Preparation process of benzimidazole compound

Abstract

The present invention relates to a method for preparing a benzimidazole derivative which can be used as a pharmaceutical product, in particular as an acid secretion inhibitor, a method for preparing an intermediate used in the method, and a novel intermediate.

Description

Technical Field

[0001] This invention relates to a method for preparing a benzimidazole derivative, a method for preparing an intermediate used in the method, and a novel intermediate. The benzimidazole derivative can be used as a pharmaceutical product, and in particular as an acid secretion inhibitor. Background Technology

[0002] Benzimidazole compounds with a substituted amide group at the 6-position can be used as potassium-competitive acid blockers (p-cab), i.e., therapeutic agents for acid-related diseases (Patent Document 1 and Patent Document 2).

[0003] Patent document 1 discloses a compound represented by general formula (A) that can be used to treat / prevent disease states mediated by acid pump inhibitory activity.

[0004] {Chemical Formula 1} in; -AB- represents -O-CH2-, -S-CH2-, -CH2-O-, or -CH2-S-; X represents an oxygen atom or NH; R 1 Represents a C1-C6 alkyl group that is unsubstituted or independently substituted with one or two substituents selected from the group consisting of hydroxyl and C1-C6 alkoxy groups; R 2 and R 3 Independently represents a hydrogen atom, C1-C6 alkyl group, C3-C7 cycloalkyl group, or heteroaryl group; R 4 R 5 R 6 and R 7 Independently representing a hydrogen atom, halogen atom, hydroxyl group, C1-C6 alkyl group, or C1-C6 alkoxy group; and R 8 It represents a hydrogen atom, a hydroxyl group, or a C1-C6 alkoxy group.

[0005] Patent Document 1 discloses a general synthetic method for benzimidazole derivatives using aniline derivatives as starting materials. The benzimidazole derivatives can be prepared by chiral separation following a concentrated reaction of a benzimidazole intermediate (BI) with a chromogen alcohol derivative.

[0006] {Chemical Formula 2} Tegoprazan is a drug used to treat acid-related diseases. It inhibits the hydrogen / potassium ion exchange ATPase (H+) in a potassium-competitive manner. + / K +-ATPase); that is, potassium-competitive acid blocker (p-cab) reacts rapidly and can control the pH of gastric juice for a long time.

[0007] The chemical name of tegorazan is (S)-4-((5,7-difluoroxenoproton-4-yl)oxy)-N,N,2-trimethyl-1H-benzo[d]imidazol-6-carboxyamide, and its chemical structure includes a benzimidazole structure with a substituted amide group at the 6-position and a chiral 5,7-difluoroxenoproton-4-oxy radical structure.

[0008] {Chemical Formula 3} Examples 1 to 3 of Patent Document 1 also disclose a method for preparing the benzimidazole intermediate (BI) of tegorazane using 4-bromo-2-nitro-6-((benzyl)oxy)aniline (B).

[0009] {Chemical Formula 4} Furthermore, compound (B) was prepared by the method described in WO2004 / 054984 (Patent Document 8) using commercially available aniline (C) as a starting material. In general, the benzimidazole intermediate (BI) of tegorazan was obtained from commercially available aniline (C) in nine steps according to conventional methods.

[0010] {Chemical Formula 5} Recently, several patent documents (Patent Documents 3-7 and 9) have disclosed improved methods for preparing benzimidazole intermediate (BI), a key intermediate of tegorazan. Patent Document 3 discloses a seven-step method for preparing benzimidazole intermediate (BI) of tegorazan from commercially available 4-aminobenzoic acid (D).

[0011] The synthetic process of tegorazane mainly involves the concentration reaction of benzimidazole intermediate (BI) with 5,7-difluorochrome-4-ol and subsequent deprotection reaction. Existing methods for preparing tegorazane suffer from problems such as complex processes, environmental unfriendliness, numerous steps, high costs, and low yields.

[0012] Therefore, there is a need to provide a simple, high-yield, safe, and environmentally friendly process for the preparation of tegorazan, which is very important for the industrial development of tegorazan.

[0013] Previous technical documents Patent documents {Patent Document 1}WO2007 / 072146 {Patent Document 2}WO2016 / 200148 {Patent Document 3} CN115594639 {Patent Document 4}WO2015 / 005615 {Patent Document 5}WO2023 / 128525 {Patent Document 6}CN112851646 {Patent Document 7} CN114805317 {Patent Document 8}WO2004 / 054984 {Patent Document 9} CN116789654 {Patent Document 10} CN111303131 {Patent Document 11} CN115108994 {Patent Document 12} CN116253685 Summary of the invention The technical problem to be solved by the invention There is a need for a cost-effective, short-step method for the preparation of benzimidazole derivatives that can be used as pharmaceutical products. Additionally, it is desirable to provide a key intermediate for this method.

[0014] This invention provides an in-depth study of an economical, short-step, and environmentally friendly method for the preparation of benzimidazole derivatives comprising tegorazan or pharmaceutically acceptable salts thereof, and an improved method for the preparation of key intermediates used in the method.

[0015] As a result, a new and improved three-step method for obtaining the key benzimidazole intermediate (BI) from a commercially available aniline derivative (I) was discovered. In addition, important novel intermediates (III) and (IV) and their new preparation methods were also discovered.

