Process for producing benzimidazole compound

Abstract

The present invention relates to a production method of benzimidazole derivatives useful as a pharmaceutical product, particularly an acid secretion inhibitor, and a production method of an intermediate used for this method, and a novel intermediate.

Description

Process for producing benzimidazole compound　The present invention relates to a production method of benzimidazole derivatives useful as a pharmaceutical product, particularly an acid secretion inhibitor, and a production method of an intermediate used for this method, and a novel intermediate.　A benzimidazole compound having a substituted amide group at the 6-position is useful as Potassium-Competitive Acid Blocker (p-cab), a therapeutic drug for an acid-related disease (PL 1 and PL 2).　PL 1 discloses a compound represented by the formula (A), which is useful for the treatment / prevention of disease conditions mediated by acid pump inhibitory activity.wherein;-A-B- represents -O-CH2-, -S-CH2-, -CH2-O-, or -CH2-S-;X represents an oxygen atom or NH;R1represents a C1-C6alkyl group being unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of a hydroxy group and a C1-C6alkoxy group; R2and R3independently represent a hydrogen atom, a C1-C6alkyl group, a C3-C7cycloalkyl group or a heteroaryl group; R4, R5, R6and R7independently represent a hydrogen atom, a halogen atom, a hydroxy group, a C1-C6alkyl group or a C1-C6alkoxy group; and R8represents a hydrogen atom, a hydroxy group or a C1-C6alkoxy group.　PL 1 discloses a general synthesis of benzimidazole derivatives using aniline derivatives as starting materials. The benzimidazole derivatives can be prepared by condensation reaction of a benzimidazole intermediate (BI) and a chromanol derivative, followed by a chiral separation as follows.　Tegoprazan inhibits hydrogen-ion / potassium-ion exchange ATPase (H+ / K+-ATPase) in a potassium-competitive manner; that is potassium-competitive acid blocker (p-cab), has quick response, can control the pH value of gastric juice for a long time, and is a medicament for treating acid related diseases.　The chemical name of tegoprazan is (S)-4-((5,7-difluorochroman-4-yl)oxy)-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide, and the chemical structure contains a benzimidazole structure having a substituted amide group at the 6-position and a chiral 5,7-difluorochroman-4-oxyl structure.　Examples 1 to 3 of PL 1 also disclose a production method of benzimidazole intermediate (BI) of tegoprazan, using 4-bromo-2-nitro-6-((phenylmethyl)oxy)aniline (B).　Furthermore, the compound (B) is prepared by the methods described in WO2004 / 054984 (PL 8), using a commercially available aniline (C) as a starting material. Totally, benzimidazole intermediate (BI) of tegoprazan is produced from commercially available aniline (C) in nine steps by the conventional method.　Recently, some patent literatures (PL 3-7, and 9) disclose an improved production method for the synthesis of benzimidazole intermediate (BI), which is a key intermediate of tegoprazan. PL 3 discloses a seven-step production method of benzimidazole intermediate (BI) of tegoprazan from commercially available 4-aminobenzoic acid (D) as follows.　The synthesis process of tegoprazan mainly involves a condensation reaction of benzimidazole intermediate (BI) and 5,7-difluorochroman-4-ol, followed by de-protecting reaction. The current production methods of tegoprazan have the problems of complicated and non-environmental friendly process, long-step, high-cost, and low yield production steps.　Therefore, to provide a simply, high yield, safety, and environmentally friendly preparation process of the tegoprazan has been desired and it has been important for the industrial development of the tegoprazan.{PL 1} WO2007 / 072146{PL 2} WO2016 / 200148{PL 3} CN115594639{PL 4} WO2015 / 005615{PL 5} WO2023 / 128525{PL 6} CN112851646{PL 7} CN114805317{PL 8} WO2004 / 054984{PL 9} CN116789654{PL 10} CN111303131{PL 11} CN115108994{PL 12} CN116253685　A cost effective, short-step production method of benzimidazole derivatives useful as a pharmaceutical product is desired. In addition, provision of a key intermediate used for this method is desired.　The present inventors have intensively studied a cost effective, short-step, environmentally friendly production method of benzimidazole derivatives including tegoprazan or a pharmaceutically acceptable salt thereof, and an improved production method of key intermediates used for this method.　As the results, a novel, improved, three-step production method of the key benzimidazole intermediate (BI) from commercially available aniline derivatives (I) is found. In addition, new important intermediates of (III) and (IV) and its new production method thereof are found.　This invention provides:[1] A method of preparing a compound represented by the formula (IX) or a pharmaceutically acceptable salt thereof,comprising steps of:(1) reacting a compound represented by the formula (I) with a compound represented by the formula (II) to give a compound represented by the formula (III); preferably, the reacting is carried out in the presence of acid anhydride, sulfonylation reagent or chlorinating agent; more preferably, the reacting comprises adding formula (I) to a mixture of formula (II) and Tf2O.(2) halogenating of the compound represented by the formula (III) to give a compound represented by the formula (IV);(3) cyclizing the compound represented by the formula (IV) to give a compound represented by the formula (V); preferably, the cyclizing is carried out in the presence of ligand and metal catalyst; more preferably the metal catalyst is copper catalyst; and(4) reacting the compound represented by the formula (V) with a compound represented by the formula (VI) to give a compound represented by the formula (VII);wherein R1is -N(C1-6alkyl)(C1-6alkyl), where two (C1-6alkyl)s may form a 4 to 6 membered heterocyclic group, -O-C1-6alkyl, or hydroxyl; R2is C1-6alkyl; R3and R4are independently C1-6alkyl or halogen; and Prot. is a protecting group.[2] A method of preparing a compound represented by the formula (III) or a salt thereof,comprising a step of reacting a compound represented by the formula (I) with a compound represented by the formula (II) to give the compound represented by the formula (III) or a salt thereof,wherein R1and R2are as defined in [1]; and Prot. is a protecting group,[3] A method of preparing a compound represented by the formula (IV) or a salt thereof, comprising a step of halogenating a compound represented by the formula (III) to give a compound represented by the formula (IV),wherein R1and R2are as defined in [1]; and Prot. is a protecting group,[4] A method of preparing a compound represented by the formula (V) or a salt thereof; comprising a step of cyclizing a compound represented by the formula (IV) to give the compound represented by the formula (V),wherein R1and R2are as defined in [1]; and Prot. is a protecting group,[5] A method of preparing a compound represented by the formula (IX) or a pharmaceutically acceptable salt thereof, comprising one or both steps of:(1) reacting a compound represented by the formula (I) with a compound represented by the formula (II) to give a compound represented by the formula (III); and(3) cyclizing the compound represented by the formula (IV) to give a compound represented by the formula (V);wherein R1and R2are as defined in [1]; and Prot. is a protecting group,[6] A method of preparing a compound represented by the formula (IX) or a pharmaceutically acceptable salt thereof,comprising steps of:(1) reacting a compound represented by the formula (I) with a compound represented by the formula (II) to give a compound represented by the formula (III); preferably, the reacting is carried out in the presence of acid anhydride, sulfonylation reagent or chlorinating agent; more preferably, the reacting comprises adding formula (I) to a mixture of formula (II) and Tf2O.(2) halogenating the compound represented by the formula (III) to give a compound represented by the formula (IV);(3a) cyclizing the compound represented by the formula (IV) to give a compound represented by the formula (VIII); preferably, the cyclizing is carried out in the presence of ligand and metal catalyst; more preferably the metal catalyst is copper catalyst; and(4a) reacting the compound represented by the formula (VIII) with a compound represented by the formula (VI) to give a compound represented by the formula (VII);wherein R1is -N(C1-6alkyl)(C1-6alkyl), where two (C1-6alkyl)s may form a 4 to 6 membered heterocyclic group, -O-C1-6alkyl, or hydroxyl; R2is C1-6alkyl; R3and R4are independently C1-6alkyl or halogen; and Prot. is a protecting group,[7] A method of preparing a compound represented by the formula (VIII) or a salt thereof; comprising a step of cyclizing a compound represented by the formula (IV) to give a compound represented by the formula (VIII);wherein R1and R2are as defined in [6]; and Prot. is a protecting group,[8] A method of preparing a compound represented by the formula (IX) or a salt thereof comprising a step of:(3a) cyclizing a compound represented by the formula (IV) to give a compound represented by the formula (VIII);wherein R1is -N(C1-6alkyl)(C1-6alkyl), where two (C1-6alkyl)s may form a 4 to 6 membered heterocyclic group, -O-C1-6alkyl, C1-6alkyl, or hydroxyl; R2is C1-6alkyl; R3and R4are independently C1-6alkyl or halogen; and Prot. is a protecting group,[9] The method according to any one of [1] to [8], wherein R1is -N(methyl)2and R2is methyl,

[0010] The method according to any one of [1] to [8], wherein the protecting group is selected from the group consisting of methyl, tert-butyl, allyl, benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, methoxymethyl, 2-(trimethylsilyl)ethoxymethyl, triphenylmethyl, diphenylmethyl, dimethylphenylmethyl, tetrahydropyranyl, tert-butoxycarbonyl, benzyloxycarbonyl, methanesulfonyl, 4-toluenesulfonyl, acetyl, and benzoyl,

[0011] The method according to any one of [1], [5], [6], [8], [9], and

[0010] , wherein R3and R4are fluoro,

[0012] The method according to any one of [1] to [8], wherein the cyclizing is carried out in the presence of metal catalyst and ligand,

[0013] The method according to

[0012] , wherein the metal catalyst is copper catalyst which is one or more selected from the groups consisting of Cu(0), copper(l) acetate, copper(l) bromide, copper(l) chloride, copper(l) iodide, copper(l) oxide, copper(ll) trifluoromethanesulfonate, copper(ll) acetate, copper(ll) bromide, copper(ll) chloride, copper(ll) iodide, copper(ll) oxide, copper(II) sulfate, tetrakis(acetonitrile)copper(I) hexafluorophosphate, and copper(II) acetylacetonate.

