h. After LCMS shows that the reaction is complete, the mixture is concentrated and purified with a chromatographic column to obtain 3.5 g of light yellow solid compound 3. Dissolve 3.5 g of compound 3 in 50 mL of DMF, then add 2.5 g of K2CO3 and 2.3 g of compound 4 at room temperature, then stir at 60°C for 16 h. After LCMS shows that the reaction is complete, the mixture is diluted with 50 mL of water, then extracted with EA for 3 times, 50 mL each time. The organic layers are combined, dried with Na2SO4, then filtered, concentrated and purified with a chromatographic column to obtain 2.5 g of white solid compound 5. Dissolve 1800 mg of compound 5 in DMSO / H2O (216 mL / 72 mL), then add 1800 mg of Cu(acac)2 and 1800 mg of BHMPO and 900 mg of LiOH.H2O, stir at 80°C under microwave for 4 h. After LCMS shows that the reaction is complete, the mixture is diluted with 200 mL of water, then extracted with EA for 3 times, 200 mL each time. The organic layers are combined and concentrated, then purified with preparative HPLC to obtain 1.2 g of brown solid compound 6. Dissolve 1.2 g of compound 6 in 15 mL of DMF, then add 922 mg of K2CO3 and 474 mg of CH3I, stir at 50°C for 16 h. After LCMS shows that the reaction is complete, the mixture is concentrated, then purified with preparative HPLC to obtain 280.46 mg of white solid end product 3DMSD01-37. Purity 99.981% (254 nm), its HPLC spectrum is shown in Figure 5. LCMS (ESI): RT 1.848 min; m / z 554.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.30 (d, J = 1.6 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.83 (dd, J = 5.6, 2.0 Hz, 1H), 7.62 (d, J = 2.4 Hz, 1H), 6.93 (dd, J = 8.8, 2.0 Hz, 1H), 6.50 - 6.21 (m, 1H), 5.21 (d, J = 10.4 Hz, 1H), 4.43 - 4.22 (m, 3H), 3.87 (s, 3H), 2.76 (t, J = 7.4 Hz, 1H), 1.60 (s, 3H), 0.77 (d, J = 6.0 Hz, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -73.506 (1CF3), -127.110 (2F), -152.380 (1F), -158.432 (1F).

[0173] The reaction scheme is as follows:

[0174] Example 6: In vitro inhibition of Nav 1.8 by compounds (IC50) 50 )

[0175] Patch clamp technique is known as the "gold standard" for studying ion channels, which uses glass microelectrode to seal with cell membrane to measure a variety of membrane channel currents. Navs are a class of transmembrane proteins, including three different states, resting state, activated state, and inactivated state. Patch clamp technique measures the changes in membrane channel current after different compounds bind to different states of Navs, to evaluate the inhibition strength of the compounds to different states of Navs.

[0176] The representative compounds of the present application are used to evaluate the inhibition strength by manual patch clamp test through measuring the effect of the compounds on Nav1.8 current by transfecting stable CHO cell lines with specific ion channels.

[0177] The manual patch clamp experimental scheme is as follows:

[0178] 1) Cell culture

[0179] Maintenance medium: CHO cells are cultured in Ham's F-12 medium containing 10% fetal bovine serum and 10 μg / mL Blasticidin S, 200 μg / mL Hygromycin B, 0.8 mg / mL G418, and 100 μg / mL Zeocin, the culture temperature is 37°C, and the carbon dioxide concentration is 5%.

[0180] Cell passage: Remove old medium and wash once with PBS, then add 1 mL of 0.25% -Trypsin-EDTA solution, incubate at 37°C for 1.5 min. When the cells are detached from the dish, add about 5 mL of 37°C preheated complete medium. Gently pipette the cell suspension to separate the aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and collect the cells by centrifugation at 1000 rpm for 5 min. For expansion or maintenance culture, seed the cells in 6 cm cell culture dishes at a cell density of 2.5 x 10 5 cells per dish (final volume: 5 mL).

[0181] To maintain the electrophysiological activity of the cells, the cell density must not exceed 80%.

[0182] Patch clamp assay, before the assay, the cells were detached with 0.25% -Trypsin-EDTA, 6.5 x 10 3 cells were plated on coverslips in 24-well plates (final volume: 500 μL), and the tetracycline was added to induce for 24-72 h before the assay.