[0016] This invention provides the following: [1] A method for preparing a compound represented by general formula (IX) or a pharmaceutically acceptable salt thereof, comprising the following steps: (1) A compound represented by general formula (I) is reacted with a compound represented by general formula (II) to obtain a compound represented by general formula (III); preferably, the reaction is carried out in the presence of an acid anhydride, a sulfonating agent or a chlorinating agent; more preferably, the reaction includes the step of adding general formula (I) to a mixture of general formula (II) and Tf2O; (2) Halogenating a compound represented by general formula (III) to obtain a compound represented by general formula (IV); (3) Cycling a compound represented by general formula (IV) to obtain a compound represented by general formula (V); preferably, the cyclization is carried out in the presence of a ligand and a metal catalyst; more preferably, the metal catalyst is a copper catalyst; and (4) Reacting a compound represented by general formula (V) with a compound represented by general formula (VI) to obtain a compound represented by general formula (VII); Among them, R 1 -N (C 1-6 alkyl) (C 1-6 Alkyl groups), of which 2 (C 1-6 Alkyl groups can form 4-6 membered heterocyclic groups, -OC 1-6 Alkyl or hydroxyl; R 2 C 1-6 Alkyl; R 3 and R 4 Independently for C 1-6 Alkyl or halogen; and Prot. is a protecting group. {Chemical Formula 7} {Chemical Formula 8} {Chemical Formula 9} {Chemical Formula 10} {Chemical Formula 11} {Chemical Formula 12} {Chemical Formula 13} {Chemical Formula 14} [2] A method for preparing a compound represented by general formula (III) or a salt thereof, {Chemical Formula 15} It includes the step of reacting a compound represented by general formula (I) with a compound represented by general formula (II) to obtain a compound represented by general formula (III) or a salt thereof. Among them, R 1 and R 2 According to [1]; and Prot. is a protecting base, [3] A method for preparing a compound represented by general formula (IV) or a salt thereof, comprising the step of halogenating a compound represented by general formula (III) to obtain a compound represented by general formula (IV), Among them, R 1 and R 2 According to [1]; and Prot. is a protecting base, {Chemical Formula 16} [4] A method for preparing a compound or a salt thereof represented by general formula (V), comprising the step of cyclizing a compound represented by general formula (IV) to obtain a compound represented by general formula (V), Among them, R 1 and R 2 According to [1]; and Prot. is a protecting base, {Chemical Formula 17} [5] A method for preparing a compound represented by general formula (IX) or a pharmaceutically acceptable salt thereof, comprising one or two of the following steps: (1) The step of reacting a compound represented by general formula (I) with a compound represented by general formula (II) to obtain a compound represented by general formula (III); and (3) Cyclate the compound represented by general formula (IV) to obtain the compound represented by general formula (V); Among them, R 1 and R 2 According to [1]; and Prot. is a protecting base, [6] A method for preparing a compound represented by general formula (IX) or a pharmaceutically acceptable salt thereof, comprising the following steps: (1) A compound represented by general formula (I) is reacted with a compound represented by general formula (II) to obtain a compound represented by general formula (III); preferably, the reaction is carried out in the presence of an acid anhydride, a sulfonating agent or a chlorinating agent; more preferably, the reaction includes the step of adding general formula (I) to a mixture of general formula (II) and Tf2O; (2) Halogenating a compound represented by general formula (III) to obtain a compound represented by general formula (IV); (3a) Cycling a compound represented by general formula (IV) to obtain a compound represented by general formula (VIII); preferably, the cyclization is carried out in the presence of a ligand and a metal catalyst; more preferably, the metal catalyst is a copper catalyst; and (4a) The step of reacting a compound represented by general formula (VIII) with a compound represented by general formula (VI) to obtain a compound represented by general formula (VII); Among them, R 1 -N (C 1-6 alkyl) (C 1-6 Alkyl groups), of which 2 (C 1-6 Alkyl groups can form 4-6 membered heterocyclic groups, -OC 1-6 Alkyl or hydroxyl; R 2 C 1-6 Alkyl; R 3 and R 4 Independently for C 1-6 Alkyl or halogen; and Prot. is a protecting group. {Chemical Formula 18} [7] A method for preparing a compound represented by general formula (VIII) or a salt thereof, comprising the step of cyclizing a compound represented by general formula (IV) to obtain a compound represented by general formula (VIII); Among them, R 1 and R 2 According to [6]; and Prot. is a protecting group, {Chemical Formula 19} [8] A method for preparing a compound or a salt thereof represented by general formula (IX), comprising the following steps: (3a) Cyclate the compound represented by general formula (IV) to obtain the compound represented by general formula (VIII); Among them, R 1 -N (C 1-6 alkyl) (C 1-6 Alkyl groups), of which 2 (C 1-6 Alkyl groups can form 4-6 membered heterocyclic groups, -OC 1-6 Alkyl, C 1-6 Alkyl or hydroxyl; R 2 C 1-6 Alkyl; R 3 and R 4 Independently for C 1-6 Alkyl or halogen; and Prot. is a protecting group. {Chemical Formula 20} {Chemical Formula 21} [9] The method according to any one of [1] to [8], wherein R 1 It is -N(methyl)2, and R 2 It is methyl.

[10] 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, dimethylbenzyl, tetrahydropiperanyl, tert-butoxycarbonyl, benzyloxycarbonyl, methanesulfonyl, 4-toluenesulfonyl, acetyl, and benzoyl.

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

[10] , wherein R 3 and R4 It is fluorine.

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

[13] According to the method of

[12] , wherein the metal catalyst is one or more copper catalysts selected from the group consisting of Cu(O), copper acetate (I), copper bromide (I), copper chloride (I), copper iodide (I), copper oxide (I), copper trifluoromethanesulfonate (II), copper acetate (II), copper bromide (II), copper chloride (II), copper iodide (II), copper oxide (II), copper sulfate (II), copper tetra(acetonitrile)hexafluorophosphate (I), and copper acetylacetonate (II).

[14] According to the method of

[12] , wherein the ligand is selected from the group comprising 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, quinoline-8-ol, 1,10-phenanthroline, proline, and oxalyl diamine derivatives such as N1,N2-bis(4-hydroxy-2,6-dimethyl)oxalamide, N1,N2-bis(1-naphthylmethyl)glyoxamide, N,N′- Dibenzyloxam, N1,N2-bis(2,4,6-trimethoxyphenyl)glyoxam and N,N′-bis(2-phenylethyl)glyoxam, 6-hydroxymethylpyridineamide derivatives such as N-(2,6-xylyl)-6-hydroxymethylpyridineamide, 6-hydroxy-N-(2,4,6-trimethoxyphenyl)methylpyridineamide, 6-hydroxy-N-(2-methylnaphth-1-yl)methylpyridineamide, 6-hydroxy-N-(naphth-1-yl)methylpyridineamide, N-([1,1'-biphenyl]-2-yl)-6-hydroxymethylpyridineamide, 6-hydroxy -N-(2-(trifluoromethyl)phenyl)methylpyridineamide, 6-hydroxy-N-(o-tolyl)methylpyridineamide, 6-hydroxy-N-phenylmethylpyridineamide, 6-hydroxy-N-(thiophen-2-ylmethyl)methylpyridineamide, 6-hydroxy-N-(naphthyl-1-ylmethyl)methylpyridineamide, N-(2,6-diisopropylphenyl)-6-hydroxymethylpyridineamide, N-(2,6-difluorophenyl)-6-hydroxymethylpyridineamide, N-(2,6-dimethoxyphenyl)-6-hydroxymethylpyridineamide and 6-hydroxy-N-(4-hydroxy-2,6-di-di-(2,6 ...di-(2,6-di-di-(2,6-di-di-(2,6-di-di-(2,6-di-di-(2,6-di-di-(2,6-di-di-(2,6-di-di-(2 The group consisting of one or more of the following: (tolyl)methylpyridine amide, 4-hydroxyquinoline-2-carboxylamide derivatives such as 4-hydroxy-N-phenylquinoline-2-carboxyl amide and N-(2,6-xylyl)-4-hydroxyquinoline-2-carboxyl amide, and 6-hydroxymethylpyridine hydrazide derivatives such as N-(1,3-dimethyl-9H-carbazole-9-yl)-6-hydroxymethylpyridine amide, N-(2,7-dimethyl-9H-carbazole-9-yl)-6-hydroxymethylpyridine amide, and N-(2,7-di-tert-butyl-9H-carbazole-9-yl)-6-hydroxymethylpyridine amide.

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

[10] , wherein the general formula (IX) is an (S)-chiral compound represented by the general formula (X), {Chemical Formula 22}

[16] According to the method of

[15] , wherein the chiral compound represented by general formula (X) is tegorazan; wherein R 1 -N(methyl)2; R 2 It is methyl; and R3 and R 4 It is fluorine.

