KR20190126525A - Novel sodium channel inhibitor compound, preparation method thereof, and pharmaceutical composition for prevention or treatment of sodium channel related diseases containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a novel sodium channel inhibiting compound, a method for producing the same, and a pharmaceutical composition for preventing or treating a sodium channel-related disease by including the same. According to the present invention, the novel sodium channel inhibiting compound is capable of inhibiting sodium channels excellently and, in particular, is a compound having excellent inhibitory activity on Nav 1.7 channel. As a pharmaceutical composition or health functional food composition containing the above as active ingredients, the present invention has beneficial effects capable of preventing, alleviating or treating sodium channel-related diseases such as pain disorders associated with sodium channel activity like Nav 1.7 channel-related diseases, specifically neuropathic pain, spontaneous provoked pain, paroxysmal extreme pain disorder, erythromelalgia, or erythromelalgia pain. The compound is represented by chemical formula 1.

Description

Novel sodium channel inhibitor compound, preparation method according to the present invention, and pharmaceutical composition for prevention or treatment of sodium channel related diseases the same as an active ingredient}

The present invention relates to novel sodium channel inhibitory compounds, methods for their preparation, and pharmaceutical compositions for the prevention or treatment of sodium channel related diseases comprising the same.

Neuropathic pain is chronic pathologic pain caused by nerve damage or abnormal neurological function (post-herpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, spinal cord injuries, etc.). It is known as one of the most severe pain. Axons and dehydration are caused by wounds and diseases affecting the peripheral nerves, resulting in neuropathic changes, initiating membrane remodeling in the damaged centripetal zone, and influencing to the intact, and in the central zone where neuropathic changes have occurred. Excessive ion release is induced to constitute an early neuropathic pain signal, excessively inducing spontaneous pain and continuously increasing dislocation to become chronic pain.

In order to treat such neuropathic pain, a method of inhibiting voltage-gated sodium channels (VGSCs) may be used. Neuropathy because VGSCs are ion channels that play a fundamental role in regulating cell stimulation and abnormal activity associated with several pathologies, including cardiac arrhythmias, epilepsy, neuropathic disease, ankylosing spasms, chronic and neuropathic pain It can be a good target for drugs for the treatment of sexual pain, and specifically, drugs that regulate the voltage-gated pore of VGSCs that selectively pass sodium ions to determine the electrical stimulation of sensory neurons. By controlling or inhibiting neuropathic afferent stimulation, it is possible to treat neuropathic pain (Non-Patent Document 1).

Sodium channels have nine variants from Nav1.1 to 1.9, which are classified based on the type of membrane protein they are made of. Diseases associated with each sodium channel from Nav1.1 to 1.9 are ivory, especially among sodium channels, Nav 1.7 is associated with neuropathic pain, genetic pain disease is associated with mutations in the SCN9A gene and is seizure It has been shown to be directly related to paroxysmal extreme pain disorder, erythromelal pain, and erythema pain, and the development of drugs targeting pain-related VGSCs is urgently needed.

Although local anesthetic, lidocaine, has been suggested in the clinic as a first-generation drug for the treatment of neuropathic pain, these first-generation drugs potentially affect sodium channels, but are non-selective sodium channel inhibitors, each of which is a subtype. There is no selectivity for Therefore, there may be systemic side effects due to CNS passage, and there are side effects that may indicate potential chronic symptoms.

Therefore, the present inventors are trying to develop a neuropathic pain treatment agent through the regulation and inhibition of VGSCs, the compound according to the present invention has a remarkably excellent inhibitory effect against Nav1.7, especially among VGSCs, central neuropathy The present invention was completed by confirming the excellent pain inhibition.

J.Pain 7 (15), Supplement 1, 2006, S3-S12

It is an object of the present invention to provide novel sodium channel inhibitory compounds.

Another object of the present invention is to provide a method for preparing the novel sodium channel inhibitory compound.

Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of sodium channel-related diseases containing the novel sodium channel inhibitory compound as an active ingredient.

Another object of the present invention to provide a dietary supplement for the prevention or improvement of sodium channel-related diseases containing the novel sodium channel inhibitory compound as an active ingredient.

In order to achieve the above object,

In one aspect of the invention,

A compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is provided.

[Formula 1]

(In Formula 1,

R ¹ is unsubstituted or substituted C _6-10 aryl or unsubstituted or substituted 5-10 membered heteroaryl including one or more heteroatoms selected from the group consisting of N, O and S,

Wherein the substituted C _6-10 aryl or substituted 5-10 atom heteroaryl is halogen, C _1-10 straight or branched alkyl, C _1-10 straight or branched alkoxy, —NO ₂ , non- Ring or substituted C _6-10 aryl, (unsubstituted or substituted 4-8 membered heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of N, O and S), (N, O and Unsubstituted or substituted 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of S), unsubstituted or substituted C _6-10 aryloxy, and unsubstituted or substituted C _6- At least one substituent selected from the group consisting of ₁₀ arylC _1-3 alkoxy,

Here again, said substituted C _6-10 aryl, substituted 4-8 atoms heterocycloalkyl, substituted 5-10 atoms heteroaryl, substituted C _6-10 aryloxy, or substituted C _{6- 10} arylC _1-3 alkoxy is one or more selected from the group consisting of C _1-5 straight or branched alkyl, unsubstituted or substituted with one or more halogens, C _1-5 linear or branched alkoxy, halogen and —CN Substituents are substituted;

R ² is hydrogen, hydroxy, or oxo (═O);

R ³ is hydrogen, methyl, ethyl, unsubstituted or substituted C _6-10 aryl, or an unsubstituted or substituted 5-10 atom comprising one or more heteroatoms selected from the group consisting of N, O and S Heteroaryl; And

R ⁴ is — (C═O) —NR ⁵ R ⁶ ), unsubstituted or substituted C _6-10 aryl, unsubstituted or substituted C _6-10 aryl-C _1-3 alkyl, N, O and S Unsubstituted or substituted 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of or unsubstituted or substituted comprising one or more heteroatoms selected from the group consisting of N, O and S 5-10 membered heteroaryl-C _1-3 alkyl,

Wherein the substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl is a group consisting of C _1-5 straight or branched alkyl, C _1-5 straight or branched alkoxy, halogen and —CN One or more substituents selected from

R ⁵ and R ⁶ are independently hydrogen or C _1-5 straight or branched alkyl).

In another aspect of the invention,

As shown in Scheme 1 below,

There is provided a method for preparing a compound represented by Chemical Formula 1, comprising the step of reacting a compound represented by Chemical Formula 2 with a compound represented by Chemical Formula 3 to prepare a compound represented by Chemical Formula 1.

Scheme 1

(In the above Reaction Scheme 1,

R ¹ , R ² , R ³ , and R ⁴ are the same as defined in Chemical Formula 1, and

X is H, or Cl).

Furthermore, in another aspect of the present invention,

Provided is a pharmaceutical composition for preventing or treating sodium channel-related diseases containing a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

In another aspect of the invention,

Provided is a health functional food composition for preventing or ameliorating sodium channel related diseases containing a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

The novel sodium channel inhibitory compound according to the present invention can inhibit sodium channel excellently, and is particularly a compound having excellent Nav 1.7 channel inhibitory activity. As a pharmaceutical composition or health functional food composition containing the same as an active ingredient, sodium Channel-related diseases, such as pain disorders associated with sodium channel activity, such as Nav 1.7 channel-related diseases such as neuropathic pain, spontaneous provoked pain, seizure pain disorders ( There are useful effects that can prevent, ameliorate, or treat diseases such as paroxysmal extreme pain disorder, erythromelalgia, or erythema pain.

Hereinafter, the present invention will be described in detail.

The following description is presented to aid in understanding the invention, and the present invention is not limited to the contents of the following description.

In one aspect of the invention,

A compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is provided.

[Formula 1]

(In Formula 1,

R ¹ is unsubstituted or substituted C _6-10 aryl or unsubstituted or substituted 5-10 membered heteroaryl including one or more heteroatoms selected from the group consisting of N, O and S,

Wherein the substituted C _6-10 aryl or substituted 5-10 atom heteroaryl is halogen, C _1-10 straight or branched alkyl, C _1-10 straight or branched alkoxy, —NO ₂ , non- Ring or substituted C _6-10 aryl, (unsubstituted or substituted 4-8 membered heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of N, O and S), (N, O and Unsubstituted or substituted 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of S), unsubstituted or substituted C _6-10 aryloxy, and unsubstituted or substituted C _6- At least one substituent selected from the group consisting of ₁₀ arylC _1-3 alkoxy,

Here again, said substituted C _6-10 aryl, substituted 4-8 atoms heterocycloalkyl, substituted 5-10 atoms heteroaryl, substituted C _6-10 aryloxy, or substituted C _{6- 10} arylC _1-3 alkoxy is one or more selected from the group consisting of C _1-5 straight or branched alkyl, unsubstituted or substituted with one or more halogens, C _1-5 linear or branched alkoxy, halogen and —CN Substituents are substituted;

R ² is hydrogen, hydroxy, or oxo (═O);

R ³ is hydrogen, methyl, ethyl, unsubstituted or substituted C _6-10 aryl, or an unsubstituted or substituted 5-10 atom comprising one or more heteroatoms selected from the group consisting of N, O and S Heteroaryl; And

R ⁴ is — (C═O) —NR ⁵ R ⁶ ), unsubstituted or substituted C _6-10 aryl, unsubstituted or substituted C _6-10 aryl-C _1-3 alkyl, N, O and S Unsubstituted or substituted 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of or unsubstituted or substituted comprising one or more heteroatoms selected from the group consisting of N, O and S 5-10 membered heteroaryl-C _1-3 alkyl,

Wherein the substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl is a group consisting of C _1-5 straight or branched alkyl, C _1-5 straight or branched alkoxy, halogen and —CN One or more substituents selected from

R ⁵ and R ⁶ are independently hydrogen or C _1-5 straight or branched alkyl).

