Preparation method and application of novel high-selectivity KV7.2 opener

Abstract

The invention belongs to the technical field of biological medicine, and particularly relates to preparation of a novel high-selectivity KV7.2 opener and application of the novel high-selectivity KV7.2 opener in antiepileptic drugs. A series of KV7.2-targeted small-molecule inhibitors are designed and synthesized, and the small-molecule inhibitors can enhance the current of a potassium ion channel KV7.2, accelerate channel activation and delay the inactivation process of the channel. The small molecule has a remarkable potential for treating epilepsy, shows efficient anti-epileptic activity in three classic epilepsy models for simulating human comprehensive attack and drug-refractory focal attack, is remarkably superior to positive control RTG, can be used for preparing anti-epileptic drugs and has a wide application prospect.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to a novel class of highly selective K+ V 7.2 Preparation methods and applications of open-opening agents. Background Technology

[0002] The voltage-gated potassium channel K encoded by the KCNQ gene V The ion channel family 7 plays a crucial role in regulating the repolarization of neuronal action potentials in the central nervous system. Dysfunction of this channel is associated with a variety of diseases, including epilepsy, neuropathic pain, and dysregulation of vascular tone, making it an important therapeutic target in the field of ion channels. V Family 7 contains five subtypes (K V 7.1-K V 7.5), each subtype consists of six transmembrane α-helices (S1-S6). Different K V The seven subtypes form functional channels through homo- or hetero-tetramer assembly, exhibiting significant differences in tissue distribution, functional properties, and kinetic characteristics.

[0003] In K V In the 7-channel family, K V 7.2 Subtypes have core value in the treatment of neurological diseases. It is related to K... V The "M channel," composed of 7.3, carries 70-80% of the potassium current in cortical neurons, playing a crucial role in regulating neuronal excitability by stabilizing the resting potential and inhibiting neuronal overexcitation. Dysfunction of this channel is closely related to the pathogenesis of epilepsy and neuropathic pain. Given K... V 7.1 Dominant cardiac repolarization, K V 7.4 and K V 7.5 are responsible for auditory conduction and vasodilation, respectively, and have different physiological functions. This functional division determines that to overcome the toxic side effects caused by the non-selective activation of existing drugs, it is necessary to develop highly selective K+. V 7.2 Opening agents are an inevitable choice.

[0004] Achieve K V The 7-subtype selectivity faces two major challenges: high sequence conservation and conformational dynamic differences. Existing strategies are struggling to overcome these challenges. V 7.2 is a highly conserved bottleneck. To address this, we utilize structural biology to identify K... V 7.2 Specific residue design and binding pockets were employed; highly selective openers were obtained through virtual screening and optimization. Their high activity was verified through multidimensional experiments using electrophysiological and animal epilepsy models, paving the way for the development of precise K-targeting agents. V The seven drugs provide new strategies and theoretical foundations. Summary of the Invention

[0005] The purpose of this invention is to screen, design, synthesize, and validate a series of targeted K-type ... V 7.2 Selective openers, this series of compounds can enhance potassium ion channels K V A current of 7.2 ppm can accelerate channel activation and delay channel inactivation. This small molecule possesses significant anti-epileptic therapeutic potential, exhibiting highly effective anti-epileptic activity in three classic epilepsy models simulating human generalized seizures, drug-resistant focal seizures, and other conditions, significantly superior to the positive control RTG. It can be used to prepare anti-epileptic drugs. Specifically, it includes the following: In a first aspect, the present invention provides a compound represented by formula (I) below, or a pharmaceutically acceptable salt, hydrate, deuterated product, or prodrug thereof;

[0006] Equation (Ⅰ), Ar is independently selected from substituted or unsubstituted C6-C. 10 Aryl or five- or six-membered heteroaryl, fused aromatic or heterocyclic ring; A1, A2, and A3 are each independently selected from CR. 1 Or N, R 1 Substituents for C; n is independently selected from 1 or 2; Q is selected independently from CR 2 Or N; W is selected independently from CR 3 Or N; X is selected independently from CR 4 Or N; where X is CR 4 When X is N, Z is independently selected from substituted or unsubstituted C1-C3 alkyl, amino, -NH-CO-, -CO-NH-, urea, hydrazide, sulfonamide, etc.; when X is N, Z is independently selected from substituted or unsubstituted C1-C3 alkyl, carbonyl, etc. Y is selected independently from CR 5 Or carbonyl; R 1 R 2 R 3 R 4 R 5 R1 and R2 are independently selected from H, substituted or unsubstituted C1-C, respectively. 10 Alkyl, substituted or unsubstituted C6-C 12 aryl or heteroaryl, substituted or unsubstituted 3-12 membered alicyclic or heterocyclic groups; The substitution refers to the substitution of one or more hydrogen atoms on a group by a substituent selected from the group consisting of: halogen atoms, carbonyl, carboxyl, hydroxyl, amino, nitro, cyano, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkoxycarbonyl, C1-C6 amide, substituted or unsubstituted C1-C6 groups. 10 alkyl.

[0007] Wherein, the substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C6-C 10 The substituents of the aryl, five-membered, or six-membered heteroaryl groups are selected from the following group: halogen atom, carbonyl, hydroxyl, carboxyl, C1-C6 alkoxycarbonyl, amino, C1-C6 amide, nitro, cyano, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C6-C 10 Aryl or five- or six-membered heteroaryl; preferably halogen atom, C1-C6 alkoxy carbonyl, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy or phenyl.

[0008] Preferably, the structural formula of the compound is shown in formula (II):

[0009] Formula (II).

[0010] Preferably, the compound has the structural formula shown in formula (Ⅲ):

[0011] Formula (III).

[0012] Preferably, Q is CR' or N; Z is CH2; R1 is H; R2 is methyl, substituted or unsubstituted phenyl; Preferably, the compound is any one of compounds Q-1 to Q-30, E-1 to E-70, and F-1 to F-50 as shown in the specification.