[17] A compound represented by general formula (III) or a geometrical isomer, tautomer, or salt thereof: {Chemical Formula 23} Among them, R 1 -N (C 1-6 alkyl) (C 1-6 Alkyl groups), of which 2 (C 1-6 Alkyl groups can form 4-6 membered heterocyclic groups, -OC 1-6 Alkyl, C 1-6 Alkyl or hydroxyl; R 2 C 1-6 Alkyl group; and Prot. is a protecting group.

[18] A compound represented by general formula (IV) or a geometrical isomer, tautomer, or salt thereof: {Chemical Formula 24} Among them, R 1 -N (C 1-6 alkyl) (C 1-6 Alkyl groups), of which 2 (C 1-6 Alkyl groups can form 4-6 membered heterocyclic groups, -OC 1-6 Alkyl, C 1-6 Alkyl or hydroxyl; R 2 C 1-6 Alkyl group; and Prot. is a protecting group.

[19] Use of a compound represented by general formula (III), a compound represented by general formula (IV), or a pharmaceutically acceptable salt thereof as an intermediate compound in the preparation of a compound represented by general formula (IX): {Chemical Formula 25} {Chemical Formula 26} {Chemical Formula 27} Among them, R 1 -N (C 1-6 alkyl) (C 1-6 Alkyl groups), of which 2 (C 1-6 Alkyl groups can form 4-6 membered heterocyclic groups, -OC 1-6 Alkyl, C 1-6 Alkyl or hydroxyl; R 2 C 1-6 Alkyl; R3 and R 4 Independently for C 1-6 Alkyl or halogen; and Prot. is a protecting group.

[20] A pharmaceutical composition comprising the compound described in

[17] or

[18] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[21] A process for preparing a pharmaceutical composition, wherein the process includes mixing the compound described in

[17] or

[18] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0017] Invention Effects This invention provides a method for preparing a benzimidazole intermediate (BI), comprising the steps of: reacting a compound represented by general formula (I) with a compound represented by general formula (II) to obtain a compound represented by general formula (III); halogenating the compound represented by general formula (III) to obtain a compound represented by general formula (IV); and cyclizing compound (IV) to obtain a compound represented by general formula (V) or a compound represented by general formula (VIII) as a key benzimidazole intermediate (BI) for tegorazan. The compound represented by general formula (V) or the compound represented by general formula (VIII) can be used to obtain tegorazan by conventional methods including a deprotection step (Patent Documents 1 and 9 to 12).

[0018] {Chemical Formula 28} Surprisingly, in step 3 of the reaction, cyclization and hydroxylation occur simultaneously. This greatly helps to reduce the preparation process.

[0019] Therefore, this application discloses a three-step synthetic method for obtaining benzimidazole intermediate (BI) from commercially available 4-amino-N,N-dimethylbenzamide as a key intermediate for tegorazane. The preparation steps in this invention are shorter than those in conventional methods. This invention enables lower preparation costs and fewer preparation steps in the preparation of commercially available active pharmaceutical ingredient (API) tegorazane.

[0020] In another embodiment, tegorazan can be prepared by using an ester substituent instead of an amide substituent in an aniline derivative (XI) as a starting material. This preparation method also achieves a short preparation process. Tegorazan is obtained from a benzimidazole intermediate (BI) having a carboxylic acid or ester substituent by conventional synthetic methods (Patent Documents 1 and 9 to 12) including the following deprotection steps.

[0021] {Chemical Formula 29} Attached Figure Description

[0022] Figure 1 It represents compound 1. 1 H NMR spectrum.

[0023] Figure 2 It represents compound 2. 1 H NMR spectrum.

[0024] Figure 3 It represents compound 3. 1 H NMR spectrum.

[0025] Figure 4 It represents compound 4. 1 H NMR spectrum.

[0026] Figure 5 It represents compound 5. 1 H NMR spectrum.

[0027] Figure 6 It represents compound 7. 1 H NMR spectrum. Detailed Implementation

[0028] The term “benzimidazole intermediate (BI)” as used in this specification refers to a benzimidazole derivative that is synthesized as an intermediate for tegorazan in combination with general formula (VI).

[0029] As used in this specification, the term "tautomer" refers to a tautomer derived from the interchange of single and adjacent double bonds, as well as the simultaneous transfer of protons. Examples of proton tautomers are keto-enol pairs, amide-imide pairs, lactam-lactam pairs, amide-imide pairs, and enamine-imide pairs. Tautomers can be maintained in equilibrium or stereofixed in one form through appropriate substitution.

[0030] The term "geometric isomer" as used in this specification refers to isomers that are oriented differently in carbon-carbon double bond, cycloalkyl ring, or bridged bicyclic system. The atoms (except H) on each side of the carbon-carbon double bond can be E (substituents on opposite sides of the carbon-carbon double bond) or Z (substituents oriented on the same side) configurations.

[0031] As used in this specification, the term "alkyl" refers to a straight-chain saturated monovalent hydrocarbon radical having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical having 3 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, butyl (including all isomers), pentyl (including all isomers), etc.

[0032] The terms “Hal.”, “halogen”, or “halo” used in this specification are intended to include fluorine, chlorine, bromine, and iodine.

[0033] The term "alkoxy" as used in this specification means -O-alkyl, such as methoxy, ethoxy, propoxy, 2-propoxy, butoxy (including all isomers), etc., but is not limited thereto.

[0034] The term "alkenyl" as used in this specification refers to a hydrocarbon radical having at least one double bond, which can be E-arranged or Z-arranged, including, but not limited to, vinyl, propenyl, 1-butenyl, 2-butenyl, etc.

[0035] The term "cycloalkyl" as used in this specification refers to monocyclic, bicyclic, or tricyclic compounds, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl, but is not limited thereto.

[0036] As used in this specification, the term "aryl" refers to an unsaturated or partially saturated monocyclic or bicyclic or 5- to 15-membered ring containing a carbon atom. Examples of such aryl groups include, but are not limited to, phenyl, naphthyl, dihydroindenyl, 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.

[0037] The term "heteroaryl" as used in this specification refers to a 5- to 15-membered ring, preferably a 5- to 10-membered ring, that may contain 1 to 4 heteroatoms selected from O, N, and S and is an unsaturated or partially saturated monocyclic or bicyclic ring.

[0038] Examples of such heteroaryl groups include phenylthio, thiazolyl, isoxazolyl, pyrazolyl, pyrazinyl, tetrazolyl, furanyl, pyrroleyl, imidazolyl, oxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, benzobenzenthio, benzotriazolyl, indoleyl, and indazole. The group includes, but is not limited to, benzoimidazolyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrazolopyridyl, pyrazolopyrimidinyl, imidazopyridyl, furanopyridyl, benzoisoxazolyl, imidazopyrazinyl, imidazopyrazinyl, imidazopyrimidinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl, quinoxalinyl, naphthidyl, pyridinolpyrimidinyl and their N-oxides and S-oxides.