In another aspect of the invention,

R ² may be hydrogen or oxo (═O).

R ³ may be hydrogen, methyl, or phenyl.

R ⁴ may be — (C═O) —NH ₂ ), C _6-10 aryl unsubstituted or substituted with one or more methoxy, or phenethyl.

In another aspect of the invention,

R ¹ is unsubstituted or substituted 5-10 membered heteroaryl including one or more heteroatoms selected from the group consisting of unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, or N, and O; ,

Wherein the substituted phenyl, substituted naphthyl, or substituted 5-10 membered heteroaryl is halogen, C _1-5 straight or branched alkyl, C _1-5 straight or branched alkoxy, —NO ₂ , Unsubstituted or substituted phenyl, (unsubstituted or substituted 4-6 membered heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of N, O and S), (N, and O from the group consisting of Unsubstituted or substituted 6-membered heteroaryl containing one or more heteroatoms selected, unsubstituted or substituted phenyloxy, and unsubstituted or substituted benzyloxy substituted with one or more substituents selected from the group consisting of Be,

Here again, the substituted phenyl, substituted 4-6 membered heterocycloalkyl, substituted 6 membered heteroaryl, substituted phenyloxy, or substituted benzyloxy are C ₁ unsubstituted or substituted with one or more halogens. One or more substituents selected from the group consisting of _-5 straight or branched alkyl, C _1-5 straight or branched alkoxy, halogen and -CN may be substituted.

In another aspect of the invention,

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In one embodiment of the invention,

The compound represented by Formula 1 may be a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is one selected from the following compound groups.

(1) (S) -2-((5- (benzyloxy) -1H-indol-3-yl) methylamino) propanamide;

(2) (S) -2-((5-bromo-1H-indol-3-yl) methylamino) propanamide;

(3) (S) -2-((5-chloro-1H-indol-3-yl) methylamino) propanamide;

(4) (S) -2-((6-fluoro-1H-indol-3-yl) methylamino) propanamide;

(5) (S) -2-((5-methoxy-1H-indol-3-yl) methylamino) propanamide;

(6) (S) -2-((7-nitro-1H-indol-3-yl) methylamino) propanamide;

(7) (S) -2-((5-chloro-1H-indol-3-yl) methylamino) -2-phenylacetamide;

(8) (S) -2-((1H-indol-3-yl) methylamino) -2-phenylacetamide;

(9) (S) -2-((5- (4-chlorophenyl) isoxazol-3-yl) methylamino) -2-phenylacetamide;

(10) (S) -2- (4- (4-fluorophenoxy) benzylamino) -2-phenylacetamide;

(11) (S) -2- (4- (4-chlorophenoxy) benzylamino) -2-phenylacetamide;

(12) 4-phenyl-N-((5- (3- (trifluoromethyl) phenyl) furan-2-yl) methyl) butan-2-amine;

(13) N- (4- (4-methylpiperazin-1-yl) benzyl) -4-phenylbutan-2-amine;

(14) N- (4-morpholinobenzyl) -4-phenylbutan-2-amine;

(15) N-((5- (4-chlorophenyl) furan-2-yl) methyl) -4-phenylbutan-2-amine;

(16) 4-phenyl-N- (4- (pyridin-4-yl) benzyl) butan-2-amine;

(17) N-((5- (4-chlorophenyl) isoxazol-3-yl) methyl) -4-phenylbutan-2-amine;

(18) N-((5- (3-chloro-4-methoxyphenyl) furan-2-yl) methyl) -4-phenylbutan-2-amine;

(19) 4-phenyl-N- (4- (pyrimidin-5-yl) benzyl) butan-2-amine;

(20) 4- (4-((4-phenylbutan-2-yl) aminomethyl) phenoxy) benzonitrile;

(21) N-((5-chloro-1H-indol-3-yl) methyl) -4-phenylbutan-2-amine;

(22) N-((1H-indol-3-yl) methyl) -4-phenylbutan-2-amine;

(23) N- (4- (4-fluorophenoxy) benzyl) -4-phenylbutan-2-amine;

(24) N- (4- (4-chlorophenoxy) benzyl) -4-phenylbutan-2-amine;

(25) N- (4-phenylbutan-2-yl)-[1,1'-biphenyl] -4-carboxamide;

(26) 3-methyl-N- (4-phenylbutan-2-yl) benzofuran-2-carboxamide;

(27) N- (4-phenylbutan-2-yl) -1-naphtamide;

(28) 3- (4-chlorophenyl) -5-methyl-N- (4-phenylbutan-2-yl) isoxazole-4-carboxamide;

(29) N-((1H-indol-3-yl) methyl) -1- (3,4,5-trimethoxyphenyl) methanamine;

(30) 1- (2-phenyl-1H-indol-3-yl) -N- (3,4,5-trimethoxyphenyl) methanamine;

(31) N- (4- (4-fluorophenoxy) benzyl) -1- (3,4,5-trimethoxyphenyl) methanamine;

(32) N- (4- (4-chlorophenoxy) benzyl) -1- (3,4,5-trimethoxyphenyl) methanamine;

(33) 1- (5- (benzyloxy) -1H-indol-3-yl) -N- (3,4,5-trimethoxybenzyl) methanamine;

(34) 1- (5-bromo-1H-indol-3-yl) -N- (3,4,5-trimethoxybenzyl) methanamine;

(35) 1- (6-fluoro-1H-indol-3-yl) -N- (3,4,5-trimethoxybenzyl) methanamine;

(36) 1- (5-methoxy-1H-indol-3-yl) -N- (3,4,5-trimethoxybenzyl) methanamine;

(37) 1- (7-nitro-1H-indol-3-yl) -N- (3,4,5-trimethoxybenzyl) methanamine;

(38) N- (3,4,5-trimethoxybenzyl)-[1,1'-biphenyl] -4-carboxamide;

(39) 3-methyl-N- (3,4,5-trimethoxybenzyl) benzofuran-2-carboxamide;

(40) N- (3,4,5-trimethoxybenzyl) -1-naphtamide; And

(41) N- (3,4,5-trimethoxybenzyl) quinoline-2-carboxamide.

The compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. It is obtained from non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids, and organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like. Examples of such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, eye Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suve Latex, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobene Sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1 Sulfonates, naphthalene-2-sulfonates, mandelate and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate produced by dissolving a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and adding an organic or inorganic acid. The solvent may be prepared by filtration and drying, or the solvent and the excess acid may be distilled under reduced pressure, dried, and then crystallized under an organic solvent.

Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. Corresponding salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg silver nitrate).

Furthermore, the present invention includes not only the compound represented by Formula 1 and pharmaceutically acceptable salts thereof, but also solvates, stereoisomers, hydrates, and the like that can be prepared therefrom.

In one aspect of the invention,

The compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof, solvate thereof, hydrate thereof and the like may be understood to be a sodium channel inhibiting compound.

In one embodiment of the invention,

The compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof, solvate thereof, hydrate thereof and the like may be understood to be a sodium channel 1.7 (Nav 1.7) inhibiting compound.

In another embodiment of the invention,

The compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, solvates thereof, hydrates thereof, and the like, exhibit excellent inhibitory activity on sodium channel 1.7, and in particular, show better inhibitory activity on sodium channel 1.7 than other subtypes. Can be understood to be a compound.

As described above,

In one embodiment of the present invention, using the following example compound as an example, it was confirmed that the sodium channel inhibitory activity, as shown in the following experimental example, in particular, excellent inhibitory activity on sodium channel 1.7.

Thus, the compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, solvates thereof, hydrates thereof, and the like, provided in the present invention, are related to the disease associated with sodium channels, that is, to the present time, the activity of sodium channels. A disease identified as being associated with, or a disease identified as being related to the expression of sodium channels, or experimentally, with regard to the activity of sodium channels, it may or may not be effective to prevent, ameliorate, improve, treat, etc. It can be understood to include all expected diseases, compounds, and the like provided in the present invention can be understood to be an effective ingredient that can exhibit the effects of prevention, improvement, improvement, treatment and the like.

In another aspect of the invention,

As shown in Scheme 1 below,

There is provided a method for preparing a compound represented by Chemical Formula 1, comprising the step of reacting a compound represented by Chemical Formula 2 with a compound represented by Chemical Formula 3 to prepare a compound represented by Chemical Formula 1.

Scheme 1

(In the above Reaction Scheme 1,

R ¹ , R ² , R ³ , and R ⁴ are the same as defined in Chemical Formula 1, and

X is H, or Cl).

Hereinafter, a method for preparing a compound represented by Chemical Formula 1 according to the present invention will be described in detail step by step.

In the method for preparing a compound represented by Formula 1 according to the present invention,

The compound represented by Chemical Formula 2 may be used as a starting material, or may be changed to a form of various salts thereof, for example, a salt with an acid, to form the starting material, but is not limited thereto. Any changeable form of starting material that may be included is included in the present invention.

Meanwhile, the compound represented by Chemical Formula 3 may be understood to be an aldehyde derivative or an acyl derivative. Therefore, those skilled in the art will readily understand that any method that can be prepared as shown in Chemical Formula 1 by a conventional organic chemical reaction, an aldehyde, or a reaction of acyl and an amine is included in the present invention without limitation. The present invention includes all of these.

In addition, the range that can be changed / modified from the reaction scheme 1, for example, a range easily changed / modified by those skilled in the art, it can be understood that it is included in the present invention, the present invention includes this.

