Small-molecule channel activator and use thereof

Abstract

Disclosed in the present invention are a small-molecule channel activator and the use thereof. Provided in the present invention are compounds represented by formula (I), and stereoisomers, pharmaceutically acceptable salts, solvates, deuterated compounds, metabolites or prodrugs thereof. The compounds of the present invention have good Kv7.2 / 3 channel activation effect, and can effectively treat central nervous system diseases such as epilepsy and pain, thus meeting the needs of patients.

Description

Channel small molecule activators and their uses

[0001] This application claims priority to Chinese patent application 2024109222025, filed on 2024 / 7 / 10. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of medicinal chemistry, specifically relating to a small molecule channel activator and its uses. Background Technology

[0003] The Kv7 subfamily of potassium channels comprises five members, encoded by genes KCNQ-1 through KCNQ-5. These five members are voltage-gated ion channels, playing crucial roles in membrane excitability across various cell types. Kv7 channels can form homotetramers from identical subunits or heterotetramers from specific subunit combinations (Delmas, P., Brown, DA, "pathways modulation neural KCNQ / M(Kv7)potassium channels" Nature Reviews Neuroscience, 2005, 6, 850). Each Kv7 subunit consists of six transmembrane segments (S1-S6) and cytoplasmic N-terminus and C-terminus; segments S1, S2, S3, and S4 constitute the voltage-sensing domain (VSD), while segments S5 and S6, along with interconnected loops, participate in the formation of the pore domain (PD). Kv7 channels feature a distinctive long intracellular C-terminus containing the domain required for tetramerization and are involved in the binding and transduction of key regulators such as phosphatidylinositol 4,5-bisphosphate (PIP2), calmodulin (CaM), synaptophysin, A kinase anchoring protein, protein kinase C, and ankylosing protein-G. (Barrese, V., Stott, JB, Greenwood, IA, “KCNQ-encoded potassium channels as therapeutic targets” Annu. Rev. Pharmacol. Toxicol. 2018, 6(58), 625-648).

[0004] Kv7 channels have attracted considerable attention due to their association with a variety of diseases. In particular, the Kv7.2 / 3 isoform tetramer, the most abundant Kv7.2 assembly in the neocortex and hippocampus, has been identified as closely associated with epilepsy, pain, and other central nervous system disorders because of its significant contributions to the maintenance of M-currents and neuronal resting membrane potential. Since activation of Kv7.2 / 3 channels can act as a brake on neuronal firing, Kv7.2 / 3 channel activators hold great potential for treating central nervous system disorders such as epilepsy and pain. (Jepps, TA, Barrese, V., and Miceli, F. “Editorial: Kv7 Channels: Structure, Physiology, and Pharmacology” Frontiers in Physiology, 2021, 12, Article 679317).

[0005] The search for Kv7 channel openers began in the early 1980s; the first selective Kv7 channel activator, retigabine, was approved in the European Union in 2011 for the treatment of epilepsy (Trobalt) and in the United States in 2010 for adjunctive therapy for adult partial seizures (Potiga). (Stafstrom, CE, Crippon, S., Kirkpatrick, P. "Ezogabine (retigabine)" Nature Review Drug Discovery, 2011, 10, 729; Jankovic, S., and Llickovic, I. "the preclinical discovery and development of ezogabine for the treatment of epilepsy" Exper. Opin. Drug Discov. 2013, 8(11), 1). This compound was initially discovered by ASTA Medica GmbH (DE4200259) and co-developed by Valeant and GSK; however, it was discontinued in June 2017 due to the blue skin side effect caused by the pigmentation of the retigabine metabolite dimer.(Clark, S., Antell, A., Kaufman, K. “new antiepileptic medication linked to blue discoloration of the skin and eyes” Ther. Adv. Drug. Safety. 2015, 6(1) 15). To address its side effects, many different molecules have been designed based on the molecular structure of retigabine and evaluated in preclinical and clinical studies (Borgini, M., Mondal, P., Liu, R., and Wipf, P. “Chemical modulation of Kv7potassium channels” RSC Med. Chem. 2021, 12, 483; Suru, A. Setal., “Flupirtine and retigabine as templates for ligand-based drug design of Kv7.2 / 3activators” Org. Biomol. Chem., 2019, 17, 4512-4522. Among them, XEN1101 developed by Xenon has entered the Phase III clinical trial for the treatment of epilepsy and seizures (US11135214); Pynegabine developed by Haikou Pharmaceutical / Shanghai Institute of Materia Medica has entered the Phase I clinical trial for the treatment of epilepsy (Zhang, Y.-M., et al., J. Med. Chem, 2021, 64, 5816, WO2015 / 1653521); and CB03-154 developed by Zhimeng Biopharmaceutical has also entered the Phase I clinical trial for the treatment of epilepsy (WO2022028548). Several other companies and universities are also researching Kv7.2 / 3 channel activators to identify novel molecules with potential medical uses (WO2016077724, WO2019183148, CN108863893, WO2018209074, CN116535353).

[0006] We hereby disclose novel small molecule Kv7.2 / 3 activators and their applications in the treatment of epilepsy, pain, and other Kv7.2 / 3-related diseases. Summary of the Invention

[0007] This invention provides a class of small-molecule channel activators and their uses. The compounds of this invention exhibit good Kv7.2 / 3 channel activation activity, providing effective treatment for central nervous system disorders such as epilepsy and pain, thus meeting the needs of patients.

[0008] On the one hand, the present invention provides a compound as shown in formula (I), its stereoisomer, its pharmaceutically acceptable salt, its solvate, its deuterated product, its metabolite or a prodrug thereof;

[0009] in,

[0010] R 1 It is a C1-C6 alkyl, C3-C6 cycloalkyl, 1-6 heteroalkyl containing 1-3 nitrogen atoms, or C6-C 10 aryl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl and C6-C 10 The aryl group is optionally substituted by 1 to 3 substituents independently selected from the following groups: halogen, C1-C3 alkyl, C1-C3 alkoxy, hydroxyl, 3-10 membered heterocyclic group;

[0011] L stands for -(CH2) n -, -O-, -S- or -NH-;

[0012] R 2 and R 3 Each of the following is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, amino, or a 1-6 heteroalkyl group containing 1-3 nitrogen or sulfur atoms, wherein the C1-C6 alkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl are optionally substituted by 1-3 substituents independently selected from the following groups: halogen, C1-C3 alkyl, C1-C3 alkoxy;

[0013] X1 is CR 5 Or N;

[0014] X2 is CH or N;

[0015] R 5 It is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 1-6 heteroalkyl or 3-10 heterocyclic group containing 1-3 nitrogen or sulfur, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl and 3-10 heterocyclic group are optionally substituted by 1-3 substituents independently selected from the following groups: halogen, C1-C3 alkyl, C1-C3 alkoxy;

[0016] R 4It is hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -(C=O)-C1-C6 alkyl, 1-6-membered heteroalkyl or 3-10-membered heterocyclic group containing 1-3 oxygen, nitrogen or sulfur, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl and 3-10-membered heterocyclic group are optionally substituted by 1-3 substituents independently selected from the following groups: halogen, C1-C3 alkyl, C1-C3 alkoxy;

[0017] V1 is a connector, -(CH2) n -、-CH(COOR a (CH2) m -or-CHR b (CH2) p -;

[0018] n is 0, 1, 2, 3 or 4;

[0019] m is 0, 1, or 2;

[0020] p is 0, 1, or 2;

[0021] R a and R b Each is independently H, deuterium, or C1-C6 alkyl;

[0022] The Y ring is a C3-C6 cycloalkyl group, C6-C 10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclic, wherein the C3-C6 cycloalkyl, C6-C 10 Aryl, 5-10-membered heteroaryl, and 3-10-membered heterocyclic groups are optionally substituted by 1-5 substituents independently selected from the following groups: deuterium, halogen, cyano, C1-C6 alkyl, and alkyl groups substituted by 1-3 R groups. x Substituted C1-C6 alkyl, C2-C6 alkenyl, with 1-3 R x Substituted C2-C6 alkenyl, C2-C6 alkynyl, with 1-3 R x Substituted C2-C6 alkynyl, C1-C6 alkoxy, with 1-3 R x Substituted C1-C6 alkoxy, C3-C6 cycloalkyl, with 1-3 R x Substituted C3-C6 cycloalkyl, amide group, 1-6-membered heteroalkyl or 3-10-membered heterocyclic group containing 1-3 nitrogen or sulfur atoms, or with 1-3 R atoms x Replacement of 3-10 membered heterocyclic groups;

[0023] R x It is a halogen, a C1-C3 alkyl or a C1-C3 alkoxy;

[0024] W can be either of the following two groups:

[0025] (I)W is R 6 ;

[0026] (II)W is V2R 7 ;

[0027] R 6 H, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, -S-C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 aryl, 5-10-membered heteroaryl, or 3-10-membered heterocyclic, wherein the C1-C6 alkyl, C1-C6 alkoxy, -S-C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 The aryl, 5-10-membered heteroaryl and 3-10-membered heterocyclic groups are optionally substituted by 1-3 substituents independently selected from the following groups: halogen, C1-C3 alkyl, C1-C3 alkoxy;

[0028] V2 is -(CH2) n -、-O-、-S-、-N(R c -, -CH2-O-, -O-CH2-, -CONH-, or -NHCO-;

[0029] R c It is hydrogen, deuterium, or C1-C6 alkyl;

[0030] R 7 Halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C4-C6 cycloalkenyl, 1-6 heteroalkyl groups containing 1-3 nitrogen or sulfur atoms, C6-C 10 aryl, 5-10-membered heteroaryl, or 3-10-membered heterocyclic group, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C4-C6 cycloalkenyl, C6-C 10 The aryl, 5-10-membered heteroaryl and 3-10-membered heterocyclic groups are optionally substituted by 1-3 substituents independently selected from the following groups: cyano, amide, halogen, C1-C3 alkyl, C1-C3 alkoxy;

[0031] The heteroatoms of the 3-10 membered heterocyclic groups are O, N, or S, and the number of heteroatoms is 1-3.

[0032] The heteroatom of the 5-10 membered heteroaryl group is O, N or S, and the number of heteroatoms is 1-3.

[0033] The compound represented by formula (I) satisfies at least one of the following six conditions:

[0034] (1)R 1 C1-C6 alkyl groups substituted with 1-3 halogens;

[0035] (2) W is V2R 7 And R 7 It can be any of the following structures;

[0036] R 10 It can be hydrogen, deuterium, halogen, cyano, or amide.

[0037] (3) X1 is N; X2 is CH;

[0038] (4) V1 is -CH(COOR) a (CH2) m -;

[0039] (5) The Y-ring is

[0040] And (6)W is R 6 ;R 6 for

[0041] In one embodiment, the C1-C6 alkyl group may be methyl, ethyl, n-propyl, or isopropyl, preferably methyl.

[0042] In one embodiment, the C3-C6 cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0043] In one embodiment, the C3-C 10 The cycloalkyl group can be monocyclic or polycyclic, wherein the polycyclic group is fused, spirocyclic, or bridged; preferably, it is a C3-C6 monocyclic cycloalkyl group or a C5-C6 monocyclic cycloalkyl group. 10 Polycyclic cycloalkyl groups, for example For example

[0044] In one embodiment, the 1-6 heteroalkyl group containing 1-3 nitrogen atoms may be a 1-3 heteroalkyl group containing 1-3 nitrogen atoms.

[0045] In one embodiment, the 1-6 heteroalkyl group containing 1-3 nitrogen or sulfur atoms may be a 1-3 heteroalkyl group containing 1-3 nitrogen or sulfur atoms, for example, a 1-3 heteroalkyl group containing 1-3 nitrogen atoms or a 1-3 heteroalkyl group containing 1-3 sulfur atoms, or, for example, a methylthio group.

[0046] In one embodiment, the 1-6 heteroalkyl group containing 1-3 oxygen, nitrogen, or sulfur atoms may be a 1-3 heteroalkyl group containing 1-3 oxygen, nitrogen, or sulfur atoms, for example, a 1-3 heteroalkyl group containing 1-3 oxygen atoms, a 1-3 heteroalkyl group containing 1-3 nitrogen atoms, or a 1-3 heteroalkyl group containing 1-3 sulfur atoms.

[0047] In one embodiment, the C6-C 10 The aryl group can be phenyl or naphthyl, preferably phenyl.

[0048] In one embodiment, the "heterocyclic group" in the 3-10 member heterocyclic group can be a heterocyclic alkyl group or a heterocyclic alkenyl group.

[0049] In one embodiment, the 3-10 member heterocyclic group can be a 3-7 member monocyclic heterocyclic group or a 7-10 member bicyclic heterocyclic group, for example... For example

[0050] In one embodiment, the halogen is fluorine, chlorine, bromine, or iodine.

[0051] In one embodiment, the C1-C6 alkoxy group may be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy, preferably methoxy.

[0052] In one embodiment, the C2-C6 alkenyl group may be a C2-C4 alkenyl group, such as a vinyl group.

[0053] In one embodiment, the C2-C6 ynyl group can be a C2-C4 ynyl group, such as an acetyl group.

[0054] In one embodiment, the 5-10 membered heteroaryl group may be a 5-7 membered monocyclic heteroaryl group or a 9-10 membered bicyclic heteroaryl group; the 5-7 membered monocyclic heteroaryl group may be, for example, pyridine, N-methylpyridine, pyrimidine, triazole, furan, thiophene, or thiazole; the 9-10 membered bicyclic heteroaryl group may be, for example... For example

[0055] In one embodiment, at least one ring of the 5-10 member heteroaryl group is aromatic.

[0056] In one embodiment, the -S-C1-C6 alkyl group may be -S-methyl, -S-ethyl, -S-n-propyl, -S-isopropyl, -S-n-butyl, -S-isobutyl, or -S-tert-butyl, preferably -S-methyl.

[0057] In one embodiment, the C4-C6 cycloalkenyl group contains one or two carbon-carbon double bonds.

[0058] In one embodiment, the C4-C6 cycloalkenyl group may be... For example

[0059] In one particular scheme, R 1 The methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pent-1-yl, methylamino, ethylamino, dimethylamino, diethylamino, phenyl, pyridyl or pyrimidinyl group is used, wherein the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pent-1-yl and phenyl group are optionally substituted by 1 to 3 substituents independently selected from the following groups: fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, hydroxyl, 1 to 6 heteroalkyl groups containing 1 to 3 oxygen, nitrogen or sulfur atoms;

[0060] Preferably, R 1 It is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pent-1-yl, fluoromethyl, difluoromethyl, trifluoromethyl or 2-hydroxypropyl-2-yl;

[0061] More preferably, R 1 It is ethyl, tert-butyl, but-2-yl, bicyclo[1.1.1]pent-1-yl, trifluoromethyl or 2-hydroxypropyl-2-yl.

[0062] In one particular scheme, R 1 It is a C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted by 1-3 substituents independently selected from the following groups: halogen, hydroxyl.

[0063] In one embodiment, L is a linking bond, -CH2-, -(CH2)2-, -(CH2)3-, -O-, -S-, or -NH-, preferably a linking bond, -CH2-, -O-, -S-, or -NH-, and more preferably a linking bond or -CH2-.

