N-Oxide Compounds and Their Uses

Abstract

The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, which is effective as a sodium channel blocker, and a method of using the compound.

Description

Technical Field

[0001] The present disclosure mainly relates to N-oxide compounds as sodium channel blockers, pharmaceutical compositions containing such compounds, and methods for treating pain, including neuropathic pain, in mammals by administering the sodium channel blockers to mammals in need thereof. The present disclosure includes methods of using and methods of manufacturing these sodium channel blockers of the present invention.

Background Art

[0002] Pain is defined by the International Association for the Study of Pain (IASP) as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage." In this second edition, two new terms, neuropathic pain and peripheral neuropathic pain, were introduced. Neuropathic pain is defined by the IASP as "pain initiated or caused by a primary lesion or dysfunction in the peripheral or central nervous system" (IASP, Classification of chronic pain (2nd edition), IASP Press, 2002, p. 210).

[0003] The treatment of pain symptoms is of great medical significance, and there is a current worldwide need for new pain treatments. In particular, urgent demands for specific treatments of pain symptoms or for treatments of specific pain symptoms have been reported in many scientific studies. Although pain is always subjective, its causes or syndromes can be classified into several subtypes.

[0004] Neuropathic pain has developed as a major health problem for a wide range of people in the past few years, and in particular, any treatment of neuropathic pain is very sensitive to the cause underlying the pain, so that a very specific treatment is also necessary. Thus, in most cases, a substance that can treat one subtype of neuropathic pain cannot treat, or at least not necessarily treat, other specific subtypes due to the very diverse nature of this general symptom called neuropathic pain.

[0005] To date, there are over 100 known types of neuropathic pain. Common acquired causes include viral infections, diabetes, injury, autoimmune diseases, and nutritional deficiencies. Some neuropathic pain may also be due to genetic or gene mutations. For the purposes of the present invention, these subtypes may be included under this heading or treated as synonyms.

[0006] Voltage-gated sodium channels (VGSCs) control the flow of sodium ions, which can trigger the excitability of nociceptors that receive pain in the peripheral nervous system. In humans, nine VGSCs have currently been identified, and some are associated with genes that alter their function. Sodium channels play an important role in painful neuropathies.

[0007] In particular, gene mutations are currently associated with the sodium channels Nav1.7, Nav1.8, and Nav1.9. Gain-of-function mutations in the gene SCN9A are associated with Nav1.7 and a painful neuropathy called hereditary erythromelalgia (IEM). The gene SCN10A is associated with Nav1.8 and small fiber neuropathy (a disease that causes severe pain attacks in the hands or feet). It can also cause autonomic pain symptoms such as palpitations, intestinal disorders, and abnormal sweating. Nav1.9 is also associated with mutations that cause painful neuropathies.

[0008] The thiazole compounds of the present disclosure provide a novel treatment for neuropathic pain as sodium channel blockers.

[0009] As an example, U.S. Patent No. 8,822,463 describes that a methylcyclohexane compound represented by the following formula is effective in the treatment of neuropathic pain.

Chemical formula

[0010] As another example, U.S. Patent No. 8,541,409 mentions the following carbamoyloxyarylalkanoylarylpiperazine compounds, which are useful as analgesics.

Chemical formula

Prior art documents

Patent documents

[0011]

Patent Document 1

Patent Document 2

Summary of the invention

Problems to be solved by the invention

[0012] An object of the present disclosure is to provide a compound useful as a sodium channel blocker.

Means for solving the problems

[0013] The present disclosure provides a novel compound of the following formula (I), or an optical isomer, stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

Chemical formula

[0014] The compound of formula (I) is useful for inhibiting the inactivated state of sodium channels.

[0015] In some embodiments, the compound of formula (I) is a compound of the following formula (II).

Chemical formula

[0016] In another embodiment, a pharmaceutical composition is provided that comprises a therapeutically effective amount of one or more of the compounds described herein and a pharmaceutically acceptable carrier.

[0017] In yet another embodiment, a method is provided for treating or preventing pain, including neuropathic pain, in a mammal in need thereof by administering a therapeutically effective amount of a compound represented by formula (I) or (II), or an optical isomer, stereoisomer, or isotopic variant thereof, or a pharmaceutically acceptable salt thereof.

Advantages of the Invention

[0018] The compounds of the present disclosure are useful as sodium channel blockers for the treatment of pain, including neuropathic pain.

Modes for Carrying Out the Invention

[0019] The following description is merely exemplary in nature and is not intended to limit the present disclosure, application, or use.

[0020] Definitions "Alkoxy" is RO-, where R is alkyl. Non-limiting examples of alkoxy groups include methoxy, ethoxy, and propoxy. In one embodiment, the alkoxy group is methoxy.

[0021] "Alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon group. In one embodiment, alkyl has 1 to 12 carbon atoms. In some embodiments, alkyl is C 1 -C 10 alkyl group, C 1 -C 6 alkyl group, or C 1 -C 4 alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

[0022] "Cycloalkyl" refers to a saturated or partially saturated monocyclic, fused polycyclic, or spiro polycyclic carbocyclic ring having 3 to 12 ring atoms per carbon ring.

[0023] "Halo" or "halogen" refers to fluorine (-F), chlorine (-Cl), bromine (-Br), or iodine (-I).

[0024] When a particular group is "substituted" (e.g., alkoxy, alkyl, cycloalkyl, etc.), the group may have one or more substituents independently selected from the list of substituents, e.g., 1 to 5 substituents, or 1 to 3 substituents, or 1 to 2 substituents.

[0025] "Pharmaceutically acceptable" means suitable for use in pharmaceutical formulations, generally considered to be safe for such use, such use being formally approved by the regulatory agencies of a country or state government, or listed in the United States Pharmacopeia or other generally recognized pharmacopeias for use in animals, particularly humans.

[0026] "Pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or carrier that is formulated and / or administered together with one or more compounds of the present disclosure and all of the components or carriers together provide a pharmaceutically acceptable carrier or vehicle, either alone or together.

[0027] "Pharmaceutically acceptable salt" refers to a salt that can enhance the desired pharmacological activity. Examples of pharmaceutically acceptable salts include acid addition salts formed with inorganic or organic acids, metal salts, and amine salts. Examples of acid addition salts formed with inorganic acids include salts formed with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of acid addition salts formed with organic acids include salts formed with acetic acid, propionic acid, caproic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxy-benzoyl)-benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methyl-bicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptanoic acid, 4,4'-methylenebis(3-hydroxy-2-naphthoic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and salts formed with muconic acid. Examples of metal salts include salts with sodium ions, potassium ions, calcium ions, magnesium ions, aluminum ions, iron ions, and zinc ions. Examples of amine salts include salts with ammonia and salts with organic nitrogen-containing bases of sufficient strength to form salts with carboxylic acids.

[0028] "Therapeutically effective amount" refers to the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effectively effect the treatment of the disease. The "therapeutically effective amount" can vary depending on the compound, the disease and its severity, the age, weight, etc. of the subject to be treated.

[0029] As used herein, where applicable, acceptable isomers such as tautomers, racemates, enantiomers, diastereomers, atropisomers, and isotopic isomers are included.

[0030] Compound The present disclosure provides a compound of formula (I) below, or an optical isomer, stereoisomer or isotopic isomer thereof, or a pharmaceutically acceptable salt thereof.

Chemical formula

[0031] In one embodiment, R1 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 10 cycloalkyl, and R2 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10It is cycloalkyl or 4- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms selected from N, O, and S, and R3 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 10 cycloalkyl, and n is an integer from 0 to 4, where the alkyl, alkoxy, and cycloalkyl may be substituted with 1 to 4 substituents selected from halogen and hydroxy.

[0032] In another embodiment, R1 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or C 3 -C 6 cycloalkyl, R2 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, or 4- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms selected from N, O, and S, and R3 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or C 3 -C 6 cycloalkyl, and n is an integer from 0 to 4, where the alkyl, alkoxy, and cycloalkyl may be substituted with 1 to 4 substituents selected from halogen and hydroxy.

[0033] In another embodiment, R1 is hydrogen or halogen.

[0034] In another embodiment, R2 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6alkoxy, or C 3 -C 10 is cycloalkyl, where the alkyl, alkoxy, and cycloalkyl may be substituted with 1 to 4 substituents selected from halogen and hydroxy.

[0035] In another embodiment, R3 is hydrogen or halogen.

[0036] In another embodiment, there is provided a compound of the following formula (II), or an optical isomer, stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.

Chemical formula

[0037] In another embodiment, R1 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 10 cycloalkyl, R2 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6Alkoxy, C 3 -C 10 is cycloalkyl or a 4- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms selected from N, O, and S, R3 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 10 cycloalkyl, R4 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl or a 4- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms selected from N, O, and S, and n is an integer from 0 to 3, where the alkyl, alkoxy, and cycloalkyl may be substituted with 1 to 4 substituents selected from halogen and hydroxy.

[0038] In another embodiment, R1 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or C 3 -C 6 cycloalkyl, R2 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl or a 4- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms selected from N, O, and S, R3 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or C 3 -C 6 cycloalkyl, R4 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4Alkoxy, C 3 -C 6 cycloalkyl, or a 4- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms selected from N, O, and S, and n is an integer from 0 to 3, wherein said alkyl, alkoxy, and cycloalkyl may be substituted with 1 to 4 substituents selected from halogen and hydroxy.

[0039] In another embodiment, R1 is hydrogen or halogen.

[0040] In another embodiment, R2 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, wherein said alkyl and alkoxy may be substituted with 1 to 4 substituents selected from halogen and hydroxy.

[0041] In another embodiment, R3 is hydrogen or halogen.

[0042] In another embodiment, R4 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 10 cycloalkyl, wherein said alkyl, alkoxy, and cycloalkyl may be substituted with 1 to 4 substituents selected from halogen and hydroxy.