On the other hand, the reaction conditions of the reaction can be changed / modified in consideration of the yield of the final target compound, and the like, the solvent, reaction time, reaction temperature, etc. can be easily understood that can be changed / modified, without being particularly limited. If it is a condition under which the compound represented by Formula 1 may be prepared, it should be understood to be included in the present invention.

The type of solvent that can be used is not limited, but, for example, dichloromethane (DCM), tetrahydrofuran, dioxane, ethyl ether, 1,2-dimethoxyethane, dimethylformamide (DMF), dimethyl sulfoxide (DMSO) And dichloroethane, acetonitrile, toluene, chlorobenzene, and at least one selected from the group consisting of acetone.

The reaction time is not particularly limited, but may be set to, for example, 1 to 48 hours, 2 to 24 hours, 3 to 20 hours, or 4 hours, or 16 hours.

The reaction temperature is also not particularly limited, but as an example, room temperature, 10-50 ° C., 20-40 ° C., 20-35 ° C., or 30-35 ° C. may be set, but is not limited thereto.

As an embodiment of the present invention, it can be carried out as in Preparation Example 1-6, Example 1-41.

Furthermore, in another aspect of the present invention,

Provided is a pharmaceutical composition for preventing or treating sodium channel-related diseases containing a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

In another aspect of the invention,

Provided is a health functional food composition for preventing or ameliorating sodium channel related diseases containing a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

In one embodiment of the invention,

The sodium channel-related disease may be understood as a disease related to the activity of the sodium channel, or a disease related to the expression of the sodium channel.

In another embodiment of the invention,

The sodium channel-related diseases may be understood to be all diseases that can develop or develop abnormalities, overexpression of sodium channels, or over-expression of sodium channels.

In another embodiment of the invention,

The sodium channel-related disease may be understood to be particularly related to sodium channel 1.7 (Nav 1.7), and in particular, to the present time, the disease related to sodium channel 1.7 (Nav 1.7) may be identified, studied, or predicted. Includes all diseases.

In another embodiment of the invention,

The sodium channel related disorders include, for example, neuropathic pain, spontaneous provoked pain, paroxysmal extreme pain disorder, erythromelalgia, or erythema pain. The disease may be a disease, and in particular, the activity of the compound, stereoisomer, or pharmaceutically acceptable salt thereof provided in the present invention may be prevented, ameliorated, improved, or directly related to sodium channel 1.7. It is a disease that can be treated, and furthermore, the pharmaceutical composition and the nutraceutical composition provided in the present invention are diseases that can be prevented, improved, improved, or treated.

In another aspect of the invention,

Compounds provided herein, stereoisomers thereof, pharmaceutically acceptable salts thereof, pharmaceutical compositions, nutraceutical compositions particularly inhibit Nav 1.7, preferably selectively inhibit Nav 1.7, For example, it selectively inhibits Nav 1.7 with better inhibitory activity than at least one of the other sodium channel subtypes (Nav 1.1, Nav 1.2, Nav 1.3, Nav 1.4, Nav 1.5, Nav 1.6, Nav 1.8, Nav 1.9), Preferably, from the effect of selectively inhibiting Nav 1.7 relative to all other sodium channel subtypes, it can be understood that the effect of prevention, amelioration, improvement or treatment in the above-mentioned diseases is achieved.

In view of this, in particular, the side effects of conventional non-selective drugs can be significantly improved, and the compounds provided by the present invention, stereoisomers thereof, pharmaceutically acceptable salts thereof, pharmaceutical compositions, and nutraceutical compositions are useful. .

In the above-described pharmaceutical composition according to the present invention, the compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof may be administered in various dosage forms, orally and parenterally, during clinical administration. If so, it may be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. which are commonly used.

Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and the like, optionally with bores such as starch, agar, alginic acid or its sodium salt, and the like. Release or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners.

Pharmaceutical compositions comprising the compound represented by Formula 1 as an active ingredient may be administered parenterally, and parenteral administration may be performed by injecting subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

In this case, the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is mixed with water with a stabilizer or a buffer to prepare a parenteral dosage form in the form of a solution or suspension, and it is an ampule or vial unit dosage form It can be prepared by. The compositions may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.

Examples of the formulation is only related to the conventional formulation, it will be readily understood by those skilled in the art that the formulation of the present invention is not limited thereto.

Furthermore, the dosage of the compound represented by Formula 1 of the present invention or a pharmaceutically acceptable salt thereof to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the subject. Based on 70 kg adult subjects, typically 0.1-1000 mg / day, preferably 1-500 mg / day, and also divided once or several times a day at regular intervals as determined by the physician or pharmacist It may also be administered.

Furthermore, the present invention provides a method for treating a sodium channel related disease comprising administering to a subject a therapeutically effective amount of a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. to provide.

At this time, the sodium channel-related diseases are as described herein.

The therapeutically effective amount refers to an amount that can treat, prevent or ameliorate the symptoms or conditions of the subject when administered into the body, depending on the method of administration. In addition, the amount may be different depending on the weight, age, sex, condition, family history of the subject to be administered, and in the present invention, the treatment method may determine a different amount of dosage according to different conditions for each subject.

The "effective amount" refers to sodium channel related disorders, such as sodium channel 1.7 related disorders, such as neuropathic pain, spontaneous provoked pain, paroxysmal extreme pain disorder. It is an amount effective for treating a disease such as erythromelalgia, or erythema pain. In another embodiment, an "effective amount" of a compound is an amount capable of inhibiting sodium channel activity or inhibiting sodium channel aberrant activity.

The compounds and compositions according to the methods of the invention can be administered using any amount and any route of administration effective for treating a disease. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Compounds of the present invention are frequently formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dose unit form” as used herein refers to physically discrete units of the formulation appropriate for the subject to be treated. It will also be understood that the total daily usage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The particular effective dosage level for any particular subject or organism depends on various factors, including: the disease to be treated and the severity of the disease; The activity of the specific compound employed; The specific composition employed; Age, weight, general health, sex and diet of the subject; Time of administration, route of administration, and rate of excretion of the specific compound employed; Duration of treatment; Certain compounds used alone or coadministered with drugs, and other factors well known in the medical arts.

The term “subject” refers to a subject in need of a compound provided herein, stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutical compositions, or nutraceutical compositions, otherwise relating to sodium channel Diseases, eg, sodium channel 1.7 related diseases, such as neuropathic pain, spontaneous provoked pain, paroxysmal extreme pain disorder, erythromelalgia, Or a subject in need of an effect of preventing, ameliorating, ameliorating, or treating a disease such as erythema pain, wherein the subject is for example an animal, preferably a non-mammalian, or a mammal, more preferably Livestock, human, most preferably human.

Hereinafter, the present invention will be described in detail by production examples, examples and experimental examples.

However, the following Preparation Examples, Examples and Experimental Examples are merely illustrative of the present invention, but the content of the present invention is not limited thereto.

Preparation Example 1 Preparation of 2-aminopropanamide Derivative

Under nitrogen gas substitution, l-alanineamide hydrochloride (0.5 mmol, 1.1 equiv.) And 0.1 g of powdered 4 ′ molecular sieve were mixed in dry MeOH. NaBH ₃ CN (0.33 mmol, 0.8 equiv.) Was added to the mixture and stirred at room temperature for 15 minutes, followed by the addition of various R ¹ CHO (0.4 mmol, 1 equiv.). The reaction mixture was heated to 30-35 ° C. and then stirred at room temperature for 4 hours. After filtration using Celite 545, the filtrate was concentrated under reduced pressure to obtain recrystallization in an EA: Hexane = 1:10 ratio to obtain a final product.

Preparation Example 2 Preparation of 2-Amino-2-phenylacetamide Derivative

The final product was obtained in the same manner as in Preparation Example 1, except that 2-amino-2-phenylastamide hydrochloride was used instead of 1-alanineamide hydrochloride used in Preparation Example 1.

Preparation Example 3 Preparation of 1-methyl-3-phenylformilamine derivative 1

Dry methylene chloride was added to a flask containing R ¹ CHO (1eq) under nitrogen gas substitution. 1-methyl-3-phenylpropyl amine (1eq) was added dropwise and stirred for 30 minutes. Then sodium triacetoxyborohydride (1.5eq) was added to the mixture, followed by stirring at room temperature for 16 hours. The solvent of the reaction was then evaporated under reduced pressure and purified by column chromatography (EA: Hex = 3: 1) to afford the final product.

Preparation Example 4 Preparation of 1-methyl-3-phenylformilamine derivative 2

10 ml of dry DMF was added to a flask containing R ¹ COCl (1eq) under nitrogen gas replacement. 1-methyl-3-phenylpropyl amine (1eq) and indium powder (1eq) were added thereto, followed by stirring at room temperature for 3-4 hours. The reaction was then extracted with ethyl acetate and washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. Then purified by column chromatography (EA: Hex = 3: 1) to give the final product.

Preparation Example 5 Preparation of 3,4,5-trimethoxybenzylamine derivative 1

Dry methylene chloride was added to a flask containing R ¹ CHO (1eq) under nitrogen gas substitution. To this was added 3,4,5-trimethoxybenzyl amine (1eq) and stirred for 30 minutes. Then sodium triacetoxyborohydride (1.5eq) was added to the mixture, followed by stirring at room temperature for 16 hours. The solvent of the reaction was then evaporated under reduced pressure. Then purified by column chromatography (EA: Hex = 3: 1) to give the final product.

Preparation Example 6 Preparation of 3,4,5-trimethoxybenzylamine derivative 2

10 ml of dry DMF was added to a flask containing R ¹ COCl (1eq) under nitrogen gas replacement. 3,4,5-trimethoxybenzyl amine (1eq) and indium powder (1eq) were added thereto, followed by stirring at room temperature for 3-4 hours. The reaction was then extracted with ethyl acetate and washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. Then purified by column chromatography (EA: Hex = 3: 1) to give the final product.