[0064] In one particular scheme, R 2 and R 3Each of the following groups is independently H, deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, amino, or a 1-6 heteroalkyl group containing 1-3 nitrogen or sulfur atoms, wherein the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups are optionally substituted by 1-3 substituents independently selected from the following groups: fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy;

[0065] Preferably, R 2 and R 3 Each of these substances independently can be fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, butoxy, methylthio, ethylthio, propylthio, fluoromethyl, difluoromethyl, trifluoromethyl, amino, aminomethyl, or aminoethyl.

[0066] More preferably, R 2 and R 3 Each can be independently methyl, methylthio, trifluoromethyl, or amino.

[0067] In one particular scheme, R 2 and R 3 Each of the following is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, amino, or a 1-6 heteroalkyl group containing 1-3 nitrogen or sulfur atoms, preferably C1-C6 alkyl or amino.

[0068] In one scheme, X1 is CH.

[0069] In one scheme, X2 is CH.

[0070] In one particular scheme, R 5 The group is H, deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a 1-6-membered heteroalkyl or 3-10-membered heterocyclic group containing 1-3 nitrogen or sulfur atoms, wherein the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and 3-10-membered heterocyclic group are optionally substituted by 1-3 substituents independently selected from the following groups: fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy;

[0071] Preferably, R 5The following are H, deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl;

[0072] More preferably, R 5 It is H or deuterium.

[0073] In one particular scheme, R 5 It can be hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 1-6 heteroalkyl or 3-10 heterocyclic group containing 1-3 nitrogen or sulfur, preferably hydrogen, halogen or C1-C6 alkyl.

[0074] In one particular scheme, R 4 The alkyl group is hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a 1-6-membered heteroalkyl or 3-10-membered heterocyclic group containing 1-3 oxygen, nitrogen, or sulfur groups, wherein the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and 3-10-membered heterocyclic group are optionally substituted by 1-3 substituents independently selected from the following groups: fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy;

[0075] Preferably, R 4 It can be hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl, formyl, acetyl, or propionyl.

[0076] More preferably, R 4 It can be hydrogen, deuterium, methyl, acetyl or prop-2-ynyl.

[0077] In one particular scheme, R 4 It is hydrogen, deuterium, C1-C6 alkyl, or -(C=O)-C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by 1-3 substituents independently selected from the following groups: halogen, C1-C3 alkyl, C1-C3 alkoxy; preferably, R 4 It is hydrogen, deuterium, C1-C6 alkyl or -(C=O)-C1-C6 alkyl.

[0078] In one scheme, V1 is a linker, -CH2-, -CH2-CH2-, or -CH(COOR) a )CH2-.

[0079] In one particular scheme, R a and R b Each is independently H or C1-C6 alkyl.

[0080] In one scheme, the Y-ring is C6-C. 10 Aryl or 5-10 heteroaryl groups;

[0081] Preferably, the specific structure of the Y-ring includes, but is not limited to, any of the following structures:

[0082] R 8 The group is H, deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a 1-6-membered heteroalkyl or 3-10-membered heterocyclic group containing 1-3 nitrogen or sulfur atoms, wherein the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and 3-10-membered heterocyclic group are substituted by 1-3 substituents independently selected from the following groups: fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy;

[0083] Preferably, R 8 It can be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, formyl, acetyl, propionyl, formamido, acetamido, propionamido, or cyano;

[0084] More preferably, R 8 It can be hydrogen, deuterium, fluorine, acetyl, formamido, or cyano;

[0085] In one embodiment, the Y ring is a C3-C6 cycloalkyl group, or a C6-C... 10 aryl or 5-10 heteroaryl, wherein the C3-C6 cycloalkyl, C6-C 10 The aryl and 5-10 heteroaryl groups are optionally substituted by 1-5 substituents independently selected from the following groups: deuterium, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, amide; preferably, the Y ring is C3-C6 cycloalkyl, C6-C6 cycloalkyl, or C6-C6 cycloalkyl. 10 Aryl or 5-10 heteroaryl compounds.

[0086] More preferably, R 6 Hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-6 heteroalkyl groups containing 1-3 nitrogen or sulfur atoms, C6-C 10Aromatic rings, 3-10 membered heterocyclic groups, wherein methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C6-C 10 The aromatic ring and the 3-10 membered heterocyclic group are optionally substituted by 1-3 substituents independently selected from the following groups: fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy;

[0087] Preferably, R 6 It is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, piperidinyl, morpholinyl, m-fluorophenyl, o-fluorophenyl, p-fluorophenyl or 6-aza-2-oxazaspiro[3.3]hept-6-yl;

[0088] More preferably, R 6 It can be hydrogen, deuterium, fluorine, methyl, trifluoromethyl, morpholino, p-fluorophenyl or 6-aza-2-oxaspiro[3.3]hept-6-yl.

[0089] In one particular scheme, R 6 H, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, -S-C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 aryl, 5-10-membered heteroaryl, or 3-10-membered heterocyclic group, wherein the C1-C6 alkyl, C1-C6 alkoxy, -S-C1-C6 alkyl, and C6-C 10 The aryl group is optionally substituted by 1 to 3 substituents independently selected from the following groups: halogen, C1-C3 alkyl, C1-C3 alkoxy;

[0090] Preferred, R 6 H, halogen, C1-C6 alkyl, C1-C6 alkoxy, -S-C1-C6 alkyl, C6-C 10 aryl or 3-10 membered heterocyclic groups, wherein the C1-C6 alkyl, C1-C6 alkoxy and C6-C 10 The aryl group may optionally be replaced by 1 to 3 substituents independently selected from the following groups: halogens, C1-C3 alkyl groups.

[0091] In one scheme, V2 is -CH2-, -O-, -S-, -N(R) c -, -O-CH2- or -CONH-.

[0092] In one particular scheme, R c It can be hydrogen, methyl, ethyl, or propyl.

[0093] In one particular scheme, R 7 The following are compounds: hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 3-methylbutyl, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and 1-6-membered heteroalkyl or 3-10-membered heterocyclic groups containing 1-3 nitrogen or sulfur atoms, wherein methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, ... tert-butyl, 3-methylbutyl, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-10 membered heterocyclic groups are optionally substituted by 1-3 substituents independently selected from the following groups: fluorine, chlorine, bromine, iodine, cyano, formamido, acetamido, propamido, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy;

[0094] Alternatively, in some other embodiments, R 7 The specific structure includes, but is not limited to, the following:

[0095] Among them, R 9 The group can be H, deuterium, fluorine, chlorine, bromine, iodine, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 3-methylbutyl, formamido, acetamido, or propamido, wherein the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and 3-methylbutyl are optionally substituted by 1 to 3 substituents independently selected from the following groups: fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy;

[0096] Preferably, R 7 The derivatives are hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 3-methylbutyl, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0097] More preferably, R 7 It can be hydrogen, methyl, tert-butyl, isopropyl, 3-methylbutyl, or trifluoromethyl.

[0098] Or, preferably, R 7 Selected from, but not limited to, the following structures:

[0099] Among them, R 9 It is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, formamido, acetamido, or propionamido; more preferably, R 9 It can be hydrogen, deuterium, fluorine, cyano or formamide.

[0100] In one particular scheme, R 7 For C3-C 10 Cycloalkyl, C4-C6 cycloalkenyl, C6-C 10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclic, wherein the C3-C6 cycloalkyl, C4-C6 cycloalkenyl, C6-C 10 The aryl, 5-10-membered heteroaryl and 3-10-membered heterocyclic groups are optionally substituted by 1-3 substituents independently selected from the following groups: cyano, amide, halogen, C1-C3 alkyl, C1-C3 alkoxy.

[0101] In one embodiment, the compound represented by formula (I) satisfies two of the following six conditions:

[0102] (1)R 1 C1-C6 alkyl groups substituted with 1-3 halogens;

[0103] (2) W is V2R 7 And R 7 It can be any of the following structures;

[0104] R 10 It can be hydrogen, deuterium, halogen, cyano, or amide.

[0105] (3) X1 is N; X2 is CH;

[0106] (4) V1 is -CH(COOR) a (CH2) m -;

[0107] (5) The Y-ring is

[0108] And (6)W is R 6 ;R 6 for

[0109] In one embodiment, the compound represented by formula (I) satisfies at least one of the following three conditions:

[0110] (1)R 1 C1-C6 alkyl groups substituted with 1-3 halogens;

[0111] (2) W is V2R 7 And R 7 It can be any of the following structures;

[0112] R 10 It can be hydrogen, deuterium, halogen, cyano, or amide.

[0113] And (3) Y ring is

[0114] In one embodiment, the compound represented by formula (I) satisfies at least one of the following three conditions:

[0115] (1)R 1 It is trifluoromethyl;

[0116] (2) W is V2R 7 And R 7 It can be any of the following structures;

[0117] R 10 It can be hydrogen, deuterium, halogen, cyano, or amide.

[0118] and (3) Y ring

[0119] In one embodiment, the compound represented by formula (I) satisfies R. 1 It is a C1-C6 alkyl group substituted with 1-3 halogens; preferably R 1 It is trifluoromethyl.

[0120] In one embodiment, the compound represented by formula (I) satisfies W = V²R. 7 And R 7 It can be any of the following structures;

[0121] R 10 It can be hydrogen, deuterium, halogen, cyano or amide.

[0122] In one embodiment, the compound represented by formula (I) satisfies that X1 is N and X2 is CH.

[0123] In one embodiment, the compound represented by formula (I) satisfies V1 as -CH(COOR) a (CH2) m -; Preferably, V1 is -CH(COOCH3)(CH2)-.

[0124] In one embodiment, the compound represented by formula (I) satisfies the condition that the Y-ring is... Or, W is R 6 Y-ring is

[0125] In one embodiment, the compound represented by formula (I) satisfies the condition that the Y ring is...

[0126] In one embodiment, the compound represented by formula (I) satisfies W = R. 6 ;R6 for

[0127] In one scheme, structural fragments for

[0128] In one scheme, structural fragments Methyl, fluorine, -OCF3, Preferred More preferably

[0129] In one scheme, ring Y is phenyl,

[0130] In one scheme, structural fragments for

[0131] In one scheme, structural fragments for

[0132] In one scheme, structural fragments for

[0133] In one particular scheme, R 1 It is a C1-C6 alkyl group substituted with 1-3 halogens, preferably trifluoromethyl.

[0134] In one embodiment, the compound represented by formula (I) is the same as the compound represented by formula (II):

[0135] The better ones, among which,

[0136] L stands for -(CH2) n -;

[0137] n is 0, 1, 2, 3 or 4;

[0138] R 2 and R 3 Each is independently hydrogen, deuterium, halogen, amino, C1-C6 alkyl, or C1-C6 alkoxy;

[0139] X1 is CH or N;

[0140] R 4 It is hydrogen, deuterium, C1-C6 alkyl, or -(C=O)-C1-C6 alkyl;

[0141] The Y ring is a C3-C6 cycloalkyl group, C6-C 10 aryl or 5-10 heteroaryl, wherein the C3-C6 cycloalkyl, C6-C 10 The aryl and 5-10 heteroaryl groups are optionally substituted by 1-5 substituents independently selected from the following groups: deuterium, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, amide;

[0142] W can be either of the following two groups:

[0143] (I)W is R 6 ;

[0144] (II)W is V2R 7 ;

[0145] R 6 H, halogen, C1-C6 alkyl, C1-C6 alkoxy, -S-C1-C6 alkyl, C6-C 10 aryl or 3-10 membered heterocyclic groups, wherein the C1-C6 alkyl, C1-C6 alkoxy and C6-C 10 The aryl group may optionally be substituted by 1 to 3 substituents independently selected from the following groups: halogens, C1-C3 alkyl groups;

[0146] V2 is -O-, -S-, or -N(R) c )-;

[0147] R c It is hydrogen, deuterium, or C1-C3 alkyl;

[0148] R 7 For C3-C 10 Cycloalkyl, C4-C6 cycloalkenyl, C6-C 10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclic, wherein the C3-C6 cycloalkyl, C4-C6 cycloalkenyl, C6-C 10 The aryl, 5-10-membered heteroaryl and 3-10-membered heterocyclic groups are optionally substituted by 1-3 substituents independently selected from the following groups: cyano, amide, halogen, C1-C3 alkyl, C1-C3 alkoxy.

[0149] In one embodiment, the compound represented by formula (I) is the same as the compound represented by formula (II):

[0150] in,

[0151] L stands for -(CH2) n-;

[0152] n is 1, 2, or 3;

[0153] R 2 and R 3 Each is independently an amino group or a C1-C6 alkyl group;

[0154] X1 is CH;

[0155] R 4 It is hydrogen or C1-C6 alkyl;

[0156] The Y-ring is C6-C 10 aryl or 5-10 heteroaryl, wherein the C6-C 10 The aryl and 5-10 heteroaryl groups are optionally substituted by 1-5 substituents independently selected from the following groups: halogens, C1-C6 alkyl groups;

[0157] W represents V2R 7 ;

[0158] V2 is -O-;

[0159] R 7 For C6-C 10 aryl or 5-10 heteroaryl, wherein the C6-C 10 The aryl and 5-10 heteroaryl groups are optionally replaced by 1-3 substituents independently selected from the following groups: halogens, C1-C3 alkyl groups.

[0160] In one scheme, W is V2R. 7 And R 7 It can be any of the following structures;

[0161] R 10 It can be hydrogen, deuterium, halogen, cyano or amide.

[0162] In one scheme, W is V2R. 7 And R 7 for

[0163] R 10 It is a halogen, preferably F.

[0164] In one scheme, structural fragments for More preferably

[0165] In one embodiment, the compound represented by formula (I) is the same as the compound represented by formula (III):

[0166] in,

[0167] R 1 It is a C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted by 1-3 substituents independently selected from the following groups: halogen, hydroxyl;

[0168] L stands for -(CH2) n -, -O-, -S- or -NH-;

[0169] n is 0, 1, 2, 3 or 4;

[0170] R 2 and R 3 Each is independently hydrogen, deuterium, halogen, amino, C1-C6 alkyl, or C1-C6 alkoxy;

[0171] X1 is CH or N;

[0172] R 4 It is hydrogen, deuterium, C1-C6 alkyl, or -(C=O)-C1-C6 alkyl;

[0173] The Y ring is a C3-C6 cycloalkyl group, C6-C 10 aryl or 5-10 heteroaryl, wherein the C3-C6 cycloalkyl, C6-C 10 The aryl and 5-10 heteroaryl groups are optionally substituted by 1-5 substituents independently selected from the following groups: deuterium, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, amide;

[0174] V2 is -O-, -S-, or -N(R) c )-;

[0175] R c It is hydrogen, deuterium, or C1-C3 alkyl;

[0176] R 7 For C3-C 10 Cycloalkyl, C4-C6 cycloalkenyl, C6-C 10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclic, wherein the C3-C6 cycloalkyl, C4-C6 cycloalkenyl, C6-C 10 The aryl, 5-10-membered heteroaryl, and 3-10-membered heterocyclic groups are optionally substituted by 1-3 substituents independently selected from the following groups: cyano, amide, halogen, C1-C3 alkoxy; preferably, R 7 For C6-C 10 Aryl, wherein the C6-C 10 The aryl group is replaced by 1-3 halogens; more preferably, R 7 It is a phenyl group, wherein the phenyl group is substituted with 1-3 F atoms.