[0013] Preferably, the compound is any one of compounds Q-1, Q-3, Q-6, Q-8, Q-11, Q-19, Q-22, Q-24, Q-26, Q-30, E-1, E-2, E-5, E-10, E-12, E-23, E-35, E-40, E-52, E-56, E-65, F-1, F-3, F-8, F-16, F-19, F-20, F-36, F-40, and F-41 as shown in the specification.

[0014] Preferably, the structural formula of the compound is: .

[0015] Secondly, the present invention provides the compounds described in the first aspect above, or pharmaceutically acceptable salts, hydrates, deuterated derivatives, or prodrugs thereof, in the preparation of K V Application of open-acting drugs in 7.2.

[0016] Thirdly, the present invention provides the use of the compounds described in the first aspect above, or pharmaceutically acceptable salts, hydrates, deuterated derivatives, or prodrugs thereof, in the preparation of drugs for treating epilepsy, etc.

[0017] Fourthly, the present invention provides that any of the compounds described above be incorporated into a pharmaceutically acceptable salt excipient to form any pharmaceutically acceptable dosage form.

[0018] Preferably, the dosage form includes tablets, injections, granules, and suspensions.

[0019] The beneficial effects of this invention are: This invention provides a novel K V 7.2 Preparation methods of selective openers and their antiepileptic uses. We identified K... V 7.2 Specific residue design combined with pockets; highly selective openers were obtained through virtual screening and optimization, and multidimensional experiments verified their efficient activation of K+. V 7.2, and demonstrated potent antiepileptic activity with no motor dysfunction side effects in animal models of epilepsy. Pharmacodynamic experiments indicate that the compounds involved in this invention can be used as therapeutic drugs for epilepsy. Attached Figure Description

[0020] Figure 1 Definition of selective binding sites and compound screening in Kv7.2.

[0021] Figure 2 Lead compound E0554 for K V Electrophysiological activity of different subtypes of the 7-potassium channel. Detailed Implementation

[0022] To make the objectives and technical solutions of this invention clearer, the embodiments of this invention are described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of this invention.

[0023] Unless otherwise stated, the experimental methods described in the embodiments of the present invention are all conventional methods; the reagents and materials used, unless otherwise specified, are all purchased from conventional biochemical reagents.

[0024] This invention uses K V 7 family sequence comparisons identified K V 7.2 A novel binding site rich in non-conserved residues in a channel voltage-sensing domain-pore domain (VSD-PD) fissure (Appendix) Figure 1Virtual screening based on this site, and subsequent electrophysiological verification, revealed a response to K. V 7.2 It has high selectivity (K V 7.2 / K V The lead compound E0554 (7.4 = 1.70) showed significant activation of the KV7.2 channel, but its overall selectivity was insufficient, and it showed limited activity against KV at 10 μM. V Channel 7.1 generates a 16% current enhancement, posing a potential risk of cardiotoxicity (see appendix). Figure 2 This invention further discloses a method for eliminating E0554's influence on K. V 7.1 Potential cardiotoxicity, enhancing its effect on K V 7.2 Selectivity of the designed and synthesized series of K V 7.2 Channel opening agent.

[0025] The structural formulas of the compounds described in this invention are as follows: Q1 (Q-1)-Q30 (Q-30), E1 (E-1)-E70 (E-70), F1 (F-1)-F50 (F-50):

[0026]

[0027] .

[0028] The synthetic routes for compounds Q1-Q30 described in this invention are shown in Route I:

[0029] Reaction conditions: a: 1,4-dioxane, 70 ℃, 5h; b: CuI, K2CO3, 1,10-phenanthroline, DMSO, 120 ℃, 24h; c: R1-NH2, MeOH, rt, 12h.

[0030] The synthetic routes for compounds E1-E70 of this invention are shown in Route II:

[0031] Reaction conditions: d: Et3N, CH2Cl2, rt, 5h; e: Cu(OAc)2, K2CO3, CH2Cl2: DMF = 1:1, 100 ℃, 18h; f: NaOH, MeOH :THF : H2O = 6 : 6 : 1, rt, 4h; g: HATU, Et3N, DMF, rt, 12h.

[0032] The synthetic routes for compounds F1-F50 of this invention are shown in Route II:

[0033] Reaction conditions: h: DMAP, THF, rt, 2 h; i: trans-N,N′-Dimethyl-1,2-cyclohexanediamine, DMF, 120 ℃, 24 h; j: methylamine, MeOH, rt, 12 h; kNaOH, CH2Cl2, rt, 6 h.

[0034] Example 1 1-(3-benzoylquinoline-6-yl)- N 3-Methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (Q3)

[0035] The synthetic route for compound Q3 is as follows:

[0036] Reaction conditions: a: 1,4-dioxane, 70 ℃, 5 h; b: CuI K2CO3, 1,10-phenanthroline, DMSO, 120 ℃, 24 h; c: methylamine, MeOH, rt, 12 h.

[0037] Method: 1-Phenylacetyl-1-one (1.3 g, 10.0 mmol) and 2-amino-5-bromobenzaldehyde (2.0 g, 10.0 mmol) were added to 20 mL of 1,4-dioxane and reacted at 70 °C for 5 h. The reaction solution was concentrated and column chromatography was used to obtain 0.33 g of intermediate 1, with a yield of 10.6%. Methyl 2-oxo-1,2-dihydro-3-pyridinecarboxylate (0.15 g, 1.0 mmol), intermediate 1 (0.31 g, 1.0 mmol), anhydrous potassium carbonate (0.15 g, 1.1 mmol), cuprous iodide (0.02 g, 0.1 mmol), and 1,10-phenanthroline (0.02 g, 0.1 mmol) were added to 10 mL of dimethyl sulfoxide and reacted at 120 °C for 24 h. After cooling to room temperature, 10 mL of purified water was added, the organic phase was separated, dried, concentrated, and subjected to column chromatography to give 0.04 g of intermediate 2, with a yield of 10.4%.