In the same manner as in Preparation Example 1-6, the following Example compound was prepared.

Example 1 Preparation of (S) -2-((5- (benzyloxy) -1H-indol-3-yl) methylamino) propanamide

R ¹ CHO of Preparation Example 1 was carried out in the same manner as in Preparation Example 1, using 5- (benzyloxy) -1H-indole-3-carbaldehyde to obtain a final target compound as a yellow powder (92.1%). .

mp 129 ° C .; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.87 (s, 1H), 8.20 (s, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.49 (s, 1H), 7.48 (s, 1H ), 7.42-7.38 (m, 3H), 6.97-6.89 (m, 4H), 5.12 (s, 2H), 3.10-3.05 (m, 3H), 1.24-1.09 (m, 3H) HR-FABMS Calcd for C ₁₉ H ₂₁ N ₃ NaO ₂ (M ⁺ + Na): 346.1526 Found: 346.1528

Example 2 Preparation of (S) -2-((5-bromo-1H-indol-3-yl) methylamino) propanamide

R ¹ CHO of Preparation Example 1 was carried out as in Preparation Example 1 using 5-bromo-1H-indole-3-carbaldehyde to give the final desired compound as a brown oil (63.2%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.02 (brs, 1H), 8.18 (s, 1H), 7.75 (dd, J = 7.2 Hz, J = 2 Hz, 2H), 7.69-7.63 (m, 2H) , 7.36-7.33 (m, 2H), 4.21 (d, J = 5.6 Hz, 1H), 4.14-4.09 (m, 2H), 1.35-1.30 (m, 2H) HR-FABMS Calcd for C ₁₂ H ₁₄ BrN ₃ NaO (M ⁺ + Na): 318.0212 Found: 318.0212

Example 3 Preparation of (S) -2-((5-chloro-lH-indol-3-yl) methylamino) propanamide

R ¹ CHO of Preparation Example 1 was used in the same manner as in Preparation Example 1, using 5-chloro-1H-indole-3-carbaldehyde to obtain a final desired compound as a reddish brown oil (29.9%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.04 (s, 1H), 7.64 (d, J = 8.8 Hz, J = 2 Hz, 1H), 7.42-7.29 (m, 3H), 7.08-7.02 (m, 1H), 6.98 (brs, 1H), 3.82-9.75 (m, 1H), 3.70-3.66 (m, 1H), 3.13-3.04 (m, 1H), 1.13-1.10 (m, 3H) HR-FABMS Calcd for C ₁₂ H ₁₄ ClN ₃ NaO (M ⁺ + Na): 274.0718 Found: 274.0720

Example 4 Preparation of (S) -2-((6-fluoro-1H-indol-3-yl) methylamino) propanamide

R ¹ CHO of Preparation Example 1 was carried out in the same manner as in Preparation Example 1, using 6-fluoro-1H-indole-3-carbaldehyde, to obtain a final desired compound as a brown oil (28.9%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.95 (brs, 1H), 7.604 (dd, J = 8.8 Hz, J = 5.6 Hz, 1H), 7.36 (brs, 1H), 7.23 (s, 1H), 7.11 (dd, J = 10 Hz, J = 2 Hz, 1H), 7.02 (brs, 1H), 6.86-6.81 (m, 1H), 3.83-3.71 (m, 2H), 3.13 (brd, J = 6.8 Hz, 1H ), 1.99 (s, 1H) 1.16-1.11 (m 3H) HR-FABMS Calcd for C 12 H 15 FN 3 O (M + + H): 236.1194 Found: 236.1198.

Example 5 Preparation of (S) -2-((5-methoxy-1H-indol-3-yl) methylamino) propanamide

R ¹ CHO of Preparation Example 1 was carried out as in Preparation Example 1 using 5-methoxy-1H-indole-3-carbaldehyde to give the final desired compound as a brown oil (6.38%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.34 (brs, 1H), 7.54-7.33 (m, 3H), 7.32-7.21 (m, 2H), 7.03-6.96 (m, 1H), 6.82-6.77 ( m, 1H), 3.83 (d, J = 3.6 Hz, 2H), 3.81-3.74 (m, 3H), 1.60 (d, J = 7.2 Hz, 3H) HR-FABMS Calcd for C ₁₃ H ₁₇ N ₃ NaO ₂ (M ⁺ + Na): 270.1213 Found: 270.1217

Example 6 Preparation of (S) -2-((7-nitro-1H-indol-3-yl) methylamino) propanamide

R ¹ CHO of Preparation Example 1 was carried out in the same manner as in Preparation Example 1, using 7-nitro-1H-indole-3-carbaldehyde to obtain a final desired compound as a yellow powder (90.2%).

mp 171 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.70 (s, 1H), 8.16 (dd, J = 7.6 Hz, J = 0.8 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.41 ( s, 1H), 7.33 (brs, 1H), 7.22 (t, J = 8 Hz, 1H), 6.98 (s, 1H), 3.88-3.76 (m, 2H), 3.08 (s, 1H), 2.26 (brs, 1H), 1.17-1.07 (m, 3H) HR-FABMS Calcd for C ₁₂ H ₁₅ N ₄ O ₃ (M ⁺ + H): 263.1139 Found: 263.1134.

Example 7 Preparation of (S) -2-((5-chloro-lH-indol-3-yl) methylamino) -2-phenylacetamide

R ¹ CHO of Preparation Example 2 was carried out in the same manner as in Preparation Example 2 using 5-chloro-lH-indole-3-carbaldehyde to give the final desired compound as a brown oil (70.3%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.51-7.45 (m, 1H), 7.41-7.37 (m, 2H), 7.35-7.27 (m, 4H), 7.10-7.01 (m, 1H), 6.54 ( s, 2H), 4.15-4.02 (m, 2H), 3.75 (d, J = 4.8hz, 1H), 1.90 (s, 1H) HR-FABMS Calcd for C ₁₇ H ₁₆ ClN ₃ NaO (M ⁺ + Na ): 336.0874 Found: 336.0872

Example 8 Preparation of (S) -2-((1H-indol-3-yl) methylamino) -2-phenylacetamide

R ¹ CHO of Preparation Example 2 was carried out in the same manner as in Preparation Example 2 using 1H-indole-3-carbaldehyde to obtain a final target compound as a brown powder (95.8%).

mp 95 ° C .; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.86 (s, 1H), 7.51 (s, 1H), 7.45 (s, 1H), 7.40 (s, 2H), 7.38-7.32 (m, 3H), 7.26 -7.24 (m, 2H), 7.09-6.98 (m, 1H), 6.98-6.94 (m, 2H), 4.28 (s, 1H), 1.85 (s, 2H), 1.23 (s, 1H) HR-FABMS Calcd for C ₁₇ H ₁₈ N ₃ O (M ⁺ + H): 280.1450 Found 280.1443

Example 9 Preparation of (S) -2-((5- (4-chlorophenyl) isoxazol-3-yl) methylamino) -2-phenylacetamide

R ¹ CHO of Preparation Example 2 was carried out in the same manner as in Preparation Example 2, using 5- (4-chlorophenyl) isoxazole-3-carbaldehyde to obtain a final target compound as a white powder (65.7%). .

mp 143 ° C .; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.88 (dd, J = 2 Hz, J = 4.4 Hz, 1H), 7.62-7.59 (m, 1H), 7.45-7.40 (m, 2H), 7.38-7.22 ( m, 4H), 7.10 (s, 1H), 7.00 (brs, 1H), 6.55 (s, 1H), 6.28 (s, 1H), 4.28 (s, 1H), 4.45 (brs, 1H), 3.69 (s , 1H), 1.89 (s, 1H) HR-FABMS Calcd for C ₁₈ H ₁₇ ClN ₃ O ₂ (M ⁺ + Na): 342.1004 Found: 342.1006

Example 10 Preparation of (S) -2- (4- (4-fluorophenoxy) benzylamino) -2-phenylacetamide

R ¹ CHO of Preparation Example 2 was carried out in the same manner as in Preparation Example 2 using 4- (4-fluorophenoxy) benzaldehyde to give the final desired compound as a white powder (93.4%).

mp 136 ° C .; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.51 (brs, 1H), 7.40-7.38 (m, 2H), 7.34-7.28 (m, 4H), 7.27-7.20 (m, 3H), 7.09 (brs, 1H), 7.05-7.02 (m, 1H), 6.94 (dd, J = 1.2 Hz, J = 2 Hz, 1H), 6.59 (brs, 1H), 6.28 (s, 1H), 4.28 (s, 1H), 4.09 (s, 1H), 3.59 ( d, J = 6.8Hz, 2H) HR-FABMS Calcd for C 21 H 2 0FN 2 O 2 (M + + H): 351.1503 Found: 351.1503.

