Thiazole compounds as sodium channel blockers

Abstract

The present disclosure provides a compound represented by Formula (I) or a pharmaceutically acceptable salt which are effective as a sodium channel blocker and a method of using the compound: (I) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4 and R5 are independently selected from hydrogen, halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C3-C6)cycloalkyl and hetero(C2-C4)cycloalkyl which contains one or more heteroatoms selected from N, O, and S; wherein each (C1-C4)alkyl, (C1-C4)alkoxy and (C3-C6)cycloalkyl are unsubstituted or substituted with one or more substituents selected from halogen and hydroxyl; A and B are each selected from S and CR6, wherein A and B are not identical, and R6 is selected from hydrogen, halogen and (C1-C4)alkyl; and X and Y are independently selected from hydrogen and (C2-C6)alkyl, or taken together with the carbon atom to which they are attached to form (C3-C6)cycloalkyl; wherein (C2-C6)alkyl is unsubstituted or substituted with (C3-C6)cycloalkyl.

Description

Thiazole compounds as Sodium Channel BlockersTECHNICAL FIELD

[0001] The present disclosure generally relates to thiazole compounds as sodium channel blockers, pharmaceutical compositions comprising the compounds, methods for treating pain including neuropathic pain in mammals by administering the sodium channel blockers to the mammals in need of treatment thereof. The present disclosure includes methods of using these inventive sodium channel blockers and processes for preparing the same.BACKGROUND

[0002] PAIN is defined by the International Association for the Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”. In this 2ndedition, two new terms have been introduced as Neuropathic Pain and Peripheral Neuropathic Pain. 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 (2nded.), IASP Press, 2002, p210).

[0003] The treatment of pain conditions is of a significant importance in medicine and there is currently a global need for new pain therapy. Especially, the urgent requirement for a specific treatment of pain conditions or as well a treatment of specific pain conditions is reported in a lot of scientific works. Even though pain is always subjective, its causes or syndromes can be classified into several subtypes.

[0004] Neuropathic pain which in the past years has developed into a major health problem in broad areas of the population also needs a very specific treatment, especially considering that any treatment of neuropathic pain is extremely sensitive to the causes behind the pain. So, in a majority of cases a substance being able to treat one subtype of neuropathic pain is not - or is at least not necessarily - able to treat other specific subtypes due to the highly diverse nature of this generalized symptom called neuropathic pain.

[0005] So far, there are more than 100 known types of neuropathic pain. Common acquired causes include viral infections, diabetes, injury, autoimmune disease, and nutritional deficiency. Some neuropathic pain can also be inherited or caused by genetic mutations. For the purpose of this invention, the subtypes can be included under this heading or to be treated as synonymous.

[0006] Voltage-gated sodium channels (VGSCs) control the flow of sodium ions that can trigger excitability of pain-sensing nociceptors in the peripheral nervous system. In humans, nine VGSCs have now been identified, and some have been linked to genes that alter their function. Sodium channels play an important role in painful neuropathy.

[0007] Especially, gene mutations have now been linked to sodium channels Navi.7, Navi.8, and Navi .9. Gain of function mutation in the gene SCN9A has been linked to Navi .7 and a painful neuropathic disorder called inherited erythromelalgia (IEM). The gene SCN10A has been linked to Navi.8 and small fiber neuropathy, a condition that causes severe pain attacks in the hands or feet. It may also cause autonomic pain symptoms such as palpitations, bowel problems, and abnormal sweating. Navi.9 has also been linked to mutation that causes painful neuropathy.

[0008] Thiazole compounds of the present disclosure provide a new form of treatment for neuropathic pain as sodium channel blockers.

[0009] For an example, U.S. Patent No. 8,822,463 describes that methylcyclohexane compounds represented by the following formula are effective in treating neuropathic pain.

[0010] For another example, U.S. Patent No. 8,541,409 mentions carbamoyloxy arylalkanoyl arylpiperazine compounds useful as analgesic agents as follows.SUMMARY

[0011] The present disclosure provides a novel compound represented by Formula (I) and a pharmaceutical acceptable salt thereof:wherein:Ri, R2, R3, R4 and R5 are independently selected from hydrogen, halogen, (Ci-C4)alkyl, (Ci- C4)alkoxy, (C3-Ce)cycloalkyl and hetero(C2-C4)cycloalkyl which contains one or more heteroatoms selected from N, O, and S; wherein each (Ci-C4)alkyl, (Ci-C4)alkoxy and (C3- Ce)cycloalkyl are unsubstituted or substituted with one or more substituents selected from halogen and hydroxyl;A and B are each selected from S and CRr„ wherein A and B are not identical, and Re is selected from hydrogen, halogen and (Ci-C4)alkyl; andX and Y are independently selected from hydrogen and (C2-Ce)alkyl, or taken together with the carbon atom to which they are attached to form (C3-Ce)cycloalkyl; wherein (C2-Ce)alkyl is unsubstituted or substituted with (C3-Ce)cycloalkyl.

[0012] The compounds of Formula (I) are useful in inhibiting sodium channel inactivated state.

[0013] In some embodiments, a compound of Formula (I) is selected from a compound ofFormula (II) and a pharmaceutical acceptable salt thereof:wherein Ri, R2, R3, R4, Rs, Re, X and Y are as defined above.

[0014] In some embodiments, a compound of Formula (I) is selected from a compound of Formula (III) and a pharmaceutical acceptable salt thereof:wherein Ri, R2, R3, R4, and R5 are as defined above.

[0015] In another embodiment, there is provided a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds described herein and a pharmaceutically acceptable carrier.

[0016] In yet another embodiment, there is provided a method of treating or preventing pain including neuropathic pain in a mammal in need thereof by administering a therapeutically effective amount of the compound represented by Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof.DETAILED DESCRIPTION

[0017] The following description is merely exemplary in nature and is not intended to limit the present disclosure, application, or uses.Definitions

[0018] “Alkoxy” is RO- where R is alkyl. Non-limiting examples of alkoxy groups include methoxy, ethoxy and propoxy. In an embodiment, the alkoxy group is methoxy.

[0019] “Alkyl” refers to a straight or branched chain saturated hydrocarbyl group. In an embodiment, alkyl has from 1 to 12 carbon atoms. In some embodiments, alkyl is a Ci-Cio alkyl group or a C1-C4 alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, Lbutyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl.

[0020] “Cycloalkyl” refers to a saturated or partially saturated, monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from 3 to 12 ring atoms per carbocycle.

[0021] ‘Halo” or “Halogen” refers to fluoro (-F), chloro (-C1), bromo (-Br), or iodo (-1).

[0022] When a particular group is "substituted" (e.g., alkoxy, alkyl, cycloalkyl, etc.), that group may have one or more substituents, for example, from one to five substituents, or from one to three substituents, or one to two substituents, independently selected from the list of substituents.

[0023] “Pharmaceutically acceptable” means suitable for use in pharmaceutical preparations, generally considered as safe for such use, officially approved by a regulatory agency of a national or state government for such use, or being listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.

[0024] “Pharmaceutically acceptable carrier” refers to a diluent, adjuvant, excipient, or carrier that alone or together provides a carrier or vehicle with which a compound or compounds of thedisclosure is formulated and / or administered, and in which every ingredient or the carrier as a whole is pharmaceutically acceptable.

[0025] “Pharmaceutically acceptable salt” refers to a salt which may enhance 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 with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. Examples of acid addition salts formed with organic acids such as acetic acid, propionic acid, hexanoic 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-hydroxyethane-sulfonic acid, benzenesulfonic acid, p- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methyl-bicyclo[2.2.2]oct-2-ene-l -carboxylic acid, gluco-heptonic acid, 4, d’methyl enebis(3-hydroxy-2-naphthoic) acid, 3 -phenylpropionic acid, trimethyl-acetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxy-naphthoic acids, salicylic acid, stearic acid and muconic acid. Examples of metal salts include salts with sodium, potassium, calcium, magnesium, aluminum, iron, and zinc ions. Examples of amine salts include salts with ammonia and organic nitrogenous bases strong enough to form salts with carboxylic acids.

[0026] “Therapeutically effective amount” refers to an amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect treatment for the disease. “Therapeutically effective amount” can vary depending on the compound, the disease and its severity, the age, the weight, etc. of the subject to be treated.

[0027] Embraced herein, where applicable, are permissible isomers such as tautomers, racemates, enantiomers, diastereomers, atropisomers, and isotopic variants.Compounds

[0028] This disclosure provides a compound represented by Formula (I) and a pharmaceutical acceptable salt:wherein:Ri, R2, R3, R4 and R5 are independently selected from hydrogen, halogen, (Ci-C4)alkyl, (Ci- C4)alkoxy, (C3-Ce)cycloalkyl and hetero(C2-C4)cycloalkyl which contains one or more heteroatoms selected from N, O, and S; wherein each (Ci-C4)alkyl, (Ci-C4)alkoxy and (C3- Ce)cycloalkyl are unsubstituted or substituted with one or more substituents selected from halogen and hydroxyl;A and B are each selected from S and CRr„ wherein A and B are not identical, and Re is selected from hydrogen, halogen and (Ci-C4)alkyl; andX and Y are independently selected from hydrogen and (C2-Ce)alkyl, or taken together with the carbon atom to which they are attached to form (C3-Ce)cycloalkyl; wherein (C2-Ce)alkyl is unsubstituted or substituted with (C3-Ce)cycloalkyl.

[0029] Ri, R2, R3, R4 and R5 are one or more substituents attached to the phenyl group of Formula (I). Thus, the phenyl group has up to 5 substituents selected from Ri, R2, R3, R4 and R5. In an embodiment, Ri is selected from hydrogen, halogen, (Ci-C4)alkyl, (Ci-C4)alkoxy and hetero(C2-C4)cycloalkyl which contains one or more heteroatoms selected from N, O, and S, wherein each (Ci-C4)alkyl and (Ci-C4)alkoxy are unsubstituted or substituted with halogen; R2 is selected from hydrogen, halogen, (Ci-C4)alkyl and (Ci-C4)alkoxy, wherein each (Ci-C4)alkyl and (Ci-C4)alkoxy are unsubstituted or substituted with halogen; R3 is selected from hydrogen, halogen, (Ci-C4)alkyl, (Ci-C4)alkoxy and (C3-Ce)cycloalkyl, wherein each (Ci-C4)alkyl, (Ci-C4)alkoxy and (C3-Ce)cycloalkyl are unsubstituted or substituted with one or more substituents selected from halogen and hydroxyl; R4 is selected from hydrogen, halogen and (Ci-C4)alkyl, wherein (Ci- C4)alkyl is unsubstituted or substituted with halogen; R5 is selected from hydrogen and halogen; and X and Y are hydrogen.