[0043] Examples of formula (I) include, but are not limited to, the following compounds. N-[(1-oxidopyridin-1-ium-2-yl)methyl]-3-[4-(trifluoromethyl)phenyl]benzamide, 3-(4-chlorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, N-[(1-Oxidepyridin-1-ium-2-yl)methyl]-3-[4-(trifluoromethoxy)phenyl]benzamide, 3-(3-Chlorophenyl)-N-[(1-oxidepyridin-1-ium-2-yl)methyl]benzamide, N-[(1-Oxidepyridin-1-ium-2-yl)methyl]-3-[3-(trifluoromethyl)phenyl]benzamide, 3-(3,4-Dichlorophenyl)-N-[(1-oxidepyridin-1-ium-2-yl)methyl]benzamide, 3-(3,5-Dichlorophenyl)-N-[(1-oxidepyridin-1-ium-2-yl)methyl]benzamide, N-[(1-Oxidepyridin-1-ium-2-yl)methyl]-3-[3-(trifluoromethoxy)phenyl]benzamide, 3-(2,4-Dichlorophenyl)-N-[(1-oxidepyridin-1-ium-2-yl)methyl]benzamide, 3-(2,5-Dichlorophenyl)-N-[(1-oxidepyridin-1-ium-2-yl)methyl]benzamide, 3-[2,4-Bis(trifluoromethyl)phenyl]-N-[(1-oxidepyridin-1-ium-2-yl)methyl]benzamide, N-[(1-Oxidepyridin-1-ium-2-yl)methyl]-3-phenyl-benzamide, 3-(4-tert-Butylphenyl)-N-[(1-oxidepyridin-1-ium-2-yl)methyl]benzamide, N-[(1-Oxidepyridin-1-ium-2-yl)methyl]-3-(p-tolyl)benzamide, 3-(4-Chloro-2-methyl-phenyl)-N-[(1-oxidepyridin-1-ium-2-yl)methyl]benzamide, 3-[2-Fluoro-4-(trifluoromethyl)phenyl]-N-[(1-oxidepyridin-1-ium-2-yl)methyl]benzamide, 3-(3-Chloro-4-fluoro-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(4-Fluorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(3,4-Difluorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(2-Chlorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, N-[(1-oxidopyridin-1-ium-2-yl)methyl]-3-[2-(trifluoromethyl)phenyl]benzamide, 3-(4-Fluoro-3-methyl-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(m-Tolyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(4-Isopropylphenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(2-Fluorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(4-Chloro-2-methoxy-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-[4-Chloro-2-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(4-Chloro-3-methyl-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(3-Chloro-5-fluoro-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(4-Chloro-3-fluoro-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(2,4-Difluorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(3,5-Difluorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, N-[(1-oxidopyridin-1-ium-2-yl)methyl]-3-(3,4,5-trifluorophenyl)benzamide, 3-(2,3-Difluorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(3-Isopropylphenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(4-Cyclopropylphenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-[4-(Difluoromethoxy)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-[2-Methyl-4-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-[4-Fluoro-3-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(2-Methoxyphenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-[3-Fluoro-5-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-[3-Fluoro-4-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-[3-Methyl-4-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-[4-(1-Hydroxy-1-methyl-ethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-[3-Methoxy-5-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-[2-Methoxy-4-(trifluoromethoxy)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(4,5-Difluoro-2-methoxy-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(4-Chloro-3-methoxy-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-[3-Methoxy-4-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-[4-Methoxy-2-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 5-(4-Chlorophenyl)-2-fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 5-(3-Chlorophenyl)-2-fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 5-(4-Chloro-2-methoxy-phenyl)-2-fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 5-(3,4-Difluorophenyl)-2-fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 5-[4-Chloro-2-(trifluoromethyl)phenyl]-2-fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 2-Fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 2-Fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]-5-[4-(trifluoromethyl)phenyl]benzamide, 2-Fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]-5-[4-(trifluoromethoxy)phenyl]benzamide, 2-Fluoro-5-[3-methoxy-4-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 2-Fluoro-5-[3-fluoro-4-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(4-Chlorophenyl)-N-[(5-fluoro-1-oxidopyridin-1-ium-2-yl)methyl]benzamide, and 2-Chloro-5-(4-chlorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide.

[0044] Synthesis of Compounds In some embodiments, the compounds of formula (I) can be prepared by the synthetic methods of Scheme I, II or III described below.

[0045] When X and Y are H, the desired compound can be prepared by the synthetic method described in Scheme I.

Chemical formula

[0046] (1-Oxidopyridin-1-ium-2-yl)methanamine hydrochloride (Int-1) is generally synthesized by protection of benzylamine, oxidation of pyridine and deprotection of the Boc group as shown in Scheme I. Usually, the desired target compound is obtained by amide coupling of Int-1 with a commercially available corresponding carboxylic acid.

[0047] Details of the reaction conditions described in Scheme I are as follows. Boc2 O was treated with a DCM solution of 2-pyridylmethanamine at 0 °C. The concentration of the starting material, 2-pyridylmethanamine, was about 0.001 - 100 moles. This reaction is preferably carried out at ambient temperature. The oxidation of the Boc-protected compound was carried out with an oxidizing agent such as mCPBA or MMPP. About 3 equivalents of the oxidizing agent were used. This reaction is preferably carried out in MeOH at 60 °C for 3 hours. As shown in Scheme I, the target compound was synthesized from Int-1 by deprotecting the Boc group in an organic solvent using an excess of HCl solution and then performing amide coupling.

[0048] When R3 is not H, the desired compound can be produced by the synthetic method described in Scheme II.

Chemical formula

[0049] As shown in Scheme II, the substituent 2-pyridylmethanamine and the corresponding carboxylic acid are coupled with an amide coupling agent such as EDC and HOBt. The target compound was synthesized by the oxidation of pyridine.

[0050] The details of the reaction conditions described in Scheme II are the same as those described in Scheme I. The concentration of each carboxylic acid as the starting material is about 0.01 - 0.1 moles.

[0051] When the corresponding carboxylic acid is not available on the market, the desired compound can be produced by the synthetic method described in Scheme III.

Chemical formula

[0052] As shown in Scheme III, the bromo-carboxylic acid compound and Int-1 react with an amide coupling agent to obtain Int-2. The final target compound can be obtained by reacting a palladium catalyst with a suitable base and solvent.

[0053] The details of the reaction conditions described in Scheme III are as follows. Above, amide coupling was described. The metal reaction of the palladium catalyst was carried out. General reaction conditions are Pd(dppf)Cl as the metal 2 , Na as the alkali 2 CO 3 , and DME as the solvent. This metal reaction was carried out under various reaction conditions depending on the reactivity of the two starting materials.

[0054] Pharmaceutical composition In one embodiment, there is provided a pharmaceutical composition comprising one or more compounds described herein and a pharmaceutically acceptable carrier. In various embodiments, the carrier includes diluents, adjuvants, excipients, other additives, or combinations of additives that singly or together provide a carrier in which the composition can be formulated or administered. The composition can take any form suitable for the desired route of administration. When the composition is administered orally, any suitable orally administrable dosage form can be used, including but not limited to tablets, capsules (filled with solid or liquid), powders, granules, syrups, and other liquids, elixirs, inhalants, troches, sugar lozenges, and solutions. Injectable compositions or intravenous infusions are also provided in the form of solutions, suspensions, and emulsions.

[0055] In certain embodiments, the pharmaceutical composition is an oral formulation. Since the compounds of formula (I) are well absorbed orally, it is generally not necessary to rely on parenteral administration. For oral administration, the compound is preferably formulated with a pharmaceutically acceptable carrier. The ratio of the carrier to the compound is not critical for the pharmacological effect of the formulation, and this ratio can vary considerably depending on the formulation conditions. In tableting, various edible pharmaceutical carriers or mixtures thereof can be included therein. Suitable carriers include, for example, a mixture of lactose, calcium hydrogen phosphate, and / or corn starch. Other pharmaceutically acceptable components, such as lubricants like magnesium stearate, may be further added.

[0056] The pharmaceutical composition according to the present disclosure may contain one or more additional therapeutic agents, for example, to increase efficacy or reduce side effects. In one embodiment, the pharmaceutical composition comprises one or more active ingredients effective for the treatment or prevention of neuropathic pain, and the active ingredients include antispasmodics such as gabapentin, pregabalin, carbamazepine, antidepressants such as duloxetine, milnacipran, and analgesics such as opioids, NSAIDs, lidocaine patches, and capsaicin patches.

[0057] Medical utility Yet another aspect of the present disclosure is to provide a method for treating or preventing a disease or condition mediated by a sodium channel, comprising administering to the mammal a therapeutically effective amount of one or more compounds of formula (I) or formula (II), or optical isomers, stereoisomers or isotopic variants thereof, or pharmaceutically acceptable salts thereof. In another embodiment, the sodium channel may be one or more selected from the group consisting of NaV 1.1, NaV 1.2, NaV 1.3, NaV 1.4, NaV 1.5, NaV 1.6, NaV 1.7, NaV 1.8, and NaV 1.9.

[0058] In another embodiment, the disease or condition may be pain. In another embodiment, the pain can be selected from nociceptive pain including pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, postoperative pain, and mixed pain types associated with the viscera, gastrointestinal tract, cranial structures, musculoskeletal system, spine, urogenital system, cardiovascular system and CNS (central nervous system) (including cancer pain, back pain, orofacial pain, and pain due to chemotherapy).

[0059] In view of the above-described mechanism of action, the compounds of the present invention are useful for the prevention or treatment of neuropathic pain. Neuropathic pain syndromes include small fiber neuropathy, lumbosacral radiculopathy, peripheral neuropathic pain, diabetic neuropathy; sciatica; nonspecific low back pain; pain in multiple sclerosis; fibromyalgia; HIV-related neuropathy; postherpetic neuralgia and trigeminal neuralgia, Morton's neuralgia, causalgia and other neuralgias; and pain due to physical injury, amputated limb, phantom limb, cancer, toxin or chronic inflammatory disease; central pain as observed in thalamic syndrome; pain with a mixture of central and peripheral components such as complex regional pain syndrome (CRPS), also known as reflex sympathetic dystrophy, but are not limited thereto.