[0014] The method according to

[0012] , wherein the ligand is one or more selected from the groups consisting of ethane-1,2-diamine, N1,N2-dimethylethane-1,2-diamine, N1,N1,N2,N2-tetramethylethane-1,2-diamine, cyclohexane-1,2-diamine, N1,N2-dimethylcyclohexane-1,2-diamine, quinolin-8-ol, 1,10-phenanthroline, proline, oxalic diamide derivatives such as N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxalamide, N1,N2-bis(1-naphthalenylmethyl)ethanediamide, N,N′-dibenzyloxamide, N1,N2-bis(2,4,6-trimethoxyphenyl)ethanediamide, andN,N′-bis(2-phenylethyl)ethanediamide, 6-hydroxypicolinamide derivatives such as N-(2,6-dimethylphenyl)-6-hydroxypicolinamide, 6-hydroxy-N-(2,4,6-trimethoxyphenyl)picolinamide, 6-hydroxy-N-(2-methylnaphthalen-1-yl)picolinamide, 6-hydroxy-N-(naphthalen-1-yl)picolinamide, N-([1,1'-biphenyl]-2-yl)-6-hydroxypicolinamide, 6-hydroxy-N-(2-(trifluoromethyl)phenyl)picolinamide, 6-hydroxy-N-(o-tolyl)picolinamide, 6-hydroxy-N-phenylpicolinamide, 6-hydroxy-N-(thiophen-2-ylmethyl)picolinamide, 6-hydroxy-N-(naphthalen-1-ylmethyl)picolinamide, N-(2,6-diisopropylphenyl)-6-hydroxypicolinamide, N-(2,6-difluorophenyl)-6-hydroxypicolinamide, N-(2,6-dimethoxyphenyl)-6-hydroxypicolinamide, and 6-hydroxy-N-(4-hydroxy-2,6-dimethylphenyl)picolinamide, 4-hydroxyquinoline-2-carboxamide derivatives such as 4-hydroxy-N-phenylquinoline-2-carboxamide, and N-(2,6-dimethylphenyl)-4-hydroxyquinoline-2-carboxamide, and 6-hydroxypicolinohydrazide derivatives such as N-(1,3-dimethyl-9H-carbazol-9-yl)-6-hydroxypicolinamide, N-(2,7-dimethyl-9H-carbazol-9-yl)-6-hydroxypicolinamide, and N-(2,7-di-tert-butyl-9H-carbazol-9-yl)-6-hydroxypicolinamide.

[0015] The method according to any one of [1], [5], [6], [8], [9], and

[0010] , wherein the formula (IX) is a (S)-chiral compound represented by formula (X),

[0016] The method according to

[0015] , the chiral compound represented by formula (X) is tegoprazan; wherein R1is -N(methyl)2; R2is methyl; and R3and R4are fluoro,

[0017] A compound represented by the formula (III) or geometric isomer, tautomeric isomer, or a salt thereof:wherein R1is -N(C1-6alkyl)(C1-6alkyl), where two (C1-6alkyl)s may form a 4 to 6 membered heterocyclic group, -O-C1-6alkyl, C1-6alkyl, or hydroxyl; R2is C1-6alkyl; and Prot. is a protecting group,

[0018] A compound represented by the formula (IV) or geometric isomer, tautomeric isomer, or a salt thereof:wherein R1is -N(C1-6alkyl)(C1-6alkyl), where two (C1-6alkyl)s may form a 4 to 6 membered heterocyclic group, -O-C1-6alkyl, C1-6alkyl, or hydroxyl; R2is C1-6alkyl; and Prot. is a protecting group.

[0019] A use of a compound represented by the formula (III), a compound represented by the formula (IV) or a pharmaceutically acceptable salt thereof as an intermediate compound for use in the manufacture of a compound represented by the formula (IX):wherein R1is -N(C1-6alkyl)(C1-6alkyl), where two (C1-6alkyl)s may form a 4 to 6 membered heterocyclic group, -O-C1-6alkyl, C1-6alkyl, or hydroxyl; R2is C1-6alkyl; R3and R4are independently C1-6alkyl or halogen; and Prot. is a protecting group.

[0020] A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to

[0017] or

[0018] , and a pharmaceutically acceptable carrier or excipient,

[0021] A process for preparing a pharmaceutical composition, wherein the process comprises mixing a compound according to