[0030] In an embodiment, Ri is hydrogen; R2 is selected from hydrogen, halogen and (Ci- C4)alkoxy; R3 is selected from halogen and (Ci-C4)alkyl, wherein (Ci-C4)alkyl is unsubstituted or substituted with one or more substituents selected from halogen and hydroxyl; R4 is hydrogen; R5 is hydrogen; Re is hydrogen; and X and Y are hydrogen.

[0031] In another embodiment, there is provided a compound of Formula (II) and a pharmaceutically acceptable salt thereof:wherein Ri, R2, R3, R4, R5, Re, X and Y are as defined above

[0032] In an embodiment, Ri is hydrogen; R2 is selected from hydrogen, halogen and (Ci- C4)alkoxy; R3 is selected from halogen and (Ci-C4)alkyl, wherein (Ci-C4)alkyl is unsubstituted or substituted with one or more substituents selected from halogen and hydroxyl; R4 is hydrogen; R5 is hydrogen; Re is hydrogen; and X and Y are hydrogen.

[0033] In an embodiment, Ri is hydrogen; R2 is selected from hydrogen, fluoro and alkoxy; R3 is selected from chloro, isopropyl and trifluoromethyl; R4 is hydrogen; R5 is hydrogen; Re is hydrogen; and X and Y are hydrogen.

[0034] Examples of Formula (II) includes, but are not limited to, the following compounds:N- [( 1 -Oxidopyridin- 1 -ium-2-yl)methyl] -2-phenylthiazole-4-carboxamide, N-[(l-Oxidopyridi-l-ium-2-yl)methyl]-2-(p-tolyl)thiazole-4-carboxamide, 2-(4-Ethylphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide, 2-(4-Isopropylphenyl)-N - [( 1 -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4-carboxamide, 2-(4-tert-Buthylphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide, 2-[4-(l -Hydroxy-1 -methyl-ethyl)phenyl]-N-[(l -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4- carboxamide,2-(4-Cyclopropylphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide, 2-(4-Chlorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide, N- [( 1 -Oxidopyridin- 1 -ium-2-yl)methyl] -2- [4-(trifhioromethyl)phenyl]thiazole-4- carboxamide,2-[4-(Difhioromethoxy)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide,N-[(l-Oxidopyridin-l-ium-2-yl)methyl]-2-[4-(trifluoromethoxy)phenyl]thiazole-4- carboxamide,2-(m-Tolyl)-N-[l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide,2-(3 -Isopropylphenyl)-N - [( 1 -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4-carboxamide, 2-(3-tert-Buthylphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide, 2-(3-Chlorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide,N- [( 1 -Oxidopyridin- 1 -ium-2-yl)methyl] -2- [3 -(trifluoromethyl)phenyl]thiazole-4- carboxamide,N- [( 1 -Oxidopyridin- 1 -ium-2-yl)methyl] -2- [3 -(trifluoromethoxy)phenyl]thiazole-4- carboxamide,2-(2,5-Dichlorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide,2-(2,4-Dichlorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide,2-(3,4-Dichlorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide,2-(3 , 5 -Diehl orophenyl)-N- [( 1 -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4-carboxamide, 2-(4-Chloro-2-methylphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide, 2-(4-Chloro-2-methoxyphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide,2-[4-Chloro-2-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide,2-[2-Chloro-4-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide,2-(4-Chloro-2-morpholinophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide,2-(2,3-Dichlorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide,2-[2,4-bis(Trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide,2- [2-Fluoro-4-(trifluoromethyl)phenyl] -N- [( 1 -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4- carboxamide,2-(3-Chloro-4-fluorophenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide, 2-(3,4-Difluorophenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide,2- [3 -Fluoro-4-(trifluoromethyl)phenyl] -N- [( 1 -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4- carboxamide,2-[3-Chloro-4-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide,2-(4-chloro-3-fluorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide,2-[4-Chloro-3-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide,2-[4-Chloro-3-(trifluoromethoxy)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide,2-(4-chloro-2-fluorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide,2-[3-Methyl-5-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide,2-(3-Chloro-4-methylphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide,2-[3-Methyl-4-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide,2-[2-Methoxy-4-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide,2-(4-Chloro-3-methylphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide,2-(3-Chloro-5-methylphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide,2- [3 -Chloro-5 -(trifluoromethyl)phenyl] -N- [( 1 -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4- carboxamide,2- [4-Fluoro-3 -(trifluoromethyl)phenyl] -N- [( 1 -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4- carboxamide,2- [3 -Fluoro-5 -(trifluoromethyl)phenyl] -N- [( 1 -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4- carboxamide,2-[2-Methyl-4-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide,2-(3-Chloro-5-fluorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide,2-[3-Methoxy-5-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide,2-[2-Methoxy-4-(trifluoromethoxy)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole- 4-carboxamide,2- [3 -Ethoxy-5 -(trifluoromethoxy)phenyl] -N - [( 1 -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4- carboxamide,2-(4-Chloro-3-methoxyphenyl)-N-[(l -oxidopyridin-1 -ium-2-yl)methyl]thiazole-4- carboxamide,2-[3-Methoxy-4-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide,2-[4-Chloro-2-(trifluoromethoxy)phenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide,N-[(l-Oxidopyridin-l-ium-2-yl)methyl]-2-(2,3,5-trichlorophenyl)thiazole-4-carboxamide,N-[l -(1 -Oxidopyridin-1 -ium-2-yl)cyclopropy]-2-[4-(trifluoromethyl)phenyl]thiazole-4- carboxide,N-[l -(1 -Oxidopyridin-1 -ium-2-yl)cyclobutyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4- carboxamide,N-[l -(1 -Oxidopyridin-1 -ium-2-yl)cyclopentyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4- carboxamide,N-[l -(1 -Oxidopyridin-1 -ium-2-yl)cy cl ohexyl] -2- [4-(trifluoromethyl)phenyl]thiazole-4- carboxamide,N-[2-Methyl-l -(1 -oxidopyridin-1 -ium-2-yl)propyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4- carboxamide,N- [2-Cyclopropyl- 1 -( 1 -oxidopyridin- 1 -ium-2-yl)ethyl] -2- [4-(trifluoromethyl)phenyl]thiazole-4-carboxamide,5-Methyl-N-[(l -oxidopyridin-1 -ium-2-yl)methyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4- carboxamide,5-Chloro-N-[(l -oxidopyridin-1 -ium-2-yl)methyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4- carboxamide,2-[2-Methoxy-4-(trifluoromethyl)phenyl]-5-methyl-N-[(l -oxidopyridin-1 -ium-2- yl)methyl]thiazole-4-carboxamide, and2-(3-Chloro-4-fluorophenyl)-5-methyl-N-[(l -oxidopyridin-1 -ium-2-yl)methyl]thiazole-4- carboxamide.

[0035] In yet another embodiment, there is provided a compound of Formula (III) and a pharmaceutically acceptable salt thereof:wherein Ri, R2, R3, R4, and R5 are as defined above

[0036] In an embodiment, Ri is hydrogen; R2 is selected from hydrogen, halogen and (Ci- C4)alkoxy; R3 is selected from halogen and (Ci-C4)alkyl, wherein (Ci-C4)alkyl is unsubstituted or substituted with one or more substituents selected from halogen and hydroxyl; R4 is hydrogen; and R5 is hydrogen.

[0037] In an embodiment, Ri is hydrogen; R2 is hydrogen; R3 is selected from chloro, trifluoromethoxy and trifluoromethyl; R4 is hydrogen; and R5 is hydrogen.

[0038] Examples of Formula (III) includes, but are not limited to, the following compounds: 4-(4-Chlorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-2-carboxamide, N-[(l-oxidopyridin-l-ium-2-yl)methyl]-4-[4-(trifluoromethoxy)phenyl]thiazole-2- carboxamide, andN-[(l-oxidopyridin-l-ium-2-yl)methyl]-4-[4-(trifluoromethyl)phenyl]thiazole-2- carboxamide .Synthesis of Compounds

[0039] In some embodiments, the compounds of Formula (I) can be prepared by the synthetic method of Scheme I, II or, III as described below.

[0040] When X and Y are H, the desired compound may be prepared by the synthetic method described in Scheme I:lnt-1Scheme I

[0041] As shown in Scheme I, (l-oxidopyridin-l-ium-2-yl)methanamine hydrochloride (Int- 1) was synthesize in by general protection of benzylamine, oxidation of pyridine and deprotection of Boc group. The desired target compounds were obtained by the general amide coupling of Int- 1 with the corresponding carboxylic acid which is commercial available.

[0042] Details of the reaction conditions described in Scheme I are as follows. To a solution of 2-Pyridylmethanamine in DCM was treated BOC2O at zero degree. The concentration of 2- pyridylmethanamine as a starting material was about 0.001 to 100 mole. This reaction was preferably carried out at an ambient temperature. Oxidation of Boc protected compound was performed by oxidant such as mCPBA or MMPP. Oxidant was used about 3 equivalents. This reaction was preferably carried out in MeOH at 60°C for 3 hours. Target compounds were synthesized from Int-1 by deprotection of Boc group using excess of HC1 solution in organic solvent followed by amide coupling as represented in Scheme I.

[0043] When X and Y are not H, the desired compound may be prepared by the synthetic method described in Scheme II:Scheme II

[0044] As shown in Scheme II, Substituent 2-pyridylmethanamine and corresponding carboxylic acid were coupled with amide coupling reagents such as EDC and HOBt. The target compounds were synthesized in oxidation of pyridine.