[0183] 2) Preparation of compound sample

[0184] Weigh an appropriate amount of the test substance, calculate the required volume of DMSO according to the formula: DMSO volume = actual compound mass x purity / (molecular weight x theoretical concentration), and then pipette the corresponding volume of DMSO to dissolve the test substance. At the same time, weigh the mass of DMSO to ensure the accuracy of the amount used by calculating the volume based on the density of the solvent. According to the final DMSO usage amount, calculate the actual stock solution concentration.

[0185] The highest test concentration of the test substance is directly diluted with extracellular fluid or the stock solution is further diluted with DMSO. Other concentrations are first diluted with DMSO from high to low concentrations to form intermediate dilutions, and then diluted with extracellular fluid to the working solution concentration. The concentration of DMSO in each working solution does not exceed 0.3%. The extracellular fluid used for detection contains 100 nM TTX to block the endogenous TTX-S (tetrodotoxin-sensitive) sodium channel present in the cells. The working solution of the test substance is sonicated for 20 min before patch clamp assay.

[0186] 3) Blockage effect of sodium ion channel in patch clamp

[0187] The voltage protocol for whole-cell patch-clamp recording of hNavl.8 sodium current is as follows: after the whole-cell configuration is formed, the cell is voltage clamped at -120 mV. First, the voltage is stepped from -130 mV to -10 mV in 10 mV steps for 5 s, then a 0 mV depolarizing pulse is given to obtain the half-inactivation voltage (Vhalf). The resting state and half-inactivated state of sodium current are detected using a double-pulse protocol. First, a first depolarizing pulse (TP1) to 0 mV for 50 ms is given to detect the resting state of sodium current. Then the voltage is adjusted to Vhalf for 5 s, followed by a return to -120 mV for 20 ms to allow recovery of channels from unbound compounds and from inactivation. A second depolarizing pulse (TP2) to 0 mV for 50 ms is given to detect the half-inactivated state of sodium current. Finally, return to the clamped voltage of -120 mV, and data is collected at 20 s intervals to observe the effect of drugs on the peak of sodium current in the two different states. Experimental data is collected by EPC 10 amplifier (HEKA) or IPA amplifier (Sutter Instrument) and stored in PatchMaster (HEKA) or Sutter Patch (within Igor) software.

[0188] Patch-clamp procedure starts with a glass capillary pulled into a recording electrode using a microelectrode puller. The electrode filled with intracellular solution is mounted into a microelectrode holder. The coverslip with cells is placed into the recording bath under an inverted microscope, and the microelectrode manipulator is operated under the inverted microscope to immerse the electrode into extracellular solution and record the electrode resistance (Rpip). The electrode is then slowly brought into contact with the cell surface, and negative pressure is applied to form a GΩ high resistance seal. Fast capacitance compensation is performed at this point, and negative pressure is applied to break the cell membrane to form a whole-cell recording configuration. Slow capacitance compensation is performed, and experimental parameters such as series resistance (Rs) are recorded. No leak compensation is applied.

[0189] After the current amplitude is stable in control extracellular solution, drug administration begins, and each drug concentration is tested after the current reaches a steady-state block (about 5 min). The blank control extracellular solution and the working solution of the test compound are gravity perfused through the recording bath from low to high concentrations to act on the cells, while liquid displacement is performed using a peristaltic pump in the recording. The current detected in the extracellular solution without compounds is used as the control for each cell. Each concentration is tested twice independently. All electrophysiological experiments are performed at room temperature.

[0190] First, the peak of sodium current after each drug concentration is tested and the control current peak The inhibition rate of each drug concentration in different states was calculated after normalization, namely The mean (Mean), standard deviation (SD) and standard error (SE) were calculated for each concentration inhibition rate, and the data were expressed as Mean ± SE.

[0191] Y = Bottom + (Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0192] The IC 50 value of the compound was calculated by the above equation, and the concentration-effect curve was non-linearly fitted, wherein the IC 50 is the half-inhibitory concentration. The calculation of IC 50 and the curve fitting were completed by using GraphPad Prism software.

[0193] The calculation results of the inhibitory activity of the compound of some embodiments on hNav1.8 are shown in Table 1 below.