Example 11 Preparation of (S) -2- (4- (4-chlorophenoxy) benzylamino) -2-phenylacetamide

R ¹ CHO of Preparation Example 2 was carried out in the same manner as in Preparation Example 2 using 4- (4-chlorophenoxy) benzaldehyde to obtain the final target compound as a white powder (63.0%).

mp 121 ° C .; ¹ H NMR (400 MHz, DMSO-d6) δ 7.52 (brs, 1H), 7.43-7.41 (m, 4H), 7.41-7.36 (m, 3H), 7.34-7.26 (m, 3H), 7.09 (brs, 1H ), 7.01-6.98 (m, 3H), 4.09 (s, 1H), 3.61 (d, J = 8hz, 3H) HR-FABMS Calcd for C ₂₁ H ₂₀ ClN ₂ O ₂ (M ⁺ + H): 367.1208 Found : 367.1209

Example 12 Preparation of 4-phenyl-N-((5- (3- (trifluoromethyl) phenyl) furan-2-yl) methyl) butan-2-amine

R ¹ CHO of Preparation Example 3 was carried out in the same manner as in Preparation Example 3 using 5- (3- (trifluoromethyl) phenyl) furan-2-carbaldehyde to obtain the final target compound as a red oil. (9.5%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.84-7.82 (m, 1H), 7.44 (d, J = 8 Hz, 1H), 7.26 (t, J = 6.4 Hz, 2H), 7.20-7.15 (m, 2H), 7.10-7.05 (m, 3H), 6.66 (s, 1H), 6.28 (s, 1H), 3.76 (s, 2H), 3.72-6.68 (m, 2H), 3.63 (d, J = 3.2 Hz , 2H), 2.74 (d, J = 6.4 Hz, 1H), 2.67 (t, J = 2 Hz, 1H), 1.52 (t, J = 7.2 Hz, 1H), 0.99 (d, J = 6.4 Hz, 1H) HR-FABMS Calcd for C ₂₂ H ₂₃ F ₃ NO (M ⁺ + H): 374.4114 Found: 374.1728

Example 13 Preparation of N- (4- (4-methylpiperazin-1-yl) benzyl) -4-phenylbutan-2-amine

R ¹ CHO of Preparation Example 3 was carried out in the same manner as in Preparation Example 3 using 4- (4-methylpiperazin-1-yl) benzaldehyde to obtain the final target compound as a pale brown oil (54.4%). .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.26-7.24 (m, 3H), 7.20-7.18 (m, 1H), 7.16-7.14 (m, 4H), 6.86-6.84 (m, 1H), 6.27 ( s, 1H), 3.17-3.07 (m, 9H), 2.45-2.42 (m, 5H), 1.55-1.49 (m, 2H), 1.00 (dd, J = 6.8 Hz, J = 1.6 Hz, 3H) HR- FABMS Calcd C ₂₂ H ₃₂ N ₃ for (M ⁺ + H): 338.2591 Found: 338.2595.

Example 14 Preparation of N- (4-morpholinobenzyl) -4-phenylbutan-2-amine

R ¹ CHO of Preparation Example 3 was used in the same manner as in Preparation Example 3, using 4-morpholinobenzaldehyde, to obtain a final target compound as a yellow powder (42.3%).

mp 87 ° C .; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.25 (d, J = 7.2 Hz, 3H), 7.22-7.14 (m, 5H), 6.88-6.85 (m, 1H), 6.28 (s, 1H), 3.74 -3.66 (m, 4H), 3.01-2.68 (m, 9H), 1.53-1.49 (2H), 1.17-1.002 (3H) HR-FABMS Calcd for C ₂₁ H ₂₈ N ₂ NaO (M ⁺ + Na): 347.2094 Found: 347.2094.

Example 15 Preparation of N-((5- (4-chlorophenyl) furan-2-yl) methyl) -4-phenylbutan-2-amine

R ¹ CHO of Preparation Example 3 was carried out in the same manner as in Preparation Example 3 using 5- (4-chlorophenyl) furan-2-carbaldehyde to obtain the final target compound as a pale brown powder (12.2%). .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.62 (s, 1H), 7.92-7.88 (m, 2H), 7.66 (t, J = 4 Hz, 1H), 7.38-7.34 (m, 2H), 7.20 ( g, J = 4 Hz, 1H), 6.95-6.91 (m, 1H), 6.98-.86 (m, 1H), 3.97-3.90 (m, 2H), 3.74 (d, J = 1.6 Hz, 1H), 3.71 (s, 1H), 3.167 (d, J = 5.2 Hz, 1H), 1.78-1.68 (m, 2H), 1.46 (q, J = 8hz, 1H) HR-FABMS Calcd for C ₂₁ H ₂₃ ClNO (M ⁺ + H): 340.8585 Found: 338.1317

Example 16 Preparation of 4-phenyl-N- (4- (pyridin-4-yl) benzyl) butan-2-amine

R ¹ CHO of Preparation Example 3 was used in the same manner as in Preparation Example 3 using 4- (pyridin-4-yl) benzaldehyde to give the final desired compound as a white powder (17.3%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.68 (d, J = 6.4 Hz, 1H), 8.40 (s, 1H), 7.90 (s, 2H), 7.77-7.75 (m, 2H), 7.26-7.24 (m, 3H), 7.20-7.15 (m, 4H), 2.67-2.61 (m, 3H), 1.82 (s, 1H), 1.52 (d, J = 6 Hz, 2H), 0.10 (d, J = 6.4 Hz , 3H) HR-FABMS Calcd for C ₂₂ H ₂₅ N ₂ (M ⁺ + H): 317.4393

Example 17 Preparation of N-((5- (4-chlorophenyl) isoxazol-3-yl) methyl) -4-phenylbutan-2-amine

R ¹ CHO of Preparation Example 3 was carried out in the same manner as in Preparation Example 3 using 5- (4-chlorophenyl) isoxazole-3-carbaldehyde to give the final desired compound as a white oil (67.6%). .

Example 18 Preparation of N-((5- (3-chloro-4-methoxyphenyl) furan-2-yl) methyl) -4-phenylbutan-2-amine

R ¹ CHO of Preparation Example 3 was carried out in the same manner as in Preparation Example 3 using 5- (3-chloro-4-methoxyphenyl) furan-2-carbaldehyde to obtain a final target compound as a brown powder. (12.6%).

mp 110 ° C .; ¹ H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J = 2 Hz, 1 H), 7.60 (dd, J = 2 Hz, J = 6 Hz, 1H), 7.21 (d, J = 7.2 Hz, 3H), 7.21 (d, J = 7.2 Hz, 3H), 7.18 (d, J = 3,2 Hz, 3H), 7.15-7.12 (m, 2H), 6.79 (d, J = 3.2 Hz, 1H), 6.29 (d, J = 3.2Hz, 1h), 4.04 (t, J = 3.2Hz, 5H), 2.09 (s, 1H) HR-FABMS Calcd for C ₂₂ H ₂₅ ClNO ₂ (M ⁺ + H): 370.8845 Found: 368.1420

Example 19 Preparation of 4-phenyl-N- (4- (pyrimidin-5-yl) benzyl) butan-2-amine

R ¹ CHO of Preparation Example 3 was carried out in the same manner as in Preparation Example 3, using 4- (pyrimidin-5-yl) benzaldehyde to obtain the final target compound as a white powder (35.0%).

mp 120.1 ° C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.17 (s, 1H), 9.13 (s, 2H), 7.75 (d, J = 7.6 Hz, 1H), 7.25 (d, J = 7.2 Hz, 3H), 7.20-7.15 (m, 5H), 2.74-2.73 (m, 3H), 1.54-1.49 (m, 4H), 1.05 (d, J = 6.4 Hz, 3H) HR-FABMS Calcd for C ₂₁ H ₂₄ N ₃ (M ⁺ + H): 318.1965 Found: 318.1963.

Example 20 Preparation of 4- (4-((4-phenylbutan-2-yl) aminomethyl) phenoxy) benzonitrile

Using R ¹ CHO of Preparation Example 3 as 4- (4-formylphenoxy) benzonitrile, the preparation was carried out in the same manner as in Preparation Example 3, to obtain a final desired compound as a yellow oil (39.5%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.84-7.81 (m, 2H), 7.43 (d, J = 2 Hz, 1H), 7.41 (s, 1H), 7.27-7.23 (m, 2H), 7.18- 7.13 (m, 3H), 7.08-7.04 (m, 4H), 3.71 (q, J = 5.6 Hz, 2H), 2.67-2.49 (m, 3H), 1.85 (s, 1H), 1.76-1.67 (m, 1H), 1.59-1.50 (m, 1H), 1.05 (d, J = 6.4 Hz, 3H) HR-FABMS Calcd for C ₂₄ H ₂₅ N ₂ O (M ⁺ + H): 357.1961 Found: 357.1958.

Example 21 Preparation of N-((5-chloro-lH-indol-3-yl) methyl) -4-phenylbutan-2-amine

R ¹ CHO of Preparation Example 3 was carried out in the same manner as in Preparation Example 3 using 5-chloro-lH-indole-3-carbaldehyde to give the final desired compound as a pale brown oil (72.2%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.02 (s, 1H), 7.69 (s, 1H), 7.35 (d, J = 8Hz, 1H), 7.28-7.25 (m, 1H), 7.24-7.23 ( m, 1H), 7.23-7.20 (m, 2H), 7.14 (d, J = 7.2 Hz, 3H), 3.89-3.86 (m, 2H), 2.68 (m, 2H), 1.55-1.50 (m, 2H) , 1.06 (d, J = 6.4 hz, 3H) HR-FABMS Calcd for C ₁₉ H ₂₂ ClN ₂ (M ⁺ -H): 311.1320 Found: 311.1317.