[0060] The compounds of the present invention are also useful for the treatment or prevention of chronic pain. Chronic pain includes chronic pain caused by inflammation or inflammation-related symptoms, osteoarthritis, rheumatoid arthritis, acute injury or trauma, upper back pain or lower back pain (caused by systemic, local or primary spinal diseases such as radiculopathy), bone pain (caused by osteoarthritis, osteoporosis, bone metastasis or unknown causes), pelvic pain, pain associated with spinal cord injury, psychogenic chest pain, non-cardiac chest pain, central pain after stroke, fascial pain, pain due to sickle cell disease, cancer pain, Fabry disease, AIDS pain, pain in the elderly, or pain due to headache, temporomandibular joint syndrome, gout, fibrosis, or thoracic outlet syndrome, particularly including rheumatoid arthritis and osteoarthritis, but are not limited thereto.

[0061] The compounds of the present invention are also useful for the treatment or prevention of acute pain due to acute injury, disease, sports medicine injury, carpal tunnel syndrome, burns, sprains and strains of muscles and bones, tendon strains, cervical-shoulder-arm pain syndrome, indigestion, gastric ulcer, duodenal ulcer, dysmenorrhea, endometriosis, or surgery (such as open heart surgery or bypass surgery), postoperative pain, pain of kidney stones, gallbladder pain, pain of gallstones, labor pain, or toothache.

[0062] The compounds of the present invention are useful for the treatment or prevention of primary headache disorders such as headache, migraine, tension-type headache, transformed migraine, or evolutionary headache, cluster headache; secondary headache disorders such as those resulting from infectious diseases, metabolic disorders, or other systemic diseases; and other acute headaches, episodic hemicrania, etc. caused by the exacerbation of the above-mentioned primary and secondary headaches.

[0063] In another embodiment, the disease or condition can be selected from the group consisting of neurological diseases, neurodegenerative diseases, inflammatory diseases, gastrointestinal (GI) tract diseases, urogenital tract diseases, mental diseases, cardiovascular diseases, and neuromuscular diseases. The compounds of the present invention are also useful for the treatment or prevention of neurological diseases such as epilepsy including simple partial seizures, complex partial seizures, secondary generalized seizures; and epilepsy including absence seizures, myoclonic seizures, atonic seizures, tonic seizures, tonic-clonic seizures, and akinetic seizures.

[0064] The compounds of the present invention are also useful for the treatment or prevention of neurodegenerative diseases of various origins including symptoms of other dementias such as Alzheimer's disease, Parkinson's disease, and Lewy body dementia, frontotemporal dementia and tauopathy; multiple sclerosis, amyotrophic lateral sclerosis, and other Parkinsonian syndromes; other spinocerebellar degenerations and Charcot-Marie-Tooth nerve diseases, traumatic brain injury, stroke, and cerebral ischemia.

[0065] The compounds of the present invention inhibit inflammatory processes that affect all body systems. Accordingly, examples of inflammatory processes of the musculoskeletal system for which the compounds are useful for treatment or prevention include, but are not intended to be comprehensive of all target diseases: arthritic diseases such as ankylosing spondylitis, cervical arthritis, fibromyalgia, gout, juvenile rheumatoid arthritis, lumbosacral arthritis, osteoarthritis, osteoporosis, psoriatic arthritis, and rheumatic diseases; diseases affecting the skin and related tissues: inflammatory diseases such as eczema, psoriasis, itching, dermatitis, and sunburn; respiratory diseases: asthma, allergic rhinitis, and respiratory distress syndrome, lung diseases involving inflammation such as asthma and bronchitis; chronic obstructive pulmonary disease; immune and endocrine diseases: periarthritis nodosa, thyroiditis, aplastic anemia, scleroderma, myasthenia gravis, multiple sclerosis and other demyelinating diseases, encephalomyelitis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis.

[0066] The compounds of the present invention are also useful for the treatment or prevention of gastrointestinal (GI) tract diseases, including but not limited to inflammatory bowel diseases such as ulcerative colitis, Crohn's disease, ileitis, pancreatitis, proctitis, celiac disease, enteropathy, microscopic colitis or collagenous colitis, eosinophilic gastroenteritis, or pouchitis occurring after rectal - colon resection and ileo - anal anastomosis, and all diseases with abdominal pain and / or abdominal discomfort such as irritable bowel syndrome including pyloric spasm, nervous dyspepsia, spastic colon, spastic colitis, spastic intestine, enteroneurosis, functional colitis, mucous colitis, diarrheal colitis, and functional dyspepsia; other gastrointestinal (GI) tract damage such as atrophic gastritis, gastritis varialoforme, ulcerative colitis, peptic ulcer, pyresis, and damage caused by Helicobacter pylori and the like; gastroptosis such as gastroesophageal reflux disease, diabetic gastroptosis; and other functional bowel diseases such as non - ulcerative dyspepsia (NUD); vomiting, diarrhea, and treatment of visceral inflammation are also useful.

[0067] The compounds of the present invention are also useful for the treatment or prevention of urogenital tract diseases such as bladder dysfunction, overactive bladder, prostatitis (chronic bacterial and chronic non-bacterial prostatitis), prostate pain, interstitial cystitis, urinary incontinence and benign prostatic hyperplasia, adnexitis, pelvic inflammation, Bartholinitis, and vaginitis. They are particularly useful for the treatment or prevention of overactive bladder and urinary incontinence.

[0068] The compounds of the present invention are also useful for the treatment or prevention of mental diseases such as bipolar disorder, mood disorder, bipolar disorder, anxiety disorder, and depression.

[0069] The compounds of the present invention are also useful for the treatment or prevention of cardiovascular or neuromuscular diseases such as tachyarrhythmia, catatonia, arrhythmia, movement disorder, neuroendocrine disorder, and ataxia.

Example

[0070] Example 1: N-[(1-oxidopyridin-1-ium-2-yl)methyl]-3-[4-(trifluoromethyl)phenyl]benzamide

Chemical formula

[0071] To a DME solution of 3-bromo-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide (0.95 mmol), 4-trifluoromethylphenylboronic acid (1.91 mmol), pd(dppf)Cl 2 (0.24 mmol), and 2N Na 2 CO 3 were added. The reaction mixture was stirred at 100 °C for 15 minutes. The reaction mixture was cooled to room temperature and filtered to remove the palladium residue. The resulting mixture was extracted with DCM and washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography to obtain N-[(1-oxidopyridin-1-ium-2-yl)methyl]-3-[4-(trifluoromethyl)phenyl]benzamide.

[0072] 1H-NMR (CDCl 3 , 500 MHz) δ = 8.28 - 8.25 (m, 1H), 8.17 (s, 1H), 7.98 - 7.96 (m, 1H), 7.82 - 7.80 (m, 1H), 7.73 - 7.71 (m, 4H), 7.58 (dd, J = 2.0, 7.5 Hz, 1H), 7.54 - 7.51 (m, 1H), 7.33 - 7.28 (m, 2H), 4.87 (d, J = 6.0 Hz, 2H).

[0073] Example 2: 3-(4-Chlorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chem.

[0074] Using 4-chlorophenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-(4-chlorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0075] 1H-NMR (CDCl 3 , 500 MHz) δ = 8.25 (d, J = 6.0 Hz, 1H), 8.00 (s, 1H), 7.92 (brs, 1H, NH), 7.75 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.56 - 7.28 (m, 8H), 4.85 (d, J = 5.5 Hz, 2H).

[0076] Example 3: N-[(1-oxidopyridin-1-ium-2-yl)methyl]-3-[4-(trifluoromethoxy)phenyl]benzamide

Chem.

[0077] Using 4-trifluoromethoxyphenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, N-[(1-oxidopyridin-1-ium-2-yl)methyl]-3-[4-(trifluoromethoxy)phenyl]benzamide was obtained according to the procedure shown in Example 1.

[0078] 1H-NMR(CDCl 3 , 500 MHz)δ = 8.26(d, J = 6.5 Hz, 1H), 8.01(s, 1H), 7.95(brs, 1H, NH), 7.77(d, J = 7.5 Hz, 1H), 7.67(d, J = 7.5 Hz, 1H), 7.61-7.28(m, 8H), 4.86(d, J = 6.0 Hz, 2H).

[0079] Example 4: 3-(3-Chlorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical formula

[0080] Using 3-chlorophenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-(3-chlorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0081] 1H-NMR(CDCl 3 , 500 MHz)δ = 8.25-8.23(m, 1H), 7.92(s, 1H), 7.83(brs, 1H, NH), 7.77-7.75(m, 1H), 7.67(d, J = 7.5 Hz, 2H), 7.58-7.29(m, 7H), 4.87(s, 2H).

[0082] Example 5: N-[(1-oxidopyridin-1-ium-2-yl)methyl]-3-[3-(trifluoromethyl)phenyl]benzamide [Chem.]

[0083] Using 3-trifluoromethylphenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, N-[(1-oxidopyridin-1-ium-2-yl)methyl]-3-[3-(trifluoromethyl)phenyl]benzamide was obtained according to the procedure shown in Example 1.

[0084] 1H-NMR(CDCl 3 , 500 MHz)δ = 8.23-8.14(m, 1H), 8.06(s, 1H), 7.95(brs, 1H, NH), 7.78-7.46(m, 8H), 7.30-7.28(m, 2H), 4.87(s, 2H).

[0085] Example 6: 3-(3,4-Dichlorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide [Chem.]

[0086] Using 3,4-dichlorophenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-(3,4-dichlorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0087] 1H-NMR(CDCl 3 , 500 MHz)δ = 8.25(d, J = 6.5 Hz, 1H), 8.03(s, 1H), 7.95(brs, 1H, NH), 7.76(d, J = 7.5 Hz, 1H), 7.69-7.28(m, 9H), 4.85(d, J = 6.5 Hz, 2H).

[0088] Example 7: 3-(3,5-Dichlorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical formula

[0089] Using 3,5-dichlorophenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, according to the procedure shown in Example 1, (3,5-dichlorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained.

[0090] 1H-NMR(CDCl 3 , 500 MHz)δ = 8.26(d, J = 6.0 Hz, 1H), 8.00(s, 1H), 7.92(brs, 1H, NH), 7.78(d, J = 8.0 Hz, 1H), 7.65(t, J = 2.5 Hz, 1H), 7.57(dd, J = 2.0, 7.5 Hz, 1H), 7.48-7.27(m, 7H), 4.85(d, J = 6.0 Hz, 2H).