[0039] The term "R" used in this specification a " represents the protecting group of a carboxylic acid. R" aThese can be any bases or substituents that do not interfere with the reaction. These bases can be added or removed by methods described in TW Greene and GM Wuts, Protective Groups in Organic Synthesis (John Wiley & Sons, New York, 2007).

[0040] The term "treating" as used in this specification includes preventing, restricting, slowing, stopping, or reversing the progression or severity of an existing symptom or condition. The term "preventing" as used in this specification includes preventing, restricting, or inhibiting the occurrence or appearance of a symptom or condition.

[0041] The articles ("a" or "an") used in this specification, unless otherwise specified, indicate both the singular and plural forms of the object they refer to.

[0042] As used in this specification, the term "halogenation" refers to a chemical reaction that introduces a halogen atom into a compound. Halogenation is described as chlorination, fluorination, bromination, iodination, etc., depending on the halogen involved. Halogenation reactions can occur by direct reaction with a halogen. This occurs on alkanes, where the reaction involves free radicals and requires high temperatures, ultraviolet radiation, or a chemical initiator.

[0043] As used in this specification, the term "cyclization" refers to the formation of a cyclic compound from a chain by forming new bonds. In this invention, cyclization and hydroxylation reactions can be carried out simultaneously or in separate steps.

[0044] As used in this specification, the term "hydroxylation" refers to the introduction of a hydroxyl group (-OH) into an organic compound. For example, alkenes can be hydroxylated using potassium permanganate or lead acetate to obtain alcohols, but are not limited to these methods. In biochemistry, various enzymes can induce hydroxylation.

[0045] As used in this specification, the term "ligand" refers to an ion or molecule that donates an electron pair to a metal atom or ion to form a coordination complex. Ligands that promote copper-catalyzed reactions are well known, ranging from classical ligands to the latest advanced ligands (reference: Chem. Rev. 2008, 108, 3054-3131). Examples of ligands used in copper-mediated reactions include 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, quinoline-8-ol, 1,10-phenanthroline, proline, and oxalyldiamine derivatives such as N1,N2-bis(4-hydroxy-2,6-dimethyl)oxalamide, N1,N2-bis(1-naphthylmethyl)glyoxalamide, N,N′-dibenzyloxalamide, and N1 N2-bis(2,4,6-trimethoxyphenyl)glyoxalamide and N,N′-bis(2-phenylethyl)glyoxalamide, 6-hydroxymethylpyridineamide derivatives such as N-(2,6-xylyl)-6-hydroxymethylpyridineamide, 6-hydroxy-N-(2,4,6-trimethoxyphenyl)methylpyridineamide, 6-hydroxy-N-(2-methylnaphthyl-1-yl)methylpyridineamide, 6-hydroxy-N-(naphthyl-1-yl)methylpyridineamide, N-([1,1'-biphenyl]-2-yl)-6-hydroxymethylpyridineamide, 6-hydroxy-N-(2 -(trifluoromethyl)phenyl)methylpyridineamide, 6-hydroxy-N-(o-tolyl)methylpyridineamide, 6-hydroxy-N-phenylmethylpyridineamide, 6-hydroxy-N-(thiophen-2-ylmethyl)methylpyridineamide, 6-hydroxy-N-(naphthyl-1-ylmethyl)methylpyridineamide, N-(2,6-diisopropylphenyl)-6-hydroxymethylpyridineamide, N-(2,6-difluorophenyl)-6-hydroxymethylpyridineamide, N-(2,6-dimethoxyphenyl)-6-hydroxymethylpyridineamide and 6-hydroxy-N-(4-hydroxy-2,6-xylylene) (2,6-dimethyl)-4-hydroxyquinoline-2-carboxylic amide, 4-hydroxyquinoline-2-carboxylic amide derivatives such as 4-hydroxy-N-phenylquinoline-2-carboxylic amide and N-(2,6-dimethyl)-4-hydroxyquinoline-2-carboxylic amide, 6-hydroxymethylpyridinyl hydrazine derivatives such as N-(1,3-dimethyl-9H-carbazole-9-yl)-6-hydroxymethylpyridinyl amide, N-(2,7-dimethyl-9H-carbazole-9-yl)-6-hydroxymethylpyridinyl amide and N-(2,7-di-tert-butyl-9H-carbazole-9-yl)-6-hydroxymethylpyridinyl amide, etc., but not limited to these.(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 HydroxylationReaction in Water: Machine-Learning Accelerated Ligands Design and ReactionOptimization). Other examples of ligands used in palladium-mediated reactions include 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (Xantphos), triphenylphosphine, tributylphosphine, 1,1'-bis(diphenylphosphino)ferrocene, tri-2-furanylphosphine, tri-o-tolylphosphine, triphenylarsine, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), 2-(dichlorohexylphosphino)biphenyl (CyJohnPhos), and 2-(dichlorohexylphosphino)biphenyl. Examples of biphenyls include (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), but they are not limited to these.

[0046] The term "oxalyldiamine derivative" as used in this specification refers to a chemical substance that can be prepared by a concentration reaction of oxalic acid with an amine or aniline (reference: Org. Process Res. Dev. 2022, 26, 1690-1750). Examples of "oxalyldiamine derivatives" include, but are not limited to, N1,N2-bis(4-hydroxy-2,6-dimethyl)oxalamide, N1,N2-bis(1-naphthylmethyl)glyoxalamide, N,N′-dibenzyloxalamide, N1,N2-bis(2,4,6-trimethoxyphenyl)glyoxalamide, and N,N′-bis(2-phenylethyl)glyoxalamide.

[0047] The term "6-hydroxymethylpyridine amide derivative" as used in this specification refers to a chemical substance that can be prepared by a concentration reaction of 6-hydroxypyridine carboxymethyl with an amine or aniline (reference: Org. Process Res. Dev. 2019, 23, 1538-1551, Org. Process Res. Dev. 2024, 28, 2732-2742). Examples of "6-hydroxymethylpyridine amide derivatives" include N-(2,6-dimethylphenyl)-6-hydroxymethylpyridine amide, 6-hydroxy-N-(2,4,6-trimethoxyphenyl)methylpyridine amide, 6-hydroxy-N-(2-methylnaphthyl-1-yl)methylpyridine amide, 6-hydroxy-N-(naphthyl-1-yl)methylpyridine amide, N-([1,1'-biphenyl]-2-yl)-6-hydroxymethylpyridine amide, 6-hydroxy-N-(2-(trifluoromethyl)phenyl)methylpyridine amide, 6-hydroxy-N-(o-methyl)methylpyridine amide, etc. Phenyl(phenyl) methylpyridine amide, 6-hydroxy-N-phenylmethylpyridine amide, 6-hydroxy-N-(thiophen-2-ylmethyl) methylpyridine amide, 6-hydroxy-N-(naphth-1-ylmethyl) methylpyridine amide, N-(2,6-diisopropylphenyl)-6-hydroxymethylpyridine amide, N-(2,6-difluorophenyl)-6-hydroxymethylpyridine amide, N-(2,6-dimethoxyphenyl)-6-hydroxymethylpyridine amide and 6-hydroxy-N-(4-hydroxy-2,6-dimethylphenyl) methylpyridine amide, but not limited thereto.