[0045] Details of the reaction conditions described in Scheme II are the same as depicted scheme I. The concentration of the each carboxylic acid as starting material was between about 0.01 to 0.1 mole.

[0046] When the corresponding carboxylic acids were not commercial available, the desired compound may be prepared by the synthetic method described in Scheme III:Scheme III

[0047] As shown in Scheme III, bromo-carboxylic acid compounds and Int-1 were reacted with amide coupling reagents to give Int-2. Palladium catalyst reaction with proper base and solvent could get the final target compounds.

[0048] Details of the reaction conditions described in Scheme III are as follows. Amide coupling explained above. Palladium catalyst metal reaction was performed. General reaction condition was Pd(dppf)Ch as a metal, Na^CCb as a base, and DME as a solvent. This metal reaction was carried out by various reaction conditions due to reactivity of two starting materials.Pharmaceutical Compositions

[0049] In one embodiment, there is provided a pharmaceutical composition comprising, in addition to one or more compounds described herein, a pharmaceutically acceptable carrier. In various embodiments, the carrier comprises a diluent, adjuvant, excipient, other additive, or a combination of additive that separately or together provide a carrier in which the compositions can be formulated or administered. The composition can take any suitable form for the desired route of administration. Where the composition is to be administered orally, any suitable orally deliverable dosage form can be used, including, without limitation, tablets, capsules (solid- or liquid-filled), powders, granules, syrups and other liquids, elixirs, inhalants, troches, lozenges, and solutions. Injectable compositions or iv infusions are also provided in the form of solutions, suspensions, and emulsions.

[0050] In particular embodiments, the pharmaceutical composition is an oral formulation. Since the compounds of Formula I absorb well orally, it is generally unnecessary to resort to parenteral administration. For oral administration, the compound is preferably formulated with a pharmaceutically acceptable carrier. The ratio of the carrier to the compound would not be critical to the pharmacological effects of the formulation, and the ratio can vary considerably depending on formulating conditions. In tableting, various edible pharmaceutical carriers or the mixture thereof can be included therein. A suitable carrier, for example, is a mixture of lactose, dibasic calcium phosphate and / or corn starch. Other pharmaceutically acceptable ingredients can be further added, including lubricants such as magnesium stearate.

[0051] A pharmaceutical composition according to the present disclosure may contain one or more additional therapeutic agents, for example, to increase the efficacy or decrease the side effects. In an embodiment, the pharmaceutical composition includes one or more active ingredientseffective to treat neuropathic pain, by including anticonvulants such as gabapentin, pregabalin, carbamazepine, antidepressants such as duloxetine, milnacipran, and analgesics such as opioids, NSAIDs, lidocaine patches and capsaicin patches.Medical Utilities

[0052] Yet another aspect of the present disclosure is to provide method of treating or preventing sodium channel-related disease such as pain including neuropathic pain in mammals, comprising administering to said mammals a therapeutically effective amount of one or more compounds of Formula (I) or a pharmaceutically acceptable salt thereof.EXAMPLESExample 1: N-[(l-Oxidopyridin-l-ium-2-yl)methyl]-2-phenylthiazole-4-carboxamide

[0053] To a solution of 2-bromo-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide (0.95 mmol) in DME was added phenyl boronic acid (1.91 mmol), pd(dppf)C12 (0.24 mmol), 2N NaiCO The reaction mixture was stirred under 100°C for 15 min. The reaction mixture was cooled to room temperature and filtered to remove palladium residues. The resulting mixture was extracted with DCM, washed water and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude was purified by flash column chromatography to provide N-[(l-oxidopyridin-l-ium-2-yl)methyl]-2-phenylthiazole-4- carboxamide.1H NMR (CDCh, 400MHz) 8 8.56(br.s, 1H), 8.28(d, 1H), 8.09(s, 1H), 7.98(m, 2H), 7.5 4(d, 1H), 7.46(m, 3H), 7.28(m, 2H), 4.88(d, 2H)Example 2: N-[(l-Oxidopyridi-l-ium-2-yl)methyl]-2-(p-tolyl)thiazole-4-carboxamide

[0054] The procedure given in Example 1 was followed using 4-methylphenylboronic acid as a reactant, instead of phenylboronic acid, to give N-[(l-oxidopyridi-l-ium-2-yl)methyl]-2-(p- tolyl)thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.47(br.s, 1H), 8.23(s, 1H), 8.00(s, 1H), 7.82(d, 2H), 7.50 (s, 1H), 7.22(m, 4H), 4.84(d, 2H), 2.37(s, 3H)Example 3: 2-(4-Ethylphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide

[0055] The procedure given in Example 1 was using 4-ethylphenylboronic acid as a reactant, instead of phenylboronic acid, to give 2-(4-ethylphenyl)-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.50(s, 1H), 8.26(d, 1H), 8.04(s, 1H), 7.88(d, 2H), 7.52(d, 1H), 7.28(m, 4H), 4.87(d, 2H), 2.69(q, 2H), 1.26(t, 3H)Example 4: 2-(4-Isopropylphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide

[0056] The procedure given in Example 1 was followed using 4-isopropyphenylboronic acid as a reactant, instead of phenylboronic acid, to give 2-(4-isopropylphenyl)-N-[(l-oxidopyridin-l- ium-2-yl)methyl]thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.51(br.s, 1H), 8.27(s, 1H), 8.05(s, 1H), 7.89(d, 2H), 7.55 (s, 1H), 7.30(d, 2H), 7.26(m, 2H), 4.88(d, 2H), 2.96(m, 1H), 1.28(d, 6H)Example 5: 2-(4- / e / 7-Biithylphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl|thiazole-4- carboxamide

[0057] The procedure given in Example 1 was followed using 4- / / 7-butylphenylboronic acid as a reactant, instead of phenylboronic acid, to give 2-(4- / / 7-buthylphenyl)-N-[( l -oxidopyridin- l-ium-2-yl)methyl]thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.50(br.s, 1H), 8.23(s, 1H), 8.04(s, 1H), 7.89(d, 2H), 7.54 (s, 1H), 7.46(d, 2H), 7.29(m, 2H), 4.91(d, 2H), 1.38(s, 9H)Example 6: 2-[4-(l-Hydroxy-l-methyl-ethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide

[0058] The procedure given in Example 1 was followed using 4-(l -hydroxy- 1-methyl- ethyl)phenylboronic acid as a reactant, instead of phenylboronic acid, to give 2- [4-(l -hydroxy- 1- methyl-ethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.54(br.s, 1H), 8.28(s, 1H), 8.07(s, 1H), 7.95(d, 2H), 7.58(m, 3H), 7.27(m, 2H), 4.89(d, 2H), 1.93(s, 1H)Example 7: 2-(4-Cyclopropylphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide

[0059] The procedure given in Example 1 was followed using 4-cyclopropylphenylboronic acid as a reactant, instead of phenylboronic acid, to give 2-(4-Cyclopropylphenyl)-N-[(l- oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.51(s, 1H), 8.26(s, 1H), 8.03(s, 1H), 7.83(d, 2H), 7.52(d, 1H), 7.24(d, 2H), 7.11(d, 2H), 4.86(d, 2H), 1.91(m, 1H), 1.02(d, 2H), 0.74(d, 2H)Example 8: 2-(4-Chlorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide

[0060] 2-(4-Chlorophenyl)thiazole-4-carboxylic acid (0.55 mmol) was dissolved in dichloromethane. The mixture was added ECDI(0.66 mmol) and HOBt (0.66) and stirred for 30 min. The resulting reaction mixture was (l-oxidopyridin-l-ium-2-yl)methanamine and stirred for overnight at ambient temperature. Water was added to terminate the reaction. The organic layer was extracted 3 times with dichloromethane, dried over magnesium sulfate and concentrated in vacuo, to give oil. The crude was purified by flash column chromatography to provide 2-(4- chlorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.57(br.s, 1H), 8.29(d, 1H), 8.10(s, 1H), 7.93(d, 2H), 7.5 5(d, 1H), 7.53(m, 2H), 7.30(m, 2H), 4.88(d, 2H)Example 9: N-[(l-Oxidopyridin-l-ium-2-yl)methyl]-2-[4-(trifluoromethyl)phenyl]thiazole- 4-carboxamide

[0061] The procedure given in Example 8 was followed using 2-(4-trifluoromethyl)thiazole- 4-carboxylic acid as a reactant, instead of 2-(4-chlorophenyl)thiazole-4-carboxylic acid, to give N- [(l-oxidopyridin-l-ium-2-yl)methyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4-carboxamide. 1H NMR(CDC13, 400MHZ) 88.57(t, 1H), 8.27(dd, 1H), 8.16(s, 1H), 8.10(d, 2H), 7.72(d, 2H), 7.54(dd, 1H), 7.28(m, 2H), 4.87(d, 2H)Example 10: 2-[4-(Difluoromethoxy)phenyl]-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide

[0062] The procedure given in Example 1 was followed using 4- (difluoromethoxy)phenylboronic acid as a reactant, instead of phenylboronic acid, to give 2- [4- (difhioromethoxy)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.59(s, 1H), 8.30(s, 1H), 8. l l(s, 1H), 8.01(d, 2H), 7.57(d, 2H), 7.29(m, 1H), 7.22(d, 2H), 6.61(t, 1H), 4.90(d, 2H)Example 11: N-[(l-Oxidopyridin-l-ium-2-yl)methyl]-2-[4- (trifluoromethoxy)phenyl]thiazole-4-carboxamide

[0063] The procedure given in Example 8 was followed using 2-(4-trifluoromethoxy)thiazole- 4-carboxylic acid as a reactant, instead of 2-(4-chlorophenyl)thiazole-4-carboxylic acid, to give N- [(l-oxidopyridin-l-ium-2-yl)methyl]-2-[4-(trifluoromethoxy)phenyl]thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.57(br.s, 1H), 8.26(s, 1H), 8.10(s, 1H), 8.02(d, 2H), 7.55 (s, Ih), 7.30(d, 2H), 7.26(m, 2H), 4.90(s, 2H)Example 12: 2-(m-Tolyl)-N-[l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide

[0064] The procedure given in Example 1 was followed using 3-methylphenylboronic acid as a reactant, instead of phenylboronic acid, to give 2-(m-tolyl)-N-[l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.50(br.s, 1H), 8.27(d, 1H), 8.07(s, 1H), 7.79(s, 1H), 7.76 (d, 1H), 7.54(m, 1H), 7.34(t, 1H), 7.28(m, 3H), 4.88(d, 2H), 2.44(s, 3H)Example 13: 2-(3-Isopropylphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide

[0065] The procedure given in Example 1 was followed using 3-isopropylphenylboronic acid as a reactant, instead of phenylboronic acid, to give 2-(3-isopropylphenyl)-N-[(l-oxidopyridin-l- ium-2-yl)methyl]thiazole-4-carboxamide.IH NMR (CDCh, 500MHz) 8 8.49(br.s, IH), 8.28(s, IH), 8.09(s, IH), 7.82(s, IH), 7.79 (d, IH), 7.56(s, IH), 7.38(m, 2H), 7.27(m, 2H)4.90(d, 2H), 3.01(m, IH), 1.32(d, 6H)Example 14: 2-(3-ter / -Buthylphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide

[0066] The procedure given in Example 1 was followed using 3- / / 7-butylphenylboronic acid as a reactant, instead of phenylboronic acid, to give 2-(3- / / 7-buthylphenyl)-N-[( l -oxidopyridin- l-ium-2-yl)methyl]thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.49(br.s, 1H), 8.28(s, 1H), 8.09(s, 1H), 7.96(s, 1H), 7.79 (d, lH)7.56(s, 1H), 7.51(d, 1H), 7.40(t, 1H), 7.27(m, 2H), 4.91(d, 1H)Example 15: 2-(3-Chlorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide

[0067] The procedure given in Example 1 was followed using 3-chlorophenylboronic acid as a reactant, instead of phenylboronic acid, to give 2-(3-chlorophenyl)-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.49(br.s, 1H), 8.27(d, 1H), 8.11(s, 1H), 7.97(s, 1H), 7.85 (d, 1H), 7.53(d, 2H), 7.42(m, 3H), 4.88(d, 2H)Example 16: N-[(l-Oxidopyridin-l-ium-2-yl)methyl]-2-[3-(trifluoromethyl)phenyl]thiazole- 4-carboxamide

[0068] The procedure given in Example 1 was followed using 3- (trifluoromethyl)phenylboronic acid as a reactant, instead of phenylboronic acid, to give N-[(l- oxidopyridin-l-ium-2-yl)methyl]-2-[3-(trifluoromethyl)phenyl]thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.49(br.s, 1H), 8.27(s, 1H), 8.15(m, 3H), 7.72(d, 1H), 7.6 0(s, 1H), 7.54(s, 1H), 7.26(m, 2H), 4.89(s, 2H)Example 17: N-[(l-Oxidopyridin-l-ium-2-yl)methyl]-2-[3- (trifluoromethoxy)phenyl]thiazole-4-carboxamide

[0069] The procedure given in Example 1 was followed using 3- (trifluoromethoxy)phenylboronic acid as a reactant, instead of phenylboronic acid, to give N-[(l- oxidopyridin-l-ium-2-yl)methyl]-2-[3-(trifluoromethoxy)phenyl]thiazole-4-carboxamide.

[0070] 1H-NMR (DMSO-d6, 200MHz) 8 8.31(br, 3H), 7.80(br, 1H), 7.31(m, 6H), 4.30(m, 1H), 4.06(m, 1H), 3.75(m, 3H), 3.00(m, 2H), 1.08(t, 3H)Example 18: 2-(2,5-Dichlorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide

[0071] The procedure given in Example 1 was followed using 2,5-dichloropehnyl boronic acid as a reactant, instead of phenylboronic acid, to give 2-(2,5-dichlorophenyl)-N-[(l-oxidopyridin-l- ium-2-yl)methyl]thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.46(br.s, 1H), 8.25(m, 3H), 7.55(s, 1H), 7.44(d, 1H), 7.3 5(d, 1H), 7.26(m, 2H), 4.89(br.s, 2H)Example 19: 2-(2,4-Dichlorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide

[0072] The procedure given in Example 1 was followed using 2,4-dichloropehnyl boronic acid as a reactant, instead of phenylboronic acid, to give 2-(2,4-dichlorophenyl)-N-[(l-oxidopyridin-l- ium-2-yl)methyl]thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.55(br.s, 1H), 8.29(m, 3H), 7.53(m, 2H), 7.38(m, 2H), 4. 88(s, 2H)Example 20: 2-(3,4-Dichlorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide

[0073] The procedure given in Example 1 was followed using 3,4-dichloropehnyl boronic acid as a reactant, instead of phenylboronic acid, to give 2-(3,4-dichlorophenyl)-N-[(l-oxidopyridin-l- ium-2-yl)methyl]thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.50(br.s, 1H), 8.28(br.s, 1H), 8.12(s, 1H), 8.07(s, 1H), 7. 81(d, 1H), 7.54(d, 2H), 7.26(m, 2H), 4.88(d, 2H)Example 21: 2-(3,5-Dichlorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide

[0074] The procedure given in Example 1 was followed using 3,5-dichloropehnyl boronic acid as a reactant, instead of phenylboronic acid, to give 2-(3,5-dichlorophenyl)-N-[(l-oxidopyridin-l- ium-2-yl)methyl]thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.48(br.s, 1H), 8.28(br.s, 1H), 8.16(s, 1H), 7.87(s, 2H), 7. 56(br.s, 1H), 7.46(s, 1H), 7.27(m, 2H), 4.89(d, 2H)Example 22: 2-(4-Chloro-2-methylphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole- 4-carboxamide

[0075] The procedure given in Example 1 was followed using 4-chloro-2-methylpehnyl boronic acid as a reactant, instead of phenylboronic acid, to give 2-(4-chloro-2-methylphenyl)-N- [(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.53(br.s, 1H), 8.27(br.s, 1H), 8.17(s, 1H), 7.70(d, 1H), 7. 53(s, 1H), 7.34(s, 1H), 7.28(m, 3H), 4.88(d, 2H), 2.64(s, 3H)Example 23: 2-(4-Chloro-2-methoxyphenyl)-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide

[0076] The procedure given in Example 1 was followed using 4-chloro-2-methoxypehnyl boronic acid as a reactant, instead of phenylboronic acid, to give 2-(4-chloro-2-methoxyphenyl)- N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.56(br.t, 1H), 8.39(d, 1H), 8.28(d, 1H), 8.14(s, 1H), 7.54 (dd, 1H), 7.26(m, 2H), 7.09(dd, 1H), 7.03(s, 1H), 4.88(d, 2H), 4.04(s, 3H)Example 24: 2-[4-Chloro-2-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide

[0077] The procedure given in Example 1 was followed using 4-chloro-2- (trifluoromethyl)phenyl boronic acid as a reactant, instead of phenylboronic acid, to give 2- [4- chloro-2-(trifluoromethyl)phenyl]-N-[(l -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4- carboxamide.1H NMR (CDCh, 500MHz) 8 8.39(br.s, 1H), 8.23(s, 2H), 7.80(s, 1H), 7.62(s, 2H), 7.50 (br.s, 1H), 7.25(m, 2H), 4.86(d, 2H)Example 25: 2-[2-Chloro-4-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide

[0078] The procedure given in Example 1 was followed using 2-chloro-4- (trifluoromethyl)phenylboronic acid as a reactant, instead of phenylboronic acid, to give 2- [2- chloro-4-(trifluoromethyl)phenyl]-N-[(l -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4- carboxamide.1H NMR (CDCh, 500MHz) 8 8.59(br.t, 1H), 8.49(s, 1H), 8.28(m, 2H), 7.77(s, 1H), 7.6 4(s, 1H), 7.55(s, 1H), 7.24(m, 2H), 4.88(d, 2H)Example 26: 2-(4-Chloro-2-morpholinophenyl)-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide

[0079] The procedure given in Example 1 was followed using 2-chloro-4- morpholinophenylboronic acid as a reactant, instead of phenylboronic acid, to give 2-(4-chloro-2- morpholinophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.59(br.s, 1H), 8.32(m, 2H), 8.16(s, lH)7.58(d, 1H), 7.30 (m, 4H), 4.90 (d, 2H), 3.96(m, 4H), 2.99(m, 4H)Example 27: 2-(2,3-Dichlorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide

[0080] The procedure given in Example 1 was followed using 2,4-dichlorophenylboronic acid as a reactant, instead of phenylboronic acid, to give 2-(2,3-dichlorophenyl)-N-[(l-oxidopyridin-l- ium-2-yl)methyl]thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.55(br.s, 1H), 8.23(m, 3H), 7.57(s, 2H), 7.35(s, 1H), 7.2 5(m, 2H), 4.88(d, 1H)Example 28: 2-[2,4-bis(Trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide

[0081] The procedure given in Example 1 was followed using 2,4- bis(trifluoromethyl)phenylboronic acid as a reactant, instead of phenylboronic acid, to give 2-[2,4- bis(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.43(br.s, 1H), 8.29(s, 1H), 8.09(s, 1H), 7.92(d, 1H), 7.85 (d, 1H), 7.47(s, 1H), 7.25(m, 3H), 4.89(d, 2H)Example 29: 2-[2-Fluoro-4-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide

[0082] The procedure given in Example 1 was followed using 2-fluoro-4- (trifluoromethyl)phenylboronic acid as a reactant, instead of phenylboronic acid, to give 2- [2- fluoro-4-(trifluoromethyl)phenyl] -N - [( 1 -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4- carboxamide.1H NMR (CDCh, 500MHz) 8 8.63(br.s, 1H), 8.52(t, 1H), 8.27(s, 2H), 7.56(d, 2H), 7.49 (d, 1H), 7.29(m, 2H), 4.88(d, 2H)Example 30: 2-(3-Chloro-4-fluorophenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide

[0083] The procedure given in Example 1 was followed using 3-chloro-4-fluorophenylboronic acid as a reactant, instead of phenylboronic acid, to give 2-(3-chloro-4-fhrorophenyl]-N-[(l- oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.52(br.s, 1H), 8.25(s, 1H), 8.07(m, 2H), 7.85(s, 1H), 7.4 0(m, 4H), 4.88(d, 2H)Example 31: 2-(3,4-Difluorophenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide

[0084] The procedure given in Example 1 was followed using 3,4-difluorophenylboronic acid as a reactant, instead of phenylboronic acid, to give 2-(3,4-difluorophenyl]-N-[(l-oxidopyridin-l- ium-2-yl)methyl]thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.53(br.s, 1H), 8.29(s, 1H), 8.10(s, 1H), 7.83(t, 1H), 7.50 (m, 3H), 7.27(m, 2H), 4.90(d, 2H)Example 32: 2-[3-Fluoro-4-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide

[0085] The procedure given in Example 1 was followed using 3-fluoro-4- (trifluoromethyl)phenylboronic acid as a reactant, instead of phenylboronic acid, to give 2- [3- fluoro-4-(trifluoromethyl)phenyl] -N - [( 1 -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4- carboxamide.1H NMR (CDCh, 500MHz) 8 8.57(br.s, 1H), 8.28(s, 1H), 8.19(s, 1H), 7.84(m, 2H),7.70 (m, 1H), 7.56(s, 1H), 7.29(m, 2H), 4.88(d, 2H)Example 33: 2-[3-Chloro-4-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide

[0086] The procedure given in Example 1 was followed using 3-chloro-4- (trifluoromethyl)phenylboronic acid as a reactant, instead of phenylboronic acid, to give 2- [3- chloro-4-(trifluoromethyl)phenyl]-N-[(l -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4- carboxamide.1H NMR (CDCh, 500MHz) 8 8.55(br.s, 1H), 8.28(s, 1H), 8.19(s, 1H), 8.12(s, 1H), 7.95 (d, 1H), 7.78(d, 1H), 7.56(s, 1H), 7.28(m, 2H), 4.89(d, 2H)Example 34: 2-(4-Chloro-3-fluorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide

[0087] The procedure given in Example 1 was followed using 4-chl oro-3 -fluorophenylboronic acid as a reactant, instead of phenylboronic acid, to give 2-(4-chloro-3-fhrorophenyl)-N-[(l- oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.53(br.s, 1H), 8.27(s, 1H), 8.24(s, 1H), 8.16(s, 1H), 8.11 (d, 1H), 7.61(d, 1H), 7.56(s, 1H), 7.26(m, 2H), 4.89(d, 2H)Example 35: 2-[4-Chloro-3-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide

[0088] The procedure given in Example 1 was followed using 4-chl oro-3 - (trifluor omethyl)phenylboronic acid as a reactant, instead of phenylboronic acid, to give 2- [4- chloro-3-(trifluoromethyl)phenyl]-N-[(l -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4- carboxamide.1H NMR (CDCh, 500MHz) 8 8.53(br.s, 1H), 8.27(s, 1H), 8.24(s, 1H), 8.16(s, 1H), 8.11 (d, 1H), 7.61(d, 1H), 7.56(s, 1H), 7.26(m, 2H), 4.89(d, 2H)Example 36: 2-[4-Chloro-3-(trifluoromethoxy)phenyl]-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide

[0089] The procedure given in Example 1 was followed using 4-chl oro-3 - (trifluor omethoxy)phenylboronic acid as a reactant, instead of phenylboronic acid, to give 2- [4- chloro-3 -(trifluoromethoxy)phenyl] -N- [( 1 -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4- carboxamide.1H NMR (CDCh, 500MHz) 8 8.52(br.s, 1H), 8.28(s, 1H), 8.14(s, 1H), 7.91(s, 1H), 7.87 (d, 1H), 7.57(m, 2H), 7.27(m, 2H), 4.88(d, 2H)Example 37: 2-(4-Chloro-2-fluorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide

[0090] The procedure given in Example 1 was followed using 4-chloro-2-fluorophenylboronic acid as a reactant, instead of phenylboronic acid, to give 2-(4-chloro-2-fhrorophenyl)-N-[(l- oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.61(br.s, 1H), 8.31(m, 2H), 8.22(s, 1H), 7.56(s, 1H), 7.30(m, 4H), 4.89(d, 2H)Example 38: 2-[3-Methyl-5-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide

[0091] The procedure given in Example 1 was followed using 3-methyl-5- (trifluoromethyl)phenylboronic acid as a reactant, instead of phenylboronic acid, to give 2- [3- methyl-5-(trifluorornethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide.1H NMR (CDCh, 400MHz) 8 8.46(br.s, 1H), 8.28(d, 1H), 8.13(s, 1H), 7.98(s, 2H), 7.54 (m, 2H), 7.28(m, 2H), 4.88(d, 2H), 2.51(s, 3H)Example 39: 2-(3-Chloro-4-methylphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole- 4-carboxamide

[0092] The procedure given in Example 1 was followed using 3-chloro-4- methylphenylboronic acid as a reactant, instead of phenylboronic acid, to give 2-(3-chloro-4- methylphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide.1H NMR (CDCh, 400MHz) 8 8.49(br.s, 1H), 8.28(d, 1H), 8.08(s, 1H), 7.96(s, 1H), 7.75 (d, 1H), 7.53(d, 1H), 7.30(m, 2H), 4.87(d, 2H), 2.43(s, 3H)Example 40: 2-[3-Methyl-4-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide

[0093] The procedure given in Example 1 was followed using 3-methyl-4- (trifluoromethyl)phenylboronic acid as a reactant, instead of phenylboronic acid, to give 2-[3- methyl-4-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide.1H NMR (CDCh, 500MHz) 8 8.54(br.s, 1H), 8.28(s, 1H), 8.14(s, 1H), 7.90(s, 1H), 7.86 (d, 1H), 7.68(d, 1H), 7.57(s, 1H), 7.27(m, 2H), 4.88(d, 2H)Example 41: 2-[2-Methoxy-4-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide

[0094] The procedure given in Example 1 was followed using 2-methoxy-4- (trifluoromethyl)phenylboronic acid as a reactant, instead of phenylboronic acid, to give 2-[2- methoxy-4-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide.1H NMR (CDCh, 400MHz) 8 8.46(br.s, 1H), 8.28(d, 1H), 8.14(s, 1H), 7.77(s, 1H), 7.69 (s, 1H), 7.55(d, 1H), 7.29(m, 3H), 4.88(d, 2H), 3.95(s, 3H)Example 42: 2-(4-Chloro-3-methylphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole- 4-carboxamide

[0095] The procedure given in Example 1 was followed using 4-chl oro-3 - methylphenylboronic acid as a reactant, instead of phenylboronic acid, to give 2-(4-chl oro-3 - methylphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.50(s, 1H), 8.27(s, 1H), 8.07(s, 1H), 7.85(s, 1H), 7.73(d, 1H), 7.55(s, 1H), 7.41(d, 1H), 7.29(m, 2H), 4.88(d, 2H), 2.46(s, 3H)Example 43: 2-(3-Chloro-5-methylphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole- 4-carboxamide

[0096] The procedure given in Example 1 was followed using 3-chloro-5- methylphenylboronic acid as a reactant, instead of phenylboronic acid, to give 2-(3-chloro-5- methylphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.46(s, 1H), 8.28(s, 1H), 8.10(s, 1H), 7.76(s, 1H), 7.66(s, 1H), 7.54(d, 1H), 7.30(m, 3H), 4.88(d, 2H), 2.42(s, 3H)Example 44: 2-[3-Chloro-5-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide

[0097] The procedure given in Example 1 was followed using 3-chloro-5- (trifluoromethyl)phenylboronic acid as a reactant, instead of phenylboronic acid, to give 2- [3- chloro-5-(trifluoromethyl)phenyl]-N-[(l -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4- carboxamide.1H NMR (CDCh, 500MHz) 8 8.49(br.s, 1H), 8.29(s, 1H), 8.29(s, 1H), 8.18(s, 1H), 8.08 (s, 1H), 7.71(s, 1H), 7.56(d, 1H), 7.27(m, 2H), 4.90(d, 2H)Example 45: 2-[4-Fluoro-3-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide

[0098] The procedure given in Example 1 was followed using 4-fluoro-3- (trifluoromethyl)phenylboronic acid as a reactant, instead of phenylboronic acid, to give 2- [4- fluoro-3 -(trifluoromethyl)phenyl] -N - [( 1 -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4- carboxamide.1H NMR (CDCh, 500MHz) 8 8.51(br.s, 1H), 8.27(s, 1H), 8.18(m, 3H), 7.54(d, 1H), 7.3 0(m, 3H), 4.88(d, 2H)Example 46: 2-[3-Fluoro-5-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide

[0099] The procedure given in Example 1 was followed using 3-fluoro-5- (trifluoromethyl)phenylboronic acid as a reactant, instead of phenylboronic acid, to give 2-[3- fluoro-5-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide.1H NMR (CDCh, 500MHz) 8 8.49(br.s, 1H), 8.27(d, 1H), 8.17(s, 1H), 7.97(s, 1H), 7.91(d, 1H), 7.54(d, 1H), 7.42(d, 1H), 7.28(m, 2H), 4.87(d, 2H)Example 47: 2-[2-Methyl-4-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide

[0100] The procedure given in Example 1 was followed using 2-methyl-4- (trifluoromethyl)phenylboronic acid as a reactant, instead of phenylboronic acid, to give 2- [2- methyl-4-(trifluorornethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide.1H NMR (CDCh, 500MHz) 8 8.57(br.s, 1H), 8.26(s, 1H), 8.22(s, 1H), 7.88(d, 1H), 7.60 (s, 1H), 7.55(m, 2H), 7.30(m, 2H), 4.88(d, 2H), 2.71(s, 3H)Example 48: 2-(3-Chloro-5-fluorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide

[0101] The procedure given in Example 1 was followed using 3-chloro-5-fluorophenylboronic acid as a reactant, instead of phenylboronic acid, to give 2-(3-chloro-5-fhrorophenyl)-N-[(l- oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.49(br.s, 1H), 8.32(d, 1H), 8.16(s, 1H), 7.76(s, 1H), 7.62 (d, 1H), 7.56(d, 1H), 7.32(m, 2H), 7.20(d, 1H), 4.91(d, 2H)Example 49: 2-[3-Methoxy-5-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide

[0102] The procedure given in Example 1 was followed using 3-methoxy-5- (trifluoromethyl)phenylboronic acid as a reactant, instead of phenylboronic acid, to give 2-[3- methoxy-5-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide.1H NMR (CDCh, 500MHz) 8 8.47(br.s, 1H), 8.29(d, 1H), 8.16(s, 1H), 7.76(s, 1H), 7.71 (s, 1H), 7.56(d, 1H), 7.31(m, 3H), 4.90(d, 2H), 3.97(s, 3H)Example 50: 2-[2-Methoxy-4-(trifluoromethoxy)phenyl]-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide

[0103] The procedure given in Example 1 was followed using 2-methoxy-5- (trifluoromethoxy)phenylboronic acid as a reactant, instead of phenylboronic acid, to give 2-[2- methoxy-4-(trifluoromethoxy)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide.1H NMR (CDCh, 500MHz) 8 8.53(br.s, 1H), 8.43(d, 1H), 8.22(d, 1H), 8.09(s, 1H), 7.4 8(d, 1H), 7.21(m, 2H), 6.92(d, 1H), 6.82(s, 1H), 4.82(d, 2H), 3.99(s, 3H)Example 51: 2-[3-Ethoxy-5-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide

[0104] The procedure given in Example 1 was followed using 3-ethoxy-5- (trifluoromethyl)phenylboronic acid as a reactant, instead of phenylboronic acid, to give 2- [3- ethoxy-5-(trifluorornethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide.1H NMR (CDCh, 500MHz) 8 8.45(br.t, 1H), 8.28(d, 1H), 8.14(s, 1H), 7.73(s, 1H), 7.68 (s, 1H), 7.55(m, 1H), 7.28(m, 3H), 4.88(d, 2H), 4.17(q, 2H), 1.49(t, 3H)Example 52: 2-(4-Chloro-3-methoxyphenyl)-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide

[0105] The procedure given in Example 1 was followed using 4-chl oro-3 - methoxyphenylboronic acid as a reactant, instead of phenylboronic acid, to give 2-(4-chl oro-3 - methoxyphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.50(br.t, 1H), 8.28(d, 1H), 8.10(s, 1H), 7.55(m, 2H), 7.4 3(m, 2H), 7.27(m, 2H), 4.88(d, 2H), 4.03(s, 3H)Example 53: 2-[3-Methoxy-4-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide

[0106] The procedure given in Example 1 was followed using 3-methoxy-4- (trifluoromethyl)phenylboronic acid as a reactant, instead of phenylboronic acid, to give 2-[3- methoxy-4-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide.1H NMR (CDCh, 400MHz) 8 8.54(br.t, 1H), 8.27(d, 1H), 8.16(s, 1H), 7.74(d, 2H), 7.55 (t, 2H)7.28(m, 2H), 4.87(d, 2H), 4.05(s, 3H)Example 54: 2-[4-Chloro-2-(trifluoromethoxy)phenyl)-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide

[0107] The procedure given in Example 1 was followed using 4-chloro-2- (trifluoromethoxy)phenylboronic acid as a reactant, instead of phenylboronic acid, to give 2-[4- chloro-2-(trifluoromethoxy)phenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide.1H NMR (CDCh, 400MHz) 8.59(br.t, 1H), 8.42(d, 1H), 8.28(d, 1H), 8.23(s, 1H), 7.55(d d, 1H), 7.44(m, 2H), 7.29(m, 2H), 4.88(d, 2H)Example 55: N-[(l-Oxidopyridin-l-ium-2-yl)methyl]-2-(2,3,5-trichlorophenyl)thiazole-4- carboxamide

[0108] The procedure given in Example 1 was followed using 2,3,5-trichlorophenylboronic acid as a reactant, instead of phenylboronic acid, to give N-[(l-oxidopyridin-l-ium-2-yl)methyl]- 2-(2,3 , 5 -trichlorophenyl)thiazole-4-carboxamide.1H NMR (CDCh, 500MHz) 8 8.47(br.s, 1H), 8.28(m, 2H), 8.20(s, 1H), 7.58(s, 1H), 7.5 4(br.s, 1H), 7.27(m, 2H), 4.88(d, 2H)Example 56: N-[l-(l-Oxidopyridin-l-ium-2-yl)cyclopropy]-2-[4- (trifluoromethyl)phenyl]thiazole-4-carboxide

[0109] The procedure given in Example 8 was followed using l-(l-oxidopyridin-l-ium-2- yl)cyclopropanamine as a reactant, instead of (l-oxidopyridin-l-ium-2-yl)methanamine, to give N- [ 1 -( 1 -oxidopyridin- 1 -ium-2-yl)cyclopropyl] -2- [4-(trifluoromethyl)phenyl]thiazole-4- carboxide.1H NMR (CDCh, 500MHz) 8 8.82(s, 1H), 8.23(d, 1H), 8.08(m, 3H), 7.71(d, 2H), 7.64 (m, 1H), 7.24(m, 2H), 1.53(m, 2H), 1.33(m, 2H)Example 57: N-[l-(l-Oxidopyridin-l-ium-2-yl)cyclobutyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4-carboxamide

[0110] To a solution of N-[l-(2-pyridyl)cyclobutyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4- carboxamide (0.91 mmol) in DCM was added m-CPBA (1.82 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure togive a residue. The crude was purified by flash column chromatography to produce N-[l-(l- oxidopyridin-l-ium-2-yl)cyclobutyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4-carboxamide.1H NMR (CDCh, 400MHz) 8.65(s, 1H), 8.12(m, 3H), 8.01(s, 1H), 7.72(d, 3H), 7.34(t,1H), 7.19(t, 1H), 2.86(m, 4H), 2.24(m, 2H), 1.88(m, 2H)Example 58: N-[l-(l-Oxidopyridin-l-ium-2-yl)cyclopentyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4-carboxamide

[0111] The procedure given in Example 57 was followed using N-[l-(2-pyridyl)cyclopentyl]- 2-[4-(trifluoromethyl)phenyl]thiazole-4-carboxamide as a reactant, instead of N-[l-(2- pyridyl)cyclobutyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4-carboxamide, to give N-[l-(l- oxidopyridin-l-ium-2-yl)cyclopentyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4-carboxamide.1H NMR (CDCh, 400MHz) 8.43(s, 1H), 8.18(d, 1H), 8.11(d, 2H), 7.99(s, 1H), 7.73(d, 2H), 7.65(dd, 1H), 7.30(m, 1H), 7.19(m, 1H), 2.89(m, 2H), 2.42(m, 2H), 1.95(m, 2H), 1.80(m, 2H)Example 59: N-[l-(l-Oxidopyridin-l-ium-2-yl)cyclohexyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4-carboxamide

[0112] The procedure given in Example 57 was followed using N-[l-(2-pyridyl)cyclohexyl]- 2-[4-(trifluoromethyl)phenyl]thiazole-4-carboxamide as a reactant, instead of N-[l-(2- pyridyl)cyclobutyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4-carboxamide, to give N-[l-(l- oxidopyridin-l-ium-2-yl)cyclohexyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4-carboxamide.1H NMR (CDCh, 400MHz) 8.36(s, 1H), 8.14(m, 3H), 8.00(s, 1H), 7.73(d, 2H), 6.61(dd, 1H), 7.29(t, 1H), 7.16(t, 1H), 3.28(d, 2H), 1.84(m, 7H), 1.41(m, 1H)Example 60: N-[2-Methyl-l-(l-oxidopyridin-l-ium-2-yl)propyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4-carboxamide

[0113] The procedure given in Example 57 was followed using N-[2-methyl-l-(2- pyridyl)propyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4-carboxamide as a reactant, instead of N- [l-(2-pyridyl)cyclobutyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4-carboxamide, to give N-[l-(l- oxidopyridin-l-ium-2-yl)cyclohexyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4-carboxamide.1H NMR (CDCh, 400MHz) 8 9.54(d, 1H), 8.24(d, 1H), 8.13(m, 3H), 7.73(d, 2H), 7.35 (m, 1H), 7.28(m, 2H), 5.06(t, 1H), 2.82(m, 1H), 1.12(d, 3H), 0.86(d, 3H)Example 61: N-[2-Cyclopropyl-l-(l-oxidopyridin-l-ium-2-yl)ethyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4-carboxamide

[0114] The procedure given in Example 57 was followed using N-[2-cyclopropyl-l-(2- pyridyl)ethyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4-carboxamide as a reactant, instead of N-[l- (2-pyridyl)cyclobutyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4-carboxamide, to give N-[l-(l- oxidopyridin-l-ium-2-yl)cyclohexyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4-carboxamide.1H NMR (DMSO-d6, 400MHz) 8 9.28(d, 1H), 8.45(s, 1H), 8.29(d, 3H), 7.94(d, 2H), 7. 59(m, 1H), 7.36(m, 1H), 5.57(m, 1H), 1.93(m, 1H), 1.78(m, 1H), 0.78(m, 1H), 0.36(m, 2H), 0.15(m, 1H), 0.057(m, 1H)Example 62: 5-Methyl-N-[(l-oxidopyridin-l-ium-2-yl)methyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4-carboxamide

[0115] The procedure given in Example 1 was followed using 4- (trifluoromethyl)phenylboronic acid and 2-bromo-5-methyl-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide as a reactant, instead of phenylboronic acid and 2-bromo-N- [(l-oxidopyridin-l-yl)methyl]thiazole-4-carboxamide, respectively, to give 5-methyl-N-[(l- oxidopyridin- 1 -ium-2-yl)methyl] -2- [4-(trifluoromethyl)phenyl]thiazole-4-carboxamide1H NMR (DMSO-d6, 400MHz) 8 9.28(d, 1H), 8.45(s, 1H), 8.29(d, 3H), 7.94(d, 2H), 7. 59(m, 1H), 7.36(m, 1H), 5.57(m, 1H), 1.93(m, 1H), 1.78(m, 1H), 0.78(m, 1H), 0.36(m, 2H), 0.15(m, 1H), 0.057(m, 1H)Example 63: 5-Chloro-N-[(l-oxidopyridin-l-ium-2-yl)methyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4-carboxamide