[0177] In one embodiment, the compound represented by formula (I) is the same as the compound represented by formula (III):

[0178] in,

[0179] R 1 It is a C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted by 1-3 substituents independently selected from the following groups: halogen, hydroxyl;

[0180] L stands for -(CH2) n -, -O-, -S- or -NH-;

[0181] n is 0, 1, or 2;

[0182] R 2 and R 3 Each is independently an amino group or a C1-C6 alkyl group;

[0183] X1 is CH or N;

[0184] R 4 It is hydrogen, deuterium, or C1-C6 alkyl;

[0185] The Y-ring is C6-C 10 aryl or 5-10 heteroaryl, wherein the C6-C 10 The aryl and 5-10 heteroaryl groups are optionally substituted by 1-5 substituents independently selected from the following groups: halogens, C1-C6 alkyl groups;

[0186] V2 is -O-;

[0187] R 7 For C6-C 10 Aryl, wherein the C6-C 10 The aryl group is replaced by 1-3 halogens; preferably, R 7 It is a phenyl group, wherein the phenyl group is substituted with 1-3 F atoms.

[0188] In one embodiment, the compound represented by formula (I) is the same as the compound represented by formula (III):

[0189] in,

[0190] R 1 It is a C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted by 1-3 substituents independently selected from the following groups: halogen, hydroxyl;

[0191] L stands for -(CH2) n -;

[0192] n is 0, 1, or 2;

[0193] R 2 and R 3 Each is independently an amino group or a C1-C6 alkyl group;

[0194] X1 is CH or N;

[0195] R 4 It is hydrogen, deuterium, or C1-C6 alkyl;

[0196] The Y ring is a phenyl group, wherein the phenyl group is optionally substituted by 1 to 5 substituents independently selected from the following groups: halogen, C1-C6 alkyl or cyano;

[0197] V2 is -O-;

[0198] R 7 The phenyl group is substituted with 1-3 F atoms; preferably, R 7 for

[0199] In one particular scheme, R 7 For C6-C 10 Aryl, wherein the C6-C 10 The aryl group is replaced by 1-3 halogens; more preferably, R 7 It is a phenyl group, wherein the phenyl group is substituted with 1-3 F atoms.

[0200] In one scheme, structural fragments for More preferably

[0201] In one embodiment, the compound represented by formula (I) is the same as the compound represented by formula (III):

[0202] in,

[0203] R 1 It is a C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted by 1-3 substituents independently selected from the following groups: halogen, hydroxyl;

[0204] L stands for -(CH2) n -, -O-, -S- or -NH-;

[0205] n is 0, 1, or 2;

[0206] R 2 and R 3 Each is independently an amino group or a C1-C6 alkyl group;

[0207] X1 is CH;

[0208] R 4 It is hydrogen or C1-C6 alkyl;

[0209] The Y-ring is C6-C 10 aryl or 5-10 heteroaryl, wherein the C6-C 10 The aryl and 5-10 heteroaryl groups are optionally substituted by 1-5 substituents independently selected from the following groups: halogens, C1-C6 alkyl groups;

[0210] V2 is -O-, -S-, or -N(R) c )-;

[0211] R c It is hydrogen, deuterium, or C1-C3 alkyl;

[0212] R 7 It can be any of the following structures;

[0213] Ideally, R 7 for

[0214] R 10 It is hydrogen, deuterium, halogen, cyano or amide group, preferably halogen, more preferably F.

[0215] In one scheme, the Y-ring is Preferred

[0216] In one scheme, the Y-ring is

[0217] In one embodiment, the compound represented by formula (I) is the same as the compound represented by formula (IV):

[0218] in,

[0219] R 1 It is a C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted by 1-3 substituents independently selected from the following groups: halogen, hydroxyl;

[0220] L stands for -(CH2) n -, -O-, -S- or -NH-;

[0221] n is 0, 1, 2, 3 or 4;

[0222] R 2 and R 3 Each is independently hydrogen, deuterium, halogen, amino, C1-C6 alkyl, or C1-C6 alkoxy;

[0223] X1 is CH or N;

[0224] R 4 It is hydrogen, deuterium, C1-C6 alkyl, or -(C=O)-C1-C6 alkyl;

[0225] Y-ring is Preferred

[0226] R 6 H, halogen, C1-C6 alkyl, C1-C6 alkoxy, -S-C1-C6 alkyl, C6-C 10 aryl or 3-10 membered heterocyclic groups, wherein the C1-C6 alkyl, C1-C6 alkoxy and C6-C 10 The aryl group is optionally substituted by 1 to 3 substituents independently selected from the following groups: halogen, C1-C3 alkyl; preferably, R 6 For C6-C 10 Aryl, wherein the C6-C 10 The aryl group may optionally be replaced by 1 to 3 substituents independently selected from the following groups: halogens, C1-C3 alkyl groups.

[0227] In one embodiment, the compound represented by formula (I) is the same as the compound represented by formula (IV):

[0228] in,

[0229] R 1 It is a C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted by 1-3 substituents independently selected from the following groups: halogen, hydroxyl;

[0230] L stands for -(CH2) n -, -O-, -S- or -NH-;

[0231] n is 0, 1, or 2;

[0232] R 2 and R 3 Each is independently an amino group or a C1-C6 alkyl group;

[0233] X1 is CH;

[0234] R 4 It is hydrogen or C1-C6 alkyl;

[0235] Y-ring is

[0236] R 6 It can be H, halogen, or C1-C6 alkyl.

[0237] In one embodiment, the compound represented by formula (I) is selected from any of the following compounds:

[0238] In another aspect, the present invention also provides any of the intermediates described herein.

[0239] In another aspect, the present invention also provides a method for preparing the compound represented by formula (I), comprising the following steps:

[0240] The compound of formula (I-1) and the compound of formula (I-2) react as follows to give the compound shown in formula (I);

[0241] In another aspect, the present invention also provides a pharmaceutical composition comprising a compound of formula (I) of the present invention, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its deuterated derivative, its metabolite or a prodrug thereof, and at least one pharmaceutical excipient. In a specific embodiment, the compound of formula (I) of the present invention is provided in the pharmaceutical composition in an effective amount. In a specific embodiment, the compound of formula (I) of the present invention is provided in a therapeutically effective amount. In a specific embodiment, the compound of general formula (I) of the present invention is provided in a preventatively effective amount.

[0242] In another aspect, the present invention also provides the use of a compound of formula (I), its stereoisomer, its pharmaceutically acceptable salt, its solvate, its deuterated derivative, its metabolite or a prodrug thereof, or the pharmaceutical composition of the present invention in the preparation of a medicament for the prevention and / or treatment of diseases related to the KCNQ2 / 3 (Kv7.2 / 3) channel.

[0243] In one protocol, the KCNQ2 / 3 (Kv7.2 / 3) channel-related disorders are epilepsy, neonatal spasms, neurotransmitter release disorders, smooth muscle contraction disorders, movement disorders, dystonia, mania, hearing impairment, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, anxiety, migraine, depression, hepatocellular carcinoma, colon cancer, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, pain (e.g., acute or chronic pain) or pain-related spastic states.

[0244] In another aspect, the present invention also provides a compound of formula (I), its stereoisomer, its pharmaceutically acceptable salt, its solvate, its deuterated derivative, its metabolite or a prodrug thereof, or the use of the pharmaceutical composition of the present invention in the preparation of a medicament for the prevention and / or treatment of diseases.

[0245] The diseases mentioned are epilepsy, neonatal spasms, neurotransmitter release disorders, smooth muscle contraction disorders, movement disorders, dystonia, mania, hearing impairment, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, anxiety, migraine, depression, hepatocellular carcinoma, colon cancer, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, pain (e.g., acute or chronic pain) or pain-related spasticity.

[0246] In another aspect, the present invention also provides a compound of formula (I), its stereoisomer, its pharmaceutically acceptable salt, its solvate, its deuterated derivative, its metabolite or a prodrug thereof, or the use of the pharmaceutical composition of the present invention in the preparation of a KCNQ2 / 3 (Kv7.2 / 3) channel activator.

[0247] In this paper, the numerical ranges defined in the substituents, such as 1-3, 1-6, 2-6, 3-6, 3-10, 6-10, 5-10, 8-10, 3-7, etc., indicate the integers within that range. For example, 1 to 3 means 1, 2, or 3; 1-6 means 1, 2, 3, 4, 5, or 6; and 2-6 means 2, 3, 4, 5, or 6.

[0248] In this document, satisfying at least one of the following conditions may satisfy one or more of them, for example, satisfying 1, 2 or 3.

[0249] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0250] "Alkyl" refers to a straight-chain or branched monovalent saturated hydrocarbon group.

[0251] "C1-C6 alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms, and "C1-C3 alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 3 carbon atoms. Examples of alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, 3-pentyl, pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl, and n-hexyl.

[0252] "C1-C6 alkoxy" refers to the group -OR, where R is a C1-C6 alkyl group. In some embodiments, C1-C3 alkoxy groups are particularly preferred. Specific alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, and 1,2-dimethylbutoxy.

[0253] In "-S-C1-C6 alkyl", C 1-6Alkyl groups are defined as described above. In some embodiments, -S-C1-C3 alkyl groups are particularly preferred. Specific -S-C1-C6 alkyl groups include, but are not limited to: -S-methyl, -S-ethyl, -S-n-propyl, -S-isopropyl, -S-n-butyl, -S-tert-butyl, -S-sec-butyl, -S-n-pentyl, -S-n-hexyl, and -S-1,2-dimethylbutyl.

[0254] "1-6 heteroalkyl groups containing 1-3 nitrogen or sulfur atoms" refers to 1-3 alkylene groups (e.g., -(CH2)-) in C1-C6 alkyl groups that are substituted with N, NH or S.

[0255] "1-6 heteroalkyl groups containing 1-3 nitrogen atoms" refers to 1-3 alkylene groups (e.g., -(CH2)-) in C1-C6 alkyl groups that are substituted with N or NH.

[0256] "1-6 heteroalkyl groups containing 1-3 oxygen, nitrogen or sulfur" refers to 1-3 alkylene groups (e.g. -(CH2)-) in C1-C6 alkyl groups being substituted with N, NH, O or S.

[0257] "C3-C6 cycloalkyl" refers to a saturated cyclic hydrocarbon group having 3 to 6 ring carbon atoms, including monocyclic or bicyclic groups, with bicyclic groups including spirocyclic, fused, and bridged rings. Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0258] “C3-C 10 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 10 ring carbon atoms, including monocyclic, bicyclic, and tricyclic systems. Bicyclic and tricyclic systems include spirocyclic, fused, and bridged rings, such as C3-C6 monocyclic cycloalkyl or C5-C6 monocyclic cycloalkyl. 10 Polycyclic cycloalkyl groups. The C3-C6 monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; the C5-C... 10 Polycyclic alkyl groups, for example For example

[0259] "C2-C6 alkenyl" refers to an alkenyl group having 2-6 carbon atoms, wherein the alkenyl group contains at least one carbon-carbon double bond. Non-limiting examples of "C2-C6 alkenyl" include, but are not limited to, vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, etc.

[0260] "C2-C6 ynyl" refers to an ynyl group having 2-6 carbon atoms, wherein the ynyl group contains at least one carbon-carbon triple bond. Non-limiting examples of "C2-C6 ynyl" include, but are not limited to, ethynyl, propynyl, butynyl, pentylyl, etc.

[0261] "3-10 membered heterocyclic group" refers to a group having a 3- to 10 membered non-aromatic ring system with a cyclic carbon atom and 1 to 3 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur, and the number of heteroatoms is 1, 2, or 3. The "heterocyclic group" in the 3- to 10 membered heterocyclic group can be a heterocyclic alkyl or heterocyclic alkenyl group, preferably a heterocyclic alkyl group. In heterocyclic groups containing one or more nitrogen atoms, the connecting point can be a carbon or nitrogen atom, provided the valence allows. In some embodiments, 3-6 membered heterocyclic groups are particularly preferred, which are 3-6 membered non-aromatic ring systems with a cyclic carbon atom and 1 to 3 cyclic heteroatoms; more preferably, 5-6 membered heterocyclic groups are 5-6 membered non-aromatic ring systems with a cyclic carbon atom and 1 to 3 cyclic heteroatoms. Exemplary heterocyclic groups include, for example... For example

[0262] "C4-C6 cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group consisting of 4 to 6 carbon atoms containing at least one carbon-carbon double bond, including monocyclic and bicyclic systems, wherein bicyclic systems include spirocyclic, fused, and bridged rings, and any ring in this system is non-aromatic. In some embodiments, C4-C6 cycloalkenyl is particularly preferred, referring to a partially unsaturated cyclic hydrocarbon group consisting of 4 to 6 carbon atoms containing at least one carbon-carbon double bond. Examples of C4-C6 cycloalkenyl include, but are not limited to, cyclopropenyl, cyclobutenyl, and cyclopentenyl (e.g., ), cyclopentadienyl, cyclohexenyl, cyclohexadienyl, etc.

[0263] "5-10 membered heteroaryl" can be a monocyclic heteroaryl or a bicyclic heteroaryl, such as a 5-7 membered monocyclic heteroaryl or a 9-10 membered bicyclic heteroaryl. At least one ring of the 5-10 membered heteroaryl is a 4n+2 aromatic ring system. When it is a bicyclic heteroaryl, at least one ring is a 4n+2 aromatic ring system. The heteroatom of the 5-10 membered heteroaryl is O, N, or S, and the number of heteroatoms is 1-3. Exemplary 5-membered heteroaryl containing one heteroatom includes, but is not limited to, pyrrole and thiophene. Exemplary 5-7 membered monocyclic heteroaryl includes, for example, pyridine, N-methylpyridine, pyrimidine, triazole, furan, thiophene, or thiazole. Exemplary bicyclic heteroaryl includes, for example... For example

[0264] Unless otherwise specified, the connection direction of the structural segments in this invention shall follow the left-right order of writing. For example, in general formula (I) In the middle, when the ring Y is When the pyrimidine ring is connected to W on the left and V1 on the right, the general formula is:

[0265] In this invention, for any functional group, when its linkage site is not specified, the functional group can be linked to other parts of the molecule through any permissible linkage site; for example, functional groups... This means that any permissible ring atom on any ring can be connected to other parts of the molecule; for example, the connection site can be on the left-hand oxygen-containing heterocycle (e.g., It can also be on the nitrogen-containing heterocycle on the right side (e.g.) ).

[0266] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0267] "Pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of the compounds of the present invention as defined above, and the salt possesses the desired pharmacological activity. Such salts include acid addition salts that form with inorganic or organic acids. Pharmaceutically acceptable salts also include base addition salts, which can be formed in the presence of acidic protons capable of reacting with inorganic or organic bases.

[0268] The terms "optional" or "optionally" refer to events or conditions that are possible but not required to occur, as described below, and the description includes both the possibility that such events or conditions occur and the possibility that they do not occur. For example, the term "optionally substituted by one or more substituents" means that something may or may not be substituted. When substituted, it means that any one or more hydrogen atoms on a particular atom are substituted by a substituent.

[0269] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by 1-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0270] The term "therapeutic effective dose" refers to the amount given to a patient that is sufficient to effectively treat the disease. Therapeutic effective doses will vary depending on the type of compound, the type of disease, the severity of the disease, the patient's age, etc., but may be adjusted as appropriate by those skilled in the art.