[0048] The term "4-hydroxyquinoline-2-carboxyamide derivative" as used in this specification refers to a chemical substance that can be prepared by a concentration reaction of 4-hydroxyquinoline-2-carboxylic acid with an amine or aniline (reference: Org. Process Res. Dev. 2019, 23, 1538-1551, Org. Process Res. Dev. 2024, 28, 2732-2742). Examples of "6-hydroxymethylpyridineamide derivatives" include, but are not limited to, 4-hydroxy-N-phenylquinoline-2-carboxyamide and N-(2,6-dimethylphenyl)-4-hydroxyquinoline-2-carboxyamide.

[0049] As used in this specification, the term "metal catalyst" refers to a chemical substance that can alter the rate of a chemical reaction. Transition metal catalysts are commonly used among metal catalysts. Examples of “metal catalysts” include, but are not limited to, tetra(triphenylphosphine)palladium (0), bis(triphenylphosphine)palladium chloride (II), copper (0), copper acetate (I), copper bromide (I), copper chloride (I), copper iodide (I), copper oxide (I), copper sulfate (II), copper trifluoromethanesulfonate (II), copper acetate (II), copper bromide (II), copper chloride (II), copper iodide (II), copper oxide (II), copper acetylacetonate (II), palladium acetate (II), palladium chloride (II), tetra(acetonitrile)copper hexafluorophosphate (I), bis(acetonitrile)palladium dichloride (II), bis(dibenzylacetone)palladium (0), tri(dibenzylacetone)dipalladium (0), [1,1'-bis(diphenylphosphino)ferrocene]-palladium dichloride (II) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium dichloride (II).

[0050] The amount of the "metal catalyst" is 0.001 equivalents to 10 equivalents relative to the matrix.

[0051] The term "anhydride" as used in this specification refers to an acylating agent or a sulfonating agent. For example, an anhydride can react with amides to produce imine ester derivatives or imine group derivatives. Examples of anhydrides include, but are not limited to, Tf₂O and Ms₂O.

[0052] The term "sulfonating agent" as used in this specification refers to a sulfonating agent. For example, a "sulfonating agent" can react with an amide to produce an imine ester derivative or an imine acyl derivative. Examples of sulfonating agents include, but are not limited to, 4-toluenesulfonyl chloride, methanesulfonyl chloride, and benzenesulfonyl chloride.

[0053] As used in this specification, the term "chlorinating agent" refers to a reagent that introduces a chlorine atom into a reactant. For example, a "chlorinating agent" can react with an amide to produce an imine acyl chloride. Examples of chlorinating agents include, but are not limited to, oxaloyl chloride, PCl5, POCl3, and SOCl2.

[0054] The term "copper catalyst" as used in this specification includes, but is not limited to, copper (0), copper acetate (I), copper bromide (I), copper chloride (I), copper iodide (I), copper oxide (I), copper trifluoromethanesulfonate (II), copper acetate (II), copper bromide (II), copper chloride (II), copper iodide (II), copper oxide (II), copper sulfate (II), copper tetra(acetonitrile)hexafluorophosphate (I), and copper acetylacetonate (II).

[0055] The amount of “copper catalyst” relative to the matrix is ​​0.001 equivalents to 10 equivalents.

[0056] The term "palladium catalyst" as used in this specification includes, for example, tetra(triphenylphosphine)palladium (0), bis(triphenylphosphine)palladium (II), palladium acetate (II), palladium chloride (II), bis(acetonitrile)palladium (II), bis(dibenzylacetone)palladium (0), tri(dibenzylacetone)palladium (0), [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium (II), but is not limited thereto.

[0057] The amount of “palladium catalyst” relative to the matrix is ​​0.001 equivalents to 10 equivalents.

[0058] As used in this specification, the term "de-radical" refers to an atom or base (charged or uncharged) that has detached from the atoms that are considered part of the matrix in a particular reaction. (Reference: IUPAC Gold Book) Examples of de-radicals include, but are not limited to, fluorides, chlorides, bromides, iodides, methanesulfonates, trifluoromethanesulfonates, benzenesulfonates, p-toluenesulfonates, alkoxy groups, ammonium salts, trialkylammonium salts, pyridinium salts, etc.

[0059] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention that is suitable for use in contact with human or lower animal tissues within a reasonable medical judgment without undue toxicity, irritation, allergic reactions, etc., in proportion to a reasonable benefit / risk ratio, and is generally water-soluble or oil-soluble or dispersible, effective for these intended uses. This term includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. Since the compounds of the present invention are useful in both free base and salt forms, practical use of the salt form is equivalent to use of the base form. A list of suitable salts can be found, for example, in SM Berge et al, J. Pharm.Sci, 1977, 66, 1, pp. 1-19, the entire contents of which are incorporated herein by reference. Salts are formed from inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, but not limited thereto); and organic acids (such as succinic acid, maleic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid or naphthalenesulfonic acid, but not limited thereto).

[0060] The term "salt" as used in this specification includes pharmaceutically acceptable salts and non-pharmaceutical acceptable salts.

[0061] The term “pharmaceutically acceptable carrier or excipient” means a carrier or excipient that can be used to prepare pharmaceutical compositions that are generally safe and non-toxic and meet biological and other requirements, including carriers or excipients acceptable for both veterinary and human pharmaceutical use. As used in the specification and claims, “pharmaceuticalally acceptable carrier / excipient” includes more than one such excipient. Examples of “carrier” or “excipient” are referenced in Processes 2021, 9(3), 470 or Handbook of Pharmaceutical Excipients: Edition 9 (2020, Edited by DJGoldfarb, et al.), but are not limited thereto.

[0062] As used in this specification, the term "Prot." refers to a non-reactive functional group that selectively shields functional groups in a compound to allow selective reactions to occur in other parts of the compound. These groups can be added or removed by methods described in TW Greene and GM Wuts, *Protective Groups in Organic Synthesis* (John Wiley & Sons, New York, 2007). Examples of such protecting groups include, but are not limited to, methyl, tert-butyl, allyl, benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, methoxymethyl, 2-(trimethylsilyl)ethoxymethyl, triphenylmethyl, diphenylmethyl, dimethylbenzyl, tetrahydropiperanyl, tert-butoxycarbonyl, benzyloxycarbonyl, methanesulfonyl, 4-toluenesulfonyl, acetyl, and benzoyl.

[0063] Suitable deprotectants include, but are not limited to, hydrogenolysis conditions (e.g., H2, Pd / C) or acidolysis conditions (e.g., HCl, TFA).

[0064] The terms “room temperature” or “rt” used in this specification refer to temperatures between 10°C and 30°C, preferably between 18°C ​​and 25°C.