Example 22 Preparation of N-((1H-indol-3-yl) methyl) -4-phenylbutan-2-amine

R ¹ CHO of Preparation Example 3 was carried out in the same manner as in Preparation Example 3 using 1H-indole-3-carbaldehyde to obtain a final desired compound as a reddish brown oil (36.5%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.80 (s, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 8 Hz, 1H), 7.28 (d, J = 8 Hz, 1H), 7.25-7.23 (m, 2H), 7.20-7.15 (m, 2H), 7.14 (t, J = 3.6 Hz, 2H), 7.08-7.04 (m, 1H), 6.98-6.95 (m, 1H) , 2.83-7.80 (m, 1H), 2.68-2.64 (m, 1H), 1.72-1.59 (m. 1H), 1.59-1.53 (m, 2H), 1.06 (p, J = 6 Hz, 3H) HR-FABMS Calcd for C ₁₉ H ₂₃ N ₂ (M ⁺ + H): 279.1783 Found: 279.1857

Example 23 Preparation of N- (4- (4-fluorophenoxy) benzyl) -4-phenylbutan-2-amine

R ¹ CHO of Preparation Example 3 was used in the same manner as in Preparation Example 3 using 4- (4-fluorophenoxy) benzaldehyde to give the final desired compound as a white powder (52.8%).

mp 125 ° C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.32-7.24 (m, 5H), 7.21-7.13 (m, 8H), 2.75 (q, J = 6.4 Hz, 4H), 1.58-1.50 (m , 3H), 1.07-1.01 (m, 3H) HR-FABMS Calcd for C ₂₃ H ₂₅ FNO (M ⁺ + H): 350.1915 Found: 350.1914

Example 24 Preparation of N- (4- (4-chlorophenoxy) benzyl) -4-phenylbutan-2-amine

R ¹ CHO of Preparation Example 3 was used in the same manner as in Preparation Example 3 using 4- (4-chlorophenoxy) benzaldehyde to give the final desired compound as a white powder (49.4%).

mp 229.9 ° C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.41 (d, J = 8.8 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.20-7.13 (m, 5H), 6.99- 6.96 (m, 2H), 2.76 (d, J = 7.2 Hz, 4H), 1.58-1.51 (m, 3H), 1.05-0.10 (m, 3H) HR-FABMS Calcd for C ₂₃ H ₂₅ ClNO (M ⁺ + H): 366.1619 Found: 366.1613

Example 25 Preparation of N- (4-phenylbutan-2-yl)-[1,1'-biphenyl] -4-carboxamide

Using R ¹ COCl of Preparation Example 4 as the biphenyl-4-carbonyl chloride, the preparation was carried out as in Preparation Example 4, whereby the final desired compound was obtained as a white powder (38.8%).

mp 157 ° C .; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (d, J = 8 Hz, 1H), 8.01-7.95 (m, 3H), 7.78-7.71 (m, 5H), 7.50 (t, J = 7.6 Hz, 2H), 7.41 (t, J = 7.6 Hz, H), 7.29-7.15 (m, 4H), 4.05 (t, J = 6 Hz, 1H), 2.67-2.60 (m, 2H), 1.91-7.15 (m, 2H), 1.19 (d, J = 6.4 Hz, 3H) HR-FABMS Calcd for C ₂₃ H ₂₄ NO (M ⁺ + H): 330.1852 Found: 330.1859.

Example 26 Preparation of 3-Methyl-N- (4-phenylbutan-2-yl) benzofuran-2-carboxamide

Using R ¹ COCl of Preparation Example 4 as 3-methylbenzofuran-2-carbonyl chloride, the preparation was carried out as in Preparation Example 4, whereby the final desired compound was obtained as a yellow oil (42.6%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.76-7.72 (m, 1H), 7.62-7.59 (m, 1H), 7.49-7.45 (m, 1H), 7.36-7.29 (m, 2H), 7.26- 7.22 (m, 2H), 7.18-7.14 (m, 1H), 4.05 (t, J = 6 Hz, 1H), 2.68-2.66 (m, 2H), 2.63-2.56 (m, 5H), 1.19 (d, J) = 7.2 Hz, 3H) HR-FABMS Calcd for C ₂₀ H ₂₂ NO ₂ 307.3862 Found: 308.1652

Example 27 Preparation of N- (4-phenylbutan-2-yl) -1-naphtamide

Using R ¹ COCl of Preparation Example 4 as 1-naphthoyl chloride, the preparation was carried out as in Preparation Example 4, whereby the final desired compound was obtained as a white powder (19.8%).

mp 121 ° C .; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.43 (d, J = 7.6 Hz, 1H), 8.18 (t, J = 7.2 Hz, 1H), 8.01-7.96 (m, 2H), 7.60-7.53 (m , 4H), 7.31-7.26 (m, 3H), 7.18 (t, J = 6.8 Hz, 1H), 4.11-4.08 (m, 1H), 2.72-2.67 (m, 2H), 1.88-1.77 (m, 2H ), 1.22 (d, J = 6.8 Hz, 3H) HR-FABMS Calcd for C ₂₁ H ₂₂ NO (M ⁺ + H): 304.1696 Found: 304.1697

Example 28 Preparation of 3- (4-chlorophenyl) -5-methyl-N- (4-phenylbutan-2-yl) isoxazole-4-carboxamide

Using R ¹ COCl of Preparation Example 4 as 3- (4-chlorophenyl) -5-methylisoxazole-4-carbonyl chloride, the preparation was carried out in the same manner as in Preparation Example 4, and the final target compound was changed to yellow oil. Obtained (24.4%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.58 (s, 1H), 7.56 (s, 1H), 7.54-7.51 (m, 2H), 7.46-7.43 (m, 4H), 7.41-7.37 (m, 1H), 7.22-7.19 (m, 1H), 4.01 (dd, J = 2Hz, J = 6Hz, 1H), 3.74 (s, 1H), 2.70 (s, 6H), 2.33 (t, J = 2Hz, 4H ) HR-FABMS Calcd for C ₂₁ H ₂₂ ClN ₂ O ₂ (M ⁺ + H): 369.1364 Found: 369.1367

Example 29 Preparation of N-((1H-indol-3-yl) methyl) -1- (3,4,5-trimethoxyphenyl) methanamine

R ¹ CHO of Preparation Example 5 was carried out in the same manner as in Preparation Example 5, using 1H-indole-3-carbaldehyde, to obtain a final target compound as a pale brown oil (46.5%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.84 (s, 1H), 7.61 (d, J = 8Hz, 1H), 7.34 (d, J = 7.6Hz, 1H), 7.08-7.04 (m, 1H) , 6.98-6.94 (m, 1H), 6.65 (d, J = 6 Hz, 2H), 3.68 (d, J = 6.8 Hz, 4H), 1.77 (s, 1H), 1.75 (s, 8H) HR-FABMS Calcd for C ₂₀ H ₂₄ N ₂ O ₃ (M ⁺ + H): 327.3896 327.1703 found 327.1706

Example 30 Preparation of 1- (2-phenyl-1H-indol-3-yl) -N- (3,4,5-trimethoxyphenyl) methanamine

R ¹ CHO of Preparation Example 5 was carried out in the same manner as in Preparation Example 5, using 2-phenyl-1H-indole-3-carbaldehyde, to obtain a final target compound as a yellow oil (30.9%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.27 (s, 1H), 7.81-7.76 (m, 1H), 7.63-7.57 (m, 1H), 7.45-7.42 (m, 1H), 7.38-7.33 ( m, 1H), 7.14-7.08 (m, 1H), 7.03-6.99 (m, 1H), 6.71 (s, 1H), 6.65 (s, 1H), 3.76 (t, J = 3.2 Hz, 9H), 3.64 -3.62 (m, 4H) HR-FABMS Calcd for C ₂₅ H ₂₇ N ₂ O ₃ (M ⁺ + H): 403.4855 403.2016 found 403.1945

Example 31 Preparation of N- (4- (4-fluorophenoxy) benzyl) -1- (3,4,5-trimethoxyphenyl) methanamine

R ¹ CHO of Preparation Example 5 was carried out as in Preparation Example 5 using 4- (4-fluorophenoxy) benzaldehyde to give the final desired compound as a white oil (54.6%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.31 (d, J = 8 Hz, 1H), 7.20-7.16 (m, 1H), 7.01-6.98 (m, 1H), 6.90 (dd, J = 2 Hz, J = 4.8 Hz, 1H), 6.62-6.61 (m, 2H), 3.72-3.71 (m, 7H), 3.61 (s, 2H), 3.59 (dd, J = 2.8 Hz, J = 1.2 Hz, 4H) HR- FABMS Calcd for C ₂₃ H ₂₅ FNO ₄ (M ⁺ + H): 398.4394 398.1762 found 398.179

Example 32 Preparation of N- (4- (4-chlorophenoxy) benzyl) -1- (3,4,5-trimethoxyphenyl) methanamine

R ¹ CHO of Preparation Example 5 was used in the same manner as in Preparation Example 5 using 4- (4-chlorophenoxy) benzaldehyde to give the final desired compound as a white oil (54.6%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.43-7.36 (m, 3H), 6.99 (dd, J = 2.4 Hz, J = 6.8 Hz, 2H), 6.65 (d, J = 1.6 Hz, 5H), 3.66 (s, 5H), 3.62 (dd, J = 2.4Hz, J = 2Hz, 8H) HR-FABMS Calcd for C ₂₃ H ₂₅ ClNO ₄ (M ⁺ + H): 397.4394 414.1467 found 414.1475

Example 33 Preparation of 1- (5- (benzyloxy) -1H-indol-3-yl) -N- (3,4,5-trimethoxybenzyl) methanamine

R ¹ CHO of Preparation Example 5 was carried out in the same manner as in Preparation Example 5, using 5- (benzyloxy) -1H-indole-3-carbaldehyde, to obtain the final target compound as a brown oil (59.3%). .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.99 (s, 1H), 7.75-7.51 (m, 2H), 7.47-7.36 (m, 2H), 7.32-7.27 (m, 2H), 7.25 (s, 1H), 7.01 (s, 1H), 6.90 (s, 1H), 6.64 (s, 1H), 5.17 (s, 1H), 4.90 (brs, 2H), 3.92 (s, 1H), 3.88-3.80 (m , 5H), 3.77-3.60 (m, 5H), 1.88-1.72 (m, 3H) HR-FABMS Calcd for C ₂₆ H ₂₉ N ₂ O ₄ (M ⁺ + H): 432.5115

Example 34 Preparation of 1- (5-Bromo-1H-indol-3-yl) -N- (3,4,5-trimethoxybenzyl) methanamine