[0271] The term "pharmaceutical excipients" refers to all substances contained in a pharmaceutical preparation other than the active pharmaceutical ingredient, and are generally divided into two main categories: excipients and additives. For details, please refer to the Pharmacopoeia of the People's Republic of China (2020 Edition) and Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0272] The term "treatment" refers to eliminating the cause of an illness or relieving symptoms.

[0273] The term "prevention" refers to reducing the risk of developing a disease.

[0274] The term "patient" refers to any animal, typically a mammal such as a human, that requires treatment or prevention of disease. Mammals include, but are not limited to: cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans.

[0275] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0276] The reagents and raw materials used in this invention are all commercially available.

[0277] The positive and progressive effects of this invention are as follows: the compounds of this invention have good KCNQ2 / 3 (Kv7.2 / 3) channel activation effects, which can provide effective treatment for central nervous system diseases such as epilepsy and pain. Detailed Implementation

[0278] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0279] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0280] This application uses the following abbreviations: ACN: Acetonitrile; DIAD: Diisopropyl azodicarbonate; DMF: N,N-dimethylformamide; EA: Ethyl acetate; EtOH: Ethanol; NMI: N-methylimidazolium; PE: Petroleum ether; TCFH: N,N,N',N'-tetramethylchloroamidine hexafluorophosphate; TEA: Triethylamine; THF: Tetrahydrofuran; XantPhos: 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene.

[0281] Compounds are named according to conventional naming rules in the field, and commercially available reagents are named according to the supplier's catalog.

[0282] 1 ¹H NMR data were collected and recorded at 400 MHz, 500 MHz, and 600 MHz using a Bruker Avance Neo liquid superconducting NMR spectrometer. DMSO-d6 was used as the solvent, and TMS (δ=0) was used as the internal standard to report the chemical shift δ values ​​(ppm). Mass spectrometry was acquired and recorded using a Waters ACQUITY UPLC, with detection using an ACQUITY UPLC BEH C8, 50 mm × 2.1 mm, 1.7 μm (20180306-C8-08) column. Mobile phase A: 0.01% TFA / H₂O; Mobile phase B: CH₃CN; Flow rate: 0.2 mL / min; Column temperature: 30 °C; Detection wavelength: UV-210 nm. High-performance liquid chromatography (HPLC) was performed using a Thermo UltiMate 3000 HPLC system with a Venusil ASB C18 (4.6*250mm, 5μm) column. Mobile phase A: pH 1.5 aqueous phosphoric acid solution; Mobile phase B: CH3CN; Flow rate: 1.0 mL / min; Column temperature: 35℃; Detection wavelength: UV-215nm; Injection volume: 2 μL; Gradient elution conditions: Elution was performed at a flow rate of 1.0 mL / min throughout, first eluting with 95% A and 5% B for 10 min, then eluting with 20% A and 80% B for 5 min, and finally eluting with 95% A and 5% B for 5 min. Percentages represent the volume percentage of the mobile phase in the eluent.

[0283] Example 1: Synthesis of Compound 1

[0284] Step 1: Synthesis of intermediate 1a

[0285] 4-Bromo-2,6-dimethylaniline (1.000 g, 5.00 mmol) was dissolved in 20 mL of acetonitrile. Then, tert-butylacetyl chloride (1.010 g, 7.50 mmol) and TEA (0.505 g, 5.00 mmol) were added. The mixture was stirred at room temperature for 3 h, and a solid product precipitated. UPLC monitoring showed no residual reactants, and LC-MS monitoring showed the target molecular weight. The product was filtered, and the filter cake was washed with 50 mL of acetonitrile to obtain 1.05 g of a white solid (70% yield, HPLC = 95%). MS m / z = 298.18 / 300.20 [M+H / M+2] +

[0286] Step 2: Synthesis of Compound 1

[0287] Intermediate 1a (300 mg, 1.01 mmol), 4-phenoxybenzylamine (220 mg, 1.11 mmol), L (29 mg, 0.051 mmol), cesium carbonate (489 mg, 1.52 mmol), and tris(dibenzylacetone)palladium (23 mg, 0.026 mmol) were added to 3 mL of toluene. The mixture was sealed in a tube at 110 °C and stirred for 20 h. LC-MS showed no residue of starting material. The reaction solution was diluted with 30 mL of ethyl acetate, filtered, and the organic phase was collected, concentrated, and purified by column chromatography to obtain 75 mg (17% yield, HPLC = 94%). 1 H NMR(500MHz,DMSO)δ9.18(s,1H),7.52(d,J=8.2Hz,2H),7.23(t,J=8.7Hz,2 H),7.09–6.94(m,6H),4.41(s,2H),2.21(s,2H),2.12(s,6H),1.05(s,9H).

[0288] MS m / z = 435.38 [M+H] +

[0289] Example 2: Synthesis of Compound 2

[0290] Step 1: Synthesis of Compound 2

[0291] Compound 1 (100 mg, 0.23 mmol) was weighed and dissolved in 5 mL of tetrahydrofuran. Formaldehyde aqueous solution (38%) (28 mg, 0.35 mmol) was weighed and 1 drop of acetic acid was added. The mixture was stirred at room temperature for 2 hours, and then sodium cyanoborohydride (36 mg, 0.58 mmol) was added. The mixture was stirred at room temperature for 4 hours. LC-MS showed no raw material remaining. 30 mL of ethyl acetate and 40 mL of saturated NaCl solution were added for extraction. The mixture was washed twice with 40 mL of saturated NaCl solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was collected. The crude product was collected by rotary evaporation under reduced pressure, yielding 101 mg of crude product. The product was purified by column chromatography (EA:PE = 1:3) to give a white solid (43 mg, 0.096 mmol, 42% yield, HPLC = 98%). 1H NMR(400MHz, DMSO–d6)δ8.80(s,1H),7.23–7.18(m,4H),7.05–7.01(m,2H),6.93(d,J=8.6 Hz,2H),6.44(s,2H),4.50(s,2H),2.93(s,3H),2.15(s,2H),2.05(s,6H),1.04(s,9H).MS m / z=449.58[M+H] +

[0292] Example 3: Synthesis of Compound 3

[0293] Step 1: Synthesis of intermediate 3a (Kv7-T111-I01)

[0294] 4-Fluorophenol (200 mg, 1.79 mmol) and cesium carbonate (871 mg, 2.68 mmol) were added to 5 mL of LDM and stirred at room temperature for 0.5 h. Then, 2-fluoropyridine-5-carboxaldehyde (224 mg, 1.79 mmol) was added, and the mixture was heated to 50 °C and stirred for 1 h. LC-MS showed no reactants remaining. The reaction was stopped, 50 mL of purified water was added, and the mixture was allowed to stand to precipitate. The precipitate was filtered, collected, and dried to give a white solid (267 mg, 1.23 mmol, 69% yield). MS m / z = 218.21 [M+H] +

[0295] Step 2: Synthesis of intermediate 3c (Kv7-T111-I02)

[0296] Weigh 581 mg (5 mmol) of 3,3-dimethyl-1-butyric acid and dissolve it in 20 mL of DMF. Then weigh 2.10 g (7.5 mmol) of TCFH and 616 mg (7.5 mmol) of NMI. Stir at room temperature for 30 minutes. Then add 831 mg (5.00 mmol) of 2,6-dimethyl-4-nitroaniline and react at room temperature for 12 hours. When no reactants remain as monitored by LC-MS, stop the reaction. Add 220 mL of purified water, allow to stand to precipitate, filter, collect the filter cake, and dry to obtain a yellow solid (1.13 g, 4.28 mmol, 86% yield). Dissolve the solid in 40 mL of anhydrous ethanol. Take 25 mL of saturated ammonium chloride solution and reduced iron powder (1.92 g, 34.24 mmol), reflux at 80 °C and stir for 3 hours. When no reactants remain as monitored by UPLC, stop the reaction. The reaction was stopped, and after cooling, the reduced iron powder and some ammonium chloride were removed by filtration. The organic phase was collected and rotary evaporated under reduced pressure, precipitating a large amount of solid. The solid was dissolved in 50 mL of anhydrous ethanol, and the remaining ammonium chloride was removed by filtration. The organic phase was collected and rotary evaporated under reduced pressure to give a white solid (923 mg, 3.94 mmol, 91% yield). MS m / z = 235.36 [M+H] +

[0297] Step 3: Synthesis of Compound 3

[0298] Weigh intermediate 3c (200 mg, 0.85 mmol), add 5 mL of tetrahydrofuran solution, weigh intermediate 3a (185 mg, 0.85 mmol), add 1 drop of acetic acid, stir at room temperature for 2 hours, then add sodium cyanoborohydride (134 mg, 2.13 mmol), stir at room temperature for 5 hours. LC-MS showed no raw material remaining. Add 30 mL of ethyl acetate and 40 mL of saturated NaCl solution, extract, then wash twice with 40 mL of saturated NaCl solution, collect the organic phase, dry with anhydrous sodium sulfate, filter, collect the organic phase, rotary evaporate under reduced pressure, and collect 327 mg of crude product. Purify by column chromatography, EA:PE = 1:2, to give a white solid (55 mg, 0.13 mmol, 15% yield, HPLC = 93%). 1 H NMR(400MHz, DMSO–d6)δ8.74(s,1H),8.11(d,J=2.1Hz,1H),7.82–7.79(m,1H),7.25–7.20(m,2H),7.17–7.13(m,2H),6. 98(d,J=8.4Hz,1H),6.29(s,2H),6.02(t,J=6.2Hz,1H),4.19(d,J=6.0Hz,2H),2.13(s,2H),1.99(s,6H),1.03(s,9H).MS m / z=436.49[M+H]+

[0299] Example 4: Synthesis of Compound 4

[0300] Step 1: Synthesis of intermediate 4a

[0301] Take p-hydroxybenzaldehyde (200 mg, 1.64 mmol), add 5 mL of tetrahydrofuran solution, weigh 3-methyl-3-hydroxymethyloxetane (167 mg, 1.64 mmol), and triphenylphosphine (430 mg, 1.64 mmol). Stir in an ice bath for 10 minutes, add DIAD (332 mg, 1.64 mmol) at 0°C, stir in an ice bath for 30 minutes, then return to room temperature and stir. React for 5 hours. UPLC monitoring showed no residual reactants, and LC-MS monitoring showed the target molecular weight, at which point the reaction was stopped. Add 30 mL of ethyl acetate and 40 mL of saturated NaCl solution for extraction, then wash twice with 40 mL of saturated NaCl solution. Collect the organic phase, dry with anhydrous sodium sulfate, filter, collect the organic phase, and rotary evaporate under reduced pressure to obtain 556 mg of crude product. Purify by column chromatography (EA:PE = 1:4) to give a colorless oil (211 mg, 1.02 mmol, 62% yield). MS m / z = 207.26[M+H]+

[0302] Step 2: Synthesis of Compound 4

[0303] Weigh intermediate 3c (200 mg, 0.85 mmol), add 5 mL of tetrahydrofuran to dissolve it, weigh intermediate 4a (175 mg, 0.85 mmol), add 1 drop of acetic acid, stir at room temperature for 2 hours, then add sodium cyanoborohydride (134 mg, 2.13 mmol), stir at room temperature for 5 hours. LC-MS showed no raw material remaining. Add 30 mL of ethyl acetate and 40 mL of saturated NaCl solution, extract, and wash twice with 40 mL of saturated NaCl solution. Collect the organic phase, dry with anhydrous sodium sulfate, filter, collect the organic phase, and rotary evaporate under reduced pressure to obtain 313 mg of crude product. Purify by column chromatography, EA:PE = 1:3, to give a white solid (53 mg, 0.12 mmol, 14% yield, HPLC = 97%). 1H NMR(600MHz,DMSO-d6)δ8.71(s,1H),7.38–7.23(m,2H),6.82(d,J=8.8Hz,2H),6.43(s,2H),5.69(s,1H), 4.57–4.34(m,2H),4.09(s,2H),3.92–3.70(m,4H),2.47(s,2H),2.18(s,6H),1.03(s,9H),0.91(s,3H).MS m / z=425.57[M+H] + .

[0304] Example 5: Synthesis of Compound 5

[0305] Step 1: Synthesis of intermediate 5a

[0306] 4-Bromo-2,6-dimethylaniline (1.000 g, 5.00 mmol) was dissolved in 20 mL of acetonitrile. Then, tert-butylacetyl chloride (1.010 g, 7.50 mmol) and TEA (0.505 g, 5.00 mmol) were added. The mixture was stirred at room temperature for 3 h, and a solid product precipitated. UPLC monitoring showed no residual reactants, and LC-MS monitoring showed the target molecular weight. The product was filtered, and the filter cake was washed with 50 mL of acetonitrile to obtain 1.05 g of a white solid (70% yield, HPLC = 95%). MS m / z = 298.18 / 300.20 [M+H / M+2] +

[0307] Step 2: Synthesis of Compound 5

[0308] Weigh intermediate 5a (300 mg, 1.01 mmol), (4-(cyclopentoxy)phenyl)methylamine (212 mg, 1.11 mmol), XantPhos (29 mg, 0.051 mmol), and cesium carbonate (489 mg, 1.52 mmol). Weigh tris(dibenzylacetone)dipalladium (23 mg, 0.026 mmol) under nitrogen atmosphere. Add 3 mL of anhydrous and oxygen-free toluene, seal the tube and stir at 110 °C for 20 h. LC-MS showed no raw material remaining. Add 30 mL of ethyl acetate to dilute the reaction solution, filter, collect the organic phase, and concentrate the organic phase under reduced pressure to obtain 547 mg. Purify by column chromatography (EA:PE = 1:4) to give a white solid (76 mg, 0.19 mmol, 19% yield, HPLC = 98%). 1H NMR (400MHz, DMSO–d6) δ8.71(s,1H),7.23(d,J=8.6Hz,2H),6.83(d,J=8.6Hz,2H),6.27(s,2H),5.90(t,J=6.0Hz,1H),4.14(d ,J=6.0Hz,2H),2.14(s,2H),1.99(s,6H),1.89(d,J=5.9Hz,2H),1.69(d,J=5.9Hz,4H),1.58(d,J=9.0Hz,2H),1.04(s,9H).MS m / z=409.57[M+H] +

[0309] Example 6: Synthesis of Compound 6

[0310] Step 1: Synthesis of intermediate 6a

[0311] Weigh 2-bromo-5-fluoropyridine (352 mg, 2 mmol), p-hydroxybenzaldehyde (244 mg, 2 mmol), XantPhos (58 mg, 0.1 mmol), cesium carbonate (1630 mg, 5 mmol), and tris(dibenzylacetone)dipalladium (46 mg, 0.05 mmol) under nitrogen atmosphere. Add 8 mL of anhydrous and oxygen-free toluene, seal the tube at 110 °C, and stir for 20 h. LC-MS showed no reactant residue. Add 10 mL of ethyl acetate to dilute the reaction solution, filter, collect the organic phase, and concentrate the organic phase under reduced pressure to obtain 489 mg. Purify by column chromatography (EA:PE = 1:4) to give a white solid (211 mg, 0.91 mmol, 46% yield). MS m / z = 218.22 [M+H] +

[0312] Step 2: Synthesis of Compound 6

[0313] Weigh intermediate 3c (200 mg, 0.85 mmol), add 5 mL of tetrahydrofuran to dissolve it, weigh intermediate 6a (185 mg, 0.85 mmol), add 1 drop of acetic acid, stir at room temperature for 2 hours, then add sodium cyanoborohydride (134 mg, 2.13 mmol), stir at room temperature for 5 hours. LC-MS showed no raw material remaining. Add 30 mL of ethyl acetate and 40 mL of saturated NaCl solution, extract, and wash twice with 40 mL of saturated NaCl solution. Collect the organic phase, dry with anhydrous sodium sulfate, filter, collect the organic phase, and rotary evaporate under reduced pressure to obtain 298 mg of crude product. Purify by column chromatography (EA:PE = 1:2) to give a white solid (75 mg, 0.17 mmol, 20% yield, HPLC = 90%). 1H NMR(600MHz,DMSO-d6)δ8.71(s,1H),8.21(dd,J=8.0,2.0Hz,1H),7.53–7.36(m,3H),7.34–7.21(m,2H),6.8 0(dd,J=8.5,4.9Hz,1H),6.43(s,2H),5.69(s,1H),4.43(s,2H),2.47(s,2H),2.18(s,6H),1.03(s,9H)., MS m / z=436.52[M+H] + .