[0065] As used in this specification, the term "reaction" refers to a chemical process in which two or more reactants come into contact with each other to produce a chemical change or transformation. For example, when reactant A and reactant B are allowed to come into contact with each other to produce a new compound C, it can be said that A and B "react" to produce C.

[0066] Salts, solvates, hydrates, complexes, homomorphs, precursors, radiolabeled derivatives, stereoisomers, and optical isomers of compounds of general formulas (VI), (VII), and (IX) may be included in the scope of "compounds used in this invention".

[0067] As used in this specification, the term "prodrug" refers to a compound with little or no pharmacological activity that is metabolized in the body and converted into a pharmacologically active drug compound. More information on the uses of prodrugs can be found in: Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (Th Higuchi and W Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E BRoche, American Pharmaceutical Association).

[0068] The term "animal" as used in this specification includes both mammalian and non-mammal subjects. Suitable examples of mammalian subjects include, but are not limited to, humans, rodents, companion animals, livestock, and primates. Suitable rodents include, but are not limited to, mice, rats, hamsters, gerbils, and guinea pigs. Suitable companion animals include, but are not limited to, cats, dogs, rabbits, and ferrets. Suitable livestock include, but are not limited to, horses, goats, sheep, pigs, cattle, llamas, and alpacas. Suitable primates include, but are not limited to, chimpanzees, lemurs, macaques, marmosets, spider monkeys, squirrel monkeys, and vervet monkeys. Suitable examples of non-mammal subjects include, but are not limited to, birds, reptiles, amphibians, and fish. Non-limiting examples of birds include chickens, turkeys, ducks, and geese. Humans are the preferred mammalian subject.

[0069] Salts and solvates having non-pharmaceutically acceptable relative ions or associated solvents are within the scope of this invention. For example, this includes salts of all intermediates used in the preparation of compounds of general formula (IX) of this invention. In some cases, the salts of intermediates are neutralized before use in the reaction, or are used directly in the reaction.

[0070] As used in this specification, the carbon atom at position 4 of general formula (VI) can be a racemic mixture, a mixture of R / S configurations, an R configuration, or an S configuration.

[0071] {Chemical Formula 30} As used in this specification, the carbon atom at position 4 of the chromogenic alkoxy moiety of general formula (VII) can be a racemic mixture, a mixture of R / S configurations, an R configuration, or an S configuration.

[0072] {Chemical Formula 31} As used in this specification, the carbon atom at position 4 of the chromogenic alkoxy moiety of general formula (IX) can be a racemic mixture, a mixture of R / S configurations, an R configuration, or an S configuration.

[0073] {Chemical Formula 32} In some compounds represented by general formulas (I) to (IX) of the present invention, more than one chiral carbon atom may be present. In this case, the compounds of general formulas (I) to (IX) exist as stereoisomers. The present invention extends to all optical isomers, including, for example, mirror-image isomers, non-mirror-image isomers, and mixtures thereof, such as stereoisomers of racemic compounds of general formulas (I) to (IX). Different stereoisomers can be separated or decomposed from each other by conventional methods, or arbitrary isomers can be obtained by conventional stereoselective or asymmetric synthesis.

[0074] The specific compounds represented by general formulas (I) to (IX) can exist in various tautomer forms, which should be understood as including all such tautomer forms and geometric isomers in this invention.

[0075] This invention also includes isotope labeling compounds, which are identical to those described in this specification, but substantially, one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be combined with the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine, and chlorine, for example... 2 H, 3 H, 11 C 13 C 14 C 18 F, 123 I and 125 I. Compounds represented by general formulas (I) to (IX) containing the aforementioned isotopes and / or other isotopes are within the scope of this invention. The isotope-labeled compounds of this invention, if combined with... 3 H, 14 Compounds containing radioactive isotopes such as tritium can be used for drug and / or substrate tissue distribution analysis. 3 H) and carbon-14 ( 14 Isotopes of C) are particularly preferred because they are easy to prepare and detect. 11 C and 18 F isotopes are particularly useful in PET (positron emission tomography), and 123I- isotopes are particularly useful in SPECT (single photon emission computed tomography), which is used for brain imaging. Additionally, heavier isotopes such as deuterium (…) can also be used… 2 When H) is substituted, it can provide specific therapeutic effects due to superior metabolic stability, such as prolonged in vivo half-life or reduced dose requirements, and is therefore preferred in some cases. The isotopic marker compounds of the present invention represented by general formulas (I) to (IX) can generally be prepared by replacing non-isotopic markers with readily available isotopic markers after performing the steps described in the following schemes and / or examples.

[0076] General Synthesis Compounds of formulas (I) through (IX) include all geometric isomers and tautomers. The compounds used in this invention can be salts, solvates, hydrates, complexes, polymorphs, precursors, radiolabeled derivatives, stereoisomers, and optical isomers of compounds of formulas (VI), (VII), and (IX). Formulas (III) and (IV) include tautomerism of double bonds and E / Z positional isomers.

[0077] (Introduction of nitrogen-protecting group (Prot.)) This reaction is described in detail in TW Greene et al., Protective Groups in Organic Synthesis, 696-926, (2007), the disclosure of which is incorporated herein by reference. Hereinafter, typical reactions involving protecting groups of benzyl, alkoxycarbonyl, or arylsulfonyl are illustrated.

[0078] Examples of nitrogen-protecting groups include halides or acid anhydrides that can be used in the above reactions, including benzyl chloride, benzyl bromide, 4-methylbenzenesulfonyl chloride, benzenesulfonyl chloride, or ditert-butyl dicarbonate; wherein, preferably, benzyl bromide, 4-methylbenzenesulfonyl chloride, or ditert-butyl dicarbonate.

[0079] 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 mixtures of these solvents. N,N-dimethylformamide is preferred.

[0080] Examples of these bases include: alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and barium 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 bicarbonates such as lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate; and amines such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, and N-methylmorpholine. Piperidine, pyridine, 4-pyrrolylpyridine, methylpyridine, 4-(N,N-dimethylamino)pyridine, 2,6-di(tert-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, DBN, DABCO, and DBU; alkali metal amines such as lithium amino, sodium amino, potassium amino, diisopropylaminolithium, diisopropylaminopotassium, diisopropylaminosodium, bis(trimethylsilyl)aminolithium, bis(trimethylsilyl)aminopotassium, or mixtures thereof. Sodium hydride or triethylamine is preferred.

[0081] (Deprotection of the protecting group (Prot.)) This reaction is described in detail in TW Greene et al., Protective Groups in Organic Synthesis, 696-926, (2007), the disclosure of which is incorporated herein by reference. The following are typical deprotection reactions involving the benzyl group.

[0082] The reaction is typically and preferably carried out in the presence of a solvent. There are no particular limitations regarding the nature of the solvent used, as long as it does not adversely affect the reaction or the reagents involved and at least partially dissolves the reagents. 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; and carboxylic acids such as acetic acid or formic acid. Among these solvents, acetic acid or tetrahydrofuran is preferred.