[0091] Example 8: N-[(1-oxidopyridin-1-ium-2-yl)methyl]-3-[3-(trifluoromethoxy)phenyl]benzamide

Chemical formula

[0092] Using 3-trifluoromethoxyphenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, according to the procedure shown in Example 1, N-[(1-oxidopyridin-1-ium-2-yl)methyl]-3-[3-(trifluoromethoxy)phenyl]benzamide was obtained.

[0093] 1H-NMR(CDCl 3, 500 MHz) δ = 8.24 (d, J = 6.5 Hz, 1H), 7.99 (s, 1H), 7.79 (brs, 1H, NH), 7.78 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.52 - 7.20 (m, 7H), 4.85 (d, J = 6.0 Hz, 2H).

[0094] Example 9: 3-(2,4-Dichlorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical Structure

[0095] Using 2,4-dichlorophenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-(2,4-dichlorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0096] 1H-NMR(CDCl 3 , 500 MHz) δ = 8.26 (d, J = 6.0 Hz, 1H), 7.82 (brs, 1H, NH), 7.79 (dd, J = 6.5, 8.0 Hz, 2H), 7.54 (dd, J = 1.5, 7.5 Hz, 2H), 7.47 (dd, J = 2.0, 7.5 Hz, 2H), 7.31 - 7.24 (m, 4H), 4.83 (d, J = 6.0 Hz, 2H).

[0097] Example 10: 3-(2,5-Dichlorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical Structure

[0098] Using 2,5-dichlorophenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-(2,5-dichlorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0099] 1H-NMR(CDCl 3 , 500 MHz)δ = 8.24(d, J = 6.5 Hz, 1H), 7.89(brs, 1H, NH), 7.82-7.80(m, 2H), 7.55-7.24(m, 8H), 4.83(d, J = 6.0 Hz, 2H).

[0100] Example 11: 3-[2,4-Bis(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical formula

[0101] Using 2,4-bis(trifluoromethyl)phenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-[2,4-bis(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0102] 1H-NMR(CDCl 3 , 500 MHz)δ = 8.25(d, J = 6.0 Hz, 1H), 7.99(s, 1H), 7.86(brs, 1H, NH), 7.84-7.82(m, 2H), 7.50(s, 1H), 7.48-7.43(m, 4H), 7.32-7.27(m, 2H), 4.83(d, J = 6.0 Hz, 2H).

[0103] Example 12: N-[(1-oxidopyridin-1-ium-2-yl)methyl]-3-phenyl-benzamide [Chemistry]

[0104] Using phenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, N-[(1-oxidopyridin-1-ium-2-yl)methyl]-3-phenyl-benzamide was obtained according to the procedure shown in Example 1.

[0105] 1H-NMR(CDCl 3 , 500 MHz) δ = 8.24(d, J = 6.0 Hz, 1H), 7.03(s, 1H), 7.95(brs, 1H, NH), 7.75 - 7.29(m, 11H), 4.84(s, 2H).

[0106] Example 13: 3-(4-tert-Butylphenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide [Chemistry]

[0107] Using 4-tert-butylphenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-(4-tert-butylphenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0108] 1H-NMR(CDCl 3 , 500 MHz) δ = 8.26(d, J = 1.0 Hz, 1H), 8.04(s, 1H), 7.88(brs, 1H, NH), 7.75 - 7.71(m, 2H), 7.57 - 7.55(m, 3H), 7.49 - 7.46(m, 3H), 7.31 - 7.27(m, 2H), 4.87(d, J = 6.5 Hz, 2H), 1.37(s, 9H).

[0109] Example 14: N-[(1-oxidopyridin-1-ium-2-yl)methyl]-3-(p-tolyl)benzamide

Chemical formula

[0110] Using p-tolylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, N-[(1-oxidopyridin-1-ium-2-yl)methyl]-3-(p-tolyl)benzamide was obtained according to the procedure shown in Example 1.

[0111] 1H-NMR(CDCl 3 , 500 MHz)δ = 8.24(d, J = 6.0 Hz, 1H), 8.01(s, 1H), 7.91(brs, 1H, NH), 7.72(d, J = 7.5 Hz, 1H), 7.68(d, J = 8.0 Hz, 1H), 7.55(d, J = 7.5 Hz, 1H), 7.49-7.43(m, 3H), 7.29-7.23(m, 4H), 4.84(d, J = 6.0 Hz, 2H), 2.39(s, 3H).

[0112] Example 15: 3-(4-chloro-2-methyl-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical formula

[0113] Using 4-chloro-2-methylphenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-(4-chloro-2-methyl-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0114] 1H-NMR(CDCl 3, 500 MHz) δ = 8.24 (d, J = 4.5 Hz, 1H), 7.90 (brs, 1H, NH), 7.76 (d, J = 8.0 Hz, 1H), 7.71 (s, 1H), 7.55 (d, J = 6.5 Hz, 1H), 7.46 - 7.27 (m, 5H), 7.20 (d, J = 8.5 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 4.83 (d, J = 5.0 Hz, 2H), 2.20 (s, 3H).

[0115] Example 16: 3-[2-Fluoro-4-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical Structure

[0116] Using 2-fluoro-4-trifluoromethylphenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0117] 1H-NMR(CDCl 3 , 500 MHz) δ = 8.24 (d, J = 5.5 Hz, 1H), 7.98 (s, 2H), 7.83 (d, J = 7.5 Hz, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.58 - 7.28 (m, 7H), 4.85 (d, J = 5.5 Hz, 2H).

[0118] Example 17: 3-(3-Chloro-4-fluoro-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical Structure

[0119] Using 3-chloro-4-fluorophenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-(3-chloro-4-fluoro-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0120] 1H-NMR(CDCl 3 , 500 MHz) δ = 8.25 (d, J = 6.5 Hz, 1H), 7.97 (s, 1H), 7.93 (brs, 1H, NH), 7.76 (d, J = 8.0 Hz, 1H), 7.63 - 7.61 (m, 2H), 7.56 (d, J = 7.5 Hz, 1H), 7.49 - 7.28 (m, 5H), 4.85 (d, J = 6.0 Hz, 2H).

[0121] Example 18: 3-(4-Fluorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical formula

[0122] Using 4-fluorophenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-(4-fluorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0123] 1H-NMR(CDCl 3, 500 MHz) δ = 8.25 (d, J = 6.0 Hz, 1H), 7.98 (s, 1H), 7.91 (brs, 1H, NH), 7.74 (d, J = 7.5 Hz, 1H), 7.65 (d, J = 7.0 Hz, 1H), 7.56 - 7.54 (m, 3H), 7.47 (t, J = 7.5 Hz, 1H), 7.31 - 7.26 (m, 2H), 7.12 (t, J = 8.5 Hz, 2H), 4.85 (d, J = 4.5 Hz, 2H).

[0124] Example 19: 3-(3,4-Difluorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical Structure

[0125] Using 3,4-difluorophenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-(3,4-difluorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0126] 1H-NMR(CDCl 3 , 500 MHz) δ = 8.25 (d, J = 6.0 Hz, 1H), 7.97 (s, 1H), 7.94 (brs, 1H, NH), 7.76 (d, J = 7.5 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.57 - 7.56 (m, 1H), 7.49 - 7.46 (m, 1H), 7.41 - 7.28 (m, 4H), 7.21 (t, J = 10.0 Hz, 1H), 4.85 (d, J = 6.0 Hz, 2H).

[0127] Example 20: 3-(2-Chlorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical Structure

[0128] Using 2-chlorophenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-(2-chlorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0129] 1H-NMR(CDCl 3 , 500 MHz)δ = 8.25(d, J = 6.5 Hz, 1H), 7.87(brs, 1H, NH), 7.85(s, 1H), 7.82(d, J = 7.5 Hz, 1H), 7.59-7.28(m, 9H), 4.85(d, J = 6.0 Hz, 2H).

[0130] Example 21: N-[(1-oxidopyridin-1-ium-2-yl)methyl]-3-[2-(trifluoromethyl)phenyl]benzamide

Chemical formula

[0131] Using 2-trifluoromethylphenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, N-[(1-oxidopyridin-1-ium-2-yl)methyl]-3-[2-(trifluoromethyl)phenyl]benzamide was obtained according to the procedure shown in Example 1.

[0132] 1H-NMR(CDCl 3 , 500 MHz)δ = 8.25(d, J = 6.0 Hz, 1H), 7.88(brs, 1H, NH), 7.84-7.74(m, 3H), 7.57-7.43(m, 5H), 7.33-7.28(m, 3H), 4.84(d, J = 6.5 Hz, 2H).

[0133] Example 22: 3-(4-Fluoro-3-methyl-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide [Chemical formula]

[0134] Using 4-fluoro-3-methylphenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-(4-fluoro-3-methyl-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0135] 1H-NMR(CDCl 3 , 500 MHz)δ = 8.26(d, J = 6.0 Hz, 1H), 7.98(s, 1H), 7.91(brs, 1H, NH), 7.73(d, J = 7.5 Hz, 1H), 7.65(d, J = 7.5 Hz, 1H), 7.59(d, J = 6.5 Hz, 1H), 7.47-7.28(m, 5H), 7.06(t, J = 9.0 Hz, 1H), 4.86(d, J = 6.0 Hz, 2H), 2.33(s, 3H).

[0136] Example 23: 3-(m-Tolyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide [Chemical formula]

[0137] Using 3-methylphenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-(m-tolyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0138] 1H-NMR(CDCl 3, 500 MHz) δ = 8.24 (d, J = 6.0 Hz, 1H), 8.02 (brs, 1H, NH), 7.90 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 7.5 Hz, 1H), 7.55 (dd, J = 2.0, 7.5 Hz, 1H), 7.47 - 7.28 (m, 6H), 7.17 (d, J = 7.5 Hz, 1H), 4.85 (d, J = 6.0 Hz, 2H), 2.41 (s, 3H).

[0139] Example 24: 3-(4-Isopropylphenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical Structure

[0140] Using 4-isopropylphenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-(4-isopropylphenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0141] 1H-NMR(CDCl 3 , 500 MHz) δ = 8.27 (d, J = 6.5 Hz, 1H), 8.03 (s, 1H), 7.91 (brs, 1H, NH), 7.75 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.58 - 7.54 (m, 3H), 7.47 (t, J = 8.0 Hz, 1H), 7.34 - 7.27 (m, 4H), 4.87 (d, J = 6.0 Hz, 2H), 2.99 - 2.94 (m, 1H), 1.30 (d, J = 7.0 Hz, 6H).