[0314] Example 7: Synthesis of Compound 7

[0315] Step 1: Synthesis of intermediate 7a

[0316] 4-Fluorophenol (200 mg, 1.79 mmol) and cesium carbonate (871 mg, 2.68 mmol) were added to 5 mL of LDM and stirred at room temperature for 0.5 h. Then, 2-fluoro-5-formylbenzonitrile (263 mg, 1.79 mmol) was added, and the mixture was heated to 50 °C and stirred for 1 h. LC-MS showed no reactants remaining. The reaction was stopped, 50 mL of purified water was added, and the mixture was allowed to stand to precipitate. The precipitate was filtered, collected, and dried to give a white solid (340 mg, 1.41 mmol, 79% yield). MS m / z = 242.24 [M+H] +

[0317] Step 3: Synthesis of Compound 7

[0318] Weigh intermediate 3c (100 mg, 0.43 mmol), add 5 mL of tetrahydrofuran to dissolve it, weigh intermediate 7a (104 mg, 0.43 mmol), add 1 drop of acetic acid, stir at room temperature for 2 hours, then add sodium cyanoborohydride (67 mg, 1.07 mmol), stir at room temperature for 5 hours. LC-MS showed no raw material remaining. Add 30 mL of ethyl acetate and 40 mL of saturated NaCl solution, extract, then wash twice with 40 mL of saturated NaCl solution, collect the organic phase, dry with anhydrous sodium sulfate, filter, collect the organic phase, rotary evaporate under reduced pressure, and collect 168 mg of crude product. Purify by column chromatography, EA:PE = 1:3, to give a white solid (43 mg, 0.094 mmol, 22% yield, HPLC = 95%). 1H NMR (600MHz, DMSO–d6) δ8.73 (s, 1H), 7.82 (d, J = 2.2Hz, 1H), 7.62–7.60 (m, 1H), 7.30–7.28 (m, 2H), 7.22–7.18 (m, 2H), 6. 90(d,J=8.7Hz,1H),6.27(s,2H),6.11(t,J=6.4Hz,1H),4.23(d,J=6.3Hz,2H),2.13(s,2H),1.99(s,6H),1.03(s,9H).MS m / z=460.59[M+H] +

[0319] Example 8: Synthesis of Compound 8

[0320] Step 1: Synthesis of Compound 8

[0321] Weigh 200 mg (0.85 mmol) of intermediate 3c and add 5 mL of tetrahydrofuran solution. Weigh 176 mg (0.85 mmol) of 2-(4-fluorophenyl)-thiazolyl-4-carboxaldehyde and add 1 drop of acetic acid. Stir at room temperature for 2 hours, then add 134 mg (2.13 mmol) of sodium cyanoborohydride and stir at room temperature for 5 hours. LC-MS showed no raw material remaining. Add 30 mL of ethyl acetate and 40 mL of saturated NaCl solution for extraction. Wash twice with 40 mL of saturated NaCl solution each time. Collect the organic phase, dry with anhydrous sodium sulfate, filter, collect the organic phase, and rotary evaporate under reduced pressure to obtain 311 mg of crude product. Purify by column chromatography (THF:PE = 1:4) to give a white solid (65 mg, 0.15 mmol, 18% yield, HPLC = 99%). 1 H NMR(600MHz,DMSO–d6)δ8.74(s,1H),8.04–7.94(m,2H),7.42(d,J=1.0Hz,1H),7.37–7.29(m,2H) ,6.36(s,2H),6.01(t,J=6.2Hz,1H),4.40–4.34(m,2H),2.14(s,2H),2.01(s,6H),1.03(s,9H).MS m / z=426.57[M+H] +

[0322] Example 9: Synthesis of Compound 9

[0323] Step 1: Synthesis of intermediate 9a

[0324] 4-Fluorophenol (200 mg, 1.79 mmol) and cesium carbonate (871 mg, 2.68 mmol) were added to 5 mL of LDM and stirred at room temperature for 0.5 h. Then, 2-chloro-3-fluoro-5-carboxypyridine (286 mg, 1.79 mmol) was added, and the mixture was heated to 50 °C and stirred for 1 h. LC-MS showed no reactants remaining, so the reaction was stopped. 50 mL of purified water was added, and the mixture was allowed to stand to precipitate. The precipitate was filtered, and the filter cake was collected and dried to obtain a reddish-brown solid. The solid was purified by column chromatography (EA:PE = 1:5) to give a white solid (200 mg, 0.85 mmol, 47% yield). MS m / z = 236.20 [M+H] +

[0325] Step 2: Synthesis of Compound 9

[0326] Weigh intermediate 3c (200 mg, 0.85 mmol), add 5 mL of tetrahydrofuran to dissolve it, weigh intermediate 9a (200 mg, 0.85 mmol), add 1 drop of acetic acid, stir at room temperature for 2 hours, then add sodium cyanoborohydride (134 mg, 2.13 mmol), stir at room temperature for 5 hours. LC-MS showed no raw material remaining. Add 30 mL of ethyl acetate and 40 mL of saturated NaCl solution, extract, and wash twice with 40 mL of saturated NaCl solution. Collect the organic phase, dry with anhydrous sodium sulfate, filter, collect the organic phase, and rotary evaporate under reduced pressure to obtain 368 mg of crude product. Purify by column chromatography, EA:PE = 1:4, to give a white solid (85 mg, 0.19 mmol, 22% yield, HPLC = 99%). 1 H NMR(600MHz,DMSO–d6)δ8.74(s,1H),7.93(d,J=1.9Hz,1H),7.81–7.79(m,1H),7.27–7.16(m,4H),6 .30(s,2H),6.04(t,J=6.4Hz,1H),4.22(d,J=6.3Hz,2H),2.13(s,2H),1.99(s,6H),1.03(s,9H).MS m / z=454.56[M+H] +

[0327] Example 10: Synthesis of Compound 10

[0328] Step 1: Synthesis of intermediate 10a

[0329] 3,4-Difluorophenol (232.86 mg, 1.79 mmol) and cesium carbonate (873.14 mg, 2.68 mmol) were added to 5 mL of ACN and stirred at room temperature for 0.5 h. Then, 6-fluoro-2-methyl-3-pyridinecarboxaldehyde (249.04 mg, 1.79 mmol) was added, and the mixture was heated to 60 °C and stirred for 3 h. LC-MS showed no reactants remaining. The reaction was stopped, the mixture was filtered, and the filtrate was collected and concentrated under reduced pressure to give a white solid (307.90 mg, 1.24 mmol, 69.02% yield). MS m / z = 250.23 [M+H] +

[0330] Step 2: Synthesis of Compound 10

[0331] Weigh intermediate 3c (100.77 mg, 0.43 mmol), add 5 mL of tetrahydrofuran to dissolve it, weigh intermediate 10a (107.16 mg, 0.43 mmol), add 1 drop of acetic acid, stir at room temperature for 2 hours, then add sodium cyanoborohydride (67.24 mg, 1.07 mmol), stir at room temperature for 5 hours. LC-MS showed no raw material remaining. Add 30 mL of ethyl acetate and 40 mL of saturated NaCl solution, extract, and wash twice with 40 mL of saturated NaCl solution. Collect the organic phase, dry with anhydrous sodium sulfate, filter, collect the organic phase, and rotary evaporate under reduced pressure to obtain 162.46 mg of crude product. Purify by column chromatography (EA:PE = 1:3) to give a white solid (43.57 mg, 0.096 mmol, 22.34% yield). 1 H NMR(400MHz, DMSO–d6)δ8.74(s,1H),7.68(d,J=8.3Hz,1H),7.55–7.39(m,1H),7.37–7.26(m,1H),7.03–6.90(m,1H),6.82(d,J =8.3Hz,1H),6.29(s,2H),5.92(t,J=5.8Hz,1H),4.18(d,J=5.8Hz,2H),2.36(s,3H),2.15(s,2H),2.01(s,6H),1.04(s,9H)., MS m / z=468.56[M+H] + .

[0332] Example 11: Synthesis of Compound 11

[0333] Step 1: Synthesis of intermediate 11a

[0334] Weigh 200 mg (1.64 mmol) of p-hydroxybenzaldehyde and add 5 mL of tetrahydrofuran solution. Weigh 161 mg (1.64 mmol) of 1-hydroxy-3-cyclohexene and 430 mg (1.64 mmol) of triphenylphosphine. Stir in an ice bath for 10 minutes. Add 332 mg (1.64 mmol) of DIAD at 0 °C and stir in an ice bath for 30 minutes. Then, purge with nitrogen for protection and heat to 65 °C. React for 3 hours. UPLC monitoring showed no residual reactants, and LC-MS monitoring showed the target molecular weight. Stop the reaction. Add 30 mL of ethyl acetate and 40 mL of saturated NaCl solution for extraction. Wash twice with 40 mL of saturated NaCl solution. Collect the organic phase, dry with anhydrous sodium sulfate, filter, collect the organic phase, and evaporate under reduced pressure to obtain 565 mg of crude product. Purify by column chromatography (EA:PE = 1:5) to give a colorless oil (172 mg, 0.85 mmol, 52% yield). MS m / z = 203.21 [M+H] +

[0335] Step 2: Synthesis of Compound 11

[0336] Weigh intermediate 3c (200 mg, 0.85 mmol), add 5 mL of tetrahydrofuran solution, weigh intermediate 11a (172 mg, 0.85 mmol), add 1 drop of acetic acid, stir at room temperature for 2 hours, then add sodium cyanoborohydride (134 mg, 2.13 mmol), stir at room temperature for 5 hours. LC-MS showed no raw material remaining. Add 30 mL of ethyl acetate and 40 mL of saturated NaCl solution, extract, then wash twice with 40 mL of saturated NaCl solution, collect the organic phase, dry with anhydrous sodium sulfate, filter, collect the organic phase, rotary evaporate under reduced pressure, and collect 323 mg of crude product. Purify by column chromatography, EA:PE = 1:3, to give a white solid (107 mg, 0.25 mmol, 30% yield, HPLC = 98%). 1 H NMR (400MHz, DMSO–d6) δ8.77(s,1H),7.29(d,J=8.6Hz,2H),6.95(d,J=8.7Hz,2H),6.33(s,2H),5.97(t,J=6.1Hz,1H),5.81–5 .59(m,2H),4.65–4.54(m,1H),4.20(d,J=6.0Hz,2H),2.48(d,J=17.3Hz,2H),2.23–2.10(m,5H),2.04(s,7H),1.09(s,9H)., MS m / z=421.58[M+H] + .

[0337] Example 12: Synthesis of Compound 12

[0338] Step 1: Synthesis of intermediate 12a

[0339] Weigh 581 mg (5 mmol) of 3-methylvaleric acid and dissolve it in 20 mL of DMF. Then weigh 2.10 g (7.5 mmol) of TCFH and 616 mg (7.5 mmol) of NMI. Stir at room temperature for 30 minutes. Then add 831 mg (5.00 mmol) of 2-6-dimethyl-4-nitroaniline and react at room temperature for 12 hours. When no reactants remain as monitored by LC-MS, stop the reaction. Add 220 mL of purified water, allow to stand to precipitate, filter, collect the filter cake, and dry to obtain a yellow solid (989 mg, 3.74 mmol, 75% yield). Dissolve the solid in 40 mL of anhydrous ethanol. Take 25 mL of saturated ammonium chloride solution and reduced iron powder (1.70 g, 30.03 mmol), reflux at 80 °C and stir for 3 hours. When no reactants remain as monitored by UPLC, stop the reaction, cool, filter to remove reduced iron powder and some ammonium chloride, collect the organic phase, and evaporate under reduced pressure to precipitate a large amount of solid. Dissolve in 50 mL anhydrous ethanol, filter to remove residual ammonium chloride, collect the organic phase, and rotary evaporate under reduced pressure to give a white solid (780.02 mg, 3.33 mmol, 89% yield). MS m / z = 235.36 [M+H] +

[0340] Step 2: Synthesis of Compound 12

[0341] Weigh 184 mg (0.85 mmol) of 4-(4-fluorophenoxy)benzaldehyde and add 5 mL of tetrahydrofuran solution. Weigh 221 mg (0.85 mmol) of intermediate 12a (Kv7-T143-I01) and add 1 drop of acetic acid. Stir at room temperature for 2 hours, then add 134 mg (2.13 mmol) of sodium cyanoborohydride and stir at room temperature for 5 hours. LC-MS showed no raw material remaining. Add 30 mL of ethyl acetate and 40 mL of saturated NaCl solution for extraction. Wash twice with 40 mL of saturated NaCl solution each time. Collect the organic phase, dry with anhydrous sodium sulfate, filter, collect the organic phase, and rotary evaporate under reduced pressure to obtain 336 mg of crude product. Purify by column chromatography (EA:PE = 1:3) to give a white solid (145 mg, 0.33 mmol, 39% yield, HPLC = 97%). 1H NMR(400MHz, DMSO–d6)δ8.78(s,1H),7.34(d,J=8.4Hz,2H),7.21(t,J=8.8Hz, 2H),7.05–7.01(m,2H),6.94(d,J=8.5Hz,2H),6.27(s,2H),6.00(t,J=6.1Hz,1 H),4.20(d,J=6.0Hz,2H),2.26–2.21(m,1H),2.07–2.01(m,1H),1.97(s,6H), 1.89–1.81(m,1H),1.43–1.34(m,1H),1.26–1.15(m,1H),0.96–0.82(m,6H).MS m / z = 435.60 [M+H] +

[0342] The compounds in Table 1 below were prepared according to the examples described above.