[0038] Intermediate 2 (0.04 g, 0.1 mmol) was added to 15 mL of methanol, followed by 15 mL of aqueous methylamine solution at room temperature. The mixture was stirred at room temperature for 12 h, and the reaction solution was concentrated. The solution was then subjected to column chromatography to obtain compound Q3 (0.03 g) in 78.3% yield. 1 H NMR (600 MHz, DMSO) δ 9.40 (q, J = 4.8 Hz, 1H), 9.29 (d, J = 2.2 Hz, 1H), 8.82 (d, J = 2.3 Hz, 1H), 8.49 (dd, J = 7.3, 2.2 Hz, 1H), 8.35 (d, J = 2.4 Hz, 1H), 8.26 (d, J = 8.9Hz, 1H), 8.15 (dd, J = 6.6, 2.2 Hz, 1H), 8.04 (dd, J = 8.9, 2.4 Hz, 1H), 7.89(dd, J = 8.2, 1.4 Hz, 2H), 7.80 – 7.73 (m, 1H), 7.63 (t, J = 7.8 Hz, 2H), 6.69(t, J = 6.9 Hz, 1H), 2.83 (d, J = 4.8 Hz, 3H). 13 C NMR (151 MHz, DMSO) δ 194.77,163.83, 161.87, 151.33, 148.56, 144.62, 143.26, 139.57, 139.23, 136.90,133.88, 131.71, 130.75, 130.44, 129.94, 129.33, 127.73, 126.77, 121.62,107.14, 26.29. MS·(ESI): 384.3 [M+H] + .

[0039] Example 2 N -Methyl-1-[3-(2-methylbenzoyl)quinoline-6-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide (Q1)

[0040] The synthesis method of compound Q1 is the same as in Example 1, except that the capping starting material 1-phenylprop-2-yn-1-one is replaced with 1-(o-tolyl)prop-2-yn-1-one. The structure was confirmed by mass spectrometry, MS·(ESI): 398.2 [M+H] + .

[0041] Example 3 N -Methyl-1-[3-(2,4-dimethylbenzoyl)quinoline-6-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide (Q6)

[0042] The synthesis method of compound Q6 is the same as in Example 1, except that the starting material 1-phenylprop-2-yn-1-one is replaced with 1-(3,5-dimethylphenyl)prop-2-yn-1-one. The structure was confirmed by mass spectrometry, MS·(ESI): 414.1 [M+H] + .

[0043] Example 4 N -Methyl-1-[3-(3,4-dimethylbenzoyl)quinoline-6-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide (Q8)

[0044] The synthesis method of compound Q8 is the same as in Example 1, except that the starting material 1-phenylprop-2-yn-1-one is replaced with 1-(3,4-dimethylphenyl)prop-2-yn-1-one. The structure was confirmed by mass spectrometry, MS·(ESI): 414.3 [M+H] + .

[0045] Example 5 N -Methyl-1-[3-(4-ethylbenzoyl)quinoline-6-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide (Q11)

[0046] The synthesis method of compound Q11 is the same as in Example 1, except that the starting material 1-phenylprop-2-yn-1-one is replaced with 1-(4-ethylphenyl)prop-2-yn-1-one. The structure was confirmed by mass spectrometry, MS·(ESI): 414.1 [M+H] + .

[0047] Example 6 N -Methyl-1-[3-(2-naphthoyl)quinoline-6-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide (Q19)

[0048] The synthesis method of compound Q19 is the same as in Example 1, except that the starting material 1-phenylprop-2-yn-1-one is replaced with 1-(naphthyl-2-yl)prop-2-yn-1-one. The structure was confirmed by mass spectrometry, MS·(ESI): 436.1 [M+H] + .

[0049] Example 7 N -Methyl-1-[3-(4-fluorobenzoyl)quinoline-6-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide (Q22)

[0050] The synthesis method of compound Q22 is the same as in Example 1, except that the starting material 1-phenylprop-2-yn-1-one is replaced with 1-(4-fluorophenyl)prop-2-yn-1-one. The structure was confirmed by mass spectrometry, MS·(ESI): 404.1 [M+H] + .

[0051] Example 8 N -Methyl-1-[3-(2,4-difluorobenzoyl)quinoline-6-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide (Q24)

[0052] The synthesis method of compound Q24 is the same as in Example 1, except that the starting material 1-phenylprop-2-yn-1-one is replaced with 1-(2,4-difluorophenyl)prop-2-yn-1-one. The structure was confirmed by mass spectrometry, MS·(ESI): 422.0 [M+H] + .

[0053] Example 9 N -Methyl-1-[3-(4-chlorobenzoyl)quinoline-6-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide (Q26)

[0054] The synthesis method of compound Q26 is the same as in Example 1, except that the starting material 1-phenylprop-2-yn-1-one is replaced with 1-(4-chlorophenyl)prop-2-yn-1-one. The structure was confirmed by mass spectrometry, MS·(ESI): 420.3 [M+H] + .

[0055] Example 10 N -Phenylacetyl-1-[3-(2-methylbenzoyl)quinoline-6-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide (Q30)

[0056] The synthesis method of compound Q30 is the same as in Example 1, except that the starting material, methylamine aqueous solution, is replaced with aniline. The structure was confirmed by mass spectrometry, MS·(ESI): 448.2 [M+H]. + .

[0057] Example 11 1-(4-Benzamidophenyl)- N 3-Methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (E10)

[0058] The synthetic route for compound E10 is as follows:

[0059] Reaction conditions: d: Et3N, CH2Cl2, rt, 5 h; e: Cu(OAc)2, K2CO3, CH2Cl2: DMF = 1:1, 100 ℃, 18 h; f: NaOH, MeOH :THF : H2O = 6 : 6 : 1, rt, 4 h; g: HATU, Et3N,DMF, rt, 12 h.

[0060] Method: p-Aminophenylboronic acid (5.00 mmol) was dissolved in dry CH2Cl2, and an appropriate amount of Et3N (2.00 eq) was added. Then, benzoyl chloride (1.2 eq) was slowly added dropwise to the mixture, and the reaction was stirred at room temperature until complete. The solvent was removed under reduced pressure, and the solid was washed with ethyl acetate to give intermediate 3 in 90% yield.