[0017] or

[0018] , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.　The present invention provides a production method of benzimidazole intermediate (BI), which includes reacting a compound represented by formula (I) and a compound represented by formula (II) to give a compound represented by formula (III), halogenating the compound represented by formula (III) to give a compound represented by formula (IV), and cyclizing the compound (IV) to give a compound represented by formula (V) or a compound represented by formula (VIII) as a key benzimidazole intermediate (BI) of tegoprazan. The compound represented by formula (V) or compound represented by formula (VIII) can be used to give tegoprazan by the conventional method (PL 1 and 9 to 12) including deprotection as follows.　In the reaction in step 3, surprisingly, the cyclization and hydroxylation reactions proceed simultaneously. This contributes significantly to the reduction of the manufacturing process.　Thus, the present application discloses a three-step synthesis method from commercially available 4-amino-N,N-dimethylbenzamide to benzimidazole intermediate (BI) as a key intermediate of tegoprazan. The production step in the present invention is shorter than that in conventional methods. The present invention can achieve lower production costs and shorter production steps in the production of commercial Active Pharmaceutical Ingredient (API) of tegoprazan.　In another embodiment, tegoprazan can be produced from ester substituent instead of amide substituent in an aniline derivative (XI) as a starting material. In this production method, a short-step production process is also achieved. Benzimidazole intermediate (BI) with carboxylic acid or ester substituent is led to tegoprazan by the conventional synthetic methods (PL 1 and 9 to 12) including deprotection as follows.Fig. 1 shows a1H NMR spectrum of Compound 1.Fig. 2 shows a1H NMR spectrum of Compound 2.Fig. 3 shows a1H NMR spectrum of Compound 3.Fig. 4 shows a1H NMR spectrum of Compound 4.Fig. 5 shows a1H NMR spectrum of Compound 5.Fig. 6 shows a1H NMR spectrum of Compound 7.　The term “benzimidazole intermediate (BI) ”, as used herein, means benzimidazole derivatives as the intermediates to be combined with formula (VI) for the synthesis of tegoprazan.　The term “tautomeric isomer” as used here, means the tautomeric form derives from the exchange of single bonds at adjacent double bonds along with the simultaneous transfer of protons. Examples of proton tautomer are ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, and enamine-imine pairs. Tautomeric forms can be in equilibrium by appropriate substitution or sterically locked into one form.　The term “geometric isomer” as used here, means isomers in which the substituent atoms are oriented differently with respect to the carbon-carbon double bond, the cycloalkyl ring, or the bridged bicyclic ring system. The atoms (other than H) on each side of the carbon-carbon double bond may be in the E (substituents on opposite sides of the carbon-carbon double bond) or Z (substituents oriented on the same side) configuration.　The term “alkyl”, as used herein, means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms), and the like.　The term “Hal.”, “halogen”, or “halo” as used herein are intended to include fluoro, chloro, bromo, and iodo.　The term “alkoxy”, as used herein, means an -O-alkyl such as, but not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy (including all isomeric forms), and the like.　The term “alkenyl”, as used herein, means a hydrocarbon radical having at least one double bond, which may be in a E- or a Z- arrangement, including, but not limited to, ethenyl, propenyl, 1-butenyl, 2-butenyl, and the like.　The term “cycloalkyl”, as used herein, means a mono-, bi-, or tricyclic ring such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl groups, and the like.　The term “aryl", as used herein, means unsaturated or partially saturated mono- or bicyclic 5-15 membered ring which consists of carbon atoms. Examples of such aryl include, but are not limited to, phenyl, naphthyl, indanyl, indenyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, 2,3-dihydro-1H-indenyl, cyclohexenyl, cyclopentenyl, (1S,4S)-bicyclo[2.2.2]oct-2-enyl, and (1R,4S)-bicyclo[2.2.1]hept-2-enyl, and the like.　The term “heteroaryl” as used herein, means unsaturated and partially saturated mono- or bicyclic 5-15 membered ring, preferably 5-10 membered ring, which may contain 1-4 heteroatoms selected from O, N and S.　Examples of such heteroaryl include, but are not limited to, thiophenyl, thiazolyl, isoxazolyl, pyrazolyl, pyrazyl, tetrazolyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothiophenyl, benzotriazolyl, indolyl, indazolyl, benzoimidazolyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrazolopyridyl, pyrazolopyrimidinyl, imidazopyridinyl, furopyridyl, benzoisoxazolyl, imidazopyrazinyl, imidazopyridazinyl, imidazopyrimidinyl, quinolyl, isoquinolyl, quinoxalyl, quinazolinyl, phthalazinyl, quinoxalinyl, naphthyridinyl, pyridopyrimidinyl, and N-oxides thereof and S-oxides thereof, and the like.　The term “Ra” as used herein, means a protecting group of carboxylic acid. Racan be any group or substituent which do not interfere with the reaction. These groups may be added or removed by methods described for each in T. W. Greene and G.M. Wuts, Protective Groups in Organic Synthesis (John Wiley & Sons, New York, 2007).　The term “treating” or “treatment”, as used herein, includes prohibiting, restraining, slowing, stopping, or reversing the progression or severity of an existing symptom or disorder. As used herein, the term “preventing" or “to prevent" includes prohibiting, restraining, or inhibiting the incidence or occurrence of a symptom or disorder.　As used herein, the article “a” or “an” refers to both the singular and plural form of the object to which it refers unless indicated otherwise.　The term “halogenating”, as used herein, means a chemical reaction in which a halogen atom is introduced into a compound. Halogenations are described as chlorination, fluorination, bromination, iodination, etc., according to the halogen involved. Halogenation reactions may take place by direct reaction with the halogen. This occurs with alkanes, where the reaction involves free radicals and requires high temperature, ultraviolet radiation, or a chemical initiator.　The term “cyclizing”, as used herein, means formation of a ring compound from a chain by formation of a new bond. In the present invention, the cyclization reaction and the hydroxylation reaction may proceed simultaneously at the same time or stepwisely.　The term “hydroxylation”, as used herein, means the introduction of a hydroxyl group (-OH) into an organic compound. For example, but not limited to, alkenes can be hydroxylated using potassium permanganate or lead ethanoate to give alcohols. In biochemistry, various enzymes can bring about hydroxylation.　The term “ligand” as used herein, refers to an ion or molecule that donates a pair of electrons to a metal atom or ion in forming a coordination complex. The ligands that promote copper-catalyzed reactions are widely known from classical to the latest advanced ligands (reference: Chem. Rev. 2008, 108, 3054-3131). Examples of ligands for copper mediated reactions include, but are not limited to ethane-1,2-diamine, N1,N2-dimethylethane-1,2-diamine, N1,N1,N2,N2-tetramethylethane-1,2-diamine, cyclohexane-1,2-diamine, N1,N2-dimethylcyclohexane-1,2-diamine, quinolin-8-ol, 1,10-phenanthroline, proline, oxalic diamide derivatives such as N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxalamide, N1,N2-bis(1-naphthalenylmethyl)ethanediamide, N,N′-dibenzyloxamide, N1,N2-bis(2,4,6-trimethoxyphenyl)ethanediamide, and N,N′-bis(2-phenylethyl)ethanediamide, 6-hydroxypicolinamide derivatives such as N-(2,6-dimethylphenyl)-6-hydroxypicolinamide, 6-hydroxy-N-(2,4,6-trimethoxyphenyl)picolinamide, 6-hydroxy-N-(2-methylnaphthalen-1-yl)picolinamide, 6-hydroxy-N-(naphthalen-1-yl)picolinamide, N-([1,1'-biphenyl]-2-yl)-6-hydroxypicolinamide, 6-hydroxy-N-(2-(trifluoromethyl)phenyl)picolinamide, 6-hydroxy-N-(o-tolyl)picolinamide, 6-hydroxy-N-phenylpicolinamide, 6-hydroxy-N-(thiophen-2-ylmethyl)picolinamide, 6-hydroxy-N-(naphthalen-1-ylmethyl)picolinamide, N-(2,6-diisopropylphenyl)-6-hydroxypicolinamide, N-(2,6-difluorophenyl)-6-hydroxypicolinamide, N-(2,6-dimethoxyphenyl)-6-hydroxypicolinamide, and 6-hydroxy-N-(4-hydroxy-2,6-dimethylphenyl)picolinamide, 4-hydroxyquinoline-2-carboxamide derivatives such as 4-hydroxy-N-phenylquinoline-2-carboxamide, and N-(2,6-dimethylphenyl)-4-hydroxyquinoline-2-carboxamide, 6-hydroxypicolinohydrazide derivatives such as N-(1,3-dimethyl-9H-carbazol-9-yl)-6-hydroxypicolinamide, N-(2,7-dimethyl-9H-carbazol-9-yl)-6-hydroxypicolinamide, and N-(2,7-di-tert-butyl-9H-carbazol-9-yl)-6-hydroxypicolinamide, and the like. (reference: Org. Process Res. Dev. 2019, 23, 1538-1551, Org. Process Res. Dev. 2022, 26, 1690-1750, Org. Process Res. Dev. 2024, 28, 2732-2742, Angewandte Chemie International Edition, 2024, accepted manuscript, Title: 6-Hydroxy Picolinohydrazides Promoted Cu(I)-Catalyzed Hydroxylation Reaction in Water: Machine-Learning Accelerated Ligands Design and Reaction Optimization)　Further, examples of ligands for palladium mediated reactions, but are not limited to 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), triphenylphosphine, tri-tert-butylphosphine, 1,1'-bis(diphenylphosphino)ferrocene, tri-2-furylphosphine, tri-o-tolylphosphine, triphenylarsine, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), 2-(dichlorohexylphosphino)biphenyl (CyJohnPhos), 2-(dicyclohexylphosphino)-2'-(dimethylamino)biphenyl (DavePhos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (tBuXPhos), 2-(di-tert-butylphosphino)biphenyl (JohnPhos), and the like.　The term “oxalic diamide derivatives” as used herein, chemical substances that can be prepared by the condensation reaction of oxalic acid and amines or anilines (reference: Org. Process Res. Dev. 2022, 26, 1690-1750). Examples of “oxalic diamide derivatives” include, but are not limited to, N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxalamide, N1,N2-bis(1-naphthalenylmethyl)ethanediamide, N,N′-dibenzyloxamide, N1,N2-bis(2,4,6-trimethoxyphenyl)ethanediamide, and N,N′-bis(2-phenylethyl)ethanediamide.　The term “6-hydroxypicolinamide derivatives” as used herein, chemical substances that can be prepared by the condensation reaction of 6-hydroxypicolinic acid and amines or anilines (reference: Org. Process Res. Dev. 2019, 23, 1538-1551, Org. Process Res. Dev. 2024, 28, 2732-2742). Examples of “6-hydroxypicolinamide derivatives” include, but are not limited to, N-(2,6-dimethylphenyl)-6-hydroxypicolinamide, 6-hydroxy-N-(2,4,6-trimethoxyphenyl)picolinamide, 6-hydroxy-N-(2-methylnaphthalen-1-yl)picolinamide, 6-hydroxy-N-(naphthalen-1-yl)picolinamide, N-([1,1'-biphenyl]-2-yl)-6-hydroxypicolinamide, 6-hydroxy-N-(2-(trifluoromethyl)phenyl)picolinamide, 6-hydroxy-N-(o-tolyl)picolinamide, 6-hydroxy-N-phenylpicolinamide, 6-hydroxy-N-(thiophen-2-ylmethyl)picolinamide, 6-hydroxy-N-(naphthalen-1-ylmethyl)picolinamide, N-(2,6-diisopropylphenyl)-6-hydroxypicolinamide, N-(2,6-difluorophenyl)-6-hydroxypicolinamide, N-(2,6-dimethoxyphenyl)-6-hydroxypicolinamide, and 6-hydroxy-N-(4-hydroxy-2,6-dimethylphenyl)picolinamide.The term “4-hydroxyquinoline-2-carboxamide derivatives” as used herein, chemical substances that can be prepared by the condensation reaction of 4-hydroxyquinoline-2-carboxylic acid and amines or anilines (reference: Org. Process Res. Dev. 2019, 23, 1538-1551, Org. Process Res. Dev. 2024, 28, 2732-2742). Examples of “6-hydroxypicolinamide derivatives” include, but are not limited to, 4-hydroxy-N-phenylquinoline-2-carboxamide, and N-(2,6-dimethylphenyl)-4-hydroxyquinoline-2-carboxamide.　