[0142] Example 25: 3-(2-Fluorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical Structure

[0143] Using 2-fluorophenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-(2-fluorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0144] 1H-NMR(CDCl 3 , 500 MHz) δ = 8.08(s, 1H), 7.82(s, 1H), 7.74(d, J = 5.0 Hz, 1H), 7.51 - 7.30(m, 8H), 7.24 - 7.06(m, 2H), 4.85 (s, 2H).

[0145] Example 26: 3-(4-chloro-2-methoxy-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical formula

[0146] Using 4-chloro-2-methoxyphenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-(4-chloro-2-methoxy-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0147] 1H-NMR(CDCl 3, 500 MHz) δ = 8.26 (d, J = 6.5 Hz, 1H), 7.92 (s, 1H), 7.89 (brs, 1H, NH), 7.77 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.57 (dd, J = 1.5, 7.5 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.33 - 7.26 (m, 2H), 7.23 (d, J = 8.0 Hz, 1H), 7.02 (dd, J = 2.0, 8.0 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 4.86 (d, J = 6.0 Hz, 2H), 3.81 (s, 3H).

[0148] Example 27: 3-[4-Chloro-2-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical formula

[0149] Using 4-chloro-2-trifluoromethylphenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-[4-chloro-2-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0150] 1H-NMR(CDCl 3 , 500 MHz) δ = 8.24 (dd, J = 1.5, 7.5 Hz, 1H), 7.90 (brs, 1H, NH), 7.84 - 7.81 (m, 1H), 7.73 (d, J = 2.5 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.33 - 7.24 (m, 5H), 4.83 (d, J = 7.5 Hz, 2H).

[0151] Example 28: 3-(4-Chloro-3-methyl-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chem.

[0152] Using 4-chloro-3-methylphenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-(4-chloro-3-methyl-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0153] 1H-NMR(CDCl 3 , 500 MHz)δ = 8.26(s, 1H), 8.02(s, 1H), 7.93(brs, 1H, NH), 7.76(d, J = 6.5 Hz, 1H), 7.68(d, J = 7.5 Hz, 1H), 7.61(s, 1H), 7.49-7.30(m, 6H), 4.88(s, 2H), 2.44(s, 3H).

[0154] Example 29: 3-(3-Chloro-5-fluoro-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chem.

[0155] Using 3-chloro-5-fluorophenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-(3-chloro-5-fluoro-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0156] 1H-NMR(CDCl 3, 500 MHz) δ = 8.25 (d, J = 6.0 Hz, 1H), 7.99 (s, 1H), 7.92 (brs, 1H, NH), 7.78 (d, J = 7.5 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.57 - 7.47 (m, 2H), 7.37 (s, 1H), 7.33 - 7.27 (m, 2H), 7.19 (d, J = 9.5 Hz, 1H), 7.08 (d, J = 8.5 Hz, 1H), 4.85 (d, J = 6.0 Hz, 2H).

[0157] Example 30: 3-(4-Chloro-3-fluoro-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical Structure

[0158] Using 4-chloro-3-fluorophenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-(4-chloro-3-fluoro-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0159] 1H-NMR(CDCl 3 , 500 MHz) δ = 8.29 (d, J = 6.0 Hz, 1H), 8.03 (s, 1H), 7.97 (brs, 1H, NH), 7.78 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 1.0 Hz, 1H), 7.65 (dd, J = 5.0, 6.0 Hz, 1H), 7.60 (dd, J = 2.0, 8.0 Hz, 1H), 7.49 - 7.28 (m, 5H), 4.87 (d, J = 6.0 Hz, 2H).

[0160] Example 31: 3-(2,4-Difluorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide [Chemical]

[0161] Using 2,4-difluorophenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-(2,4-difluorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0162] 1H-NMR(CDCl 3 , 500 MHz) δ = 8.25 (d, J = 6.0 Hz, 1H), 7.92 (s, 1H), 7.90 (brs, 1H, NH), 7.78 (d, J = 7.5 Hz, 1H), 7.63 (d, J = 7.0 Hz, 1H), 7.56 (dd, J = 1.0, 6.0 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.43 - 7.40 (m, 1H), 7.38 - 7.27 (m, 2H), 6.98 - 6.89 (m, 2H), 4.86 (d, J = 6.0 Hz, 2H).

[0163] Example 32: 3-(3,5-Difluorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide [Chemical]

[0164] Using 3,5-difluorophenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-(3,5-difluorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0165] 1H-NMR(CDCl 3, 500 MHz) δ = 8.27 (d, J = 6.0 Hz, 1H), 7.99 (s, 1H), 7.94 (brs, 1H, NH), 7.78 (d, J = 7.5 Hz, 1H), 7.66 - 7.27 (m, 5H), 7.13 - 7.10 (m, 2H), 6.82 - 6.78 (m, 1H), 4.86 (d, J = 6.0 Hz, 2H).

[0166] Example 33: N - [(1 - Oxidepyridin - 1 - ylium - 2 - yl)methyl] - 3 - (3,4,5 - trifluorophenyl)benzamide

Chemical Structure

[0167] Using 3,4,5 - trifluorophenylboronic acid as a reactant instead of 4 - trifluoromethylphenylboronic acid, following the procedure shown in Example 1, N - [(1 - oxidepyridin - 1 - ylium - 2 - yl)methyl] - 3 - (3,4,5 - trifluorophenyl)benzamide was obtained.

[0168] 1H - NMR(CDCl 3 , 500 MHz) δ = 8.31 (d, J = 6.0 Hz, 1H), 7.95 (s, 1H), 7.87 (brs, 1H, NH), 7.76 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 1.5 Hz, 1H), 7.62 - 7.33 (m, 4H), 7.22 - 7.17 (m, 2H), 4.91 (d, J = 6.0 Hz, 2H).

[0169] Example 34: 3 - (2,3 - difluorophenyl) - N - [(1 - oxidepyridin - 1 - ylium - 2 - yl)methyl]benzamide

Chemical Structure

[0170] Using 2,3-difluorophenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-(2,3-difluorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0171] 1H-NMR(CDCl 3 , 500 MHz)δ = 8.27(d, J = 6.0 Hz, 1H), 7.97(s, 1H), 7.95(brs, 1H, NH), 7.83(d, J = 8.0 Hz, 1H), 7.68(d, J = 7.5 Hz, 1H), 7.58(d, J = 7.5 Hz, 1H), 7.52(t, J = 7.5 Hz, 1H), 7.35-7.27(m, 2H), 7.21-7.14(m, 3H), 4.87(d, J = 6.0 Hz, 2H).

[0172] Example 35: 3-(3-Isopropylphenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical formula

[0173] Using 3-isopropylphenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-(3-isopropylphenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0174] 1H-NMR(CDCl 3, 500 MHz) δ = 8.25 (d, J = 6.5 Hz, 1H), 8.03 (s, 1H), 7.89 (brs, 1H, NH), 7.71 (dd, J = 7.5, 14.0 Hz, 2H), 7.56 (d, J = 7.5 Hz, 1H), 7.48 - 7.29 (m, 7H), 4.85 (d, J = 6.0 Hz, 2H), 2.99 - 2.94 (m, 1H), 1.29 (d, J = 6.5 Hz, 6H).

[0175] Example 36: 3-(4-Cyclopropylphenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical Structure

[0176] Using 4-cyclopropylphenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-(4-cyclopropylphenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0177] 1H-NMR(CDCl 3 , 500 MHz) δ = 8.25 (d, J = 6.5 Hz, 1H), 8.02 (s, 1H), 7.93 (brs, 1H, NH), 7.74 - 7.68 (m, 2H), 7.57 (dd, J = 2.0, 8.0 Hz, 1H), 7.51 - 7.45 (m, 3H), 7.33 - 7.26 (m, 2H), 7.15 (d, J = 8.0 Hz, 2H), 4.86 (d, J = 6.0 Hz, 2H), 1.97 - 1.92 (m, 1H), 1.03 - 0.98 (m, 2H), 0.77 - 0.75 (m, 2H).

[0178] Example 37: 3-[4-(Difluoromethoxy)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical Structure

[0179] Using 4-difluoromethoxyphenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-[4-(difluoromethoxy)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0180] 1H-NMR(CDCl 3 , 500 MHz)δ = 8.26(d, J = 6.5 Hz, 1H), 8.02(s, 1H), 7.97(brs, 1H, NH), 7.78-7.51(m, 5H), 7.34-7.29(m, 3H), 7.22(d, J = 8.5 Hz, 2H), 6.58(d, J = 74.0 Hz, 1H), 4.88(d, J = 6.0 Hz, 2H).

[0181] Example 38: 3-[2-Methyl-4-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical formula

[0182] Using 2-methyl-4-(trifluoromethyl)phenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-[2-methyl-4-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0183] 1H-NMR(CDCl 3, 500 MHz) δ = 8.25 (d, J = 6.5 Hz, 1H), 7.97 (brs, 1H, NH), 7.83 (d, J = 7.5 Hz, 1H), 7.75 (s, 1H), 7.53 - 7.27 (m, 8H), 4.85 (d, J = 6.5 Hz, 2H), 2.29 (s, 3H).

[0184] Example 39: 3-[4-Fluoro-3-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical Structure

[0185] Using 4-fluoro-3-(trifluoromethyl)phenylboronic acid instead of 4-trifluoromethylphenylboronic acid as the reactant, following the procedure shown in Example 1, 3-[4-fluoro-3-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained.

[0186] 1H-NMR(CDCl 3 , 500 MHz) δ = 8.25 (d, J = 6.5 Hz, 1H), 8.03 (s, 1H), 7.89 (brs, 1H, NH), 7.84 - 7.33 (m, 9H), 4.90 (d, J = 6.5 Hz, 2H).