[0343] Table 1 Compounds of this application

[0344] Example 13: Synthesis of Compound 61

[0345] Step 1: Synthesis of intermediate 61a

[0346] 4-Bromo-2,6-dimethylphenyl isocyanate (452 ​​mg, 2 mmol) was dissolved in 5 mL of DMF by stirring. Then, sec-butanol (149 mg, 2 mmol) and TEA (242 mg, 2.4 mmol) were added, and the mixture was heated to 60 °C and stirred for 5 h. LC-MS showed no reactants remaining. The reaction was stopped, 55 mL of purified water was added, and the mixture was allowed to stand to precipitate. The precipitate was filtered, and the filter cake was collected and purified by column chromatography to give a white solid (300 mg, 1.00 mmol, 50% yield). MS m / z = 300.22 / 302.18 [M+H / M+2] +

[0347] Step 2: Synthesis of Compound 61

[0348] Intermediate 61a (Kv7-T190-I01) (272 mg, 1 mmol), 4-(4-fluorophenoxy)benzylamine (217 mg, 1 mmol), XantPhos (29 mg, 0.051 mmol), and cesium carbonate (489 mg, 1.52 mmol) were weighed under nitrogen atmosphere. Tris(dibenzylacetone)palladium (23 mg, 0.026 mmol) was added, and 5 mL of anhydrous and oxygen-free toluene was added. The mixture was sealed and stirred at 110 °C for 12 h. LC-MS showed no raw material remaining. 30 mL of ethyl acetate was added to dilute the reaction solution, and the mixture was filtered. The organic phase was collected and concentrated under reduced pressure to obtain 412 mg. The solution was purified by column chromatography (EA:PE = 1:4) to give a white solid (125 mg, 0.29 mmol, 29% yield, HPLC = 99%). 1 H NMR(400MHz, DMSO–d6)δ8.11(s,1H),7.35(d,J=8.4Hz,2H),7.21(t,J=8.8Hz,2H),7.11–7.00(m,2H),6.94(d,J=8.5Hz,2H),6.28(s,2H),6.0 1(t,J=6.0Hz,1H),4.67–4.60(m,1H),4.21(d,J=5.8Hz,2H),2.00(s,6H),1.58–1.51(m,2H),1.18(d,J=6.3Hz,3H),0.90(t,J=7.4Hz,3H).MS m / z=437.60[M+H] +

[0349] Example 14: Synthesis of Compound 62

[0350] Step 1: Synthesis of intermediate 62a

[0351] Weigh 630.75 mg (5 mmol) of bicyclo[1.1.1]pentane-1-acetic acid, dissolve in 20 mL of DMF, then weigh 2.10 g (7.5 mmol) of TCFH and 616 mg (7.5 mmol) of NMI. Stir at room temperature for 30 minutes, then add 831 mg (5.00 mmol) of 2-6-dimethyl-4-nitroaniline. React at room temperature for 12 hours. LC-MS monitoring showed no residual reactants, so the reaction was stopped. Add 220 mL of purified water, allow to stand to precipitate, filter, collect the filter cake, and dry to obtain a yellow solid (1.11 g, 4.05 mmol, 81% yield). Dissolve in 40 mL of anhydrous ethanol, then add 25 mL of saturated ammonium chloride solution and reduced iron powder (1.81 g, 32.40 mmol). Reflux at 80 °C with stirring for 3 hours. UPLC monitoring showed no residual reactants. The reaction was stopped, and after cooling, the reduced iron powder and some ammonium chloride were removed by filtration. The organic phase was collected and rotary evaporated under reduced pressure, precipitating a large amount of solid. The solid was dissolved in 50 mL of anhydrous ethanol, and the remaining ammonium chloride was removed by filtration. The organic phase was collected and rotary evaporated under reduced pressure to give a white solid (900.52 mg, 3.69 mmol, 91% yield). MS m / z = 245.32 [M+H] +

[0352] Step 2: Synthesis of Compound 62

[0353] Weigh 184 mg (0.85 mmol) of 4-(4-fluorophenoxy)benzaldehyde and add 5 mL of tetrahydrofuran solution. Weigh 208 mg (0.85 mmol) of intermediate 62a and add 1 drop of acetic acid. Stir at room temperature for 2 hours, then add 134 mg (2.13 mmol) of sodium cyanoborohydride and stir at room temperature for 5 hours. LC-MS showed no raw material remaining. Add 30 mL of ethyl acetate and 40 mL of saturated NaCl solution for extraction. Wash twice with 40 mL of saturated NaCl solution each time. Collect the organic phase, dry with anhydrous sodium sulfate, filter, collect the organic phase, and rotary evaporate under reduced pressure to obtain 324 mg of crude product. Purify by column chromatography (EA:PE = 1:3) to give a white solid (167 mg, 0.37 mmol, 44% yield, HPLC = 96%). 1 H NMR (400MHz, DMSO) δ8.75(s,1H),7.35(d,J=8.6Hz,2H),7.21(t,J=8.8Hz,2H),7.05–7.01(m,2H),6.94(d,J =8.6Hz,2H),6.28(s,2H),6.05(s,1H),4.21(s,2H),2.47(s,1H),2.39(s,2H),1.98(s,6H),1.76(s,6H).MS m / z=445.56[M+H]+

[0354] Example 15: Synthesis of Compound 63

[0355] Step 1: Synthesis of Compound 63

[0356] Compound 62 (102 mg, 0.23 mmol) was weighed and dissolved in 5 mL of tetrahydrofuran. Formaldehyde aqueous solution (38%) (28 mg, 0.35 mmol) was weighed and 1 drop of acetic acid was added. The mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (36 mg, 0.58 mmol) was then added and stirred at room temperature for 4 hours. LC-MS showed no residue. 30 mL of ethyl acetate and 40 mL of saturated NaCl solution were added for extraction. The mixture was washed twice with 40 mL of saturated NaCl solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was collected. The crude product was collected by rotary evaporation under reduced pressure, yielding 106 mg of crude product. Column chromatography was used for purification (EA:PE = 1:3) to give a white solid (47 mg, 0.10 mmol, 45% yield, HPLC = 97%). 1 H NMR(600MHz,DMSO–d6)δ8.81(s,1H),7.32–7.29(m,1H),7.23–7.18(m,2H),7.03–6.99(m,2H),6.95(d,J=7.6Hz,1H ),6.81–6.79(m,2H),6.39(s,2H),4.51(s,2H),2.92(s,3H),2.47(s,1H),2.41(s,2H),2.03(s,6H),1.77(s,6H).MS m / z=459.56[M+H] +

[0357] Example 16: Synthesis of Compound 64

[0358] Step 1: Synthesis of intermediate 64a

[0359] Dissolve 4-bromo-2,6-dimethylphenyl isocyanate (452 ​​mg, 2 mmol) in 5 mL of DMF with stirring. Add ethanol (92 mg, 2 mmol) and TEA (242 mg, 2.4 mmol), heat to 60 °C, and stir for 5 h. LC-MS showed no reactants remaining. Stop the reaction, add 55 mL of purified water, allow to stand to precipitate, filter, collect the filter cake, and purify by column chromatography to give a white solid (305 mg, 1.12 mmol, 56% yield). MS m / z = 272.12 / 274.20 [M+H / M+2] +

[0360] Step 2: Synthesis of Compound 64

[0361] Intermediate 64a (272 mg, 1 mmol), 4-(4-fluorophenoxy)benzylamine (217 mg, 1 mmol), XantPhos (29 mg, 0.051 mmol), cesium carbonate (489 mg, 1.52 mmol), and tris(dibenzylacetone)palladium (23 mg, 0.026 mmol) were weighed under nitrogen atmosphere. 5 mL of anhydrous and oxygen-free toluene was added, and the mixture was stirred at 110 °C for 30 h. LC-MS showed no residual starting material. 30 mL of ethyl acetate was added to dilute the reaction solution, and the mixture was filtered. The organic phase was collected and concentrated under reduced pressure to obtain 398 mg. The solution was purified by column chromatography (EA:PE = 1:4) to give a white solid (135 mg, 0.33 mmol, 33% yield, HPLC = 98%). 1 H NMR(400MHz, DMSO–d6)δ8.18(s,1H),7.35(d,J=8.4Hz,2H),7.22(t,J=8.8Hz,2H),7.07–7.01(m,2H),6.94(d,J=8.5Hz ,2H),6.28(s,2H),6.03(t,J=5.6Hz,1H),4.21(d,J=5.3Hz,2H),4.06–4.01(m,2H),2.00(s,6H),1.25–1.17(m,3H).MS m / z=409.47[M+H] +

[0362] Example 17: Synthesis of Compound 65

[0363] Step 1: Synthesis of intermediate 65a

[0364] Weigh tert-butyl (4-bromo-2,6-dimethylphenyl)carbamate (300 mg, 1 mmol), 4-(4-fluorophenoxy)benzylamine (239 mg, 1.10 mmol), L (29 mg, 0.05 mmol), cesium carbonate (815 mg, 2.50 mmol), and tris(dibenzylacetone)palladium (23 mg, 0.025 mmol) under nitrogen atmosphere. Add 3 mL of anhydrous and oxygen-free toluene, seal the tube and stir for 12 h at 110 °C. LC-MS showed no reactant residue. Dilute the reaction solution with 10 mL of ethyl acetate, filter, collect the organic phase, and concentrate the organic phase under reduced pressure to obtain 455 mg. Purify by column chromatography (EA:PE = 1:4) to give a white solid (340 mg, 0.79 mmol, 79% yield). MS m / z = 437.52 [M+H] +

[0365] Step 2: Synthesis of intermediate 65b

[0366] Intermediate 65a (300 mg, 0.68 mmol) was dissolved in 6 mL of ethanol. 5 mL of 6 mol / L HCl / EtOH solution was added, and the mixture was stirred at room temperature for 3 h. TLC monitoring showed no residual reactants. Subsequent LC-MS monitoring showed the target molecular weight. The reaction solution was concentrated under reduced pressure to obtain a white solid (250 mg, 0.61 mmol, 90% yield). MS m / z = 337.40 [M+H] +

[0367] Step 3: Synthesis of Compound 65

[0368] Weigh β-hydroxyisovaleric acid (48 mg, 0.41 mmol), N,N-diisopropylethylamine (120 mg, 0.62 mmol), and HATU (181 mg, 0.62 mmol). Add 3 mL of DMF and stir at room temperature for 0.5 h. Then add intermediate 65b (153 mg, 0.41 mmol) and N,N-diisopropylethylamine (160 mg, 0.82 mmol). Stir at room temperature and react for 3 h. When no reactants remain as monitored by UPLC, stop the reaction. Add 30 mL of ethyl acetate and 40 mL of saturated NaCl solution for extraction. Wash twice with 40 mL of saturated NaCl solution each time. Collect the organic phase, dry with anhydrous sodium sulfate, filter, collect the organic phase, and rotary evaporate under reduced pressure to obtain 166 mg of crude product. Purify by column chromatography (EA:PE = 1:2) to give a white solid (52 mg, 0.12 mmol, 29% yield, HPLC = 97%). 1 H NMR(600MHz, DMSO–d6)δ8.88(s,1H),7.34(d,J=8.6Hz,2H),7.21(t,J=8.8Hz,2H),7.04–7.02(m,2H),6.94(d,J=8.6Hz ,2H),6.28(s,2H),6.03(t,J=6.2Hz,1H),4.89(s,1H),4.20(d,J=6.1Hz,2H),2.37(s,2H),1.99(s,6H),1.22(s,6H).MS m / z=437.54[M+H] +

[0369] Example 18: Synthesis of Compound 66

[0370] Step 1: Synthesis of intermediate 66a

[0371] 300 mg (1 mmol) of tert-butyl (4-bromo-2,6-dimethylphenyl)carbamate, 239 mg (1.1 mmol) of 4-(4-fluorophenoxy)benzylamine, 29 mg (0.05 mmol) of L, and 815 mg (2.50 mmol) of cesium carbonate were weighed under nitrogen atmosphere. Tris(dibenzylacetone)dipalladium (23 mg, 0.025 mmol) was added, and 3 mL of anhydrous and oxygen-free toluene was added. The mixture was sealed and stirred at 110 °C for 20 h. LC-MS showed no residue. 10 mL of ethyl acetate was added to dilute the reaction solution. The mixture was filtered, and the organic phase was collected and concentrated under reduced pressure to obtain 455 mg. 340 mg of the purified product was obtained by column chromatography (EA:PE = 1:6).

[0372] Step 2: Synthesis of compound 66b

[0373] Take 300 mg (0.68 mmol) of 66a, dissolve it in 6 mL of ethanol, add 5 mL of 6 mol / L HCl / EtOH, stir at room temperature, and react for 3 h. TLC monitoring showed no residual reactants. Subsequent LC-MS monitoring showed the target molecular weight. The reaction solution was concentrated under reduced pressure to obtain 250 mg of 66b.

[0374] Step 3: Synthesis of Compound 66

[0375] Weigh 5,5,5-trifluorovaleric acid (48 mg, 0.41 mmol), N,N-diisopropylethylamine (120 mg, 0.62 mmol), and HATU (181 mg, 0.62 mmol). Add 3 mL of dichloromethane and stir at room temperature for 0.5 h. Then add 66b (153 mg, 0.41 mmol) and N,N-diisopropylethylamine (160 mg, 0.82 mmol), and add 2 drops of DMF. Stir at room temperature and react for 3 h. When no reactants remain as monitored by UPLC, stop the reaction. Add 30 mL of dichloromethane and 40 mL of saturated NaCl solution for extraction. Wash twice with 40 mL of saturated NaCl solution each time. Collect the organic phase, dry with anhydrous sodium sulfate, filter, collect the organic phase, and evaporate under reduced pressure to obtain 166 mg of crude product. Purify by column chromatography (EA:PE = 1:2) to give 66.42 mg of product (28% yield, HPLC purity = 93%). 1H NMR(400MHz,Chloroform-d)δ8.60(s,1H),7.35–7.30(m,2H),7.15–7.02(m,4H),6.95–6.82(m,2H),6.41(s,2H),5.12(t, J=5.2Hz,1H),4.43(dt,J=5.2,1.0Hz,2H),2.50(t,J=7.4Hz,2H),2.35–2.23(m,2H),2.20(s,6H),1.76(p,J=7.8Hz,2H).MS m / z=475.34[M+H] + .

[0376] The compounds in Table 2 below were prepared according to Example 18, compound 66.

[0377] Table 2

[0378] Example 19: Synthesis of Compound 72

[0379] Compound 66 (109 mg, 0.23 mmol) was weighed and dissolved in 5 mL of tetrahydrofuran. Formaldehyde aqueous solution (38%) (28 mg, 0.35 mmol) was weighed and dissolved in 1 drop of acetic acid. The mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (36 mg, 0.58 mmol) was then added and stirred at room temperature for 5 hours. LC-MS showed no residue. 30 mL of ethyl acetate and 40 mL of saturated NaCl solution were added for extraction. The mixture was washed twice with 40 mL of saturated NaCl solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was collected again. The crude product was evaporated under reduced pressure to obtain 106 mg. Column chromatography was used for purification (EA:PE = 1:3) to give compound 72.56 mg (49% yield, HPLC purity 95%). 1 H NMR(400MHz,DMSO–d6)δ8.96(s,1H),7.29–7.17(m,4H),7.01–7.07(m,2H),6.94(d,J=8.6Hz,2H ),6.45(s,2H),4.50(s,2H),2.94(s,3H),2.42–2.23(m,4H),2.04(s,6H),1.85–1.77(m,2H).MS m / z=489.50[M+H] + .

[0380] Biological evaluation

[0381] Activity Example 1: Activation effect of the disclosed compound on KCNQ2 / 3 in patch-clamp assay.

[0382] Automated patch-clamp technique was used to investigate the activation effect of the test substance on KCNQ2 / 3 potassium channels. Electrophysiological assays were performed using a fully automated patch-clamp QPatch48X (Sophion) device. The experimental procedures are as follows:

[0383] 1) Compound preparation

[0384] Prepare extracellular solution KCNQ-001-1 (140mM NaCl, 5mM KCl, 1mM MgCl2·6H2O, 2mM CaCl2·2H2O, 5mM D-Glucose, 10mM HEPES, pH adjusted to 7.4 with NaOH) and intracellular solution KCNQ-001-2 (125mM K-Aspartic, 20mM KCl, 10mM EGTA, 1mM MgCl2·6H2O, 5mM Mg-ATP, 5mM HEPES, pH adjusted to 7.2 with KOH).