The term “metal catalyst” as used herein, chemical substances that can be changed the rate of chemical reactions. In general, transition metal catalysts are widely used among metal catalysts. Examples of “metal catalyst” include, but are not limited to, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(ll) chloride, copper(0), copper(l) acetate, copper(l) bromide, copper(l) chloride, copper(l) iodide, copper(l) oxide, copper(II) sulfate, copper(ll) trifluoromethanesulfonate, copper(ll) acetate, copper(ll) bromide, copper(ll) chloride, copper(ll) iodide, copper(ll) oxide, copper(II) acetylacetonate, palladium(ll) acetate, palladium(ll) chloride, tetrakis(acetonitrile)copper(I) hexafluorophosphate, bis(acetonitrile)dichloropalladium(II), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0), [1,1'-bis(diphenylphosphino)ferrocene] palladium(ll) dichloride, and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II).　Amount of “metal catalyst” is 0.001 equivalent to 10 equivalent against a substrate.　The term “acid anhydride” as used here, means acylating or sulfonylation reagents. For example, “acid anhydride” can be reacted with amide to afford imidate derivatives or imidoyl derivatives. Examples of acid anhydride include, but are not limited to, Tf2O and Ms2O.　The term “sulfonylation reagent” as used here, means sulfonylation reagents. For example, “sulfonylation reagent” can be reacted with amide to afford imidate derivatives or imidoyl derivatives. Examples of sulfonylation reagent include, but are not limited to, 4-toluenesulfonyl chloride, methanesulfonyl chloride, and benzenesulfonyl chloride.　The term “chlorinating reagent” as used here, means reagents to introduce chlorine atom to a reactant. For example, “chlorinating reagent” can be reacted with amide to afford imidoyl chloride. Examples of chlorinating reagent include, but are not limited to, oxalyl chloride, PCl5, POCl3, and SOCl2.　The term “copper catalyst” as used herein, includes, but not limited to, such as copper(0), copper(l) acetate, copper(l) bromide, copper(l) chloride, copper(l) iodide, copper(l) oxide, copper(ll) trifluoromethanesulfonate, copper(ll) acetate, copper(ll) bromide, copper(ll) chloride, copper(ll) iodide, copper(ll) oxide, copper(II) sulfate, tetrakis(acetonitrile)copper(I) hexafluorophosphate, and copper(II) acetylacetonate.　Amount of “copper catalyst” is 0.001 equivalent to 10 equivalent against a substrate.　The term “palladium catalyst” as used herein, includes, but not limited to, such as tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(ll) chloride, palladium(ll) acetate, palladium(ll) chloride, bis(acetonitrile)dichloropalladium(II), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0), [1,1'-bis(diphenylphosphino)ferrocene] palladium(ll) dichloride, and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II).　Amount of “palladium catalyst” is 0.001 equivalent to 10 equivalent against a substrate.　The term “leaving group” as used herein, is an atom or group (charged or uncharged) that becomes detached from an atom in what is considered to be the residual or main part of the substrate in a specified reaction. (reference: IUPAC Gold Book) Examples of leaving group include, but are not limited to fluoride, chloride, bromide, iodide, methanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate, alkoxy, ammonium salt, trialkylammonium salt, pyridinium salt, and the like.　The term “pharmaceutically acceptable salt” means a salt of a compound of the disclosure which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, generally water or oil-soluble or dispersible, and effective for their intended use. The term includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. As the compounds of the present disclosure are useful in both free base and salt form, in practice, the use of the salt form amounts to use of the base form. Lists of suitable salts are found in, e.g., S.M. Berge et al, J. Pharm. Sci, 1977, 66, 1, pp. 1-19, which is hereby incorporated by reference in its entirety. The acid salts formed with inorganic acids, e.g., but not limited to, hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids, e.g., but not limited to, succinic, maleic, formic, acetic, trifluoroacetic, propionic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.　The term “salt” as used herein, includes pharmaceutically acceptable salt and non- pharmaceutically acceptable salt.The term "pharmaceutically acceptable carrier or excipient" means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. "pharmaceutically acceptable carrier / excipient" as used in the specification and claims includes both one and more than one such excipient. Examples of “carrier” or “excipient” are referenced , but are not limited to, Processes 2021, 9(3), 470 orHandbook of Pharmaceutical Excipients: Edition 9 (2020, Edited by D.J.Goldfarb, et al.).　The term “Prot.” as used herein, is a “protecting group” includes non-reactive functional groups which selectively mask a functional group in a chemical compound in order to allow a selective reaction(s) to occur elsewhere on said chemical compound. These groups may be added or removed by methods described for each in T. W. Greene and G.M. Wuts, Protective Groups in Organic Synthesis (John Wiley & Sons, New York, 2007). Examples of such protecting group include, but are not limited to, methyl, tert-butyl, allyl, benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, methoxymethyl, 2-(trimethylsilyl)ethoxymethyl, triphenylmethyl, diphenylmethyl, dimethylphenylmethyl, tetrahydropyranyl, tert-butoxycarbonyl, benzyloxycarbonyl, methanesulfonyl, 4-toluenesulfonyl, acetyl, and benzoyl.　The suitable deprotection reagents include, but are not limited to hydrogenolytic conditions (e.g. H2, Pd / C) or acidolytic conditions (e.g. HCl, TFA).　The term “room temperature” or “rt” as used herein, means a temperature comprised between 10oC and 30oC, preferably 18 to 25oC.　The term “reacting” as used herein, refers to a chemical process or processes in which two or more reactants are allowed to come into contact with each other to effect a chemical change or transformation. For example, when reactant A and reactant B are allowed to come into contact with each other to afford a new chemical compound(s) C, A is said to have “reacted" with B to produce C.　Included within the scope of the “compounds used in the present invention” may be salts, solvates, hydrates, complexes, polymorphs, prodrugs, radiolabeled derivatives, stereoisomers and optical isomers of the compounds of formula (VI), (VII), and (IX).　The term “prodrugs” as used herein, means a compound with little or no pharmacological activity that metabolizes inside the body and converts into a pharmacologically active drug compound. Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association).　The term “animal” as used herein, includes a mammalian subject or a non-mammalian subject. Examples of suitable mammalian subject may include, without limit, human, rodents, companion animals, livestock, and primates. Suitable rodents may include, but are not limited to, mice, rats, hamsters, gerbils, and guinea pigs. Suitable companion animals may include, but are not limited to, cats, dogs, rabbits, and ferrets. Suitable livestock may include, but are not limited to, horses, goats, sheep, swine, cattle, llamas, and alpacas. Suitable primates may include, but are not limited to, chimpanzees, lemurs, macaques, marmosets, spider monkeys, squirrel monkeys, and vervet monkeys. Examples of suitable non-mammalian subject may include, without limit, birds, reptiles, amphibians, and fish. Non-limiting examples of birds include chickens, turkeys, ducks, and geese. The preferred mammalian subject is a human.　Salts and solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present invention. For example, salts of all intermediates in the preparation of compounds of formula (IX) in the present invention are included. In some cases, the salts of the intermediates are neutralized and used in the reaction or directly used in the reaction.　As used herein, the carbon at 4-position of formula (VI) may be racemic, a mixture of R / S configurations, R or S configuration.　As used herein, the carbon atom at 4-position of the chromanyloxy part of formula (VII) may be racemic, a mixture of R / S configurations, R or S configuration.　As used herein, the carbon atom at 4-position of the chromanyloxy part of formula (IX) may be racemic, a mixture of R / S configurations, R or S configuration.　In certain of the compounds represented by formulae (I) to (IX) in the present invention, there may be one or more chiral carbon atoms. In such cases, compounds of formulae (I) to (IX) exist as stereoisomers. The invention extends to all optical isomers such as stereoisomeric forms of the compounds of formulae (I) to (IX) including enantiomers, diastereoisomers and mixtures thereof, such as racemates. The different stereoisomeric forms may be separated or resolved one from the other by conventional methods or any given isomer may be obtained by conventional stereoselective or asymmetric syntheses.　Certain of the compounds represented by formulae (I) to (IX) herein can exist in various tautomeric forms and it is to be understood that the invention encompasses all such tautomeric forms and geometric isomers.　The invention also includes isotopically-labeled compounds, which are identical to those described herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, and chlorine, such as2H,3H,11C,13C,14C,18F,123I and125I. Compounds represented by formulae (I) to (IX) that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Isotopically-labeled compounds represented by formulae (I) to (IX) in the present invention, for example those into which radioactive isotopes such as3H,14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H, and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability.11C and18F isotopes are particularly useful in PET (positron emission tomography), and123I isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds represented by formulae (I) to (IX) in the invention can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples below, then substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.General Synthesis　A compound of formulae (I) to (IX) includes all geometric and tautomeric isomers. The compounds used in the present invention may be salts, solvates, hydrates, complexes, polymorphs, prodrugs, radiolabeled derivatives, stereoisomers and optical isomers of the compounds of formula (VI), (VII), and (IX). The formula (III) and formula (IV) include the tautomerism of double bond and regioisomer of E / Z.(Introduction of the nitrogen-protecting group (Prot.))　This reaction is described in detail by T. W. Greene et al., Protective Groups in Organic Synthesis, 696-926, (2007), and the disclosures of which are incorporated herein by reference. The following exemplifies a typical reaction involving the protecting group of benzyl, alkoxycarbonyl or arylsulfonyl.　Examples of the nitrogen-protecting groups include: halide or anhydride usable in the above reaction include benzyl chloride, benzyl bromide, 4-methylphenylsulfonyl chloride, phenylsulfonyl chloride or di-tert-butyl-dicarbonate; of these, benzyl bromide, 4-methylbenzenesulfonyl chloride or di-tert-butyl-dicarbonate is preferred.　Examples of suitable solvents include: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons, such as benzene, toluene and nitrobenzene; amides, such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide and hexamethylphosphoric triamide; nitriles, such as acetonitrile and benzonitrile; sulfoxides, such as dimethyl sulfoxide and sulfolane; alcohols, such as methanol, ethanol, propanol, 2-propanol, ethylene glycol and butanol; or mixed solvents thereof. Of these, N,N-dimethylformamide is preferred.　