[0187] Example 40: 3-(2-Methoxyphenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical Structure

[0188] Using 2-methoxyphenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-(2-methoxyphenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0189] 1H-NMR(CDCl 3 , 500 MHz)δ = 8.31(d, J = 6.0 Hz, 1H), 7.95(s, 1H), 7.87(brs, 1H, NH), 7.79(d, J = 7.5 Hz, 1H), 7.70(d, J = 8.0 Hz, 1H), 7.59(d, J = 7.0 Hz, 1H), 7.49(t, J = 7.5 Hz, 1H), 7.40-7.30(m, 4H), 7.07(t, J = 7.0 Hz, 1H), 7.03(d, J = 8.0 Hz, 1H), 4.89(d, J = 5.0 Hz, 2H), 3.85(s, 3H).

[0190] Example 41: 3-[3-Fluoro-5-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical formula

[0191] Using 3-fluoro-5-trifluoromethylphenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-[3-fluoro-5-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0192] 1H-NMR(CDCl 3, 500 MHz) δ = 8.36 (d, J = 6.0 Hz, 1H), 8.11 (s, 1H), 8.04 (brs, 1H, NH), 7.83 (d, J = 7.5 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 7.61 - 7.52 (m, 4H), 7.38 - 7.30 (m, 2H), 4.89 (d, J = 6.0 Hz, 2H).

[0193] Example 42: 3-[3-Fluoro-4-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical formula

[0194] Using 3-fluoro-4-trifluoromethylphenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-[3-fluoro-4-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0195] 1H-NMR(CDCl 3 , 500 MHz) δ = 8.31 (d, J = 6.0 Hz, 1H), 8.19 (s, 1H), 7.99 (brs, 1H, NH), 7.83 (d, J = 7.5 Hz, 1H), 7.72 - 7.30 (m, 8H), 4.88 (d, J = 6.0 Hz, 2H).

[0196] Example 43: 3-[3-Methyl-4-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical formula

[0197] Using 3-methyl-4-(trifluoromethyl)phenylboronic acid as a reactant instead of 4-(trifluoromethyl)phenylboronic acid, 3-[3-methyl-4-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0198] 1H-NMR(CDCl 3 , 500 MHz)δ = 8.39(d, J = 6.0 Hz, 1H), 8.08(s, 1H), 7.94(brs, 1H, NH), 7.80(d, J = 7.5 Hz, 1H), 7.73-7.29(m, 8H), 4.88(d, J = 6.0 Hz, 2H), 2.57(s, 3H).

[0199] Example 44: 3-[4-(1-Hydroxy-1-methyl-ethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical formula

[0200] Using 1-hydroxy-1-methyl-ethylphenylboronic acid as a reactant instead of 4-(trifluoromethyl)phenylboronic acid, 3-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0201] 1H-NMR(CDCl 3 , 500 MHz)δ = 8.26(d, J = 6.0 Hz, 1H), 8.05(s, 1H), 7.92(brs, 1H, NH), 7.76(d, J = 7.5 Hz, 1H), 7.73(d, J = 8.0 Hz, 1H), 7.61-7.28(m, 8H), 4.88(d, J = 6.0 Hz, 2H), 1.64(s, 6H).

[0202] Example 45: 3-[3-Methoxy-5-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical formula

[0203] Using 3-methoxy-5-trifluoromethylphenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-[3-methoxy-5-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0204] 1H-NMR(CDCl 3 , 500 MHz)δ = 8.27(d, J = 6.0 Hz, 1H), 8.06(s, 1H), 7.92(brs, 1H, NH), 7.79(d, J = 7.5 Hz, 1H), 7.72(d, J = 8.0 Hz, 1H), 7.59-7.30(m, 6H), 7.14(s, 1H), 4.88(d, J = 6.0 Hz, 2H), 3.92(s, 3H).

[0205] Example 46: 3-[2-Methoxy-4-(trifluoromethoxy)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical formula

[0206] Using 2-methoxy-4-trifluoromethoxyphenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-[2-methoxy-4-(trifluoromethoxy)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0207] 1H-NMR(CDCl 3, 500 MHz) δ = 8.24 (d, J = 6.0 Hz, 1H), 7.91 (s, 1H), 7.86 (brs, 1H, NH), 7.77 (d, J = 7.5 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.55 - 7.28 (m, 5H), 6.90 (d, J = 7.0 Hz, 1H), 6.82 (s, 1H), 7.59 - 7.30 (m, 6H), 7.14 (s, 1H), 4.85 (d, J = 6.0 Hz, 2H), 3.82 (s, 3H).

[0208] Example 47: 3-(4,5-Difluoro-2-methoxy-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical Structure

[0209] Using 4,5-difluoro-2-methoxyphenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-(4,5-difluoro-2-methoxy-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0210] 1H-NMR(CDCl 3 , 500 MHz) δ = 8.25 (d, J = 6.0 Hz, 1H), 7.89 (s, 1H), 7.88 (brs, 1H, NH), 7.76 (d, J = 2.5 Hz, 1H), 7.58 - 7.54 (m, 2H), 7.45 (t, J = 7.5 Hz, 1H), 7.30 - 7.28 (m, 2H), 7.13 (t, J = 10.0 Hz, 1H), 6.79 (dd, J = 7.0, 12.0 Hz, 1H), 4.84 (d, J = 6.0 Hz, 2H), 3.76 (s, 3H).

[0211] Example 48: 3-(4-Chloro-3-methoxyphenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chem.

[0212] Using 4-chloro-3-methoxyphenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-(4-chloro-3-methoxyphenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0213] 1H-NMR(CDCl 3 , 500 MHz)δ = 8.25(d, J = 6.0 Hz, 1H), 8.01(s, 1H), 7.91(brs, 1H, NH), 7.75-7.73(m, 1H), 7.68-7.66(m, 1H), 7.56-7.50(m, 1H), 7.48-7.41(m, 2H), 7.31-7.27(m, 2H), 7.12-7.10(m, 2H), 4.85(d, J = 6.0 Hz, 2H), 3.79(s, 3H).

[0214] Example 49: 3-[3-Methoxy-4-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chem.

[0215] Using 3-methoxy-4-trifluoromethylphenylboronic acid as a reactant instead of 4-trifluoromethylphenylboronic acid, 3-[3-methoxy-4-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0216] 1H-NMR(CDCl3 , 500 MHz) δ = 8.24 (d, J = 6.0 Hz, 1H), 8.03 (s, 1H), 7.96 (brs, 1H, NH), 7.72 - 7.27 (m, 7H), 7.22 - 7.18 (m, 2H), 4.90 (d, J = 6.0 Hz, 2H), 3.98 (s, 3H).

[0217] Example 50: 3 - [4 - Methoxy - 2 - (trifluoromethyl)phenyl] - N - [(1 - oxidopyridin - 1 - ylium - 2 - yl)methyl]benzamide

Chemical Structure

[0218] Using 4 - methoxy - 2 - trifluoromethylphenylboronic acid as a reactant instead of 4 - trifluoromethylphenylboronic acid, 3 - [4 - methoxy - 2 - (trifluoromethyl)phenyl] - N - [(1 - oxidopyridin - 1 - ylium - 2 - yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0219] 1H - NMR (CDCl 3 , 500 MHz) δ = 8.25 (d, J = 6.0 Hz, 1H), 7.91 - 7.80 (m, 2H), 7.73 (s, 1H), 7. (dd, J = 2.0, 7.5 Hz, 1H), 7.43 (d, J = 5.5 Hz, 2H), 7.31 - 7.21 (m, 4H), 7.07 (dd, J = 2.5, 8.5 Hz, 1H), 4.83 (d, J = 6.0 Hz, 2H), 3.89 (s, 3H).

[0220] Example 51: 5 - (4 - Chlorophenyl) - 2 - fluoro - N - [(1 - oxidopyridin - 1 - ylium - 2 - yl)methyl]benzamide

Chemical Structure

[0221] Using 4-chlorophenylboronic acid and 5-bromo-2-fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide as reactants instead of 4-trifluoromethylphenylboronic acid and 3-bromo-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide respectively, 5-(4-chlorophenyl)-2-fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 1.

[0222] 1H-NMR(CDCl 3 , 500 MHz)δ = 8.25-8.19(m, 2H), 8.18(brs, 1H, NH), 7.63(dq, J = 2.5, 4.5 Hz, 1H), 7.55(d, J = 2.0 Hz, 1H), 7.53(d, J = 2.0 Hz, 2H), 7.49(d, J = 8.5 Hz, 2H), 7.41-7.29(m, 2H), 7.21-7.17(m, 1H), 4.88(d, J = 6.0 Hz, 2H).

[0223] Example 52: 5-(3-chlorophenyl)-2-fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical Structure

[0224] Using 3-chlorophenylboronic acid as a reactant instead of 4-chlorophenylboronic acid, 5-(3-chlorophenyl)-2-fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 51.

[0225] 1H-NMR(CDCl 3 , 500 MHz)δ = 8.28-8.24(m, 3H), 7.65-7.18(m, 9H), 4.88(d, J = 6.0 Hz, 2H).

[0226] Example 53: 5-(4-Chloro-2-methoxyphenyl)-2-fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical formula

[0227] Using 4-chloro-2-methoxyphenylboronic acid as a reactant instead of 4-chlorophenylboronic acid, 5-(4-chloro-2-methoxyphenyl)-2-fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 51.

[0228] 1H-NMR(CDCl 3 , 500 MHz)δ = 8.27(d, J = 6.0 Hz, 1H), 8.14-8.12(m, 2H), 7.53-7.51(m, 2H), 7.28-7.26(m, 2H), 7.20(d, J = 8.0 Hz, 1H), 7.15(t, J = 3.0 Hz, 1H), 6.99(dd, J = 1.5, 5.0 Hz, 1H), 6.94(d, J = 2.0 Hz, 1H), 4.87(d, J = 6.0 Hz, 2H), 3.79(s, 3H).

[0229] Example 54: 5-(3,4-Difluorophenyl)-2-fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical formula

[0230] Using 3,4-difluorophenylboronic acid as a reactant instead of 4-chlorophenylboronic acid, 5-(3,4-difluorophenyl)-2-fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 51.