R ¹ CHO of Preparation Example 5 was carried out as in Preparation Example 5 using 5-bromo-1H-indole-3-carbaldehyde to give the final desired compound as a brown oil (74.2%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.12 (s, 1H), 8.26 (brs, 1H), 7.57 (s, 1H), 7.36-7.29 (m, 2H), 7.26-7.15 (m, 1H) , 7.10 (s, 1H), 4.67 (s, 1H), 4.17 (d, J = 5.6 Hz, 2H), 3.86 (s, 2H), 1.86 (s, 2H), 1.58 (s, 3H), 1.23 ( s, 4H) HR-FABMS Calcd for C ₁₉ H ₂₂ BrN ₂ O ₃ (M ⁺ + H): 406.2856 405.0808 found 405.0793

Example 35 Preparation of 1- (6-Fluoro-1H-indol-3-yl) -N- (3,4,5-trimethoxybenzyl) methanamine

R ¹ CHO of Preparation Example 5 was carried out in the same manner as in Preparation Example 5 using 6-fluoro-1H-indole-3-carbaldehyde to obtain the final desired compound as a red oil (67.6%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.24-7.15 (m, 6H), 4.85 (d, J = 5.2 Hz, 2H), 4.61 (s, 2H), 4.01 (s, 3H), 3.91 (d , J = 6.4Hz, 6H) HR-FABMS Calcd for C ₂₃ H ₂₅ FNO ₄ 345.3800

Example 36 Preparation of 1- (5-methoxy-1H-indol-3-yl) -N- (3,4,5-trimethoxybenzyl) methanamine

R ¹ CHO of Preparation Example 5 was carried out in the same manner as in Preparation Example 5 using 5-methoxy-1H-indole-3-carbaldehyde to give the final desired compound as a red oil (66.1%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.67 (s, 1H), 7.23 (s, 1H), 7.21-7.18 (m, 1H), 7.10-7.07 (m, 1H), 6.72-6.67 (m 1H ), 6.65 (d, J = 7.6 Hz, 2H), 3.80 (s, 3H), 3.76-3.73 (m, 12H), 3.66-3.61 (m, 3H) HR-FABMS Calcd for C ₂₀ H ₂₆ N ₂ O ₄ (M ⁺ + H): 357.1809 Found: 357.1813

Example 37 Preparation of 1- (7-nitro-1H-indol-3-yl) -N- (3,4,5-trimethoxybenzyl) methanamine

R ¹ CHO of Preparation Example 5 was carried out in the same manner as in Preparation Example 5, using 7-nitro-1H-indole-3-carbaldehyde to give a final desired compound as a yellow powder (88.4%).

mp 121.1 ° C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.70 (s, 1H), 8.16 (d, J = 7.8Hz, 1H), 8.10 (d, J = 8Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.22 (t, J = 5.5 Hz, 1H), 6.65 (2, 2H), 6.27 (s, 1H), 3.89 (s, 1H), 3.75 (d, J = 9.2 Hz, 6H ), 3.65 (d, J = 3.2 Hz, 2H), 3.62 (d, J = 2.4 Hz, 4H) C ₁₉ H ₂₃ N ₃ O ₅ (M ⁺ + H): 372.1554 Found: 372.1556

Example 38 Preparation of N- (3,4,5-trimethoxybenzyl)-[1,1'-biphenyl] -4-carboxamide

Using R ¹ COCl of Preparation 6 as the biphenyl-4-carbonyl chloride, it was carried out as in Preparation 6, to obtain the final target compound as a white powder (17.8%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (t, J = 6 Hz), 7.99 (dd, J = 2 Hz, J = 1.7 Hz), 7.79-7.72 (m, 4H), 7.52-7.48 (m, 2H), 7.43-7.39 (m, 1H), 4.44 (d, J = 5.6 Hz, 2H), 3.76 (s, 6H), 3.63 (s, 3H) HR-FABMS Calcd for C ₂₃ H ₂₅ NO ₄ (M ⁺ + H): 378.1700 Found: 378.1705

Example 39 Preparation of 3-Methyl-N- (3,4,5-trimethoxybenzyl) benzofuran-2-carboxamide

Using R ¹ COCl of Preparation Example 6 as 3-methylbenzofuran-2-carbonyl chloride, the preparation was carried out as in Preparation Example 6, whereby the final desired compound was obtained as a yellow powder (21.9%).

mp 169 ° C .; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.03 (t, J = 6hz, 1H), 7.74 (d, J = 3.6Hz, 1H), 7.59 (d, J = 4.2Hz, 1H), 7.50-7.46 (m, 1H), 7.35 (t, J = 7.6 Hz, 1H), 6.68 (s, 2H), 4.39 (d, J = 6.4 Hz, 2H), 3.75 (s, 6H), 3.63 (s, 3H) , 2.54-2.50 (m, 3H) HR-FABMS Calcd for C ₂₀ H ₂₃ NO ₅ (M ⁺ + H): 356.1492 Found: 356.1494.

Example 40 Preparation of N- (3,4,5-trimethoxybenzyl) -1-naphtamide

Using R ¹ COCl of Preparation Example 6 as 1-naphthoyl chloride, the preparation was carried out as in Preparation Example 6, whereby the final desired compound was obtained as a yellow powder (52.4%).

mp 156 ° C .; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.05 (d, J = 6 Hz, 1H), 8.21-8.19 (m, 1H), 8.03-8.01 (m, 1H), 8.00-7.97 (m, 1H), 7.64 (dd, J = 1.2 Hz, J = 6.4 Hz, 1H), 7.58-7.54 (m, 3H), 4.49 (d, J = 6.4 Hz, 2H), 3.78 (s, 6H), 3.65 (s, 3H ) HR-FABMS Calcd for C ₂₁ H ₂₄ NO ₄ (M ⁺ + H): 352.1543 Found: 352.1547.

Example 41 Preparation of N- (3,4,5-trimethoxybenzyl) quinoline-2-carboxamide

Using R ¹ COCl of Preparation 6 as the quinoline-2-carbonyl chloride, it was carried out as in Preparation 6, to obtain the final target compound as an orange powder (27.7%).

mp 154.8 ° C .; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.36 (t, J = 6Hz, 1H), 8.59 (s, 1H), 8.56 (s, 1H), 8.19 (s, 1H), 8.13 (s, 1H) , 8.10 (s, 1H), 8.08 (s, 1H), 7.90-7.85 (m, 1H), 7.75-7.71 (m, 1H), 6.92 (s, 2H), 4.50 (d, 2H), 3.75 (s , 6H), 3.63 (s, 3H), HR-FABMS Calcd for C ₂₀ H ₂₂ N ₂ O ₄ (M ⁺ + H): 353.1496 Found: 353.1499.

The chemical structures of the compounds prepared in Examples 1-41 are shown in Table 1 below.

Example constitutional formula Example constitutional formula One

22

2

23

3

24

4

25

5

26

6

27

7

28

8

29

9

30

10

31

11

32

12

33

13

34

14

35

15

36

16

37

17

38

18

39

19

40

20

41

21

Experimental Example 1 Evaluation of Sodium Channel Inhibition Effect

In order to evaluate the inhibitory effect on the sodium channel of the compound according to the present invention, the following voltage / ion probe reader (VIPR) assay was performed.

In vitro experiments were sent to SB Drug Discovery Company (Glasgow, UK) for VIPR assay of the synthetic material of this experiment.

Specifically, HEK cells expressing hNav1.7 hNav1.8 ion channels were planted in poly-D-lysine-coated black-walled, white-bottomed 96-well biocoated plates and incubated in 100 μL culture for 24 hours prior to analysis. Incubated. The next day, membrane potential staining was performed according to the manufacturer's instructions. That is, the contents of one bottle of the dye was dissolved in 10 ml of Hepes-HBSS buffer (pH7.4) or a large bottle of the dye (component A) dye for buffer in 100 ml of buffer. Hepes-HBSS and dye solution were preheated to 37 ° C. in advance, 90 μl dye was added to the wells (190 μl total) and incubated at 37 ° C. for 60 minutes. Standard inhibitors (TTX) were tested with each assay. 10 μl of compound was added 10 minutes before the plate was read. Flexstation was set to add 50 μl of channel activator and veratridine and fluorescence was read at 530 nm excitation and 565 nm emission. Each well was read at 1.52 second intervals for 120 seconds, and the sodium channel inhibition effect of each compound is shown in Table 2 as a percentage (% inhibition).

Example Nav1.7
10 uM
% inhibition Nav1.8
10 uM
% inhibition One 5.13 19.7 2 59.9 27.4 3 2.46 20.7 4 5 4.30 18.3 6 7 3.45 8 9 1.77 10 31.3 11.3 11 3.68 19.5 12 104 54.4 13 66.4 4.97 14 87.1 10.2 15 34.6 42.2 16 17 18 65.9 6.75 19 29.8 20 106 42.2 21 38.5 22 14.2 23 33.9 24 10.2 25 84.0 31.2 26 27 4.12 59.2 28 24.4 29 16.4 30 12.1 3.30 31 16.6 32 15.2 33 34.9 5.87 34 27.0 13.9 35 38.2 36 23.7 37 4.08 8.81 38 6.90 18.3 39 40 41 71.7 19.3

Looking at Table 2, all of the compound according to the present invention was found to have excellent sodium channel inhibitory activity. On the other hand, the inhibitory active compound selective to Nav1.7 was confirmed to be Examples 2, 12, 13, 14, 18, 20, 25, and 41 compounds.

Accordingly, the compound according to the present invention has excellent sodium channel inhibitory activity, and may be useful for sodium channel-related diseases as a pharmaceutical composition or health functional food containing the same as an active ingredient, for example, Nav 1.7-related. It can be usefully used for the treatment of pathological pain such as dermatosis, paroxysmal pain, erythema pain, and the like.