[0061] Intermediate 1 (4.00 mmol) was added to a dry 50 mL round-bottom flask and dissolved in 20 mL of a mixed solution of CH2Cl2 and DMF. Methyl 2-oxo-1,2-dihydro-3-pyridinecarboxylate (1.2 eq), copper acetate (0.15 eq), and K2CO3 (2 eq) were added sequentially to the mixed solution, and the mixture was refluxed at 100 °C for 18 h. After the reaction was completed by TLC monitoring, the mixture was extracted with ethyl acetate (3 × 50 mL), the organic phases were combined, the solvent was removed under reduced pressure, and the mixture was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain intermediate 4 (methyl 1-(4-benzamidophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate) in 30% yield. 1 H NMR (600 MHz, DMSO) δ 10.46 (s, 1H), 8.17 – 8.06 (m, 1H), 8.03 – 7.87 (m, 5H), 7.67 – 7.59 (m, 1H), 7.56 (t, J= 7.2 Hz, 2H), 7.40 (dd, J = 8.8, 1.1 Hz, 2H), 6.45 – 6.36 (m, 1H), 3.76 (d, J = 1.1 Hz, 3H). 13 C NMR (151 MHz, DMSO) δ 166.24,165.60, 165.07, 158.69, 158.67, 145.14, 144.85, 144.68, 144.50, 139.72,136.22, 136.20, 135.18, 132.24, 128.93, 128.20, 127.59, 127.56, 121.49,121.13, 121.03, 104.97, 104.93, 60.90, 52.31, 40.51, 14.61. Intermediate 4 (3 mmol) was added to a 50 mL round-bottom flask containing solvent (MeOH : THF : H2O = 6 mL : 6 mL : 1 mL), and NaOH (2 eq) was added. The mixture was stirred at room temperature until the reaction was complete (ERKH : MeOH = 20 : 1). The pH was adjusted to 2 by adding concentrated hydrochloric acid, and the mixture was filtered. The filter cake was washed with a small amount of ethyl acetate to give intermediate 5 (1-(4-benzamidophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid) in 95% yield. 1 H NMR (600 MHz, DMSO) δ 10.57(s, 1H), 8.50 (dd, J = 7.3, 2.1 Hz, 1H), 8.23 ​​(dd, J = 6.6, 2.1 Hz, 1H), 7.99(ddd, J = 15.7, 7.4, 1.6 Hz, 4H), 7.67 – 7.60 (m, 1H), 7.56 (dd, J = 8.3, 6.9Hz, 2H), 7.54 – 7.50 (m, 2H), 6.81 (t, J = 6.9 Hz, 1H). 13C NMR (151 MHz, DMSO)δ 166.34, 165.23, 164.27, 146.64, 145.73, 140.42, 135.05, 134.83, 132.32,128.94, 128.24, 127.44, 121.14, 117.74, 108.92, 49.06, 40.46. An appropriate amount of intermediate 5 (2 mmol) was dissolved in a 50 mL round-bottom flask containing 10 mL of DMF. Methylamine, HATU, and Et3N were added sequentially, and the mixture was stirred at room temperature until the reaction was complete. Extraction was performed with EtOAc (3 × 50 mL). The organic phases were combined, the solvent was removed under reduced pressure, and the product was purified by column chromatography (dichloromethane:methanol = 50:1) to obtain 30 mg of the final product, yield: 35%. MS·(ESI): 348.3 [M+H] + . 1 H NMR (600 MHz, DMSO- d 6) δ 10.48 (s, 1H), 9.48 (d, J = 5.0 Hz, 1H), 8.44 (dd, J = 7.2, 2.2 Hz, 1H), 8.03 – 7.97 (m, 3H), 7.96 – 7.90 (m, 2H), 7.65 – 7.60 (m, 1H), 7.57 (dd, J = 8.2, 6.8 Hz, 2H), 7.49 – 7.41 (m, 2H), 6.65– 6.56 (m, 1H), 2.83 (d, J = 4.8 Hz, 3H). 13 C NMR (151 MHz, DMSO- d 6) δ 166.26,164.01, 161.90, 144.15, 143.54, 139.89, 135.96, 135.16, 132.26, 128.94,128.20, 127.58, 121.34, 120.97, 106.74, 26.23. MS·(ESI): 348.3 [M+H] + .

[0062] Example 12 N -Methyl-1-(4-(2-methylbenzamido)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (E1)

[0063] The synthesis of compound E1 was similar to that of E10, except that the starting material benzoyl chloride was replaced with 2-methylbenzoyl chloride. The product structure was confirmed by mass spectrometry (MS·(ESI): 360.2 [MH)). - .

[0064] Example 13 N -Methyl-1-(4-(3-methylbenzamido)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (E2)

[0065] The synthesis of compound E2 was similar to that of E10, except that the starting material benzoyl chloride was replaced with 3-methylbenzoyl chloride. The product structure was confirmed by mass spectrometry, MS·(ESI): 360.1 [MH] - .

[0066] Example 14 N-Methyl-1-(4-(4-methylbenzamido)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (E3)

[0067] The synthesis of compound E3 is similar to that of E10, except that the starting material benzoyl chloride is replaced with p-methylbenzoyl chloride. MS (ESI): 360.2 [MH] - . 1 H NMR (600 MHz, DMSO) δ 10.38 (s, 1H), 9.48 (q, J = 4.8Hz, 1H), 8.43 (dd, J = 7.2, 2.2 Hz, 1H), 7.99 (dd, J = 6.6, 2.2 Hz, 1H), 7.97 –7.84 (m, 4H), 7.47 – 7.39 (m, 2H), 7.39 – 7.33 (m, 2H), 6.60 (dd, J = 7.2, 6.6Hz, 1H), 2.82 (d, J = 4.8 Hz, 3H), 2.40 (s, 3H). 13C NMR (151 MHz, DMSO) δ166.04, 164.01, 161.90, 144.14, 143.55, 142.32, 139.97, 135.85, 132.26,129.45, 128.24, 127.54, 121.33, 120.94, 106.74, 26.23, 21.51. MS·(ESI):360.2 [MH] - .