[0385] The test compound was prepared as a 10 mM stock solution using DMSO. On the day of the experiment, it was then dissolved in extracellular fluid to prepare a working solution of the required concentration, ensuring that the DMSO concentration was 0.1%.

[0386] 2) Cell Culture

[0387] HEK-293 cell lines stably expressing KCNQ2 / 3 potassium channels were cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg / mL G418 at 37°C and 5% carbon dioxide.

[0388] 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 about 1 min. When the cells detach from the bottom of the dish, add about 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 10 cm cell culture dishes at a density of 6 × 10⁶ cells per dish. 5 Cells (final volume: 5 mL).

[0389] To maintain the electrophysiological activity of cells, the cell density must not exceed 80%.

[0390] Before patch-clamp assay, cells were separated using 0.25% trypsin-EDTA solution, digestion was stopped by adding culture medium, and the cells were centrifuged, resuspended, and counted. The cell density was adjusted to 2-3 × 10⁻⁶ cells / year. 6 Cells / mL were collected, and then the cells were gently mixed on a balanced shaker for 15-20 minutes at room temperature before being analyzed.

[0391] 3) Patch clamp testing

[0392] First, the prepared cells are placed on a centrifuge in the Qpatch workbench and washed using multiple centrifugation / resuspension methods to replace the cell culture medium with extracellular fluid. An MTP-96 plate is removed and placed in the MTP source position. The QPlate chip is removed and placed in the QPlate source position. The robotic arm scans the barcodes on the MTP-96 plate and the QPlate chip and picks them up to the measurement station. Intracellular fluid and extracellular fluid are aspirated from the liquid pools and added to the intracellular fluid pool and cell and compound pool of the QPlate chip, respectively. At the measurement station, all measurement sites on the QPlate undergo initial quality control. The quality control process includes aspirating the cell suspension from the centrifuge's cell container and positioning the cells onto the chip wells using a pressure controller to establish a high-resistance seal, forming a whole-cell recording mode. Once a stable control current baseline is obtained, the test substances are sequentially aspirated from the MTP-96 plate according to their concentration and applied to the cells.

[0393] The voltage stimulation protocol for whole-cell patch-clamp recording of KCNQ2 / 3 currents was as follows: after whole-cell sealing, the cell membrane voltage was clamped at -80 mV for 50 ms, then stepped from -80 mV in 10 mV increments for 3 s, depolarized to -30 mV and held for 500 ms, and finally returned to the clamp voltage of -80 mV and held for 50 ms. The effect of the drug on the KCNQ2 / 3 currents was observed. Experimental data were acquired by Qpatch and stored in a connected server.

[0394] Each drug concentration was set for single-dose administration until the efficacy stabilized. Blank control solution and working solution of the test compound were applied to the cells sequentially from low to high concentrations. The current detected in each cell in the compound-free solution served as its control group. Each concentration was measured independently in duplicate using at least two cells. All electrophysiological experiments were performed at room temperature.

[0395] 4) Data Analysis

[0396] IV curve calculation: First, plot the IV curve for each concentration with step voltage as the horizontal axis and normalized current as the vertical axis.

[0397] Activation or inhibition effect: Calculate the inhibition fold (% inhibition) or activation fold (% increase) of the current amplitude after each concentration at a voltage corresponding to +40 mV relative to the control current amplitude using the following equation.

[0398] Inhibition%=(1-(Steady current compound) / (Steady current vehicle))*100%,

[0399] Increase%=(Steady current compound) / (Steady current vehicle)*100%

[0400] Activation curve: The activation curve is fitted by the Boltzmann equation, i.e., I / Imax=1 / (1+exp((V1 / 2-Vm) / к)), where Imax is the maximum normalized tail current amplitude, V1 / 2 is the half-maximally activated voltage, Vm is the test voltage, and к is the slope factor of the activation curve, which reflects the speed of activation.

[0401] Curve fitting was performed using GraphPad Prism 8.

[0402] The effects of the compounds in this application on in vitro biological models are shown in Table 3.

[0403] Table 3. Effects of the compounds of this application in in vitro models. *The percentage increase in current in HEK293 cells expressing KCNQ2 / 3 was measured at a compound concentration of 1 μM, 100%.

[0404] Example 2: Analgesic effect of the disclosed compound in a rat formalin model

[0405] 1) Drug activity testing

[0406] Three days after the rats adapted to the experimental environment, they were weighed and numbered at the base of their tails.

[0407] ​A training diaper was placed on the experimental table, and a white cylinder was placed on top of it. Thirty minutes before the formal test, a metal plate was attached to the left hind paw of the rats. The rats were then placed in the transparent white cylinder to acclimatize. The rats were administered medication by gavage 15 minutes prior to the test (the Sham group received no medication). Then, 50 μL of 2% formalin was injected subcutaneously into the dorsal side of the left hind paw to establish the model (the Sham group did not receive formalin). Subsequently, the animals were placed in a spontaneous movement analyzer, which automatically recorded the number of times the rats withdrew, raised, or licked their paws. Data from 0-60 minutes after formalin injection were statistically analyzed.

[0408] 2) Detection indicators

[0409] Following injection of 2% formalin, the number of movements (foot lifts and licks of the injected foot) from 0 to 60 minutes after injection were recorded and analyzed, including the cumulative number of foot lifts during the early acute phase (Phase I: 0-9 minutes) and the late tense phase (Phase II: 10-60 minutes).

[0410] Calculate MPE% (Maximum Possible Effect as a percentage)

[0411] MPE% = [(Vehicle-sham) - (Drug-treated group - Sham)] / (Vehicle-sham) x 100%

[0412] Remark:

[0413] ①Calculate the MPE of each group based on the standard that MPE% = 100% for the Sham group and MPE% = 0 for the vehicle group.

[0414] ② The number of exercise cycles for the Sham group was subtracted to eliminate the influence of background noise on the experiment.

[0415] 3) Data collection and statistical analysis

[0416] All indicators are expressed as mean ± standard error. Data were analyzed using GraphPad prim 8.0.1 software. The statistical method employed was univariate analysis with additional Dunnett's multiple comparison test to compare the statistical differences between groups. A p-value < 0.05 was considered statistically significant.

[0417] The effects of the compounds in this application on in vivo biological models are shown in Table 4.

[0418] Table 4. Effects of the compounds in this application in in vivo biological models. *Maximum possible analgesic effect (MPE%), measured when rats were orally administered at 10 mg / kg. D was defined as 40 < MPE% ≤ 50%, C as 50 < MPE% ≤ 70%, B as 70 < MPE% ≤ 90%, and A as MPE% > 90%.

[0419] Active Example 3: Pharmacokinetic evaluation of the compounds of the present disclosure

[0420] Experimental procedure:

[0421] Sprague-Dawley rats (male, 6 - 8 weeks old, JH Laboratory Animal Co., LTD) were used and administered a single oral gavage dose (XEN-1101: 1 mg / kg, N = 3; Compound 1: 3 mg / kg, N = 3). Plasma samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 h after dosing. The plasma samples were obtained by centrifugation (2000 g, 4 °C, 5 min). 10 μL aliquots of the samples were added to a 96-well plate along with 200 μL of an acetonitrile solution containing an internal standard, mixed and shaken, and then centrifuged (5800 rpm, 4 °C, 10 min). 70 μL of the supernatant was transferred to a new 96-well plate. 2 μL of the solution was injected into the LC-MS / MS. The plasma drug concentration was quantitatively analyzed by the LC-MS / MS analysis method, and the pharmacokinetic parameters were calculated.

[0422] Experimental results:

[0423] The pharmacokinetic parameters of the compounds of the present application in Sprague-Dawley rats are shown in Table 5.

[0424] Table 5 Pharmacokinetic parameters of the compounds of the present application in Sprague-Dawley rats

[0425] Experimental conclusion:

[0426] The compounds of the present invention have good pharmacokinetic properties. Compared with XEN-1101, the half-life of Compound 1 in vivo is reduced, the metabolic process is faster, the peak concentration C max is significantly reduced, avoiding the accumulation of the drug in the body and having good safety.

Claims

1. A compound of formula (I), its stereoisomer, its pharmaceutically acceptable salt, its solvate, its deuterated product, its metabolite or its prodrug; in, R 1 It is a C1-C6 alkyl, C3-C6 cycloalkyl, 1-6 heteroalkyl containing 1-3 nitrogen atoms, or C6-C 10 aryl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl and C6-C 10 The aryl group is optionally substituted by 1 to 3 substituents independently selected from the following groups: halogen, C1-C3 alkyl, C1-C3 alkoxy, hydroxyl, 3-10 membered heterocyclic group; L stands for -(CH2) n -, -O-, -S- or -NH-; R 2 and R 3 Each of the following is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, amino, or a 1-6 heteroalkyl group containing 1-3 nitrogen or sulfur atoms, wherein the C1-C6 alkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl are optionally substituted by 1-3 substituents independently selected from the following groups: halogen, C1-C3 alkyl, C1-C3 alkoxy; X1 is CR 5 Or N; X2 is CH or N; R 5 It is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 1-6 heteroalkyl or 3-10 heterocyclic group containing 1-3 nitrogen or sulfur, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl and 3-10 heterocyclic group are optionally substituted by 1-3 substituents independently selected from the following groups: halogen, C1-C3 alkyl, C1-C3 alkoxy; R 4 It is hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -(C=O)-C1-C6 alkyl, 1-6-membered heteroalkyl or 3-10-membered heterocyclic group containing 1-3 oxygen, nitrogen or sulfur, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl and 3-10-membered heterocyclic group are optionally substituted by 1-3 substituents independently selected from the following groups: halogen, C1-C3 alkyl, C1-C3 alkoxy; V1 is a connector, -(CH2) n -、-CH(COOR a (CH2) m -or-CHR b (CH2) p -; n is 0, 1, 2, 3 or 4; m is 0, 1, or 2; p is 0, 1, or 2; R a and R b Each is independently H, deuterium, or C1-C6 alkyl; The Y ring is a C3-C6 cycloalkyl group, C6-C 10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclic, wherein the C3-C6 cycloalkyl, C6-C 10 Aryl, 5-10-membered heteroaryl, and 3-10-membered heterocyclic groups are optionally substituted by 1-5 substituents independently selected from the following groups: deuterium, halogen, cyano, C1-C6 alkyl, and alkyl groups substituted by 1-3 R groups. x Substituted C1-C6 alkyl, C2-C6 alkenyl, with 1-3 R x Substituted C2-C6 alkenyl, C2-C6 alkynyl, with 1-3 R x Substituted C2-C6 alkynyl, C1-C6 alkoxy, with 1-3 R x Substituted C1-C6 alkoxy, C3-C6 cycloalkyl, with 1-3 R x Substituted C3-C6 cycloalkyl, amide group, 1-6 heteroalkyl group containing 1-3 nitrogen or sulfur atoms, 3-10 heterocyclic group, or group with 1-3 R atoms x Replacement of 3-10 membered heterocyclic groups; R x It is a halogen, a C1-C3 alkyl or a C1-C3 alkoxy; W can be either of the following two groups: (I)W is R 6 ; (II)W is V2R 7 ; R 6 H, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, -S-C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 aryl, 5-10-membered heteroaryl, or 3-10-membered heterocyclic, wherein the C1-C6 alkyl, C1-C6 alkoxy, -S-C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 The aryl, 5-10-membered heteroaryl and 3-10-membered heterocyclic groups are optionally substituted by 1-3 substituents independently selected from the following groups: halogen, C1-C3 alkyl, C1-C3 alkoxy; V2 is -(CH2) n -、-O-、-S-、-N(R c -, -CH2-O-, -O-CH2-, -CONH-, or -NHCO-; R c It is hydrogen, deuterium, or C1-C6 alkyl; R 7 Halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C4-C6 cycloalkenyl, 1-6 heteroalkyl groups containing 1-3 nitrogen or sulfur atoms, C6-C 10 aryl, 5-10-membered heteroaryl, or 3-10-membered heterocyclic group, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C4-C6 cycloalkenyl, C6-C 10 The aryl, 5-10-membered heteroaryl and 3-10-membered heterocyclic groups are optionally substituted by 1-3 substituents independently selected from the following groups: cyano, amide, halogen, C1-C3 alkyl, C1-C3 alkoxy; The heteroatoms of the 3-10 membered heterocyclic groups are O, N, or S, and the number of heteroatoms is 1-3. The heteroatom of the 5-10 membered heteroaryl group is O, N or S, and the number of heteroatoms is 1-3. The compound represented by formula (I) satisfies at least one of the following six conditions: (1)R 1 C1-C6 alkyl groups substituted with 1-3 halogens; (2) W is V2R 7 And R 7 It can be any of the following structures; R 10 It can be hydrogen, deuterium, halogen, cyano, or amide. (3) X1 is N; X2 is CH; (4) V1 is -CH(COOR) a (CH2) m -; (5) The Y-ring is And (6)W is R 6 ;R 6 for 2. The compound of formula (I) as claimed in claim 1, characterized in that, The compound represented by formula (I) satisfies one or more of the following conditions: (1) The C1-C6 alkyl group is methyl, ethyl, n-propyl or isopropyl, preferably methyl; (2) The C3-C6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (3) The C3-C 10 The cycloalkyl group can be monocyclic or polycyclic, wherein the polycyclic group is fused, spirocyclic, or bridged; the C3-C 10 Cycloalkyl groups are preferably C3-C6 monocyclic cycloalkyl groups or C5-C6 monocyclic cycloalkyl groups. 10 Polycyclic cycloalkyl groups, for example For example (4) The 1-6 heteroalkyl group containing 1-3 nitrogen atoms is a 1-3 heteroalkyl group containing 1-3 nitrogen atoms; (5) The 1-6 heteroalkyl group containing 1-3 nitrogen or sulfur is a 1-3 heteroalkyl group containing 1-3 nitrogen or sulfur, for example, a 1-3 heteroalkyl group containing 1-3 nitrogen or a 1-3 heteroalkyl group containing 1-3 sulfur; (6) The 1-6 heteroalkyl group containing 1-3 oxygen, nitrogen or sulfur is a 1-3 heteroalkyl group containing 1-3 oxygen, nitrogen or sulfur, for example, a 1-3 heteroalkyl group containing 1-3 oxygen, a 1-3 heteroalkyl group containing 1-3 nitrogen or a 1-3 heteroalkyl group containing 1-3 sulfur. (7) The C6-C 10 The aryl group is phenyl or naphthyl, preferably phenyl; (8) The "heterocyclic group" in the 3-10 member heterocyclic group is a heterocyclic alkyl group or a heterocyclic alkenyl group; (9) The 3-10 member heterocyclic group is a 3-7 member monocyclic heterocyclic group or a 7-10 member bicyclic heterocyclic group, for example For example (10) The halogen is fluorine, chlorine, bromine or iodine; (11) The C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, preferably methoxy; (12) The C2-C6 alkenyl group is a C2-C4 alkenyl group, such as vinyl; (13) The C2-C6 ynyl group is a C2-C4 ynyl group, such as an ethynyl group; (14) The 5-10 membered heteroaryl group is a 5-7 membered monocyclic heteroaryl group or a 9-10 membered bicyclic heteroaryl group; the 5-7 membered monocyclic heteroaryl group is, for example, pyridine, N-methylpyridine, pyrimidine, triazole, furan, thiophene, or thiazole; the 9-10 membered bicyclic heteroaryl group is, for example, pyridine, N-methylpyridine, pyrimidine, triazole, furan, thiophene, or thiazole; For example (15) The 5-10 membered heteroaryl group has at least one ring that is aromatic; (16) The -S-C1-C6 alkyl group is -S-methyl, -S-ethyl, -S-n-propyl, -S-isopropyl, -S-n-butyl, -S-isobutyl or -S-tert-butyl, preferably -S-methyl; (17) The C4-C6 cycloalkenyl group contains one or two carbon-carbon double bonds; The C4-C6 cycloalkenyl group described in (18) is For example 3. The compound of formula (I) as described in claim 1, characterized in that, The compound represented by formula (I) satisfies one or more of the following conditions: (1)R 1 It is a C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl group is optionally substituted by 1-3 substituents independently selected from the following groups: halogen, hydroxyl; preferably, R 1 It is ethyl, tert-butyl, but-2-yl, bicyclo[1.1.1]pent-1-yl, trifluoromethyl, or 2-hydroxypropyl-2-yl; (2) L is a linking bond, -CH2-, -(CH2)2-, -(CH2)3-, -O-, -S- or -NH-, preferably a linking bond, -CH2-, -O-, -S- or -NH-; (3)R 2 and R 3 Each of them is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, amino, or 1-6 heteroalkyl containing 1-3 nitrogen or sulfur atoms, preferably C1-C6 alkyl or amino; (4) X1 is CH; (5) X2 is CH; (6)R 5 It is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 1-6 heteroalkyl or 3-10 heterocyclic group containing 1-3 nitrogen or sulfur atoms, preferably hydrogen, halogen or C1-C6 alkyl; preferably, R 5 For H or deuterium; (7)R 4 It is hydrogen, deuterium, C1-C6 alkyl, or -(C=O)-C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by 1-3 substituents independently selected from the following groups: halogen, C1-C3 alkyl, C1-C3 alkoxy; preferably, R 4 It is hydrogen, deuterium, C1-C6 alkyl, or -(C=O)-C1-C6 alkyl; (8) V1 is a connecting key, -CH2-, -CH2-CH2- or -CH(COOR) a CH2-; (9)R a and R b Each is independently H or C1-C6 alkyl; (10) The Y ring is a C3-C6 cycloalkyl group, C6-C 10 aryl or 5-10 heteroaryl, wherein the C3-C6 cycloalkyl, C6-C 10 The aryl and 5-10 heteroaryl groups are optionally substituted by 1-5 substituents independently selected from the following groups: deuterium, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, amide; preferably, the Y ring is C3-C6 cycloalkyl, C6-C6 cycloalkyl, or C6-C6 cycloalkyl. 10 Aryl or 5-10 heteroaryl groups; (11)R 6 H, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, -S-C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 aryl, 5-10-membered heteroaryl, or 3-10-membered heterocyclic group, wherein the C1-C6 alkyl, C1-C6 alkoxy, -S-C1-C6 alkyl, and C6-C 10 The aryl group is optionally substituted by 1 to 3 substituents independently selected from the following groups: halogen, C1-C3 alkyl, C1-C3 alkoxy; Preferred, R 6 H, halogen, C1-C6 alkyl, C1-C6 alkoxy, -S-C1-C6 alkyl, C6-C 10 aryl or 3-10 membered heterocyclic groups, wherein the C1-C6 alkyl, C1-C6 alkoxy and C6-C 10 The aryl group may optionally be substituted by 1 to 3 substituents independently selected from the following groups: halogens, C1-C3 alkyl groups; and (12)R 7 For C3-C 10 Cycloalkyl, C4-C6 cycloalkenyl, C6-C 10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclic, wherein the C3-C6 cycloalkyl, C4-C6 cycloalkenyl, C6-C 10 The aryl, 5-10-membered heteroaryl and 3-10-membered heterocyclic groups are optionally substituted by 1-3 substituents independently selected from the following groups: cyano, amide, halogen, C1-C3 alkyl, C1-C3 alkoxy; Preferably, R 7 Selected from, but not limited to, the following structures: Among them, R 9 It is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, formamido, acetamido, or propionamido; more preferably, R 9 It can be hydrogen, deuterium, fluorine, cyano or formamide.