[0194] Table 1

[0195] It can be seen that the compound of the present disclosure has a significant blocking effect on the activity of NaV1.8 channel.

[0196] Example 7: Test of inhibitory activity of compound on hERG ion channel of HEK293 cell

[0197] The inhibitory effect of the compound on hERG potassium channel was studied by using a manual patch clamp technique (the gold standard for evaluating hERG safety), and the risk of causing ventricular repolarization toxicity was evaluated.

[0198] Using DMSO as the blank control stock solution, an appropriate amount of DMSO was added to the extracellular fluid to prepare 0.3% DMSO extracellular fluid, i.e. the blank control working solution.

[0199] Cisapride was used as a positive control, and Cisapride was prepared into 1000nM, 100nM, 10nM, 1nM and 0.1nM working solutions with extracellular fluid, ensuring that the DMSO concentration was 0.3%. The solubility of the sample was observed, and all concentrations were completely dissolved without visible precipitate.

[0200] The test substance was prepared into 0.3μM, 1μM, 3μM, and 10μM working solutions with DMSO and extracellular fluid, and the DMSO content was not more than 0.3%.

[0201] Extracellular fluid: K-007-1

[0202] 140NaCI, 3.5 mM KCI, 1 mM MgCI2-6H2O, 2 mM CaCI2-2H2O, 10 mM D- Glucose, 10 mM HEPES, 1.25 mM NaH2P04-2H2O, pH adjusted to 7.4 with NaOH.

[0203] Cell Internal Solution: K-002-2

[0204] 20 mM KCI, 115 mM K-Aspartic, 1 mM MgCI2-6H2O, 5 mM EGTA, 10 mM HEPES, 2 mM Na2-ATP, pH adjusted to 7.2 with KOH.

[0205] Cells were HEK-293 cell line stably expressing hERG potassium channel.

[0206] The voltage protocol for whole-cell patch clamp recording of hERG current was as follows: after forming the whole-cell seal, the cell membrane was clamped at -80 mV. The clamping voltage was stepped from -80 mV to -90 mV for 0.1 s, then returned to -80 mV for 0.1 s, then stepped to 40 mV for 0.5 s, then ramped from 40 mV to -80 mV (voltage change was -1.2 V / s) for 0.1 s. The data was collected every 5 s to observe the effect of drugs on hERG tail current. The experimental data was collected by an IPA amplifier (Sutter Instrument) and stored in Sutter Patch (with Igor Pro) software.

[0207] Patch clamp operation first used a microelectrode puller to pull a glass capillary into a recording electrode, then the electrode filled with intracellular solution was installed in the microelectrode holder, then the cell-coated coverslip was placed in the recording bath under the inverted microscope, then the microelectrode manipulator was operated under the inverted microscope to immerse the electrode in the extracellular solution and record the electrode resistance (Rpip). Then the electrode was slowly contacted to the cell surface, and negative pressure was given to form a GΩ high resistance seal. At this time, fast capacitance compensation was performed, and negative pressure was continued to suck the cell membrane to form a whole-cell recording mode. Finally, slow capacitance compensation was performed and experimental parameters such as series resistance (Rs) were recorded. No leakage compensation was given.

[0208] The hERG current was recorded in whole-cell configuration. The experiment was started after the hERG current was stable. Each drug concentration was applied for 5 min (or until the current was stable) before the addition of a saturating concentration of 1 μM of the hERG channel blocker E-4031. Each test compound was tested at multiple concentrations. The cell- plated coverslips were placed in the recording bath under an inverted microscope. The blank control and test compound working solutions were applied using a perfusion system. The solvent control and test compound working solutions were applied sequentially to the recording bath in order of decreasing concentration. The current in each cell in the absence of compound was used as its own control. Each concentration was tested in at least three cells in triplicate. All electrophysiological experiments were performed at 37 ± 2 °C. The IC50values of the test compounds for the hERG current were calculated by fitting the concentration-effect curve. 50 The results are summarized below:

[0209] The following criteria were used to judge the inhibitory effect of the test compounds on hERG:

[0210] Very strong inhibition: IC 50 <0.1 μM

[0211] Strong inhibition: 0.1 μM < IC 50 ≤ 1 μM

[0212] Moderate inhibition: 1 μM < IC 50 ≤ 10 μM

[0213] Weak inhibition or no inhibition: IC 50 > 10 μM

[0214] An IC 50 > 10 μM indicates that the test compound has weak or no inhibitory effect on the hERG channel in the concentration range tested, indicating that the compound has a low risk of causing cardiotoxicity.