[0068] Example 15 N -Methyl-1-(4-(2,4-dimethylbenzamido)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (E5)

[0069] The synthesis of compound E5 was similar to that of E10, except that the starting material benzoyl chloride was replaced with 2,4-dimethylbenzoyl chloride. The product structure was confirmed by mass spectrometry (MS·(ESI): 374.3 [MH)). - .

[0070] Example 16 N -Methyl-1-(4-(3-ethylbenzamido)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (E12)

[0071] The synthesis of compound E12 was similar to that of E10, except that the starting material benzoyl chloride was replaced with 3-ethylbenzoyl chloride. The product structure was confirmed by mass spectrometry (MS·(ESI): 360.2 [MH)). - .

[0072] Example 17 N -Methyl-1-(4-(3-isopropylbenzamido)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (E23)

[0073] The synthesis of compound E23 was similar to that of E10, except that the starting material benzoyl chloride was replaced with 3-isopropylbenzoyl chloride. The product structure was confirmed by mass spectrometry (MS·(ESI): 390.2 [M+H)). + .

[0074] Example 18 N -Methyl-1-(4-(4-fluorobenzamido)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (E35)

[0075] The synthesis of compound E35 is similar to that of E10, except that the starting material benzoyl chloride is replaced with p-fluorobenzoyl chloride. MS·(ESI): 366.1 [M+H] + . 1 H NMR (600 MHz, DMSO) δ 10.48 (s, 1H), 9.47 (q, J = 4.9Hz, 1H), 8.43 (ddd, J = 7.2, 2.3, 1.1 Hz, 1H), 8.14 – 8.03 (m, 2H), 7.99 (ddd, J = 6.6, 2.3, 1.1 Hz, 1H), 7.95 – 7.87 (m, 2H), 7.49 – 7.43 (m, 2H), 7.40(td, J = 8.9, 1.2 Hz, 2H), 6.60 (td, J = 6.9, 1.1 Hz, 1H), 2.82 (dd, J = 4.8, 1.1 Hz, 3H). 13 C NMR (151 MHz, DMSO) δ 165.13, 164.01, 163.83, 161.90, 144.16,143.54, 139.79, 136.02, 131.59, 131.57, 131.01, 130.95, 127.60, 121.34,121.02, 115.97, 115.83, 106.75, 40.51, 26.23. MS·(ESI): 366.1 [M+H] + .

[0076] Example 19 N -Methyl-1-(4-(3,4-difluorobenzamido)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (E40)

[0077] The synthesis of compound E40 was similar to that of E10, except that the starting material benzoyl chloride was replaced with 3,4-difluorobenzoyl chloride. The product structure was confirmed by mass spectrometry (MS·(ESI): 382.2 [MH)). - .

[0078] Example 20 N-Methyl-1-(4-(4-trifluoromethylbenzamido)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (E52)

[0079] The synthesis of compound E52 was similar to that of E10, except that the starting material benzoyl chloride was replaced with 4-trifluoromethylbenzoyl chloride. The product structure was confirmed by mass spectrometry, MS·(ESI): 416.2 [M+H] + .

[0080] Example 21 1-[4-(1-naphthoylamino)phenyl]- N 3-Methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (E56)

[0081] The synthesis of compound E56 was similar to that of E10, except that the starting material benzoyl chloride was replaced with 1-naphthoyl chloride. The product structure was confirmed by mass spectrometry, MS·(ESI): 398.2 [M+H] + .

[0082] Example 22 1-[4-benzoylaminophenyl]- N -(1 H (-indol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide (E65)

[0083] The synthesis of compound E65 is similar to that of E10, except that the starting material methylamine reacting with intermediate 5 is replaced with 5-aminoindole. The product structure was confirmed by mass spectrometry, MS·(ESI): 449.1 [M+H] + .

[0084] Example 23 1-(1-benzoyl-1 H -indol-5-yl)- N 3-Methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (F3)

[0085] The synthetic route for compound F3 is as follows:

[0086] Reaction conditions: h: DMAP, THF, rt, 2 h; i: trans-N,N′-Dimethyl-1,2-cyclohexanediamine, DMF, 120 ℃, 24 h; j: methylamine, MeOH, rt, 12 h; kNaOH, CH2Cl2, rt, 6 h.

[0087] Methods: Di-tert-butyl dicarbonate (15.5 mmol) was added to a THF (50 mL) solution of 5-bromoindole (5.0 mmol) and DMAP (6.1 mg, 0.05 mmol). The reaction mixture was stirred at room temperature for 2 hours, followed by concentration under reduced pressure. The residue was purified by column chromatography to give intermediate 6. CuI (0.2 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (0.4 mmol), methyl 2-oxo-1,2-dihydropyridine-3-carboxylic acid (1.0 mmol), intermediate 6 (1.2 mmol), potassium carbonate (2.0 mmol), and DMF (10 mL) were added sequentially to a dry reaction flask. The reaction flask was evacuated and purged with nitrogen (cycled three times), and the mixture was then heated to 120 °C and stirred for 24 hours. After the reaction was complete, the crude product mixture was diluted with chloroform (15 mL), filtered through diatomaceous earth, and eluted with additional chloroform (20 mL). The filtrate was washed successively with ammonia solution and brine. The combined aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by rapid column chromatography to give intermediate 7 (white solid, 74% yield).

[0088] Intermediate 7 (1.0 mmol) was dissolved in methanol (10 mL), and an aqueous solution of methylamine (10 mL) was added at room temperature. The mixture was stirred for 12 hours and then concentrated under reduced pressure. Intermediate 8 was obtained by column chromatography.