[0231] 1H-NMR (CDCl 3 , 500 MHz) δ = 8.30 - 8.19 (m, 3H), 7.61 - 7.18 (m, 7H), 4.87 (d, J = 6.0 Hz, 2H).

[0232] Example 55: 5-[4-Chloro-2-(trifluoromethyl)phenyl]-2-fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical Structure

[0233] Using 4-chloro-2-trifluoromethylphenylboronic acid as a reactant instead of 4-chlorophenylboronic acid, 5-[4-chloro-2-(trifluoromethyl)phenyl]-2-fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 51.

[0234] 1H-NMR (CDCl 3 , 500 MHz) δ = 8.29 (d, J = 6.0 Hz, 1H), 8.27 (brs, 1H, NH), 7.99 (dd, J = 2.5, 7.0 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.54 - 7.23 (m, 7H), 7.17 (dd, J = 8.5, 11.5 Hz, 1H), 4.86 (d, J = 6.0 Hz, 2H).

[0235] Example 56: 2-Fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical Structure

[0236] Using 2-methoxy-4-(trifluoromethoxy)phenylboronic acid as a reactant instead of 4-chlorophenylboronic acid, 2-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 51.

[0237] 1H-NMR(CDCl 3 , 500 MHz)δ = 8.26(d, J = 1.5 Hz, 1H), 8.13(dd, J = 2.5, 7.5 Hz, 2H), 7.58(dt, J = 2.5, 5.0 Hz, 1H), 7.51(dd, J = 2.5, 7.5 Hz, 1H), 7.29-7.25(m, 3H), 7.15(dd, J = 9.0, 12.0 Hz, 1H), 6.87(dd, J = 1.0, 8.5 Hz, 1H), 6.80(d, J = 2.0 Hz, 1H), 4.86(d, J = 6.0 Hz, 2H), 3.80(s, 3H).

[0238] Example 57: 2-Fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]-5-[4-(trifluoromethyl)phenyl]benzamide

Chemical formula

[0239] Using 4-(trifluoromethyl)phenylboronic acid as a reactant instead of 4-chlorophenylboronic acid, 2-fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]-5-[4-(trifluoromethyl)phenyl]benzamide was obtained according to the procedure shown in Example 51.

[0240] 1H-NMR(CDCl 3, 500 MHz) δ = 8.24 - 8.22 (m, 3H), 7.64 - 7.61 (m, 5H), 7.49 (dd, J = 2.0, 7.5 Hz, 1H), 7.24 - 7.15 (m, 3H), 4.84 (d, J = 6.0 Hz, 2H).

[0241] Example 58: 2-Fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]-5-[4-(trifluoromethoxy)phenyl]benzamide

Chemical formula

[0242] Using 4-(trifluoromethoxy)phenylboronic acid as a reactant instead of 4-chlorophenylboronic acid, 2-fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]-5-[4-(trifluoromethoxy)phenyl]benzamide was obtained according to the procedure shown in Example 51.

[0243] 1H-NMR(CDCl 3 , 500 MHz) δ = 8.28 - 8.18 (m, 3H), 7.64 - 7.53 (m, 4H), 7.32 - 7.18 (m, 5H), 4.89 (d, J = 5.0 Hz, 2H).

[0244] Example 59: 2-Fluoro-5-[3-methoxy-4-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical formula

[0245] Using 3-methoxy-4-(trifluoromethyl)phenylboronic acid as a reactant instead of 4-chlorophenylboronic acid, 2-fluoro-5-[3-methoxy-4-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 51.

[0246] 1H-NMR(CDCl 3 , 500 MHz)δ = 8.29-8.21(m, 3H), 7.68-7.53(m, 3H), 7.32-7.16(m, 4H), 7.14(s, 1H), 4.89(d, J = 6.0 Hz, 2H), 3.96(s, 3H).

[0247] Example 60: 2-Fluoro-5-[3-fluoro-4-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical formula

[0248] Using 3-fluoro-4-(trifluoromethyl)phenylboronic acid as a reactant instead of 4-chlorophenylboronic acid, 2-fluoro-5-[3-fluoro-4-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained according to the procedure shown in Example 51.

[0249] 1H-NMR(CDCl 3 , 500 MHz)δ = 8.29-8.23(m, 3H), 7.67-7.38(m, 5H), 7.31-7.21(m, 3H), 4.86(d, J = 5.5 Hz, 2H).

[0250] Example 61: 3-(4-Chlorophenyl)-N-[(5-fluoro-1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical formula

[0251] Instead of 5-bromo-2-fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(4-chlorophenyl)-N-[(5-fluoropyridin-2-yl)methyl]benzamide 3-bromo-5-fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was used as the reactant, and according to the procedure shown in Example 51, 3-(4-chlorophenyl)-N-[(5-fluoro-1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained.

[0252] 1H-NMR(CDCl 3 , 500 MHz)δ = 8.19(dd, J = 2.5, 4.0 Hz, 1H), 7.99(d, J = 1.5 Hz, 1H), 7.75(d, J = 1.0 Hz, 1H), 7.73(brs, 1H, NH), 7.69-7.41(m, 7H), 7.13-7.09(m, 1H), 4.81(d, J = 6.0 Hz, 2H).

[0253] Example 62: 2-Chloro-5-(4-chlorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide

Chemical formula

[0254] Instead of 5-bromo-2-fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 5-bromo-2-chloro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was used as the reactant, and according to the procedure shown in Example 51, 2-chloro-5-(4-chlorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide was obtained.

[0255] 1H-NMR(DMSO-d 6, 500 MHz) δ = 9.17 (t, J = 7.5 Hz, 1H), 8.34 - 8.32 (m, 2H), 7.88 (d, J = 3.0 Hz, 1H), 7.81 - 7.37 (m, 7H), 4.56 (d, J = 7.5 Hz, 2H).

[0256] hNav1.7 channel assay Using the whole-cell patch-clamp technique, the inhibitory effect of the compound of the example on the human Nav1.7 channel stably expressed in HEK293 cells was investigated. The human Nav1.7 recombinant cell line (CYL3011-precisION) was purchased from Eurofins.

[0257] The state-dependent inhibition of the example was evaluated using a double-pulse protocol every 10 seconds. From a holding potential of -90 mV, after a prepulse (-120 mV for 200 ms), test pulse 1 (TP1: 0 mV for 1 s) was given, and then, after an interpulse (-100 mV for 20 ms), test pulse 2 (TP2: 0 mV for 20 ms) was induced.

[0258] The peak current amplitudes of test pulses TP1 (resting state inhibition) and TP2 (inactivation state inhibition) were measured. The following solutions were used for the screening assay: External (mM): 145 NaCl, 1 MgCl 2 , 1.8 CaCl 2 , 10 HEPES, 5 glucose, pH 7.4, 300 mOsm, Internal (mM): 120 CsF, 10 NaCl, 10 EGTA, 10 HEPES, pH 7.2, 290 mOsm.

[0259] The inhibition of hNav1.7 in the inactivated state was calculated as follows: % Inhibition (inactivated state) = (1 - (I TP2 of TA / I TP2 of control)) × 100%, where I TP2 (inward peak Na+ current) of control and I TP2 of TA are the ones generated by TP2 in the presence of control (vehicle only) and the test article (TA) of the example, respectively.

[0260] According to one embodiment of the present invention, the compounds of the examples do not show significant inhibition against the resting state of hNav1.7, indicating that the adverse potential of the examples is relatively low.

[0261] [Table 1] TIFF2025516035000073.tif210168

[0262] The inhibitory activity means the inhibition rate against the inactivated state of hNav1.7 at 10 μM. + : 10 - 40%, ++ : 40 - 70%, +++ : 70 - 100%.

[0263] As described herein, it has been observed that the compounds of the present disclosure have an inhibitory affinity for voltage - dependent sodium channels. As a result, these compounds are shown to be potentially useful for the treatment of pain, including neuropathic pain, by blocking the activity of sodium channels.

[0264] Rat spinal nerve ligation model The analgesic effect was examined by the spinal nerve ligation (SNL) model (also called the Chung model) (Kim and Chung, 1992). The SNL model is one of the most frequently used animal models for the evaluation of neuropathic pain behavior.

[0265] Briefly, the distal end of the dorsal root ganglion of the fifth lumbar spinal nerve was ligated with silk suture. After 2 weeks of recovery, the mechanical allodynia of the affected paw of the animal was evaluated using von Frey filaments. The pre-dose baseline was obtained with allodynia defined as a paw withdrawal threshold (PWT) < 4 g using the Dixon's Up-Down method (Chaplan et al., 1994). Subsequently, the test compound (30 mg / kg) or vehicle was administered orally, and the PWT was measured 2 hours after treatment. The statistical mean PWT values of the vehicle control group and the drug treatment group were calculated, and the maximum possible effect rate (%MPE) value was determined based on the following formula.

[0266] %MPE = [(PWT after administration - PWT before administration) / (Cut-off PWT - PWT before administration)] × 100

[0267] [Table 2]

[0268] In vivo efficacy means %MPE at an oral dose of 30 mg / kg. + : 10 - 40%, ++ : 40 - 70%, +++ : 70 - 100%.

[0269] As described above, it was observed that the compounds of the present disclosure have an analgesic effect useful for the treatment of pain including neuropathic pain.

Claims

1. The following formula (I): 【Chemical Formula 1】 (wherein R1 is hydrogen, halogen, alkyl, alkoxy, or cycloalkyl, R2 is hydrogen, halogen, alkyl, alkoxy, cycloalkyl, or a 4- to 10-membered heterocycloalkyl containing one or more heteroatoms selected from N, O, and S, R3 is hydrogen, halogen, alkyl, alkoxy, or cycloalkyl, and n is an integer from 0 to 4, wherein the alkyl, alkoxy, and cycloalkyl may be substituted with one or more substituents selected from halogen and hydroxy.) or an optical isomer, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt thereof.

2. R1 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 10 cycloalkyl, and R2 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, or 4- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms selected from N, O, and S, R3 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 10 cycloalkyl, and n is an integer from 0 to 4, wherein the alkyl, alkoxy, and cycloalkyl may be substituted with 1 to 4 substituents selected from halogen and hydroxy, the compound according to Claim 1, or an optical isomer, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt thereof.