Examples of such bases include: alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal hydrides, such as lithium hydride, sodium hydride and potassium hydride; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; alkali metal carbonates, such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal hydrogencarbonates, such as lithium hydrogencarbonate, sodium hydrogencarbonate and potassium hydrogencarbonate; amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(tert-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, DBN, DABCO and DBU; alkali metal amides, such as lithium amide, sodium amide, potassium amide, lithium diisopropyl amide, potassium diisopropyl amide, sodium diisopropyl amide, lithium bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide; or mixed bases thereof. Of these, sodium hydride or triethylamine is preferred.(Deprotection of Protecting group (Prot.))　This reaction is described in detail by T. W. Greene et al., Protective Groups in Organic Synthesis, 696-926, (2007), and the disclosures of which are incorporated herein by reference. The following exemplifies a typical reaction involving the deprotecting group of benzyl.　The reaction is normally and preferably effected in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent. Examples of suitable solvents include: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; amides, such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide and hexamethylphosphoric triamide; alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol; carboxylic acid, such as acetic acid or formic acid. Of these solvents, acetic acid or tetrahydrofuran is preferred.　The reaction is carried out in the presence of a palladium catalyst under the hydrogen gas. There is no particular restriction on the nature of the palladium catalyst to be employed, and any palladium catalyst commonly used in reactions of this type may equally be used here. Examples of such palladium catalysts include: palladium metal, palladium-carbon, palladium hydroxide. Of these, palladium-carbon or palladium hydroxide is preferred. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of from about 0oC to about 1000oC. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 10 minutes to about 24 hours, will usually suffice.　The reaction is carried out in the presence or absence of a base. There is likewise no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type may equally be used here. Examples of such bases include: alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, cesium hydroxide, barium hydroxide, and potassium hydroxide; alkali metal hydrides, such as lithium hydride, sodium hydride and potassium hydride; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; alkali metal carbonates, such as lithium carbonate, sodium carbonate, cesium carbonate, and potassium carbonate; alkali metal hydrogencarbonates, such as lithium hydrogencarbonate, sodium hydrogencarbonate and potassium hydrogencarbonate; alkali metal phosphates, such as tripotassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate; amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, N,N-diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 2,6-lutidine, 4-(N,N-dimethylamino)pyridine, 2,4,6-collidine, 2,6-di(tert-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, DBN, DABCO and DBU; alkali metal amides, such as lithium amide, sodium amide, potassium amide, lithium diisopropyl amide, potassium diisopropyl amide, sodium diisopropyl amide, lithium bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide. Of these, lithium hydroxide, sodium hydroxide, tripotassium phosphate, sodium hydrogen carbonate, triethylamine, pyridine, or 2,6-lutidine is preferred.　The reaction is carried out in the presence or absence of a solvent or co-solvent mixture. There is likewise no particular restriction on the nature of the solvents used, and any solvents commonly used in reactions of this type may equally be used here. Examples of such solvents include: water; acetonitrile; alcohols such as methanol, ethanol, propanol,1-butanol, 2-methyl-2-butanol, 4-methyl-2-pentanol, cyclohexanol, and ethylene glycol; ethers such as diethyl ether, 1,2-dimethoxyethane, tert-butyl methyl ether, cyclopentyl methyl ether,dioxane, tetrahydrofuran, and 2-methyltetrahydrofuran; hydrocarbons such as hexane, heptane, cyclohexane, benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform; ketones such as acetone and methylethylketone; amides such as dimethylformamide, dimethylacetamide, and N-methylpyrrolidone; sulfoxides such as dimethylsulfoxide and sulfolane; esters such as ethyl acetate, and acids such as formic acid, acetic acid and trifluoroacetic acid. Preferably examples of solvents which can be mixed with one or more solvents selected from: water; acetonitrile; alcohols such as methanol, ethanol, and propanol; ethers such as diethyl ether, tert-butyl methyl ether, dioxane, and tetrahydrofuran; hydrocarbons such as hexane, heptane, cyclohexane, benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ketones such as acetone and methylethylketone; amides such as dimethylformamide and dimethylacetamide; sulfoxides such as dimethylsulfoxide and sulfolane; and esters such as ethyl acetate. In general, solvents are used for dissolving and diluting substrates, but solvents are also used for extraction, washing, purification by column chromatography, HPLC, and recrystallization.　The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of from about 0oC to about 200oC. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 1 minutes to about 72 hours will usually suffice.　The salts of the compounds used in the present invention may be neutralized and used in the reaction or directly used in the reaction.　All of the compounds can be prepared by the procedures described in the general methods presented below or by the specific methods described in the Example part, or by routine modifications thereof. The present invention also encompasses any one or more of these processes for preparing the compound of formula (V), in addition to any novel intermediates used therein.　In the following general methods, descriptors (R1, R2, Prot., and Hal.) are as previously defined for the compound of the formula (III) unless otherwise stated. All starting materials in the following general syntheses may be commercially available. In the following general methods, starting materials and synthetic compounds could form salt with an acid or a base. If the starting material is formed salt, the reaction can also be carried out in the presence of excess base or neutralized with acid or base before using the reaction.<Scheme 1>　In Step-1 of Scheme 1, a compound of formula (III) can be prepared by a reaction of a compound of formula (I) with a mixture of compound of formula (II) and a suitable reagent in the presence of a suitable base in an inert solvent.　Examples of a suitable reagent include, but not limited to, Tf2O, Ms2O, MsCl, oxalyl chloride, TsCl, PCl5, POCl3, and SOCl2.　Examples of a suitable base include, but not limited to, triethylamine, pyridine, 2,6-lutidine, 2,4,6-collidine, N-methylmorpholine, and N,N-diisopropylethylamine.　Examples of suitable solvent include, such as dichloromethane, THF, 1,4-dioxane, DMF, DMSO, MeCN, DMA, NMP, and toluene.　The reaction can be carried out at a temperature of from about -20 to 200oC, more preferably from about 0 to 40oC.　Reaction times are, in general, from about 30 minutes to 48 hours, more preferably from about 1 hour to 24 hours.　The molar ratio of a compound formula (I), compound (II), a suitable reagent, and a suitable base is 1:0.7:1:1.5 to 1:3:6:12, but is not limited to this.　In Step-2 of Scheme 1, a compound of formula (IV) can be prepared by halogenation of a compound of formula (III). The halogenation is conducted by reacting a compound of formula (III) with a halogenating reagent in a suitable solvent.　Examples of a halogenating reagent include, but not limited to, such as N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, N-chlorophthalimide, N-bromophthalimide, N-iodophthalimide, N-chlorosaccharin, N-bromosaccharin, N-iodosaccharin, 1,3-dichloro-5,5-dimethylhydantoin, 1,3-dibromo-5,5-dimethylhydantoin, 1,3-diiodo-5,5-dimethylhydantoin, sodium dichloroisocyanurate, dibromoisocyanuric acid, trichloroisocyanuric acid, chlorine, bromine, and iodine.　Examples of suitable solvent include, but not limited to, such as dichloromethane, THF, 1,4-dioxane, DMF, DMSO, MeCN, DMA, AcOH, and NMP.　The reaction can be carried out at a temperature of from about -20 to 200oC, more preferably from about 0 to 80oC.　Reaction times are, in general, from about 30 minutes to 48 hours, more preferably from about 1 hour to 24 hours.　The molar ratio of a compound formula (III), and a halogenating reagent is 1:0.5 to 1:10, but is not limited to this.<Scheme 2>　In Scheme 2, a compound of formula (V) can be prepared from a compound of formula (IV) by a cyclization and hydroxylation in the presence of a suitable copper catalyst, a suitable ligand, and a suitable base in an inert solvent.　Example of a suitable copper catalyst include, but not limited to, such as copper(0), copper(l) acetate, copper(l) bromide, copper(l) chloride, copper(l) iodide, copper(l) oxide, copper(ll) trifluoromethanesulfonate, copper(ll) acetate, copper(ll) bromide, copper(ll) chloride, copper(ll) iodide, copper(ll) oxide, copper(II) sulfate, tetrakis(acetonitrile)copper(I) hexafluorophosphate, and copper(II) acetylacetonate.　Examples of a suitable ligand include, but not limited to, such as ethane-1,2-diamine, N1,N2-dimethylethane-1,2-diamine, N1,N1,N2,N2-tetramethylethane-1,2-diamine, cyclohexane-1,2-diamine, N1,N2-dimethylcyclohexane-1,2-diamine, quinolin-8-ol, 1,10-phenanthroline, proline, oxalic diamide derivatives such as N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxalamide, N1,N2-bis(1-naphthalenylmethyl)ethanediamide, N,N′-dibenzyloxamide, N1,N2-bis(2,4,6-trimethoxyphenyl)ethanediamide, and N,N′-bis(2-phenylethyl)ethanediamide, 6-hydroxypicolinamide derivatives such asN-(2,6-dimethylphenyl)-6-hydroxypicolinamide, 6-hydroxy-N-(2,4,6-trimethoxyphenyl)picolinamide, 6-hydroxy-N-(2-methylnaphthalen-1-yl)picolinamide, 6-hydroxy-N-(naphthalen-1-yl)picolinamide, N-([1,1'-biphenyl]-2-yl)-6-hydroxypicolinamide, 6-hydroxy-N-(2-(trifluoromethyl)phenyl)picolinamide, 6-hydroxy-N-(o-tolyl)picolinamide, 6-hydroxy-N-phenylpicolinamide, 6-hydroxy-N-(thiophen-2-ylmethyl)picolinamide, 6-hydroxy-N-(naphthalen-1-ylmethyl)picolinamide, N-(2,6-diisopropylphenyl)-6-hydroxypicolinamide, N-(2,6-difluorophenyl)-6-hydroxypicolinamide, N-(2,6-dimethoxyphenyl)-6-hydroxypicolinamide, and 6-hydroxy-N-(4-hydroxy-2,6-dimethylphenyl)picolinamide, 4-hydroxyquinoline-2-carboxamide derivatives such as 4-hydroxy-N-phenylquinoline-2-carboxamide, and N-(2,6-dimethylphenyl)-4-hydroxyquinoline-2-carboxamide, and 6-hydroxypicolinohydrazide derivatives such as N-(1,3-dimethyl-9H-carbazol-9-yl)-6-hydroxypicolinamide, N-(2,7-dimethyl-9H-carbazol-9-yl)-6-hydroxypicolinamide, and N-(2,7-di-tert-butyl-9H-carbazol-9-yl)-6-hydroxypicolinamide.　Examples of a suitable base include, but not limited to, such as sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, tripotassium phosphate, cesium carbonate, potassium carbonate, and sodium carbonate.　Examples of suitable solvent or co-solvent mixture include, but not limited to, such as water, dichloromethane, THF, 1,4-dioxane, DMF, DMSO, sulfolane, MeCN, DMA, NMP, and toluene.　The reaction can be carried out at a temperature of from about -20 to 200oC, more preferably from about 60 to 150oC. Reaction times are, in general, from about 30 minutes to 48 hours, more preferably from about 3 hours to 24 hours.　The molar ratio of a compound formula (IV), a suitable copper catalyst, a suitable ligand, and a suitable base is 1:0.01:0.01:1 to 1:5:5:30, but is not limited to this.<Scheme 3>　In Scheme 3, a compound of formula (VIII) can be prepared from a compound of formula (IV) by a cyclization in the presence of a suitable copper catalyst or a suitable palladium catalyst, a suitable ligand, and a suitable base in an inert solvent.　