[0083] The reaction is carried out in hydrogen gas in the presence of a palladium catalyst. There are no particular limitations on the properties of the palladium catalyst used; any palladium catalyst commonly used in this type of reaction can be used in this specification. Examples of such palladium catalysts include palladium metal, palladium on carbon, and palladium hydroxide. Palladium on carbon or palladium hydroxide are preferred. The reaction can be carried out over a wide range of temperatures, and the precise reaction temperature is not critical to this invention. The preferred reaction temperature depends on factors such as the nature of the solvent and the starting material. However, the reaction is generally suitable for temperatures ranging from about 0°C to about 1000°C. The reaction time also varies considerably, depending on many factors, especially the reaction temperature and the nature of the starting material and the solvent used. However, provided the reaction is carried out under the preferred conditions described above, the reaction typically takes from about 10 minutes to about 24 hours.

[0084] The reaction is carried out with or without a base. Similarly, there are no particular limitations on the nature of the base used; any base commonly used in such reactions may be used in this specification. Examples of such bases include: alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and barium 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 bicarbonates such as lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate; alkali metal phosphates such as tripotassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, trisodium hydrogen phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate; amines such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, N, N-Diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolylpyridine, methylpyridine, 2,6-dimethylpyridine, 4-(N,N-dimethylamino)pyridine, 2,4,6-trimethylpyridine, 2,6-di(tert-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, DBN, DABCO, and DBU; alkali metal amines such as aminolithium, aminosodium, aminopotassium, diisopropylaminolithium, diisopropylaminopotassium, diisopropylaminosodium, bis(trimethylsilyl)aminolithium, and bis(trimethylsilyl)aminopotassium. Preferably, lithium hydroxide, sodium hydroxide, tripotassium phosphate, sodium bicarbonate, triethylamine, pyridine, or 2,6-dimethylpyridine.

[0085] The reaction is carried out with or without a solvent or co-solvent mixture. Similarly, there are no particular limitations on the nature of the solvent used; any solvent commonly used in such reactions may be used in this specification. 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-butylmethyl ether, cyclopentylmethyl 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 methyl ethyl ketone; amides such as dimethylformamide, dimethylacetamide, and N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide and sulfolane; esters such as ethyl acetate; and acids such as formic acid, acetic acid, and trifluoroacetic acid. Preferred examples of solvents miscible with more than one solvent are 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 methyl ethyl ketone; amides such as dimethylformamide and dimethylacetamide; sulfoxides such as dimethyl sulfoxide and sulfolane; and esters such as ethyl acetate. Typically, solvents are used for dissolving and diluting matrices, but they are also used for extraction, rinsing, column chromatography purification, HPLC, and recrystallization.

[0086] The reaction can proceed over a wide range of temperatures, and the precise reaction temperature is not critical to this invention. The preferred reaction temperature depends on factors such as the nature of the solvent and the starting material. However, the reaction is generally suitable for temperatures ranging from about 0°C to about 200°C. The reaction time also varies considerably, depending on many factors, particularly the reaction temperature and the nature of the starting material and the solvent. However, provided the reaction is carried out under the preferred conditions described above, the reaction period typically ranges from about 1 minute to about 72 hours.

[0087] The salts of the compounds used in this invention can be neutralized before being used in the reaction, or they can be used directly in the reaction.

[0088] All compounds can be prepared by the steps described in the following general methods section, by the specific methods illustrated in the examples section, or by conventional modifications of these methods. This invention includes not only one or more methods for preparing compounds of general formula (V), but also any novel intermediates used therein.

[0089] In the following general methods, unless otherwise specified, the descriptor (R) 1 R 2(Prot. and Hal.) as specified above for compounds of general formula (I). The starting materials in the following general synthesis can all be commercially available. In the following general methods, the starting materials and the synthesized compounds can be salted using an acid or base. When salting the starting materials, the reaction can also be carried out in the presence of an excess base, or by neutralization with an acid or base before the reaction.

[0090] <Option 1> {Chemical Formula 33} In step-1 of scheme 1, the compound of general formula (III) can be prepared by reacting a compound of general formula (I) with a compound of general formula (II) and a suitable reagent in the presence of a suitable base and in an inert solvent.

[0091] Examples of suitable reagents include, but are not limited to, Tf₂O, Ms₂O, MsCl, oxalyl chloride, TsCl, PCl₅, POCl₃ and SOCl₂.

[0092] Suitable bases include, but are not limited to, triethylamine, pyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine, N-methylmorpholine, and N,N-diisopropylethylamine.

[0093] Examples of suitable solvents include dichloromethane, THF, 1,4-dioxane, DMF, DMSO, MeCN, DMA, NMP, and toluene.

[0094] The reaction can be carried out at a temperature of about -20 to 200°C, more preferably at a temperature of about 0 to 40°C.

[0095] Typically, the reaction time is about 30 minutes to 48 hours, more preferably about 1 hour to 24 hours.

[0096] The molar ratio of compounds of general formula (I), compounds (II), suitable reagents and suitable bases is 1:0.7:1:1.5 to 1:3:6:12, but is not limited thereto.

[0097] In step-2 of scheme 1, compounds of general formula (IV) can be prepared by halogenation of compounds of general formula (III). Halogenation is carried out by reacting a compound of general formula (III) with a halogenating agent in a suitable solvent.

[0098] Examples of halogenating agents include, but are not limited to, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, N-chlorophthalimide, N-bromophthalimide, N-iodophthalimide, N-chlorosaccharin, N-bromosaccharin, N-iodosaccharin, 1,3-dichloro-5,5-dimethylallantoin, 1,3-dibromo-5,5-dimethylallantoin, 1,3-diiodo-5,5-dimethylallantoin, sodium dichloroisocyanurate, dibromoisocyanuric acid, trichloroisocyanuric acid, chlorine, bromine, and iodine.

[0099] Examples of suitable solvents include, but are not limited to, dichloromethane, THF, 1,4-dioxane, DMF, DMSO, MeCN, DMA, AcOH, and NMP.

[0100] The reaction can be carried out at a temperature of about -20 to 200°C, more preferably at a temperature of about 0 to 80°C.

[0101] Typically, the reaction time is about 30 minutes to 48 hours, more preferably about 1 hour to 24 hours.

[0102] The molar ratio of the compound of general formula (III) to the halogenating agent is 1:0.5 to 1:10, but is not limited to this.

[0103] <Option 2> {Chemical Formula 34} In Scheme 2, compounds of general formula (V) can be prepared from compounds of general formula (IV) in the presence of a suitable copper catalyst, a suitable ligand, and a suitable base, in an inert solvent, by cyclization and hydroxylation.

[0104] Examples of suitable copper catalysts include, but are not limited to, copper (0), copper acetate (I), copper bromide (I), copper chloride (I), copper iodide (I), copper oxide (I), copper trifluoromethanesulfonate (II), copper acetate (II), copper bromide (II), copper chloride (II), copper iodide (II), copper oxide (II), copper sulfate (II), copper tetra(acetonitrile)hexafluorophosphate (I), and copper acetylacetonate (II).