Claims (11)

A compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

(In Formula 1,
R ¹ is unsubstituted or substituted C _6-10 aryl or unsubstituted or substituted 5-10 membered heteroaryl including one or more heteroatoms selected from the group consisting of N, O and S,
Wherein the substituted C _6-10 aryl or substituted 5-10 atom heteroaryl is halogen, C _1-10 straight or branched alkyl, C _1-10 straight or branched alkoxy, —NO ₂ , non- Ring or substituted C _6-10 aryl, (unsubstituted or substituted 4-8 membered heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of N, O and S), (N, O and Unsubstituted or substituted 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of S), unsubstituted or substituted C _6-10 aryloxy, and unsubstituted or substituted C _6- At least one substituent selected from the group consisting of ₁₀ arylC _1-3 alkoxy,
Here again, said substituted C _6-10 aryl, substituted 4-8 atoms heterocycloalkyl, substituted 5-10 atoms heteroaryl, substituted C _6-10 aryloxy, or substituted C _{6- 10} arylC _1-3 alkoxy is one or more selected from the group consisting of C _1-5 straight or branched alkyl, unsubstituted or substituted with one or more halogens, C _1-5 linear or branched alkoxy, halogen and —CN Substituents are substituted;

R ² is hydrogen, hydroxy, or oxo (═O);

R ³ is hydrogen, methyl, ethyl, unsubstituted or substituted C _6-10 aryl, or an unsubstituted or substituted 5-10 atom comprising one or more heteroatoms selected from the group consisting of N, O and S Heteroaryl; And

R ⁴ is — (C═O) —NR ⁵ R ⁶ ), unsubstituted or substituted C _6-10 aryl, unsubstituted or substituted C _6-10 aryl-C _1-3 alkyl, N, O and S Unsubstituted or substituted 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of or unsubstituted or substituted comprising one or more heteroatoms selected from the group consisting of N, O and S 5-10 membered heteroaryl-C _1-3 alkyl,
Wherein the substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl is a group consisting of C _1-5 straight or branched alkyl, C _1-5 straight or branched alkoxy, halogen and —CN One or more substituents selected from
R ⁵ and R ⁶ are independently hydrogen or C _1-5 straight or branched alkyl).
The method of claim 1,
R ² is hydrogen or oxo (═O);
R ³ is hydrogen, methyl, or phenyl; And
Wherein R ⁴ is — (C═O) —NH ₂ ), C _6-10 aryl unsubstituted or substituted with one or more methoxy, or phenethyl, Compound, stereoisomer thereof or pharmaceutical composition thereof Acceptable salts.
The method of claim 1,
R ¹ is unsubstituted or substituted 5-10 membered heteroaryl including one or more heteroatoms selected from the group consisting of unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, or N, and O; ,
Wherein the substituted phenyl, substituted naphthyl, or substituted 5-10 membered heteroaryl is halogen, C _1-5 straight or branched alkyl, C _1-5 straight or branched alkoxy, —NO ₂ , Unsubstituted or substituted phenyl, (unsubstituted or substituted 4-6 membered heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of N, O and S), (N, and O from the group consisting of Unsubstituted or substituted 6-membered heteroaryl containing one or more heteroatoms selected, unsubstituted or substituted phenyloxy, and unsubstituted or substituted benzyloxy substituted with one or more substituents selected from the group consisting of Be,
Here again, the substituted phenyl, substituted 4-6 membered heterocycloalkyl, substituted 6 membered heteroaryl, substituted phenyloxy, or substituted benzyloxy are C ₁ unsubstituted or substituted with one or more halogens. At least one substituent selected from the group consisting of _-5 linear or branched alkyl, C _1-5 straight or branched alkoxy, halogen and -CN, a compound, a stereoisomer thereof or a pharmaceutically acceptable thereof Possible salts.
The method of claim 1,
R ¹ is

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

Compound, its stereoisomer or pharmaceutically acceptable salt thereof.
The method of claim 1,
The compound represented by Formula 1 is any one selected from the following compound group, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
(1) (S) -2-((5- (benzyloxy) -1H-indol-3-yl) methylamino) propanamide;
(2) (S) -2-((5-bromo-1H-indol-3-yl) methylamino) propanamide;
(3) (S) -2-((5-chloro-1H-indol-3-yl) methylamino) propanamide;
(4) (S) -2-((6-fluoro-1H-indol-3-yl) methylamino) propanamide;
(5) (S) -2-((5-methoxy-1H-indol-3-yl) methylamino) propanamide;
(6) (S) -2-((7-nitro-1H-indol-3-yl) methylamino) propanamide;
(7) (S) -2-((5-chloro-1H-indol-3-yl) methylamino) -2-phenylacetamide;
(8) (S) -2-((1H-indol-3-yl) methylamino) -2-phenylacetamide;
(9) (S) -2-((5- (4-chlorophenyl) isoxazol-3-yl) methylamino) -2-phenylacetamide;
(10) (S) -2- (4- (4-fluorophenoxy) benzylamino) -2-phenylacetamide;
(11) (S) -2- (4- (4-chlorophenoxy) benzylamino) -2-phenylacetamide;
(12) 4-phenyl-N-((5- (3- (trifluoromethyl) phenyl) furan-2-yl) methyl) butan-2-amine;
(13) N- (4- (4-methylpiperazin-1-yl) benzyl) -4-phenylbutan-2-amine;
(14) N- (4-morpholinobenzyl) -4-phenylbutan-2-amine;
(15) N-((5- (4-chlorophenyl) furan-2-yl) methyl) -4-phenylbutan-2-amine;
(16) 4-phenyl-N- (4- (pyridin-4-yl) benzyl) butan-2-amine;
(17) N-((5- (4-chlorophenyl) isoxazol-3-yl) methyl) -4-phenylbutan-2-amine;
(18) N-((5- (3-chloro-4-methoxyphenyl) furan-2-yl) methyl) -4-phenylbutan-2-amine;
(19) 4-phenyl-N- (4- (pyrimidin-5-yl) benzyl) butan-2-amine;
(20) 4- (4-((4-phenylbutan-2-yl) aminomethyl) phenoxy) benzonitrile;
(21) N-((5-chloro-1H-indol-3-yl) methyl) -4-phenylbutan-2-amine;
(22) N-((1H-indol-3-yl) methyl) -4-phenylbutan-2-amine;
(23) N- (4- (4-fluorophenoxy) benzyl) -4-phenylbutan-2-amine;
(24) N- (4- (4-chlorophenoxy) benzyl) -4-phenylbutan-2-amine;
(25) N- (4-phenylbutan-2-yl)-[1,1'-biphenyl] -4-carboxamide;
(26) 3-methyl-N- (4-phenylbutan-2-yl) benzofuran-2-carboxamide;
(27) N- (4-phenylbutan-2-yl) -1-naphtamide;
(28) 3- (4-chlorophenyl) -5-methyl-N- (4-phenylbutan-2-yl) isoxazole-4-carboxamide;
(29) N-((1H-indol-3-yl) methyl) -1- (3,4,5-trimethoxyphenyl) methanamine;
(30) 1- (2-phenyl-1H-indol-3-yl) -N- (3,4,5-trimethoxyphenyl) methanamine;
(31) N- (4- (4-fluorophenoxy) benzyl) -1- (3,4,5-trimethoxyphenyl) methanamine;
(32) N- (4- (4-chlorophenoxy) benzyl) -1- (3,4,5-trimethoxyphenyl) methanamine;
(33) 1- (5- (benzyloxy) -1H-indol-3-yl) -N- (3,4,5-trimethoxybenzyl) methanamine;
(34) 1- (5-bromo-1H-indol-3-yl) -N- (3,4,5-trimethoxybenzyl) methanamine;
(35) 1- (6-fluoro-1H-indol-3-yl) -N- (3,4,5-trimethoxybenzyl) methanamine;
(36) 1- (5-methoxy-1H-indol-3-yl) -N- (3,4,5-trimethoxybenzyl) methanamine;
(37) 1- (7-nitro-1H-indol-3-yl) -N- (3,4,5-trimethoxybenzyl) methanamine;
(38) N- (3,4,5-trimethoxybenzyl)-[1,1'-biphenyl] -4-carboxamide;
(39) 3-methyl-N- (3,4,5-trimethoxybenzyl) benzofuran-2-carboxamide;
(40) N- (3,4,5-trimethoxybenzyl) -1-naphtamide; And
(41) N- (3,4,5-trimethoxybenzyl) quinoline-2-carboxamide.
As shown in Scheme 1 below,
A method for preparing a compound represented by Chemical Formula 1 according to claim 1 comprising the step of reacting a compound represented by Chemical Formula 2 with a compound represented by Chemical Formula 3 to prepare a compound represented by Chemical Formula 1.
Scheme 1

(In the above Reaction Scheme 1,
R ¹ , R ² , R ³ , and R ⁴ are as defined in Formula 1 of claim 1, and
X is H, or Cl).
A pharmaceutical composition for the prevention or treatment of sodium channel-related diseases, comprising the compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
The method of claim 7, wherein
The sodium channel is sodium channel 1.7 (Nav 1.7), characterized in that the pharmaceutical composition.
The method of claim 7, wherein
The sodium channel-related disease is characterized in that the neuropathic pain, spontaneous provoked pain, paroxysmal extreme pain disorder, erythromelalgia, or erythema pain, Pharmaceutical compositions.
Claim 1, a stereoisomer, or a health functional food composition for the prevention or improvement of sodium channel-related diseases containing a pharmaceutically acceptable salt thereof as an active ingredient.
The method of claim 10,
The sodium channel-related disease is characterized in that the neuropathic pain, spontaneous provoked pain, paroxysmal extreme pain disorder, erythromelalgia, or erythema pain, Health food composition.