[0089] Intermediate 8 (1.0 mmol), sodium hydroxide (0.4 g, 1.0 mmol), and tetrabutylammonium bromide (0.05 mmol) were dissolved in anhydrous dichloromethane (5 mL). Benzoyl chloride (0.14 g, 1.0 mmol) was then added at 0–5 °C. The reaction mixture was stirred at room temperature for 6 hours, and then water (10 mL) was added. The organic phase was separated, dried, concentrated under reduced pressure, and purified by column chromatography to give a white solid product F3 (yield 41.5%). MS·(ESI): 372.1 [M+H] + , 1 H NMR (600 MHz, DMSO-) d6) δ 9.54 (d, J = 5.6 Hz, 1H), 8.52 (dd, J = 7.2, 2.2 Hz, 1H), 8.42 (d, J = 8.7 Hz, 1H), 8.11 (dd, J = 6.6, 2.2 Hz, 1H), 7.92 – 7.82 (m, 3H), 7.81 – 7.77 (m, 1H), 7.69 (t, J = 7.6 Hz, 2H), 7.60 (d, J = 3.6 Hz, 1H), 7.50 (dd, J = 8.7, 2.2 Hz, 1H), 6.90 (d, J = 3.7 Hz, 1H), 6.69 (t, J = 6.9 Hz, 1H), 2.88 (d, J = 4.8 Hz, 3H). 13 C NMR (151 MHz, DMSO- d 6) δ 168.78, 164.02, 162.07,144.21, 143.78, 136.64, 135.34, 134.11, 132.83, 131.37, 130.25, 129.66,129.28, 123.86, 121.39, 120.01, 116.46, 108.81, 106.70, 26.23.

[0090] Example 24 N -Methyl-1-[1-(2-methylbenzoyl)-1 H [-indol-5-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide (F1)

[0091] The synthesis of compound F1 was similar to that of F3, except that the starting material benzoyl chloride, which reacts with intermediate 8, was replaced with 2-methylbenzoyl chloride. The product structure was confirmed by mass spectrometry, MS·(ESI): 386.2 [M+H] + .

[0092] Example 25 N -Methyl-1-[1-(4-ethylbenzoyl)-1 H [-indol-5-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide (F8)

[0093] The synthesis of compound F8 was similar to that of F3, except that the starting material benzoyl chloride reacting with intermediate 8 was replaced with 4-ethylbenzoyl chloride. The product structure was confirmed by mass spectrometry, MS·(ESI): 400.1 [M+H] + .

[0094] Example 26 N -Methyl-1-[1-(4-propylbenzoyl)-1 H [-indol-5-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide (F16)

[0095] The synthesis of compound F16 is similar to that of F3, except that the starting material benzoyl chloride reacting with intermediate 8 is replaced with 4-propylbenzoyl chloride. The product structure was confirmed by mass spectrometry, MS·(ESI): 414.2 [M+H] + .

[0096] Example 27 N -Methyl-1-[1-(3,4-dipropylbenzoyl)-1 H [-indol-5-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide (F19)

[0097] The synthesis of compound F19 was similar to that of F3, except that the starting material benzoyl chloride, which reacts with intermediate 8, was replaced with 3,4-dipropylbenzoyl chloride. The product structure was confirmed by mass spectrometry, MS·(ESI): 456.3 [M+H] + .

[0098] Example 28 N -Methyl-1-[1-(2-Butylbenzoyl)-1 H [-indol-5-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide (F20)

[0099] The synthesis of compound F20 is similar to that of F3, except that the starting material benzoyl chloride, which reacts with intermediate 8, is replaced with 2-butylbenzoyl chloride. The product structure was confirmed by mass spectrometry, MS·(ESI): 428.2 [M+H] + .

[0100] Example 29 N -Methyl-1-[1-(4-chlorobenzoyl)-1 H [-indol-5-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide (F36)

[0101] The synthesis of compound F36 was similar to that of F3, except that the starting material benzoyl chloride, which reacts with intermediate 8, was replaced with 4-chlorobenzoyl chloride. The product structure was confirmed by mass spectrometry, MS·(ESI): 406.1 [M+H] + .

[0102] Example 30 N -Methyl-1-[1-(4-trifluoromethylbenzoyl)-1 H [-indol-5-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide (F40)

[0103] The synthesis of compound F40 is similar to that of F3, except that the starting material benzoyl chloride, which reacts with intermediate 8, is replaced with 4-trifluoromethylbenzoyl chloride. The structure of the product was confirmed by mass spectrometry, MS·(ESI): 440.2 [M+H] + .

[0104] Example 31 N -Methyl-1-[1-(3-trifluoromethylbenzoyl)-1 H [-indol-5-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide (F41)

[0105] The synthesis of compound F41 was similar to that of F3, except that the starting material benzoyl chloride, which reacts with intermediate 8, was replaced with 3-trifluoromethylbenzoyl chloride. The product structure was confirmed by mass spectrometry, MS·(ESI): 440.2 [M+H] + .

[0106] Example 32 Electrophysiological activity test of the compound (1) Cell culture and transfection Cell passage and spreading: The stable K expression cells used in this experiment V 7.1, K V 7.2, K V 7.2 / 7.3 and K V Cell lines from channel 7.4 were cultured in appropriate media (DMEM, DMEM / F12, or F12), supplemented with 10% fetal bovine serum and 1% penicillin-dextrose antibody, and cultured at 37°C and 5% CO2 saturated humidity. K expression was achieved. V7.2 CHO cells were cultured in DMEM / F12 (Gibco) medium. When the cell confluence reached 80%–90%, the medium was discarded, and the cell culture was terminated by trypsin digestion. The cells were then resuspended as a cell suspension. Part of the suspension was used for further passage (seeding density approximately 20%), and the remainder was seeded on coverslips for subsequent electrophysiological experiments.

[0107] Cell transfection: CHO cells were transfected at a rate of 5 × 10⁻⁶. 4 The cells were seeded in 24-well plates and transfected when the confluence reached 60–70%. A transfection mixture was prepared in 520 µL of DMEM / F12 medium, and 500 ng of the target plasmid, 300 ng of green fluorescent protein (GFP) plasmid, and 1.5 µL of FuGENE® HD transfection reagent (Promega (Beijing) Biotechnology Co., Ltd.) were added sequentially. After gentle mixing, the mixture was incubated at room temperature for 15–20 minutes. The mixture was then added to the cell culture wells and incubated for another 24–48 hours. Electrophysiological recordings were performed after successful transfection was confirmed by GFP fluorescence.