[0116] The procedure given in Example 62 was followed using and 2-bromo-5-chloro-N-[(l- oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide as a reactant, instead of 2-bromo-5- methyl-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide, to give 5-chloro-N-[(l- oxidopyridin- 1 -ium-2-yl)methyl] -2- [4-(trifluoromethyl)phenyl]thiazole-4-carboxamide1H NMR (CDCh, 400MHz) 8.62(br.t, 1H), 8.27(d, 1H), 7.99(d, 2H), 7.72(d, 2H), 7.55(d d, 1H), 7.28(m, 2H), 4.83(d, 2H)Example 64: 2-[2-Methoxy-4-(trifluoromethyl)phenyl]-5-methyl-N-[(l-oxidopyridin-l-ium- 2-yl)methyl]thiazole-4-carboxamide

[0117] The procedure given in Example 62 was followed using 2-methoxy-4- (trifluoromethyl)phenylboronic acid as a reactant, instead of 4-(trifluoromethyl)phenylboronic acid, to give 2-[2-methoxy-4-(trifluorornethyl)phenyl]-5-methyl-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide.1H NMR (CDCh, 400MHz) 8.62(br.t, 1H), 8.51(d, 2H), 8.27(d, 1H), 7.53(dd, 1H), 7.34 (d, 1H), 7.23(m, 2H), 4.84(d, 2H), 4.07(s, 3H), 2.87(s, 3H)Example 65: 2-(3-Chloro-4-fluorophenyl)-5-methyl-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide

[0118] The procedure given in Example 62 was followed using 3-chloro-4- fluorophenylboronic acid as a reactant, instead of 4-(trifluoromethyl)phenylboronic acid, to give 2-[2-methoxy-4-(trifluoromethyl)phenyl]-5-methyl-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide.1H NMR (CDCh, 400MHz) 8.54(br.t, 1H), 8.26(d, 1H), 7.96(dd, 1H), 7.77(m, 1H), 7.53 (m, 1H), 7.24(m, 3H), 4.82(d, 2H), 2.85(s, 3H)Example 66: 4-(4-Chlorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-2- carboxamide

[0119] The procedure given in Example 8 was followed using 4-(4-chlorophenyl)thiazole-2- carboxylic acid as a reactant, instead of 2-(4-chlorophenyl)thiazole-4-carboxylic acid, to give 4- (4-chlorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-2-carboxamide.1H NMR (CDCh, 500MHz) 8 8.57(br.s, 1H), 8.29(d, 1H), 7.86(m, 2H), 7.67(s, 1H), 7.5 3(dd, 1H), 7.40(d, 2H), 7.27(m, 2H), 4.87(d, 2H)Example 67: N-[(l-Oxidopyridin-l-ium-2-yl)methyl]-4-[4- (trifluoromethoxy)phenyl]thiazole-2-carboxamide

[0120] The procedure given in Example 8 was followed using 4- [4- (trifluoromethoxy)phenyl]thiazole-2-carboxylic acid as a reactant, instead of 2-(4- chlorophenyl)thiazole-4-carboxylic acid, to give N-[(l-oxidopyridin-l-ium-2-yl)methyl]-4-[4- (trifluoromethoxy)phenyl]thiazole-2-carboxamide.1H NMR (CDCh, 500MHz) 8 8.58(br.t, 1H), 8.28(d, 1H), 7.95(d, 2H), 7.70(s, 1H), 7.53 (dd, 1H), 7.27(m, 4H), 4.87(d, 2H)Example 68: N-[(l-Oxidopyridin-l-ium-2-yl)methyl]-4-[4-(trifluoromethyl)phenyl]thiazole- 2-carboxamide

[0121] The procedure given in Example 8 was followed using 4- [4- (trifluoromethyl)phenyl]thiazole-2-carboxylic acid as a reactant, instead of 2-(4- chlorophenyl)thiazole-4-carboxylic acid, to give N-[(l-oxidopyridin-l-ium-2-yl)methyl]-4-[4- (trifluoromethyl)phenyl]thiazole-2-carboxamide.1H NMR (CDCh, 500MHz) 8 8.58(br.t, 1H), 8.28(d, 1H), 7.95(d, 2H), 7.70(s, 1H), 7.53 (dd, 1H), 7.27(m, 4H), 4.87(d, 2H) hNavl.7 channel assay

[0122] Whole cell patch clamp technique was used to investigate the inhibitory effects of the compound of Examples on human Navi.7 channels, stably expressed in HEK293 cells. Human Navi.7 recombinant cell line (CYL3011-precisION) was purchased from Eurofins.Two-pulse protocol was used every 10 seconds to assess the state-dependent inhibition by Examples. From the holding potential of -90 mV, pre-pulse (200ms at -120mV) was followed by test pulsel (TP1: Is at OmV), then test pulse2 (TP2: 20ms at OmV) was evoked after inter-pulse (20ms at -lOOmV).Peak current amplitudes were measured for test pulses TP1 (resting phase inhibition) and TP2 (inactivated phase inhibition). The following solutions were used for screening assay: External (mM): 145 NaCl, 1 MgCh, 1.8 CaCh, 10 Hepes, 5 Glucose, pH 7.4, 300 mOsm; Internal (mM): 120 CsF, 10 NaCl, 10 EGTA, 10 HEPES, pH 7.2, 290 mOsm.The inhibition on the inactivated state of hNavl.7 was calculated as: % inhibition (inactivation state) = (1 - (ITP2, TA / ITP2, Control) x 100%, where ITP2 (the inward peak Na+ currents), Control and ITP2, TA were elicited by the TP2 in control (vehicle only) and in the presence of a test article (TA) indicating Examples, respectively.According to one embodiment of the present invent, compounds of examples did not show significant inhibitions on the resting state of hNavl.7, indicating relatively lower adverse potentials of Examples.The % inhibition on the inactivated state of hNavl.7 channel of Examples is presented in Table 1.

[0123] Table 1

[0124] As described herein, the compounds of the present disclosure were observed to have inhibiting affinity against voltage-dependent sodium channels. The results indicate that the compounds can be useful to treat pain including neuropathic pain by blocking the activities of sodium channels.Rat Spinal Nerve Ligation model

[0125] Analgesic efficacy was examined through the Spinal Nerve Ligation (SNL) model, also known as the Chung model (Kim and Chung, 1992). SNL model is one of the most frequently used animal models for the assessment of neuropathic pain behavior.

[0126] Briefly, the lumbar 5 spinal nerve is ligated with silk suture distal to the dorsal root ganglion. After two weeks of recovery, mechanical allodynia in the affected paw of animals was evaluated using von Frey filaments. Using the Dixons Up-Down method (Chaplan et al, 1994), a pre-drug baseline was taken with allodynia defined as a paw withdrawal threshold (PWT) <4 g. Test compounds (at 30 mg / kg) or vehicle were then orally administered, and PWT was determined two hours after the treatment. Statistical mean values of PWT for vehicle control and drug treatment groups were calculated, and the percent of maximum possible effect (%MPE) value was determined according to the following formula; %MPE = [(post-drug PWT - pre-drug PWT) / (cutoff PWT - pre-drug PWT)] x 100.The % MPE of Examples is presented in Table 2.

[0127] Table 2

[0128] As described above, the compounds of the present disclosure were observed to have analgesic efficacy which is useful for the treatment of pain including neuropathic pain.

Claims

WHAT IS CLAIMED IS:

1. A compound of F ormula (I) :or a pharmaceutically acceptable salt thereof, whereinRi, R2, R3, R4 and R5 are independently selected from hydrogen, halogen, (Ci-C4)alkyl, (Ci- C4)alkoxy, (C3-Ce)cycloalkyl and hetero(C2-C4)cycloalkyl which contains one or more heteroatoms selected from N, O, and S; wherein each (Ci-C4)alkyl, (Ci-C4)alkoxy and (C3- Ce)cycloalkyl are unsubstituted or substituted with one or more substituents selected from halogen and hydroxyl;A and B are each selected from S and CRr„ wherein A and B are not identical, and Re is selected from hydrogen, halogen and (Ci-C4)alkyl; andX and Y are independently selected from hydrogen and (C2-Ce)alkyl, or taken together with the carbon atom to which they are attached to form (C3-Ce)cycloalkyl; wherein (C2-Ce)alkyl is unsubstituted or substituted with (C3-Ce)cycloalkyl.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , whereinRi is selected from hydrogen, halogen, (Ci-C4)alkyl, (Ci-C4)alkoxy and hetero(C2- C4)cycloalkyl which contains one or more heteroatoms selected from N, O, and S, wherein each (Ci-C4)alkyl and (Ci-C4)alkoxy are unsubstituted or substituted with halogen;R2 is selected from hydrogen, halogen, (Ci-C4)alkyl and (Ci-C4)alkoxy, wherein each (Ci- C4)alkyl and (Ci-C4)alkoxy are unsubstituted or substituted with halogen;R3 is selected from hydrogen, halogen, (Ci-C4)alkyl, (Ci-C4)alkoxy and (C3-Ce)cycloalkyl, wherein each (Ci-C4)alkyl, (Ci-C4)alkoxy and (C3-Ce)cycloalkyl are unsubstituted or substituted with one or more substituents selected from halogen and hydroxyl;R4 is selected from hydrogen, halogen and (Ci-C4)alkyl, wherein (Ci-C4)alkyl is unsubstituted or substituted with halogen;R5 is selected from hydrogen and halogen; andX and Y are hydrogen.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, whereinRi is hydrogen;R2 is selected from hydrogen, halogen and (Ci-C4)alkoxy;R3 is selected from halogen and (Ci-C4)alkyl, wherein (Ci-C4)alkyl is unsubstituted or substituted with one or more substituents selected from halogen and hydroxyl;R4 is hydrogen;R5 is hydrogen;Re is hydrogen; andX and Y are hydrogen.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound of Formula (I) is a compound of Formula (II):whereinRi, R2, R3, R4 and R5 are independently selected from hydrogen, halogen, (Ci-C4)alkyl, (Ci- C4)alkoxy, (C3-Ce)cycloalkyl and hetero(C2-C4)cycloalkyl which contains one or more heteroatoms selected from N, O, and S; wherein each (Ci-C4)alkyl, (Ci-C4)alkoxy and (C3- Ce)cycloalkyl are unsubstituted or substituted with one or more substituents selected from halogen and hydroxyl;Re is selected from hydrogen, halogen and (Ci-C4)alkyl; andX and Y are independently selected from hydrogen and (C2-Ce)alkyl, or taken together with the carbon atom to which they are attached to form (C3-Ce)cycloalkyl; wherein (C2-Ce)alkyl is unsubstituted or substituted with (C3-Ce)cycloalkyl.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 4, whereinRi is hydrogen;R2 is selected from hydrogen, halogen and (Ci-C4)alkoxy;R3 is selected from halogen and (Ci-C4)alkyl, wherein (Ci-C4)alkyl is unsubstituted or substituted with one or more substituents selected from halogen and hydroxyl;R4 is hydrogen;R5 is hydrogen;Re is hydrogen; andX and Y are hydrogen.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 4, wherein Ri is hydrogen;R2 is selected from hydrogen, fluoro and alkoxy;R3 is selected from chloro, isopropyl and trifluoromethyl;R4 is hydrogen;R5 is hydrogen;Re is hydrogen; andX and Y are hydrogen.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 4, which is selected from the group consisting of:N- [( 1 -Oxidopyridin- 1 -ium-2-yl)methyl] -2-phenylthiazole-4-carboxamide, N-[(l-Oxidopyridi-l-ium-2-yl)methyl]-2-(p-tolyl)thiazole-4-carboxamide, 2-(4-Ethylphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide, 2-(4-Isopropylphenyl)-N - [( 1 -oxidopyridin- 1 -ium-2-yl)methyl] thiazole-4-carboxamide, 2-(4-tert-Buthylphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide, 2- [4-( 1 -Hydroxy- 1 -methyl-ethyl)phenyl] -N - [( 1 -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4- carboxamide,2-(4-Cyclopropylphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide, 2-(4-Chlorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide, N- [( 1 -Oxidopyridin- 1 -ium-2-yl)methyl] -2- [4-(trifhioromethyl)phenyl]thiazole-4- carboxamide,2-[4-(Difluoromethoxy)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide,N- [( 1 -Oxidopyridin- 1 -ium-2-yl)methyl] -2- [4-(trifluoromethoxy)phenyl]thiazole-4- carboxamide, 2-(m-Tolyl)-N-[l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide,2-(3 -Isopropylphenyl)-N - [( 1 -oxidopyridin- 1 -ium-2-yl)methyl] thiazole-4-carboxamide, 2-(3-tert-Buthylphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide, 2-(3-Chlorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide, N- [( 1 -Oxidopyridin- 1 -ium-2-yl)methyl] -2- [3 -(trifluoromethyl)phenyl]thiazole-4- carboxamide,N- [( 1 -Oxidopyridin- 1 -ium-2-yl)methyl] -2- [3 -(trifluoromethoxy)phenyl]thiazole-4- carboxamide, 2-(2,5-Dichlorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide, 2-(2,4-Dichlorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide, 2-(3,4-Dichlorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide, 2-(3,5-Dichlorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide, 2-(4-Chloro-2-methylphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide, 2-(4-Chloro-2-methoxyphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide,2- [4-Chloro-2-(trifluoromethyl)phenyl] -N- [( 1 -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4- carboxamide,2- [2-Chloro-4-(trifluoromethyl)phenyl] -N- [( 1 -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4- carboxamide,2-(4-Chloro-2-morpholinophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide,2-(2,3-Dichlorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide, 2-[2,4-bis(Trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide,2- [2-Fluoro-4-(trifluoromethyl)phenyl] -N- [( 1 -oxidopyridin- 1 -ium-2-y l)methyl]thiazole-4- carboxamide,2-(3 -Chloro-4-fluorophenyl] -N- [( 1 -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4-carboxamide,2-(3 ,4-Difluorophenyl] -N- [( 1 -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4-carboxamide,2- [3 -Fluoro-4-(trifluoromethyl)phenyl] -N- [( 1 -oxidopyridin- 1 -ium-2-y l)methyl]thiazole-4- carboxamide,2- [3 -Chloro-4-(trifluoromethyl)phenyl] -N- [( 1 -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4- carboxamide,2-(4-chloro-3 -fluorophenyl)-N- [( 1 -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4-carboxamide,2- [4-Chloro-3 -(trifluoromethyl)phenyl] -N- [( 1 -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4- carboxamide,2- [4-Chloro-3 -(trifluoromethoxy)phenyl] -N- [( 1 -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4- carboxamide,2-(4-chloro-2-fluorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide, 2-[3-Methyl-5-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide,2-(3-Chloro-4-methylphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide,2-[3-Methyl-4-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide,2-[2-Methoxy-4-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide,2-(4-Chloro-3-methylphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide, 2-(3-Chloro-5-methylphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide, 2- [3 -Chloro-5 -(trifluoromethyl)phenyl] -N- [( 1 -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4- carboxamide,2- [4-Fluoro-3 -(trifluor omethyl)phenyl] -N- [( 1 -oxidopyridin- 1 -ium-2-y l)methyl]thiazole-4- carboxamide,2-[3-Fluoro-5-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide,2-[2-Methyl-4-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide,2-(3-Chloro-5-fluorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide, 2-[3-Methoxy-5-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide,2-[2-Methoxy-4-(trifluoromethoxy)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide,2-[3-Ethoxy-5-(trifluoromethoxy)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide,2-(4-Chloro-3-methoxyphenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide,2-[3-Methoxy-4-(trifluoromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide,2- [4-Chloro-2-(trifluoromethoxy)phenyl)-N - [( 1 -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4- carboxamide,N-[(l-Oxidopyridin-l-ium-2-yl)methyl]-2-(2,3,5-trichlorophenyl)thiazole-4-carboxamide,N-[l-(l-Oxidopyridin-l-ium-2-yl)cyclopropy]-2-[4-(trifluoromethyl)phenyl]thiazole-4- carboxide,N-[l-(l-Oxidopyridin-l-ium-2-yl)cyclobutyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4- carboxamide,N-[l-(l-Oxidopyridin-l-ium-2-yl)cyclopentyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4- carboxamide,N-[l-(l-Oxidopyridin-l-ium-2-yl)cyclohexyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4- carboxamide,N-[2-Methyl-l -(1 -oxidopyridin- 1 -ium-2-yl)propyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4- carboxamide,N- [2-Cyclopropyl- 1 -( 1 -oxidopyridin- 1 -ium-2-yl)ethyl] -2- [4- (trifluoromethyl)phenyl]thiazole-4-carboxamide,5-Methyl-N-[(l-oxidopyridin-l-ium-2-yl)methyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4- carboxamide,5-Chloro-N-[(l -oxidopyridin- l-ium-2-yl)methyl]-2-[4-(trifluoromethyl)phenyl]thiazole-4- carboxamide,2-[2-Methoxy-4-(trifluoromethyl)phenyl]-5-methyl-N-[(l-oxidopyridin-l-ium-2- yl)methyl]thiazole-4-carboxamide, and 2-(3-Chloro-4-fluorophenyl)-5-methyl-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 7, which is selected from the group consisting of:2-(4-Isopropylphenyl)-N- [( 1 -oxidopyridin- 1 -ium-2-yl)methyl]thiazole-4-carboxamide, N- [( 1 -Oxidopyridin- 1 -ium-2-yl)methyl] -2- [4-(trifluoromethyl)phenyl]thiazole-4- carboxamide, 2-(4-chloro-3-fluorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4-carboxamide, and2-[3-Methoxy-4-(trifhioromethyl)phenyl]-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-4- carboxamide.

9. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound of Formula (I) is a compound of Formula (III):whereinRi, R2, R3, R4 and R5 are independently selected from hydrogen, halogen, (Ci-C4)alkyl, (Ci- C4)alkoxy, (C3-Ce)cycloalkyl and hetero(C2-C4)cycloalkyl which contains one or more heteroatoms selected from N, O, and S; wherein each (Ci-C4)alkyl, (Ci-C4)alkoxy and (C3- Ce)cycloalkyl are unsubstituted or substituted with one or more substituents selected from halogen and hydroxyl.

10. The compound or a pharmaceutically acceptable salt thereof according to claim 9, whereinRi is hydrogen;R2 is selected from hydrogen, halogen and (Ci-C4)alkoxy;R3 is selected from halogen and (Ci-C4)alkyl, wherein (Ci-C4)alkyl is unsubstituted or substituted with one or more substituents selected from halogen and hydroxyl;R4 is hydrogen; andR5 is hydrogen.

11. The compound or a pharmaceutically acceptable salt thereof according to claim 9, wherein Ri is hydrogen;R2 is hydrogen;R3 is selected from chloro, trifluoromethoxy and trifluoromethyl;R4 is hydrogen; andR5 is hydrogen.

12. The compound or a pharmaceutically acceptable salt thereof according to claim 9, which is selected from the group consisting of: 4-(4-Chlorophenyl)-N-[(l-oxidopyridin-l-ium-2-yl)methyl]thiazole-2-carboxamide, N-[(l-oxidopyridin-l-ium-2-yl)methyl]-4-[4-(trifluoromethoxy)phenyl]thiazole-2- carboxamide, andN-[(l-oxidopyridin-l-ium-2-yl)methyl]-4-[4-(trifluoromethyl)phenyl]thiazole-2-carboxamide.

13. A pharmaceutical composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable carrier.

14. The pharmaceutical composition of claim 13 for treating or preventing sodium channel-related disease.

15. The pharmaceutical composition of claim 14, wherein the sodium channel-related diseases is pain including neuropathic pain.

16. The pharmaceutical composition of claim 13, which is an oral formulation.

17. The pharmaceutical composition of claim 13, further comprising an active ingredient which is effective for treating or preventing pain including neuropathic pain.

18. A method of treating or preventing sodium channel-related disease, comprising : administering a therapeutically effective amount of the compound or a pharmaceuticallyacceptable salt thereof according claim 1 to a mammal in need thereof.

19. The method according to claim 18, wherein the sodium channel-related disease is pain including neuropathic pain.

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