3. R1 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or C 3 -C 6 cycloalkyl, and R2 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, or 4- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms selected from N, O, and S, R3 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or C 3 -C 6 cycloalkyl, and n is an integer from 0 to 4, wherein the alkyl, alkoxy, and cycloalkyl may be substituted with 1 to 4 substituents selected from halogen and hydroxy, the compound according to Claim 1, or an optical isomer, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt thereof.

4. R1 is hydrogen or halogen, the compound according to Claim 1, or an optical isomer, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt thereof.

5. R2 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 10 cycloalkyl, and wherein the alkyl, alkoxy, and cycloalkyl may be substituted with 1 to 4 substituents selected from halogen and hydroxy, the compound according to Claim 1, or an optical isomer, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt thereof.

6. R3 is hydrogen or halogen, the compound according to Claim 1, or an optical isomer, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt thereof.

7. The compound of formula (I) is of formula (II): 【Chemical 2】 (wherein R1 is hydrogen, halogen, alkyl, alkoxy, or cycloalkyl, R2 is hydrogen, halogen, alkyl, alkoxy, cycloalkyl, or a 4- to 10-membered heterocycloalkyl containing one or more heteroatoms selected from N, O, and S, R3 is hydrogen, halogen, alkyl, alkoxy, or cycloalkyl, R4 is hydrogen, halogen, alkyl, alkoxy, cycloalkyl, or 4- to 10-membered heterocycloalkyl containing one or more heteroatoms selected from N, O, and S, and n is an integer from 0 to 3, wherein the alkyl, alkoxy, and cycloalkyl may be substituted with one or more substituents selected from halogen and hydroxy. A compound according to claim 1, or an optical isomer, stereoisomer, or isotopic variant thereof, or a pharmaceutically acceptable salt thereof.

8. R1 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 10 cycloalkyl, and R2 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, or 4- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms selected from N, O, and S, R3 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 10 cycloalkyl, and R4 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, or 4- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms selected from N, O, and S, and n is an integer from 0 to 3, wherein the alkyl, alkoxy, and cycloalkyl may be substituted with 1 to 4 substituents selected from halogen and hydroxy. A compound according to claim 7, or an optical isomer, stereoisomer, or isotopic variant thereof, or a pharmaceutically acceptable salt thereof.

9. R1 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or C 3 -C 6 cycloalkyl, and R2 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, or 4- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms selected from N, O, and S, R3 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or C 3 -C 6 cycloalkyl, and R4 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, or 4- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms selected from N, O and S, and n is an integer from 0 to 3, wherein the alkyl, alkoxy, and cycloalkyl may be substituted with 1 to 4 substituents selected from halogen and hydroxy. A compound according to claim 7, or an optical isomer, stereoisomer, or isotopic variant thereof, or a pharmaceutically acceptable salt thereof.

10. R1 is hydrogen or halogen. A compound according to claim 7, or an optical isomer, stereoisomer, or isotopic variant thereof, or a pharmaceutically acceptable salt thereof.

11. R2 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, and wherein the alkyl and alkoxy may be substituted with 1 to 4 substituents selected from halogen and hydroxy. A compound according to claim 7, or an optical isomer, stereoisomer, or isotopic variant thereof, or a pharmaceutically acceptable salt thereof.

12. R3 is hydrogen or halogen. A compound according to claim 7, or an optical isomer, stereoisomer, or isotopic variant thereof, or a pharmaceutically acceptable salt thereof.

13. R4 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 10 cycloalkyl, and wherein the alkyl, alkoxy, and cycloalkyl may be substituted with 1 to 4 substituents selected from halogen and hydroxy. A compound according to claim 7, or an optical isomer, stereoisomer, or isotopic variant thereof, or a pharmaceutically acceptable salt thereof.

14. N-[(1-Oxidepyridin-1-ium-2-yl)methyl]-3-[4-(trifluoromethyl)phenyl]benzamide, 3-(4-Chlorophenyl)-N-[(1-oxidepyridin-1-ium-2-yl)methyl]benzamide, N-[(1-Oxidepyridin-1-ium-2-yl)methyl]-3-[4-(trifluoromethoxy)phenyl]benzamide, 3-(3-Chlorophenyl)-N-[(1-oxidepyridin-1-ium-2-yl)methyl]benzamide, N-[(1-Oxidepyridin-1-ium-2-yl)methyl]-3-[3-(trifluoromethyl)phenyl]benzamide, 3-(3,4-Dichlorophenyl)-N-[(1-oxidepyridin-1-ium-2-yl)methyl]benzamide, 3-(3,5-Dichlorophenyl)-N-[(1-oxidepyridin-1-ium-2-yl)methyl]benzamide, N-[(1-Oxidepyridin-1-ium-2-yl)methyl]-3-[3-(trifluoromethoxy)phenyl]benzamide, 3-(2,4-Dichlorophenyl)-N-[(1-oxidepyridin-1-ium-2-yl)methyl]benzamide, 3-(2,5-Dichlorophenyl)-N-[(1-oxidepyridin-1-ium-2-yl)methyl]benzamide, 3-[2,4-Bis(trifluoromethyl)phenyl]-N-[(1-oxidepyridin-1-ium-2-yl)methyl]benzamide, N-[(1-Oxidepyridin-1-ium-2-yl)methyl]-3-phenyl-benzamide, 3-(4-tert-Butylphenyl)-N-[(1-oxidepyridin-1-ium-2-yl)methyl]benzamide, N-[(1-Oxidepyridin-1-ium-2-yl)methyl]-3-(p-tolyl)benzamide, 3-(4-Chloro-2-methyl-phenyl)-N-[(1-oxidepyridin-1-ium-2-yl)methyl]benzamide, 3-[2-Fluoro-4-(trifluoromethyl)phenyl]-N-[(1-oxidepyridin-1-ium-2-yl)methyl]benzamide, 3-(3-Chloro-4-fluoro-phenyl)-N-[(1-oxidepyridin-1-ium-2-yl)methyl]benzamide, 3-(4-Fluorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(3,4-Difluorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(2-Chlorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, N-[(1-oxidopyridin-1-ium-2-yl)methyl]-3-[2-(trifluoromethyl)phenyl]benzamide, 3-(4-Fluoro-3-methyl-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(m-Tolyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(4-Isopropylphenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(2-Fluorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(4-Chloro-2-methoxy-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-[4-Chloro-2-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(4-Chloro-3-methyl-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(3-Chloro-5-fluoro-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(4-Chloro-3-fluoro-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(2,4-Difluorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(3,5-Difluorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, N-[(1-oxidopyridin-1-ium-2-yl)methyl]-3-(3,4,5-trifluorophenyl)benzamide, 3-(2,3-Difluorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(3-Isopropylphenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(4-Cyclopropylphenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-[4-(Difluoromethoxy)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-[2-Methyl-4-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-[4-Fluoro-3-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(2-Methoxyphenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-[3-Fluoro-5-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-[3-Fluoro-4-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-[3-Methyl-4-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-[4-(1-Hydroxy-1-methyl-ethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-[3-Methoxy-5-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-[2-Methoxy-4-(trifluoromethoxy)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(4,5-Difluoro-2-methoxy-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(4-Chloro-3-methoxy-phenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-[3-Methoxy-4-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-[4-Methoxy-2-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 5-(4-Chlorophenyl)-2-fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 5-(3-Chlorophenyl)-2-fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 5-(4-Chloro-2-methoxy-phenyl)-2-fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 5-(3,4-Difluorophenyl)-2-fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 5-[4-Chloro-2-(trifluoromethyl)phenyl]-2-fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 2-Fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 2-Fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]-5-[4-(trifluoromethyl)phenyl]benzamide, 2-Fluoro-N-[(1-oxidopyridin-1-ium-2-yl)methyl]-5-[4-(trifluoromethoxy)phenyl]benzamide, 2-Fluoro-5-[3-methoxy-4-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 2-Fluoro-5-[3-fluoro-4-(trifluoromethyl)phenyl]-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide, 3-(4-Chlorophenyl)-N-[(5-fluoro-1-oxidopyridin-1-ium-2-yl)methyl]benzamide, and The compound according to claim 1, or an optical isomer, stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of 2-chloro-5-(4-chlorophenyl)-N-[(1-oxidopyridin-1-ium-2-yl)methyl]benzamide.

15. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

16. The pharmaceutical composition according to claim 15 for treating or preventing a disease or condition mediated by a sodium channel.

17. The pharmaceutical composition according to claim 16, wherein the sodium channel is one or more selected from the group consisting of NaV 1.1, NaV 1.2, NaV 1.3, NaV 1.4, NaV 1.5, NaV 1.6, NaV 1.7, NaV 1.8, and NaV 1.

9.

18. The pharmaceutical composition according to claim 16, wherein the disease or condition is pain.

19. The pharmaceutical composition according to claim 18, wherein the pain is selected from the group consisting of acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain including postoperative pain, and mixed pain types associated with the viscera, gastrointestinal tract, cranial structures, musculoskeletal system, spine, urogenital system, cardiovascular system and CNS (central nervous system) (including cancer pain, back pain, orofacial pain, and pain due to chemotherapy).

20. The pharmaceutical composition according to claim 16, wherein the disease or condition is selected from the group consisting of neurological diseases, neurodegenerative diseases, inflammatory diseases, gastrointestinal (GI) tract diseases, urogenital tract diseases, mental diseases, cardiovascular diseases, and neuromuscular diseases.

21. The pharmaceutical composition according to claim 15, which is an oral formulation.

22. The pharmaceutical composition according to claim 15, further comprising an active ingredient effective for treating or preventing pain including neuropathic pain.

23. The pharmaceutical composition according to claim 22, wherein the active ingredient is selected from the group consisting of opioid receptor agonists or antagonists, sodium channel blockers, calcium channel blockers, potassium channel blockers, pregabalin, gabapentin, antidepressants, lithium and valproate.

24. A method for treating or preventing a disease or condition mediated by a sodium channel, the method comprising administering to a mammal in need thereof a therapeutically effective amount of the compound according to claim 1, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharmaceutically acceptable salt thereof.

25. Use of the compound according to claim 1, or an optical isomer, stereoisomer or isotopic variant thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or condition mediated by a sodium channel.

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