[0108] (2) cDNA plasmids and mutant plasmids K V 7.5 and K V 7.3 cDNA plasmids (NM_001160132.2, AF091247) were provided by Hebei Medical University. V 7.2 Mutant plasmid (F112L-K) V 7.2, N289L-K V 7.2, Y118A-K V 7.2, W288A-K V 7.2) Constructed by Wuhan Zhongmaiying Biotechnology Co., Ltd., and verified to be correct by sequencing.

[0109] (3) Electrophysiological experiments Patch-clamp experiments were performed at room temperature using an EPC-10 amplifier and whole-cell recording mode. Glass electrode resistance was maintained at 3–6 MΩ. The experiment utilized a gravity-driven perfusion system to maintain external fluid stability and administer medication. The signal sampling rate was 10 kHz, with a 2 kHz filter, and 60%–80% series resistance compensation was applied after whole-cell formation. Ka was recorded. + When using channel current, the solution formulation is as follows: Extracellular fluid: 144 mmol / L NaCl (Sigma), 5 mmol / L KCl, 10 mmol / L HEPES, 1 mmol / L MgCl2, 10 mmol / L D-glucose (D-Glu), 2 mmol / L CaCl2, pH adjusted to 7.3 with NaOH; Intracellular fluid: 150 mmol / L KCl, 1 mmol / L MgCl2, 5 mmol / L EDTA, 10 mmol / L HEPES, 5 mmol / L MgATP, pH adjusted to 7.2 with KOH.

[0110] The electrophysiological recording parameters were as follows: the cell membrane clamping voltage was set to -80 mV. The test stimulation included a single pulse (-10 mV) and step depolarization (…). 120 mV to +40 mV, step 10 mV). (Passed) Calculate the relative current (I / I0) based on the current value at 10 mV, and then... 120 mV induced tail current analysis half-maximum activation voltage (ΔV) 1 / 2 ).

[0111] (4) Data statistics Experimental data were processed using Microsoft Excel and Origin 8.0 software. Voltage-dependent activation curves were fitted using the Boltzmann equation, dose-response curves using the Hill equation, and activation / deactivation biomechanics curves using a single exponential equation.

[0112] Boltzmann equations:

[0113] Where Gmax is the maximum conductance, Gmin is the minimum conductance, V1 / 2 is the voltage at which the maximum conductance is reached (50%), and S is the slope factor.

[0114] Hill's equation:

[0115] In the formula, EC 50 The half-maximal effective concentration (the drug concentration that produces 50% of the maximum effect) is given by P, where P is the Hill coefficient.

[0116] The compound of this invention is effective against K V 7.2 The opening activity of potassium channels is shown in Table 1.

[0117] Table 1. The effect of compounds on K V 7.2 Potassium channel opening activity

[0118] a I / I control represents the ratio of K V 7.2 channel current in the presence of 10 μM compounds to the control current (I control ) at a test potential of -10mV (n=6). +++: (>1.80), ++: (1.30—1.80), +: (<1.30) As shown in Table 1, the listed compounds have a significant effect on K. V 7.2 Compounds exhibiting varying degrees of opening activity were identified among the 30 compounds tested. Compounds marked with +++ (i.e., opening factor > 1.80), such as Q1, Q3, E10, F3, and F16, showed different levels of opening activity. Furthermore, the activity differences between compounds like E1, E2, E5, E10, and E56 indicate that structural tweaks (such as changes in substituent position or type) significantly impact opening activity. Experiments revealed that F3 affects K... V 7.2 It has a significant opening effect (EC) 50 = 1.64 ± 0.45 μM), further measurements were performed on the effect of 10 μM F3 on K. V The 7-channel subtypes showed significant differences, which could significantly enhance K V 7.2 Current (1.92 times) and K V It provides 7.2 / 7.3 (2.39 times) current, but has almost no opening effect on other subtypes. Its effect on K... V The selectivity index of 7.2 / 7.3 (M channel) is particularly prominent (K) V 7.1: SI = 1865; K V 7.4: SI = 1624).

[0119] Molecular dynamics simulations and amino acid mutation studies jointly revealed the highly selective binding mechanism of F3. This compound is stably bound to K through hydrogen bonding with Y118 and N289, and π-π stacking interactions with F112 and Y118. V 7.2 VSD-PD gap. This invention further confirms that mutations in key residues F112, Y118, and N289 all lead to a significant weakening or disappearance of the activation effect. Furthermore, F3, in combination with RTG or ztz240, exhibits a synergistic activation effect, and 10 μM F3 can effectively activate the RTG key site mutant (W236L-K). V 7.2), confirming that its site of action differs from known K. V7. Opening agents provide the basis for achieving subtype-selective activation.

[0120] Example 33: Pharmacodynamic evaluation of representative compounds in an epilepsy model Based on compounds Q3, E10, E3, E35, and F3, K V The highly selective activation of channels 7.2 / 7.3 was utilized in this invention, employing a maximal electroconvulsive shock (MES) model, a pentylenetetrazol (PTZ)-induced epilepsy model, and a 6Hz electrical stimulation model to systematically evaluate its therapeutic effects on acute and chronic epileptic seizures. The specific methods are as follows: Mice used in the experiments were housed in a standard environment (22 ± 1℃, 12-hour light-dark cycle). The experimental procedures strictly adhered to animal welfare and ethical guidelines and were approved by the Animal Ethics Committee of Hebei Medical University. Maximum Electroconvulsive Therapy (MES): Using a GRASS Technologies S48 Stimulator, stimulation parameters were set to 60 Hz and 110 V. C57BL / 6 mice were randomly divided into a solvent control group and five drug dosage groups. Electrical stimulation was administered one hour after intraperitoneal administration. The incidence of seizures was recorded using hind limb rigidity as the observation index. Pentylenetetrazole (PTZ)-induced epilepsy model experiment: C57BL / 6 mice were randomly divided into a solvent control group and five drug dosage groups. The control group received intraperitoneal injection of physiological saline, while the drug group received different doses of the test drug. One hour later, PTZ (80 mg / kg) was injected intraperitoneally to induce the epilepsy model. The model was observed and recorded for 30 minutes, with hind limb rigidity used as the observation index, and the drug protection rate was calculated. Experiment on 6Hz electrical stimulation to ignite an epilepsy model: C57BL / 6 mice were randomly divided into a solvent control group and five dosage groups for the test drug. The electroconvulsive device was set with stimulation parameters of 44 mA, 0.2 ms pulse width, 3 s duration, and 6 Hz frequency. Before stimulation, 0.5% lidocaine solution was applied topically to the eyes, followed by stimulation with a corneal electrode. Epilepsy seizure behavior was observed and recorded within 30 minutes. After successful modeling by continuous stimulation for about 3 weeks, the drug was administered intraperitoneally once a day for 3 consecutive days. One hour after drug administration, electrical stimulation was used to ignite the drug, and the therapeutic effect was observed.