Example of a suitable copper catalyst include, but not limited to, such as copper(0), copper(l) acetate, copper(l) bromide, copper(l) chloride, copper(l) iodide, copper(l) oxide, copper(ll) trifluoromethanesulfonate, copper(ll) acetate, copper(ll) bromide, copper(ll) chloride, copper(ll) iodide, copper(ll) oxide, copper(II) sulfate, tetrakis(acetonitrile)copper(I) hexafluorophosphate, and copper(II) acetylacetonate.　Example of a suitable palladium catalyst include, but not limited to, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(ll) chloride, palladium(ll) acetate, palladium(ll) chloride, bis(acetonitrile)dichloropalladium(II), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0), [1,1'-bis(diphenylphosphino)ferrocene] palladium(ll) dichloride, and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II).　Examples of a suitable copper ligand include, but not limited to, such as ethane-1,2-diamine, N1,N2-dimethylethane-1,2-diamine, N1,N1,N2,N2-tetramethylethane-1,2-diamine, cyclohexane-1,2-diamine, N1,N2-dimethylcyclohexane-1,2-diamine, quinolin-8-ol, 1,10-phenanthroline, proline, oxalic diamide derivatives such as N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxalamide, N1,N2-bis(1-naphthalenylmethyl)ethanediamide, N,N′-dibenzyloxamide, N1,N2-bis(2,4,6-trimethoxyphenyl)ethanediamide, and N,N′-bis(2-phenylethyl)ethanediamide, 6-hydroxypicolinamide derivatives such asN-(2,6-dimethylphenyl)-6-hydroxypicolinamide, 6-hydroxy-N-(2,4,6-trimethoxyphenyl)picolinamide, 6-hydroxy-N-(2-methylnaphthalen-1-yl)picolinamide, 6-hydroxy-N-(naphthalen-1-yl)picolinamide, N-([1,1'-biphenyl]-2-yl)-6-hydroxypicolinamide, 6-hydroxy-N-(2-(trifluoromethyl)phenyl)picolinamide, 6-hydroxy-N-(o-tolyl)picolinamide, 6-hydroxy-N-phenylpicolinamide, 6-hydroxy-N-(thiophen-2-ylmethyl)picolinamide, 6-hydroxy-N-(naphthalen-1-ylmethyl)picolinamide, N-(2,6-diisopropylphenyl)-6-hydroxypicolinamide, N-(2,6-difluorophenyl)-6-hydroxypicolinamide, N-(2,6-dimethoxyphenyl)-6-hydroxypicolinamide, and 6-hydroxy-N-(4-hydroxy-2,6-dimethylphenyl)picolinamide, 4-hydroxyquinoline-2-carboxamide derivatives such as 4-hydroxy-N-phenylquinoline-2-carboxamide, and N-(2,6-dimethylphenyl)-4-hydroxyquinoline-2-carboxamide, and 6-hydroxypicolinohydrazide derivatives such as N-(1,3-dimethyl-9H-carbazol-9-yl)-6-hydroxypicolinamide, N-(2,7-dimethyl-9H-carbazol-9-yl)-6-hydroxypicolinamide, and N-(2,7-di-tert-butyl-9H-carbazol-9-yl)-6-hydroxypicolinamide.Further, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), triphenylphosphine, tri-tert-butylphosphine, 1,1'-bis(diphenylphosphino)ferrocene, tri-2-furylphosphine, tri-o-tolylphosphine, triphenylarsine, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), 2-(dichlorohexylphosphino)biphenyl (CyJohnPhos), 2-(dicyclohexylphosphino)-2'-(dimethylamino)biphenyl (DavePhos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (tBuXPhos), and 2-(di-tert-butylphosphino)biphenyl (JohnPhos).　Examples of a suitable base include, but not limited to, such as sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, tripotassium phosphate, cesium carbonate, potassium carbonate, sodium carbonate, and sodium bicarbonate.　Examples of suitable solvent or co-solvent mixture include, but not limited to, such as water, dichloromethane, THF, 1,4-dioxane, DMF, DMSO, MeCN, DMA, NMP, and toluene.　The reaction can be carried out at a temperature of from about -20 to 200oC, more preferably from about 60 to 130oC. Reaction times are, in general, from about 30 minutes to 48 hours, more preferably from about 3 hours to 24 hours.　The molar ratio of a compound formula (IV), a suitable copper catalyst, a suitable ligand, and a suitable base is 1:0.01:0.01:1 to 1:5:5:10, but is not limited to this.<Scheme 4>　In Scheme 4, a compound of formula (V) can be prepared from a compound of formula (VIII) by a hydroxylation in the presence of a suitable copper catalyst, a suitable ligand, and a suitable base in an inert solvent.　Example of a suitable copper catalyst include, but not limited to, such as copper(0), copper(l) acetate, copper(l) bromide, copper(l) chloride, copper(l) iodide, copper(l) oxide, copper(ll) trifluoromethanesulfonate, copper(ll) acetate, copper(ll) bromide, copper(ll) chloride, copper(ll) iodide, copper(ll) oxide, copper(II) sulfate, tetrakis(acetonitrile)copper(I) hexafluorophosphate, and copper(II) acetylacetonate.　Examples of a suitable ligand include, but not limited to, such as ethane-1,2-diamine, N1,N2-dimethylethane-1,2-diamine, N1,N1,N2,N2-tetramethylethane-1,2-diamine, cyclohexane-1,2-diamine, N1,N2-dimethylcyclohexane-1,2-diamine, quinolin-8-ol, 1,10-phenanthroline, proline, oxalic diamide derivatives such as N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxalamide, N1,N2-bis(1-naphthalenylmethyl)ethanediamide, N,N′-dibenzyloxamide, N1,N2-bis(2,4,6-trimethoxyphenyl)ethanediamide, and N,N′-bis(2-phenylethyl)ethanediamide, 6-hydroxypicolinamide derivatives such asN-(2,6-dimethylphenyl)-6-hydroxypicolinamide, 6-hydroxy-N-(2,4,6-trimethoxyphenyl)picolinamide, 6-hydroxy-N-(2-methylnaphthalen-1-yl)picolinamide, 6-hydroxy-N-(naphthalen-1-yl)picolinamide, N-([1,1'-biphenyl]-2-yl)-6-hydroxypicolinamide, 6-hydroxy-N-(2-(trifluoromethyl)phenyl)picolinamide, 6-hydroxy-N-(o-tolyl)picolinamide, 6-hydroxy-N-phenylpicolinamide, 6-hydroxy-N-(thiophen-2-ylmethyl)picolinamide, 6-hydroxy-N-(naphthalen-1-ylmethyl)picolinamide, N-(2,6-diisopropylphenyl)-6-hydroxypicolinamide, N-(2,6-difluorophenyl)-6-hydroxypicolinamide, N-(2,6-dimethoxyphenyl)-6-hydroxypicolinamide, and 6-hydroxy-N-(4-hydroxy-2,6-dimethylphenyl)picolinamide, 4-hydroxyquinoline-2-carboxamide derivatives such as 4-hydroxy-N-phenylquinoline-2-carboxamide, and N-(2,6-dimethylphenyl)-4-hydroxyquinoline-2-carboxamide, and 6-hydroxypicolinohydrazide derivatives such as N-(1,3-dimethyl-9H-carbazol-9-yl)-6-hydroxypicolinamide, N-(2,7-dimethyl-9H-carbazol-9-yl)-6-hydroxypicolinamide, and N-(2,7-di-tert-butyl-9H-carbazol-9-yl)-6-hydroxypicolinamide.　Examples of a suitable base include, but not limited to, such as sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, tripotassium phosphate, cesium carbonate, and potassium carbonate.　Examples of suitable solvent or co-solvent mixture include, but not limited to, such as water, dichloromethane, THF, 1,4-dioxane, DMF, DMSO, MeCN, DMA, NMP, and toluene.　The reaction can be carried out at a temperature of from about -20 to 200oC, more preferably from about 60 to 130oC. Reaction times are, in general, from about 30 minutes to 48 hours, more preferably from about 3 hours to 24 hours.　The molar ratio of a compound formula (VIII), a suitable copper catalyst, a suitable ligand, and a suitable base is 1:0.01:0.01:1 to 1:5:5:30, but is not limited to this.Examples　Throughout the instant application, the following abbreviations are used with the following meanings:Ac AcetylBn BenzylDABCO 1,4-diazabicyclo[2.2.2]octaneDBN 1,5-diazabicyclo[4.3.0]non-5-eneDBU 1,8-diazabicyclo[5.4.0]undec-7-eneDCM　 DichloromethaneDMA N,N-DimethylacetamideDMF N,N-DimethylformamideDMSO　Dimethyl sulfoxideESI Electrospray ionizationEtOAc Ethyl acetateHPLC High-Performance liquid chromatographyLC Liquid chromatographyLG Leaving groupMeCN AcetonitrileMeOH MethanolMHz　　MegahertzMS Mass spectrometryMs MesylMs2O　 Methanesulfonic anhydrideNMR Nuclear magnetic resonanceNMP N-methylpyrrolidonert　　　 Room temperaturetBuOMe tert-Butyl Methyl EtherTEA TriethylamineTf TrifluoromethanesulfonylTFA　　 Trifluoroacetic acidTf2O　　Trifluoromethanesulfonic anhydrideTHF　　TetrahydrofuranTs TosylUPLC Ultra performance liquid chromatographyUV　　 Ultraviolet　Mass spectral data (ESI) are obtained by Waters ACQUITY UPLC H-Class with QDa mass spectrometer and ACQUITY PDA detector. NMR data are determined by 400 MHz (JEOL JNM-ECZ400S) using deuterated chloroform (99.8% D) or dimethyl sulfoxide (99.9% D) as solvent unless indicated otherwise, relative to tetramethylsilane (TMS) as internal standard in parts per million (ppm), and each peak has a margin of error of + / - 0.05 (ppm); conventional abbreviations used are: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, etc. Chemical symbols have their usual meanings; M (mol(s) per liter), L (liter(s)), mL (milliliter(s)), g (gram(s)), mg (milligram(s)), mol (moles), mmol (millimoles).　The invention is illustrated in the following non-limiting examples in which, unless stated otherwise: all reagents are commercially available, all operations are carried out at room or ambient temperature, that is, in the range of about 18-25oC; reactions are monitored by LC-MS and reaction times are given for illustration only; the structure and purity of all isolated compounds are assured by at least one of the following techniques: mass spectrometry or NMR. Yields are given for illustrative purposes only. Column chromatography is carried out using Biotage SNAP KP-Sil, Biotage SNAP Isolute NH2. If necessary, the residual metal in reaction can be removed by using an appropriate scavenger for metal removal. The purification of compounds using reverse phase HPLC is performed by the following apparatus and conditions.HPLC:Apparatus: Waters MS-trigger AutoPurification (registered trademark) systemColumn: Waters XBridge C8, 19 mm x 50 mm, 5 micrometer particle or Waters XBridge C18, 19 mm x 50 mm, 5 micrometer particleMobile phase: (A) 0.05% (v / v) ammonia aqueous solution, (B) MeCNFlow rate: 20 mL / min.Gradient: A / B (95 / 5) to A / B (5 / 95) in 5 min.　Each prepared compound is generally named by ChemDraw (version 19.1, PerkinElmer Informatics).Synthesis part　The invention is further described in detail with examples below, but this does not limit the present invention.　Compound 1, Compound 2, Compound 5, and Compound 6 include all geometric and tautomeric isomers.Example 1 (Synthesis of benzimidazole intermediate (BI): Compound 3)Compound 3:1-benzyl-4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide<Step-1>: Synthesis of 4-((1-(benzylamino)ethylidene)amino)-N,N-dimethylbenzamide (Compound 2)　To a solution of N-benzylacetamide (4.01 g, 26.9 mmol), pyridine (4.78 mL, 59.1 mmol) in DCM (100 mL) is added Tf2O (8.34 g, 29.6 mmol) at 0oC under nitrogen atmosphere. The mixture is stirred at rt for 2 hours. Then, to the reaction mixture is added 4-amino-N,N-dimethylbenzamide (4.41 g, 26.9 mmol), pyridine (4.78 mL, 59.1 mmol) at rt. The mixture is stirred at rt for 3 hours under nitrogen atmosphere. After completion of the reaction, to the mixture is added saturated aqueous sodium bicarbonate (150 mL) and the mixture is stirred at rt for 20 minutes. The organic layer is separated. The water layer is extracted with DCM (50 mL). The combined organic layer is dried over sodium sulfate, filtered and concentrated to give Compound 2 (10.1 g) as a crude oil. The crude oil is used for the next step without further purification.1H-NMR (400 MHz, CDCl3) delta 7.40-7.26 (7H, m), 6.79 (2H, d, J = 7.8 Hz), 4.73 (1H, br s), 4.53 (2H, d, J = 4.1 Hz), 3.05 (6H, br s), 1.81 (3H, s).MS (ESI) m / z: 296.4 (M+H)+.<Step-2>: Synthesis of 4-(N'-benzylacetimidamido)-3,5-dibromo-N,N-dimethylbenzamide (Compound 1)　To a solution of 4-((1-(benzylamino)ethylidene)amino)-N,N-dimethylbenzamide (Compound 2, prepared in Step-1 of Example 1, 10.1 g of crude oil, theoretically 26.9 mmol) in acetonitrile (80 mL) is added N-bromosuccinimide (10.05 g, 56.5 mmol) at 0oC. The mixture is stirred at rt for 2 hours. After completion of the reaction, the reaction mixture is concentrated. The residual solid is purified by column chromatography on amino-gel eluting with 0-50% EtOAc in hexane. After the solvent is evaporated, to the residue in EtOAc (15 mL) is slowly added heptane (30 mL) at rt. A precipitate is appeared. The precipitate is collected and dried in vacuo to give Compound 1 (7.96 g, 65.3% yield from 4-amino-N,N-dimethylbenzamide) as a solid.1H-NMR (400 MHz, CDCl3) delta 7.59 (2H, s), 7.48-7.42 (2H, m), 7.37-7.32 (2H, m), 7.32-7.25 (1H, m), 4.92 (1H, br s), 4.66 (2H, d, J = 4.6 Hz), 3.05 (6H, br s), 1.75 (3H, s).MS (ESI) m / z: 454.1 (M+H)+.