[0215] Example 8: Pharmacokinetic evaluation

[0216] Male C57 / 6J mice were used as the test animals, and LC / MS / MS was used to determine the drug concentration in the plasma of the C57 / 6J mice at different times after oral gavage (PO) and tail vein injection (IV) of the compounds of the examples. The pharmacokinetic behavior of the compounds of the present disclosure in mice was studied, and their pharmacokinetic characteristics were evaluated.

[0217] 1) Test drug

[0218] Example 5 Compound 3 DMSD01-37, VX-548.

[0219] 2) Test animals

[0220] C57 / 6J mice, male, 3 mice per group. After fasting overnight, the mice were administered by oral gavage and tail vein injection, respectively.

[0221] 3) Drug preparation

[0222] A certain amount of the compound of the example or VX-548 was weighed, respectively, and added to the drug dissolving enzyme to prepare a uniform solution of 1.0 mg / mL or 3.0 mg / mL.

[0223] 4) Administration

[0224] The administration dose of the test compound was 5 mg / kg (IV), 10 mg / kg (PO); the administration volume was 5.0 mL / kg (IV) and 10.0 mL / kg.

[0225] The administration dose of VX-548 was 5 mg / kg (IV), 30 mg / kg (PO); the administration volume was 5.0 mL / kg (IV) and 10.0 mL / kg.

[0226] 5) Operation

[0227] Before administration and 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, 24 h after administration (IV) and 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, 24 h (PO), 0.03 mL of blood was collected from the eye socket, placed in an EDTA-K2 anticoagulant tube, centrifuged at 10,000 rpm for 1 minute (4°C), and the plasma was separated within 1 hour and stored at -20°C for testing. The blood collection to centrifugation process was operated under ice bath conditions. Food was given 4 hours after administration.

[0228] Whole blood was collected in centrifuge tubes containing EDTA-K2 at the specified times and placed on wet ice (0°C). The actual time of collection was recorded. Blood samples were centrifuged at 4000g for 5 minutes at 4°C to obtain plasma. Plasma samples were stored in polypropylene tubes, quickly frozen in a freezer, and stored at -75°C ± 15°C until LC- / MS / MS analysis. Fresh blood was taken from the remaining untreated mice. After centrifugation, the plasma was collected and combined as a control plasma for bioanalysis. Protein precipitation was used as a sample pretreatment method, 10 uL of plasma sample + 200 uL of precipitant, after centrifugation, 100 uL of supernatant was taken, 100 uL of diluent was added, mixed uniformly, and then subjected to LC- / MS / MS analysis. The pharmacokinetic parameters of the compound of the example in C57 / 6J mice are as follows:

[0229] The structure of VX-548 is as follows:

[0230] From the above results, the test compound has better exposure, longer half-life and higher bioavailability than the control compound. The experimental results show that the compound of the embodiment has obvious pharmacokinetic advantages. The above advantages ultimately clinically show that the test compound can achieve the same analgesic effect with less dosing frequency and lower dosage, improve patient compliance and reduce treatment cost.

[0231] From the above drug research data, it can be seen that the compound of the present application has obvious inhibitory effect on Nav1.8 ion channel activity, and some compounds have obvious advantages in cell activity, ion channel selectivity, hERG safety, mouse pharmacokinetics and other drug parameters. It can be used as a Nav1.8 inhibitor and has a wide application prospect in the fields of analgesia, atrial fibrillation, Bucha syndrome, etc.

[0232] The above only describes the preferred embodiments of the present application, and does not limit the present application in any form. Although the present application has been disclosed as above with the preferred embodiments, it is not intended to limit the present application. Any skilled person in the art can make some changes or modifications to the above-mentioned technical content without departing from the scope of the technical solution of the present application, and any simple modification, equivalent change and modification of the above-mentioned embodiments, which do not depart from the technical solution of the present application, are still within the scope of the present application.