[0121] Example 34: Neurotoxicity test observation of representative compounds The rotarod test was used to assess the potential neurotoxicity of representative compounds Q3, E10, E3, E35, and F3. Mice underwent rotarod training (20 r / min) for three consecutive days before the formal experiment. After successful training, mice were randomly divided into a solvent control group and five dosage groups for the test drugs. One hour after gavage administration, the time the mice spent on the rotarod was recorded. Each animal was tested three times, and the average value was taken. The toxicity was evaluated by comparing the average value with the control group.

[0122] In various classic mouse models of epilepsy, K V 7.2 All open-label formulations exhibited good antiepileptic activity and safety. In the PTZ-induced model, all compounds significantly prolonged seizure latency and shortened seizure duration in a dose-dependent manner. In the 6Hz corneal electrical stimulation model, all compounds reduced the incidence of higher-order seizures and shortened seizure duration. In the maximal electroconvulsive therapy (MES) experiment, the anticonvulsant efficacy of F3 at a dose of 20 mg / kg achieved a 100% protection rate. More importantly, the rotarod experiment demonstrated that F3 did not affect motor coordination at high doses (150 mg / kg), indicating that F3 has a broader therapeutic safety window and excellent preclinical development potential. Specific experimental data are shown in Table 2 below.

[0123] Table 2. Pharmacodynamic and toxicity evaluations of representative compounds

[0124] In summary, the K prepared by this invention V 7.2 Selective openers have promising applications in the treatment of epilepsy.

Claims

1. A compound represented by formula (I) below, or a pharmaceutically acceptable salt, hydrate, deuterated derivative, or prodrug thereof; Equation (Ⅰ), in, Ar is independently selected from substituted or unsubstituted C6-C. 10 Aryl or five- or six-membered heteroaryl, fused aromatic or heterocyclic ring; A1, A2, and A3 are each independently selected from CR. 1 Or N, R 1 Substituents for C; n is independently selected from 1 or 2; Q is selected independently from CR 2 Or N; W is selected independently from CR 3 Or N; X is selected independently from CR 4 Or N; where X is CR 4 When X is N, Z is independently selected from substituted or unsubstituted C1-C3 alkyl, amino, -NH-CO-, -CO-NH-, urea, hydrazide, sulfonamide, etc.; when X is N, Z is independently selected from substituted or unsubstituted C1-C3 alkyl, carbonyl, etc. Y is selected independently from CR 5 Or carbonyl; R 1 R 2 R 3 R 4 R 5 R1 and R2 are independently selected from H, substituted or unsubstituted C1-C, respectively. 10 Alkyl, substituted or unsubstituted C6-C 12 aryl or heteroaryl, substituted or unsubstituted 3-12 membered alicyclic or heterocyclic groups; The substitution refers to the substitution of one or more hydrogen atoms on a group by a substituent selected from the group consisting of: halogen atoms, carbonyl, carboxyl, hydroxyl, amino, nitro, cyano, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkoxycarbonyl, C1-C6 amide, substituted or unsubstituted C1-C6 groups. 10 alkyl.

2. The compound of claim 1, or its pharmaceutically acceptable salt, hydrate, deuterated derivative, or prodrug, characterized in that, The structural formula of the compound is shown in formula (II): Formula (II).

3. The compound of claim 1, or its pharmaceutically acceptable salt, hydrate, deuterated derivative, or prodrug, characterized in that, The structural formula of the compound is shown in formula (Ⅲ): Formula (III).

4. The compound of claim 3, or a pharmaceutically acceptable salt, hydrate, deuterated derivative, or prodrug thereof, characterized in that, Q is CR 2 Or N; Z is CH2; R1 is H; R2 is methyl, substituted or unsubstituted phenyl.

5. The compound of claim 4 or a pharmaceutically acceptable salt, hydrate, deuterated derivative, or prodrug thereof, characterized in that, The compounds are any of compounds Q-1 to Q-30, E-1 to E-70, and F-1 to F-50 as shown in the specification.

6. The compound of claim 5 or a pharmaceutically acceptable salt, hydrate, deuterated derivative, or prodrug thereof, characterized in that, The compounds are as shown in the specification, including any one of compounds Q-1, Q-3, Q-6, Q-8, Q-11, Q-19, Q-22, Q-24, Q-26, Q-30, E-1, E-2, E-3, E-5, E-10, E-12, E-23, E-35, E-40, E-52, E-56, E-65, F-1, F-3, F-8, F-16, F-19, F-20, F-36, F-40, and F-41.

7. The compound of claim 6 or a pharmaceutically acceptable salt, hydrate, deuterated derivative, or prodrug thereof, characterized in that, The structural formula of the compound is: .

8. The compound as described in any one of claims 1-7, or a pharmaceutically acceptable salt, hydrate, deuterated derivative, or prodrug thereof, in the preparation of K V 7.2 Application in opener drugs.

9. The use of the compound as described in any one of claims 1-7, or a pharmaceutically acceptable salt, hydrate, deuterated derivative, or prodrug thereof, in the preparation of an antiepileptic drug.

10. The compound of any one of claims 1-7 is incorporated into a pharmaceutically acceptable salt excipient to form any pharmaceutically acceptable dosage form.

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