<Step-3>: Synthesis of 1-benzyl-4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide (Compound 3)　A mixture of Compound 1 (200 mg, 0.441 mmol), N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxalamide (29 mg, 0.088 mmol, purchased from Angene or Combi-blocks), Cu(OAc)2(16 mg, 0.088 mmol), and 4 mol / L LiOH aqueous solution (0.44 mL, 1.765 mmol) in DMSO (0.44 mL) is stirred in a sealed tube at 110oC for 13 hours. After completion of the reaction, to the mixture is added saturated aqueous ammonium chloride. The resultant mixture is extracted with DCM-MeOH (5:1, 3 mL, 3 times). The combined organic layer is concentrated. The resultant residue is purified by column chromatography on silica-gel eluting with 0-5% MeOH in DCM to give Compound 3 (51 mg, 37.4% yield) as a solid.1H-NMR (400 MHz, DMSO-d6) delta 9.99 (1H, s), 7.37-7.24 (3H, m), 7.12 (2H, d, J = 7.8 Hz), 6.96 (1H, s), 6.55 (1H, s), 5.45 (2H, s), 2.90 (6H, br s), 2.52 (3H, s).MS (ESI) m / z: 310.4 (M+H)+.Alternative reaction from Compound 1 to Compound 3 using 6-hydroxy-N-(4-hydroxy-2,6-dimethylphenyl)picolinamide as a ligandPreparation of 6-hydroxy-N-(4-hydroxy-2,6-dimethylphenyl)picolinamide as a ligandTo a solution of 6-hydroxypicolinic acid (2.00 g, 14.38 mmol), 4-amino-3,5-dimethylphenol (2.07 g, 15.10 mmol), TEA (4.01 mL, 28.80 mmol) in THF (10 mL) is added propylphosphonic acid anhydride (greater than or equal to 50 wt.% in EtOAc, 10.8 mL) at 0oC. The mixture is stirred at rt for 2 hours. To the mixture is added 2 mol / L NaOH and water (adjusted to pH4-6). The mixture is extracted with DCM. The organic layer is dried over sodium sulfate, filtered and concentrated. The residue is suspended in MeOH-water (30 mL-40 mL). The mixture is stirred at rt for 3 days. The precipitate is collected and washed withtBuOMe. The solid is dried in vacuo to give 6-hydroxy-N-(4-hydroxy-2,6-dimethylphenyl)picolinamide (1.02 g, 27.5% yield) as a solid.1H-NMR (400 MHz, DMSO-d6) delta 11.12 (1H, brs), 9.57 (1H, s), 9.25 (1H, s), 7.72 (1H, t, J = 7.3 Hz), 7.29 (1H, s), 6.75 (1H, d, J = 8.2 Hz), 6.51 (2H,s), 2.07 (6H, s).MS (ESI) m / z: 259.3 (M+H)+.A mixture of Compound 1 (5.00 g, 11.03 mmol), 6-hydroxy-N-(4-hydroxy-2,6-dimethylphenyl)picolinamide (399 mg, 1.55 mmol), CuI (147 mg, 0.772 mmol), and tripotassium phosphate (14.05 g, 66.2 mmol) in DMSO (10 mL) and water (10 mL) is degassed with nitrogen three times. The mixture is stirred at 80oC for 1 day under nitrogen atmosphere. Further, to the reaction mixture is added 6-hydroxy-N-(4-hydroxy-2,6-dimethylphenyl)picolinamide (285 mg, 1.10 mmol) and CuI (105 mg, 0.552 mmol) at rt. The mixture is stirred at 80oC for 7.5 hours under nitrogen atmosphere. After completion of the reaction, the mixture is cooled to rt and poured into saturated aqueous ammonium chloride (150 mL). A precipitate is appeared. The resultant mixture is stirred at rt for 1 day. The precipitate is collected and dried in vacuo. The solid (3.80 g) is suspended in DCM (38 mL). The mixture is filtered by using Celite pad and the cake is rinsed with DCM (100 mL). The filtrate is concentrated to give a brown solid (3.42 g). The solid (3.42 g) is suspended in EtOAc (34 mL) and stirred at 80oC for 3 hours. After cooled to rt, the solid is collected and dried to give Compound 3 (2.65 g, 78.0% yield) as a solid.1H-NMR (400 MHz, DMSO-d6) delta 9.94 (1H, brs ), 7.38-7.21 (3H, m), 7.12 (2H, d, J = 7.3 Hz), 6.96 (1H, s), 6.53 (1H, s), 5.44 (2H, s), 2.90 (6H, s), 2.51 (3H, s).MS (ESI) m / z: 310.2 (M+H)+.Example 2 (Synthesis of benzimidazole intermediate (BI): Compound 4)Compound 4:1-benzyl-4-bromo-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide　A mixture of Compound 1 (300 mg, 0.662 mmol), N1,N2-dimethylethane-1,2-diamine (5.8 mg, 0.066 mmol), CuI (12 mg, 0.066 mmol), and tripotassium phosphate (281 mg, 1.324 mmol) in DMSO (0.66 mL) is stirred in a sealed tube at 110oC for 1 day. After completion of the reaction, to the mixture is added 10% aqueous ammonia (3 mL). The resultant mixture is extracted with EtOAc (3 mL, 2 times). The combined organic layer is concentrated. The resultant residue is purified by column chromatography on silica-gel eluting with 50% EtOAc in DCM to give Compound 4 (205 mg, 83% yield) as a gum.1H-NMR (400 MHz, CDCl3) delta 7.50 (1H, d, J = 1.4 Hz), 7.35-7.28 (4H, m), 7.05-7.01 (2H, m), 5.32 (2H, s), 3.01 (3H, br s), 2.96 (3H, br s), 2.64 (3H, s).MS (ESI) m / z: 372.3 (M+H)+.Example 3 (Synthesis of benzimidazole intermediate (BI): Compound 7)Compound 7:1-benzyl-4-hydroxy-2-methyl-1H-benzo[d]imidazole-6-carboxylic acid<Step-1>: Synthesis of methyl 4-((1-(benzylamino)ethylidene)amino)benzoate (Compound 6)　To a solution of N-benzylacetamide (1.50 g, 10.05 mmol), 2,6-lutidine (2.34 mL, 20.11 mmol) in DCM (30 mL) is added Tf2O (3.12 g, 11.06 mmol) at 0oC under nitrogen atmosphere. The mixture is stirred at rt for 1 hour. Then, to the reaction mixture is added methyl 4-aminobenzoate (1.67 g, 11.06 mmol) at rt. The mixture is stirred at rt for 1 day under nitrogen atmosphere. After completion of the reaction, to the mixture is added saturated aqueous sodium bicarbonate and stirred at rt for 20 minutes. The organic layer is separated. The water layer is extracted with DCM. The combined organic layer is dried over sodium sulfate, filtered and concentrated to give Compound 6 (5.21 g) as a crude oil. The crude oil is used for the next step without further purification.MS (ESI) m / z: 283.3 (M+H)+.<Step-2>: Synthesis of methyl 4-(N'-benzylacetimidamido)-3,5-dibromobenzoate (Compound 5)　To a solution of methyl 4-((1-(benzylamino)ethylidene)amino)benzoate (Compound 6, prepared in Step-1 of Example 3, 5.21 g of crude oil, theoretically 10.06 mmol) in acetonitrile (30 mL) is added N-bromosuccinimide (7.16 g, 40.2 mmol) at rt. The mixture is stirred at rt for 2 hours. After completion of the reaction, the reaction mixture is concentrated. The residual solid is purified by column chromatography on silica-gel eluting with 0-15% EtOAc in hexane. After the solvent is evaporated, the residual solid is suspended in diisopropyl ether. The precipitate is collected and dried in vacuo to give Compound 5 (1.12 g, 25.3% yield from methyl 4-aminobenzoate) as a solid.1H-NMR (400 MHz, CDCl3) delta 8.19 (2H, s), 7.45 (2H, d, J = 7.3 Hz), 7.37 (2H, t, J = 7.3 Hz), 7.31 (1H, d, J = 7.3 Hz), 4.66 (2H, d, J = 4.6 Hz), 3.90 (3H, s), 2.91 (1H, br s), 1.77 (3H, br s).MS (ESI) m / z: 441.1 (M+H)+.<Step-3>: Synthesis of 1-benzyl-4-hydroxy-2-methyl-1H-benzo[d]imidazole-6-carboxylic acid (Compound 7)　A mixture of Compound 5 (50 mg, 0.114 mmol), N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxalamide (7.5 mg, 0.023 mmol), CuSO4(3.6 mg, 0.023 mmol), and 4 mol / L LiOH aqueous solution (0.23 mL, 0.909 mmol) in DMSO (0.23 mL) is stirred in a sealed tube at 110oC for 5 hours. After completion of the reaction, to the mixture is added 10% aqueous citric acid solution. A precipitate is appeared and collected. The solid is purified by reverse phase HPLC to give Compound 7 (4.1 mg, 12.8% yield) as a solid.1H-NMR (400 MHz, DMSO-d6) delta 9.99 (1H, br s), 7.52 (1H, s), 7.38-7.22 (3H, m), 7.16 (1H, s), 7.09 (2H, d, J = 7.3 Hz), 5.49 (2H, s), 2.54 (3H, s). (The proton signal of the -COOH is not observed)MS (ESI) m / z: 283.3 (M+H)+.Example 4 (Scale-up Synthesis of Compound 3 (BI))Compound 3:1-benzyl-4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide<Step-1>: Synthesis of 4-((1-(benzylamino)ethylidene)amino)-N,N-dimethylbenzamide (Compound 2)　To a solution of N-benzylacetamide (18.2 g, 122 mmol), pyridine (21.7 mL, 268 mmol) in DCM (200 mL) is added dropwise Tf2O (22.0 mL, 134 mmol) over 10 minutes at 0oC under nitrogen atmosphere. The mixture is stirred at rt for 2 hours. Then, to the reaction mixture is added 4-amino-N,N-dimethylbenzamide (20.0 g, 122 mmol), pyridine (21.7 mL, 268 mmol) at 0oC. The mixture is stirred at rt for 3 hours under nitrogen atmosphere. After completion of the reaction, to the mixture is added saturated aqueous sodium bicarbonate (200 mL) and stirred at rt for 20 minutes. The organic layer is separated. The water layer is extracted with DCM (50 mL). The combined organic layer is dried over sodium sulfate, filtered and concentrated to give Compound 2 (58.7 g) as a crude oil. The crude oil is used for the next step without further purification.1H-NMR (400 MHz, CDCl3) delta 7.30-7.26 (7H, m), 7.04 (2H, t, J = 7.8 Hz), 4.72 (1H, br s), 4.57 (2H, br s), 3.11-2.96 (6H, m), 2.13 (3H, s).MS (ESI) m / z: 296.4 (M+H)+.<Step-2>: Synthesis of 4-(N'-benzylacetimidamido)-3,5-dibromo-N,N-dimethylbenzamide (Compound 1)　To a solution of 4-((1-(benzylamino)ethylidene)amino)-N,N-dimethylbenzamide (Compound 2, prepared in Step-1 of Example 4, 58.7 g of crude oil, theoretically 122 mmol) in acetonitrile (300 mL) is added 1,3-Dibromo-5,5-dimethylhydantoin (36.6 g, 128 mmol) at 0oC. The mixture is stirred at rt for 2 hours. After completion of the reaction, the reaction mixture is concentrated. To the residue is added 2 mol / L NaOH aqueous solution (150 mL) andtBuOMe / EtOAc / MeCN (1:1:1, 660 mL). The organic layer is separated. The water layer is extracted withtBuOMe (110 mL). The combined organic layer is washed with brine (110 mL). The organic layer is dried over sodium sulfate, filtered and concentrated to give crude oil (58.9 g). The crude oil (58.9 g) is through an amino-gel (Chromatorex: Registered Trademark) pad (75 g, eluted with EtOAc (1250 mL)). The filtrate is concentrated. The residue was dissolved in EtOAc (100 mL). To the solution is slowly added heptane (400 mL) at rt. A precipitate is appeared. The suspension is stirred at rt for 1 day. The precipitate is collected, washed with 20% EtOAc in heptane (100 mL), and dried in vacuo to give Compound 1 (42.7 g, 77.0% yield from 4-amino-N,N-dimethylbenzamide) as a solid.1H-NMR (400 MHz, CDCl3) delta 7.59 (2H, s), 7.45 (2H, d, J = 7.3 Hz), 7.36 (2H, t, J = 7.3 Hz), 7.30 (1H, d, J = 7.3 Hz), 4.89 (1H, br s), 4.66 (2H, d, J = 4.6 Hz), 3.05 (6H, br s), 1.76 (3H, s).MS (ESI) m / z: 454.1 (M+H)+.<Step-3>: Synthesis of 1-benzyl-4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide (Compound 3)　A mixture of Compound 1 (20.00 g, 44.1 mmol), N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxalamide (1.45 g, 4.41 mmol), CuSO4(704 mg, 4.41 mmol), and LiOH・H2O (11.11 g, 265 mmol) in DMSO (80 mL) and water (20 mL) is degassed with nitrogen five times. The mixture is stirred at 120oC for 3 hours under nitrogen atmosphere. After completion of the reaction, to the mixture is cooled to rt and added 2 mol / L NaOH aqueous solution (10 mL). The mixture is washed withtBuOMe (50 mL, 3 times). The water layer is poured into saturated aqueous ammonium chloride (800 mL) and water (100 mL). A precipitate is appeared. The resultant mixture is stirred at rt for 3 days. The precipitate is collected and dried in vacuo. The solid (13.17 g) is suspended in DCM (86 mL). The mixture is filtered by using Celite pad and the cake is rinsed with DCM (100 mL). The filtrate is concentrated to give a brown solid (11.12 g). The solid (11.12 g) is suspended in EtOAc (111 mL) and stirred at 80oC for 2 hours. After cooled to rt, the solid is collected and dried to give Compound 3 (8.01 g, 58.7% yield) as a solid.1H-NMR (400 MHz, DMSO-d6) delta 9.94 (1H, brs ), 7.38-7.20 (3H, m), 7.12 (2H, d, J = 6.9 Hz), 7.01 (1H, brs), 6.50 (1H, brs), 5.46 (2H, s), 2.90 (6H, s), 2.50 (3H, s).MS (ESI) m / z: 310.2 (M+H)+.　All publications, including but not limited to, issued patents, patent applications, and journal articles, cited in this application are each herein incorporated by reference in their entirety. Although the invention has been described above with reference to the disclosed embodiments, those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention. It should be understood that various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims.　The present invention relates to a production method of benzimidazole derivatives useful as pharmaceutical products, particularly an acid secretion inhibitor, and a production method of an intermediate used for this method, and a novel intermediate. Especially, the present invention relates to a production method of tegoprazan.