Claims

1. A compound of Formula (I): ###0001### (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof. wherein R a1 , R a2 , R a3 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl, 3-8 membered heterocyclyl, -Z-C(O)NR a R b , -Z-C(O)-OR c , -Z-C(O)-R c , -Z-OC(O)-R c , -C(O)-Z-OR c , -O-Z-C(O)-R c , -Z-P(O)-R c , -Z-P(O)O-R c , -Z-OP(O)-R c , -Z-OP(O)O-R c , -Z-S(O)-R c , -Z-S(O)2-R c , -Z-S(O)2-O-R c , -Z-O-S(O)2-R c , -Z-O-S(O)2-O-R c , Z is selected from the group consisting of a bond, -O-, -S-, -NH-, C1-C12alkylene; and said alkyl, alkoxy, cycloalkyl, heterocyclyl, alkylene is optionally substituted with one or more (e.g. 2, 3, 4, 5, etc.) substituents selected from the group consisting of halogen, hydroxyl, cyano, C1-C6alkyl, C1-C6alkoxy, amino, C3-C8cycloalkyl; R a , R b , R c each independently is selected from the group consisting of 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 means optionally substituted with 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 independently is selected from the group consisting of hydrogen, halogen, hydroxy, C1-C6alkyl, C1-C6alkoxy, and said alkyl, alkoxy is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, C1-C6alkyl, C1-C6alkoxy, amino; or any two R a1 , R a2 , R a3 , R b1 , R b2 together with the intervening ring atoms form a 5-7 membered ring, which can be saturated or unsaturated carbocyclic or heterocyclic ring; the heterocyclic ring optionally containing one or more N, O, S(=O) m heteroatoms; which 5-7 membered ring can optionally be substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, C1-C6alkyl, C1-C6alkoxy, amino; M1, M2are each independently selected from C, O, S(=O) m , N-R n , wherein R n is selected from the group consisting of: hydrogen, C1-C6 alkyl; preferably, R n is selected from the group consisting of: hydrogen, methyl or ethyl, most preferably R n is selected from hydrogen; X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 each independently selected from the group consisting of a bond, C, N, O, C=O, S(=O) m ; R c1 , R c2 , R c3 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, Ci-C6alkyl, Ci-C6alkoxy, -C(=0)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 independently is selected from the group consisting of hydrogen, hydroxyl, amino, C1-C6alkyl, C1-C6alkoxy; L1is selected from the group consisting of: a bond, O, CH2, NH; m, n are each independently 0, 1 or 2; in formula (I), represents a single or double bond.

2. The compound of claim 1, wherein The compounds have a structure according to Formula (I-A): wherein 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, L1, as defined in claim 1.

3. The compound of claim 1, wherein R a1 with R b1 or R b2 to form a 5-8 membered carbocyclic or 5-8 membered heterocyclic ring.

4. The compound of claim 1, wherein R b1 , R b2 , R b3 , R b4 are each independently selected from the group consisting of hydrogen, methyl, trifluoromethyl, ethyl, methoxy, ethoxy.

5. The compound of claim 1, wherein M1, M2are independently selected from the group consisting of O, -NH-.

6. The compound of claim 1, wherein X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 each independently selected from the group consisting of a bond, C, N, O, C=0, S(=0)2.

7. The compound of claim 1, wherein R c1 , R c2 , R c3 are each independently selected from the group consisting of hydrogen, hydroxyl, amino, fluorine, cyano, oxo, methyl, -C(=0)NH2, -C(=0)NHCH3, -C(=0)NHC2H5.

8. The compound of any one of claims 1 to 7, wherein The compound is selected from the group consisting of:

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

10. The pharmaceutical composition of claim 9, wherein The pharmaceutical composition is used in a method for treating, ameliorating, or preventing a disease or condition associated with sodium channel modulation; preferably, the disease or condition is pain.

11. Use of a compound, or a pharmaceutically acceptable salt or hydrate thereof, as claimed in any one of claims 1 to 8, wherein The pharmaceutical composition is used in a method for treating, ameliorating, or preventing a disease or condition associated with sodium channel modulation; preferably, the disease or condition is pain.

12. The use according to claim 11, characterized in that, The pain or disease is selected from the group consisting of chronic pain, bowel pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence, pathological cough, or cardiac arrhythmia.

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