4. The compound of formula (I) as claimed in claim 1, characterized in that, The compound represented by formula (I) satisfies at least one of the following three conditions: (1)R 1 It is a C1-C6 alkyl group substituted with 1-3 halogens, preferably trifluoromethyl; (2) W is V2R 7 And R 7 It can be any of the following structures; R 10 It can be hydrogen, deuterium, halogen, cyano, or amide. And (3) Y ring is Preferred 5. The compound of formula (I) as claimed in claim 1, characterized in that, The compound represented by formula (I) satisfies one or more of the following conditions: (1) Structural Fragments for (2) Structural Fragments Methyl, fluorine, -OCF3, (3) Ring Y is phenyl, (4) Structural Fragments for (5) Structural Fragments for and (6) structural fragments for Preferred More preferably 6. The compound of formula (I) according to any one of claims 1-5, characterized in that, The compound represented by formula (I) satisfies one of the following schemes: Option 1: The compound represented by formula (I) is the same as the compound represented by formula (II): The better ones, among which, L stands for -(CH2) n -; n is 0, 1, 2, 3 or 4; R 2 and R 3 Each is independently hydrogen, deuterium, halogen, amino, C1-C6 alkyl, or C1-C6 alkoxy; X1 is CH or N; R 4 It is hydrogen, deuterium, C1-C6 alkyl, or -(C=O)-C1-C6 alkyl; The Y ring is a C3-C6 cycloalkyl group, C6-C 10 aryl or 5-10 heteroaryl, wherein the C3-C6 cycloalkyl, C6-C 10 The aryl and 5-10 heteroaryl groups are optionally substituted by 1-5 substituents independently selected from the following groups: deuterium, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, amide; W can be either of the following two groups: (I)W is R 6 ; (II)W is V2R 7 ; R 6 H, halogen, C1-C6 alkyl, C1-C6 alkoxy, -S-C1-C6 alkyl, C6-C 10 aryl or 3-10 membered heterocyclic groups, wherein the C1-C6 alkyl, C1-C6 alkoxy and C6-C 10 The aryl group may optionally be substituted by 1 to 3 substituents independently selected from the following groups: halogens, C1-C3 alkyl groups; V2 is -O-, -S-, or -N(R) c )-; R c It is hydrogen, deuterium, or C1-C3 alkyl; R 7 For C3-C 10 Cycloalkyl, C4-C6 cycloalkenyl, C6-C 10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclic, wherein the C3-C6 cycloalkyl, C4-C6 cycloalkenyl, C6-C 10 The aryl, 5-10-membered heteroaryl and 3-10-membered heterocyclic groups are optionally substituted by 1-3 substituents independently selected from the following groups: cyano, amide, halogen, C1-C3 alkyl, C1-C3 alkoxy; Option 2: The compound represented by formula (I) is the same as the compound represented by formula (II): in, L stands for -(CH2) n -; n is 1, 2, or 3; R 2 and R 3 Each is independently an amino group or a C1-C6 alkyl group; X1 is CH; R 4 It is hydrogen or C1-C6 alkyl; The Y-ring is C6-C 10 aryl or 5-10 heteroaryl, wherein the C6-C 10 The aryl and 5-10 heteroaryl groups are optionally substituted by 1-5 substituents independently selected from the following groups: halogens, C1-C6 alkyl groups; W represents V2R 7 ; V2 is -O-; R 7 For C6-C 10 aryl or 5-10 heteroaryl, wherein the C6-C 10 The aryl and 5-10 heteroaryl groups are optionally substituted by 1-3 substituents independently selected from the following groups: halogens, C1-C3 alkyl groups; Option 3: The compound represented by formula (I) is the same as the compound represented by formula (III): in, R 1 It is a C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted by 1-3 substituents independently selected from the following groups: halogen, hydroxyl; L stands for -(CH2) n -, -O-, -S- or -NH-; n is 0, 1, 2, 3 or 4; R 2 and R 3 Each is independently hydrogen, deuterium, halogen, amino, C1-C6 alkyl, or C1-C6 alkoxy; X1 is CH or N; R 4 It is hydrogen, deuterium, C1-C6 alkyl, or -(C=O)-C1-C6 alkyl; The Y ring is a C3-C6 cycloalkyl group, C6-C 10 aryl or 5-10 heteroaryl, wherein the C3-C6 cycloalkyl, C6-C 10 The aryl and 5-10 heteroaryl groups are optionally substituted by 1-5 substituents independently selected from the following groups: deuterium, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, amide; V2 is -O-, -S-, or -N(R) c )-; R c It is hydrogen, deuterium, or C1-C3 alkyl; R 7 For C3-C 10 Cycloalkyl, C4-C6 cycloalkenyl, C6-C 10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclic, wherein the C3-C6 cycloalkyl, C4-C6 cycloalkenyl, C6-C 10 The aryl, 5-10-membered heteroaryl, and 3-10-membered heterocyclic groups are optionally substituted by 1-3 substituents independently selected from the following groups: cyano, amide, halogen, C1-C3 alkoxy; preferably, R 7 For C6-C 10 Aryl, wherein the C6-C 10 The aryl group is replaced by 1-3 halogens; more preferably, R 7 The phenyl group is wherein the phenyl group is substituted by 1-3 F atoms; Option 4: The compound represented by formula (I) is the same as the compound represented by formula (III): in, R 1 It is a C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted by 1-3 substituents independently selected from the following groups: halogen, hydroxyl; L stands for -(CH2) n -, -O-, -S- or -NH-; n is 0, 1, or 2; R 2 and R 3 Each is independently an amino group or a C1-C6 alkyl group; X1 is CH; R 4 It is hydrogen or C1-C6 alkyl; The Y-ring is C6-C 10 aryl or 5-10 heteroaryl, wherein the C6-C 10 The aryl and 5-10 heteroaryl groups are optionally substituted by 1-5 substituents independently selected from the following groups: halogens, C1-C6 alkyl groups; V2 is -O-, -S-, or -N(R) c )-; R c It is hydrogen, deuterium, or C1-C3 alkyl; R 7 It can be any of the following structures; Ideally, R 7 for R 10 It is hydrogen, deuterium, halogen, cyano or amide group, preferably halogen, more preferably F; Option 5: The compound represented by formula (I) is the same as the compound represented by formula (IV): in, R 1 It is a C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted by 1-3 substituents independently selected from the following groups: halogen, hydroxyl; L stands for -(CH2) n -, -O-, -S- or -NH-; n is 0, 1, 2, 3 or 4; R 2 and R 3 Each is independently hydrogen, deuterium, halogen, amino, C1-C6 alkyl, or C1-C6 alkoxy; X1 is CH or N; R 4 It is hydrogen, deuterium, C1-C6 alkyl, or -(C=O)-C1-C6 alkyl; Y-ring is Preferred R 6 H, halogen, C1-C6 alkyl, C1-C6 alkoxy, -S-C1-C6 alkyl, C6-C 10 aryl or 3-10 membered heterocyclic groups, wherein the C1-C6 alkyl, C1-C6 alkoxy and C6-C 10 The aryl group is optionally substituted by 1 to 3 substituents independently selected from the following groups: halogen, C1-C3 alkyl; preferably, R 6 For C6-C 10 Aryl, wherein the C6-C 10 The aryl group is optionally substituted by 1 to 3 substituents independently selected from the following groups: halogen, C1-C3 alkyl; Option Six: The compound represented by formula (I) is the same as the compound represented by formula (IV): in, R 1 It is a C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted by 1-3 substituents independently selected from the following groups: halogen, hydroxyl; L stands for -(CH2) n -, -O-, -S- or -NH-; n is 0, 1, or 2; R 2 and R 3 Each is independently an amino group or a C1-C6 alkyl group; X1 is CH; R 4 It is hydrogen or C1-C6 alkyl; Y-ring is R 6 It can be H, halogen, or C1-C6 alkyl; Option Seven: The compound represented by formula (I) is the same as the compound represented by formula (III): in, R 1 It is a C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted by 1-3 substituents independently selected from the following groups: halogen, hydroxyl; L stands for -(CH2) n -, -O-, -S- or -NH-; n is 0, 1, or 2; R 2 and R 3 Each is independently an amino group or a C1-C6 alkyl group; X1 is CH or N; R 4 It is hydrogen, deuterium, or C1-C6 alkyl; The Y-ring is C6-C 10 aryl or 5-10 heteroaryl, wherein the C6-C 10 The aryl and 5-10 heteroaryl groups are optionally substituted by 1-5 substituents independently selected from the following groups: halogens, C1-C6 alkyl groups; V2 is -O-; R 7 For C6-C 10 Aryl, wherein the C6-C 10 The aryl group is replaced by 1-3 halogens; preferably, R 7 The phenyl group is wherein the phenyl group is substituted by 1-3 F atoms; Option 8: The compound represented by formula (I) is the same as the compound represented by formula (III): in, R 1 It is a C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally substituted by 1-3 substituents independently selected from the following groups: halogen, hydroxyl; L stands for -(CH2) n -; n is 0, 1, or 2; R 2 and R 3 Each is independently an amino group or a C1-C6 alkyl group; X1 is CH or N; R 4 It is hydrogen, deuterium, or C1-C6 alkyl; The Y ring is a phenyl group, wherein the phenyl group is optionally substituted by 1 to 5 substituents independently selected from the following groups: halogen, C1-C6 alkyl or cyano; V2 is -O-; R 7 The phenyl group is substituted with 1-3 F atoms; preferably, R 7 for 7. The compound of formula (I) as claimed in claim 1, characterized in that, The compound represented by formula (I) is selected from any of the following compounds:

8. A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1-7, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a deuterated thereof, a metabolite thereof or a prodrug thereof, and at least one pharmaceutical excipient.

9. The use of a compound of formula (I) as claimed in any one of claims 1-7, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its deuterated derivative, its metabolite or its prodrug, or the pharmaceutical composition as claimed in claim 8 in the preparation of a medicament for the prevention and / or treatment of KCNQ2 / 3 channel-related diseases; The KCNQ2 / 3 channel-related diseases are preferably epilepsy, neonatal spasms, neurotransmitter release disorders, smooth muscle contraction disorders, movement disorders, dystonia, mania, hearing impairment, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, anxiety, migraine, depression, hepatocellular carcinoma, colon cancer, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, pain or pain-related spasticity. The pain can be acute or chronic.

10. The use of a compound of formula (I) as claimed in any one of claims 1-7, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its deuterated derivative, its metabolite or its prodrug, or the pharmaceutical composition as claimed in claim 8 in the preparation of a medicament for the prevention and / or treatment of a disease; The diseases mentioned are epilepsy, neonatal spasms, neurotransmitter release disorders, smooth muscle contraction disorders, movement disorders, dystonia, mania, hearing impairment, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, anxiety, migraine, depression, hepatocellular carcinoma, colon cancer lesions, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, pain or pain-related spasticity. The pain can be acute or chronic.

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