Claims

1. A method of preparing a compound represented by the formula (IX) or a pharmaceutically acceptable salt thereof, comprising steps of: (1) reacting a compound represented by the formula (I) with a compound represented by the formula (II) to give a compound represented by the formula (III); (2) halogenating of the compound represented by the formula (III) to give a compound represented by the formula (IV); (3) cyclizing the compound represented by the formula (IV) to give a compound represented by the formula (V); and (4) reacting the compound represented by the formula (V) with a compound represented by the formula (VI) to give a compound represented by the formula (VII); wherein R1is -N(C1-6alkyl)(C1-6alkyl), where two (C1-6alkyl)s may form a 4 to 6 membered heterocyclic group, -O-C1-6alkyl, or hydroxyl; R2is C1-6alkyl; R3and R4are independently C1-6alkyl or halogen; and Prot. is a protecting group.

2. A method of preparing a compound represented by the formula (III) or a salt thereof, comprising a step of reacting a compound represented by the formula (I) with a compound represented by the formula (II) to give the compound represented by the formula (III) or a salt thereof, wherein R1and R2are as defined in claim 1;and Prot. is a protecting group.

3. A method of preparing a compound represented by the formula (IV) or a salt thereof, comprising a step of halogenating a compound represented by the formula (III) to give a compound represented by the formula (IV), wherein R1and R2are as defined in claim 1;and Prot. is a protecting group.

4. A method of preparing a compound represented by the formula (V) or a salt thereof; comprising a step of cyclizing a compound represented by the formula (IV) to give the compound represented by the formula (V), wherein R1and R2are as defined in claim 1;and Prot. is a protecting group.

5. A method of preparing a compound represented by the formula (IX) or a pharmaceutically acceptable salt thereof comprising one or both steps of: (1) reacting a compound represented by the formula (I) with a compound represented by the formula (II) to give a compound represented by the formula (III); and (3) cyclizing the compound represented by the formula (IV) to give a compound represented by the formula (V); wherein R1and R2are as defined in claim 1;and Prot. is a protecting group.

6. A method of preparing a compound represented by the formula (IX) or a pharmaceutically acceptable salt thereof, comprising steps of: (1) reacting a compound represented by the formula (I) with a compound represented by the formula (II) to give a compound represented by the formula (III); (2) halogenating the compound represented by the formula (III) to give a compound represented by the formula (IV); (3a) cyclizing the compound represented by the formula (IV) to give a compound represented by the formula (VIII); and (4a) reacting the compound represented by the formula (VIII) with a compound represented by the formula (VI) to give a compound represented by the formula (VII); wherein R1is -N(C1-6alkyl)(C1-6alkyl), where two (C1-6alkyl)s may form a 4 to 6 membered heterocyclic group, -O-C1-6alkyl, or hydroxyl; R2is C1-6alkyl; R3and R4are independently C1-6alkyl or halogen; and Prot. is a protecting group.

7. A method of preparing a compound represented by the formula (VIII) or a salt thereof; comprising a step of cyclizing a compound represented by the formula (IV) to give a compound represented by the formula (VIII); wherein R1and R2are as defined in claim 6;and Prot. is a protecting group.

8. A method of preparing a compound represented by the formula (IX) or a salt thereof comprising a step of: (3a) cyclizing a compound represented by the formula (IV) to give a compound represented by the formula (VIII); wherein R1is -N(C1-6alkyl)(C1-6alkyl), where two (C1-6alkyl)s may form a 4 to 6 membered heterocyclic group, -O-C1-6alkyl, C1-6alkyl, or hydroxyl; R2is C1-6alkyl; R3and R4are independently C1-6alkyl or halogen; and Prot. is a protecting group.

9. The method according to any one of claims 1 to 8, wherein R1is -N(methyl)2and R2is methyl.

10. The method according to any one of claims 1 to 8, wherein the protecting group is selected from the group consisting of methyl, tert-butyl, allyl, benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, methoxymethyl, 2-(trimethylsilyl)ethoxymethyl, triphenylmethyl, diphenylmethyl, dimethylphenylmethyl, tetrahydropyranyl, tert-butoxycarbonyl, benzyloxycarbonyl, methanesulfonyl, 4-toluenesulfonyl, acetyl, and benzoyl.

11. The method according to any one of claims 1, 5, 6, 8, 9, and 10, wherein R3and R4are fluoro.

12. The method according to any one of claims 1 to 8, wherein the cyclizing is carried out in the presence of metal catalyst and ligand.

13. The method according to claim 12, wherein the metal catalyst is copper catalyst which is one or more selected from the groups consisting of Cu(0), copper(l) acetate, copper(l) bromide, copper(l) chloride, copper(l) iodide, copper(l) oxide, copper(ll) trifluoromethanesulfonate, copper(ll) acetate, copper(ll) bromide, copper(ll) chloride, copper(ll) iodide, copper(ll) oxide, copper(II) sulfate, tetrakis(acetonitrile)copper(I) hexafluorophosphate, and copper(II) acetylacetonate.

14. The method according to claim 12, wherein the ligand is one or more selected from the groups consisting of ethane-1,2-diamine, N1,N2-dimethylethane-1,2-diamine, N1,N1,N2,N2-tetramethylethane-1,2-diamine, cyclohexane-1,2-diamine, N1,N2-dimethylcyclohexane-1,2-diamine, quinolin-8-ol, 1,10-phenanthroline, proline, oxalic diamide derivatives such as N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxalamide, N1,N2-bis(1-naphthalenylmethyl)ethanediamide, N,N′-dibenzyloxamide, N1,N2-bis(2,4,6-trimethoxyphenyl)ethanediamide, and N,N′-bis(2-phenylethyl)ethanediamide, 6-hydroxypicolinamide derivatives such asN-(2,6-dimethylphenyl)-6-hydroxypicolinamide, 6-hydroxy-N-(2,4,6-trimethoxyphenyl)picolinamide, 6-hydroxy-N-(2-methylnaphthalen-1-yl)picolinamide, 6-hydroxy-N-(naphthalen-1-yl)picolinamide, N-([1,1'-biphenyl]-2-yl)-6-hydroxypicolinamide, 6-hydroxy-N-(2-(trifluoromethyl)phenyl)picolinamide, 6-hydroxy-N-(o-tolyl)picolinamide, 6-hydroxy-N-phenylpicolinamide, 6-hydroxy-N-(thiophen-2-ylmethyl)picolinamide, 6-hydroxy-N-(naphthalen-1-ylmethyl)picolinamide, N-(2,6-diisopropylphenyl)-6-hydroxypicolinamide, N-(2,6-difluorophenyl)-6-hydroxypicolinamide, N-(2,6-dimethoxyphenyl)-6-hydroxypicolinamide, and 6-hydroxy-N-(4-hydroxy-2,6-dimethylphenyl)picolinamide, 4-hydroxyquinoline-2-carboxamide derivatives such as 4-hydroxy-N-phenylquinoline-2-carboxamide, and N-(2,6-dimethylphenyl)-4-hydroxyquinoline-2-carboxamide, and 6-hydroxypicolinohydrazide derivatives such as N-(1,3-dimethyl-9H-carbazol-9-yl)-6-hydroxypicolinamide, N-(2,7-dimethyl-9H-carbazol-9-yl)-6-hydroxypicolinamide, and N-(2,7-di-tert-butyl-9H-carbazol-9-yl)-6-hydroxypicolinamide.

15. The method according to any one of claims 1, 5, 6, 8, 9, and 10, wherein the formula (IX) is a (S)-chiral compound represented by formula (X).

16. The method according to claim 15, the chiral compound represented by formula (X) is tegoprazan; wherein R1is -N(methyl)2; R2is methyl; and R3and R4are fluoro.

17. A compound represented by the formula (III) or geometric isomer, tautomeric isomer, or a salt thereof: wherein R1is -N(C1-6alkyl)(C1-6alkyl), where two (C1-6alkyl)s may form a 4 to 6 membered heterocyclic group, -O-C1-6alkyl, C1-6alkyl, or hydroxyl; R2is C1-6alkyl; and Prot. is a protecting group.

18. A compound represented by the formula (IV) or geometric isomer, tautomeric isomer, or a salt thereof: wherein R1is -N(C1-6alkyl)(C1-6alkyl), where two (C1-6alkyl)s may form a 4 to 6 membered heterocyclic group, -O-C1-6alkyl, C1-6alkyl, or hydroxyl; R2is C1-6alkyl; and Prot. is a protecting group.

19. A use of a compound represented by the formula (III), a compound represented by the formula (IV) or a pharmaceutically acceptable salt thereof as an intermediate compound for use in the manufacture of a compound represented by the formula (IX): wherein R1is -N(C1-6alkyl)(C1-6alkyl), where two (C1-6alkyl)s may form a 4 to 6 membered heterocyclic group, -O-C1-6alkyl, C1-6alkyl, or hydroxyl; R2is C1-6alkyl; R3and R4are independently C1-6alkyl or halogen; and Prot. is a protecting group.

20. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to claim 17 or 18, and a pharmaceutically acceptable carrier or excipient.

21. A process for preparing a pharmaceutical composition, wherein the process comprises mixing a compound according to claim 17 or 18, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

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