[0105] Examples of suitable ligands include, for example, 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, quinoline-8-ol, 1,10-phenanthroline, proline, and oxalyldiamine derivatives such as N1,N2-bis(4-hydroxy-2,6-dimethyl)oxalamide, N1,N2-bis(1-naphthylmethyl)glyoxalamide, N,N′-dibenzyloxalamide, N1,N2 - bis(2,4,6-trimethoxyphenyl)glyoxalamide and N,N′-bis(2-phenylethyl)glyoxalamide, 6-hydroxymethylpyridineamide derivatives such as N-(2,6-xylyl)-6-hydroxymethylpyridineamide, 6-hydroxy-N-(2,4,6-trimethoxyphenyl)methylpyridineamide, 6-hydroxy-N-(2-methylnaphthyl-1-yl)methylpyridineamide, 6-hydroxy-N-(naphthyl-1-yl)methylpyridineamide, N-([1,1'-biphenyl]-2-yl)-6-hydroxymethylpyridineamide, 6-hydroxy-N-(2-( Trifluoromethylphenyl)methylpyridineamide, 6-hydroxy-N-(o-tolyl)methylpyridineamide, 6-hydroxy-N-phenylmethylpyridineamide, 6-hydroxy-N-(thiophen-2-ylmethyl)methylpyridineamide, 6-hydroxy-N-(naphthyl-1-ylmethyl)methylpyridineamide, N-(2,6-diisopropylphenyl)-6-hydroxymethylpyridineamide, N-(2,6-difluorophenyl)-6-hydroxymethylpyridineamide, N-(2,6-dimethoxyphenyl)-6-hydroxymethylpyridineamide and 6-hydroxy-N-(4-hydroxy-2,6-dimethylphenyl) ) methylpyridine amide, 4-hydroxyquinoline-2-carboxyamide derivatives such as 4-hydroxy-N-phenylquinoline-2-carboxyamide and N-(2,6-dimethyl)-4-hydroxyquinoline-2-carboxyamide and 6-hydroxymethylpyridine hydrazide derivatives such as N-(1,3-dimethyl-9H-carbazole-9-yl)-6-hydroxymethylpyridine amide, N-(2,7-dimethyl-9H-carbazole-9-yl)-6-hydroxymethylpyridine amide and N-(2,7-di-tert-butyl-9H-carbazole-9-yl)-6-hydroxymethylpyridine amide, but not limited thereto.

[0106] Suitable bases include, but are not limited to, sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, tripotassium phosphate, cesium carbonate, potassium carbonate, and sodium carbonate.

[0107] Examples of suitable solvents or co-solvent mixtures include, but are not limited to, water, dichloromethane, THF, 1,4-dioxane, DMF, DMSO, sulfolane, MeCN, DMA, NMP, and toluene.

[0108] The reaction can be carried out at a temperature of about -20 to 200°C, more preferably at a temperature of about 60 to 150°C. Typically, the reaction time is about 30 minutes to 48 hours, more preferably about 3 hours to 24 hours.

[0109] The molar ratio of compounds of general formula (IV), suitable copper catalysts, suitable ligands and suitable bases is 1:0.01:0.01:1 to 1:5:5:30, but is not limited thereto.

[0110] <Option 3> {Chemical Formula 35} In Scheme 3, compounds of general formula (VIII) can be prepared by cyclization of compounds of general formula (IV) in the presence of a suitable copper or palladium catalyst, a suitable ligand, and a suitable base in an inert solvent.

[0111] Examples of suitable copper catalysts include, but are not limited to, copper (0), copper acetate (I), copper bromide (I), copper chloride (I), copper iodide (I), copper oxide (I), copper trifluoromethanesulfonate (II), copper acetate (II), copper bromide (II), copper chloride (II), copper iodide (II), copper oxide (II), copper sulfate (II), copper tetra(acetonitrile)hexafluorophosphate (I), and copper acetylacetonate (II).

[0112] Examples of suitable palladium catalysts include, but are not limited to, tetra(triphenylphosphine)palladium (0), bis(triphenylphosphine)chlorine (II), palladium acetate (II), palladium chloride (II), bis(acetonitrile)palladium (II), bis(dibenzylacetone)palladium (0), tri(dibenzylacetone)palladium (0), [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium (II).

[0113] Suitable examples of copper ligands include, for instance, 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, quinoline-8-ol, 1,10-phenanthroline, proline, and oxalyldiamine derivatives such as N1,N2-bis(4-hydroxy-2,6-dimethyl)oxalamide, N1,N2-bis(1-naphthylmethyl)glyoxalamide, N,N′-dibenzyloxalamide, N1,N... 2-Bis(2,4,6-trimethoxyphenyl)glyoxalamide and N,N′-bis(2-phenylethyl)glyoxalamide, 6-hydroxymethylpyridineamide derivatives such as N-(2,6-xylyl)-6-hydroxymethylpyridineamide, 6-hydroxy-N-(2,4,6-trimethoxyphenyl)methylpyridineamide, 6-hydroxy-N-(2-methylnaphthyl-1-yl)methylpyridineamide, 6-hydroxy-N-(naphthyl-1-yl)methylpyridineamide, N-([1,1'-biphenyl]-2-yl)-6-hydroxymethylpyridineamide, 6-hydroxy-N-(2- (trifluoromethyl)phenyl)methylpyridine amide, 6-hydroxy-N-(o-tolyl)methylpyridine amide, 6-hydroxy-N-phenylmethylpyridine amide, 6-hydroxy-N-(thiophen-2-ylmethyl)methylpyridine amide, 6-hydroxy-N-(naphthyl-1-ylmethyl)methylpyridine amide, N-(2,6-diisopropylphenyl)-6-hydroxymethylpyridine amide, N-(2,6-difluorophenyl)-6-hydroxymethylpyridine amide, N-(2,6-dimethoxyphenyl)-6-hydroxymethylpyridine amide and 6-hydroxy-N-(4-hydroxy-2,6-xylene) (2,6-dimethyl)-4-hydroxyquinoline-2-carboxylic amide, 4-hydroxyquinoline-2-carboxylic amide derivatives such as 4-hydroxy-N-phenylquinoline-2-carboxylic amide and N-(2,6-dimethyl)-4-hydroxyquinoline-2-carboxylic amide, and 6-hydroxymethylpyridinyl hydrazine derivatives such as N-(1,3-dimethyl-9H-carbazole-9-yl)-6-hydroxymethylpyridinyl amide, N-(2,7-dimethyl-9H-carbazole-9-yl)-6-hydroxymethylpyridinyl amide and N-(2,7-di-tert-butyl-9H-carbazole-9-yl)-6-hydroxymethylpyridinyl amide, but not limited thereto.

[0114] Additionally, 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (Xantphos), triphenylphosphine, tri-tert-butylphosphine, 1,1'-bis(diphenylphosphino)ferrocene, tri-2-furanylphosphine, tri-o-tolylphosphine, triphenylarsine, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), 2-(dichlorohexylphosphino)biphenyl (CyJohnPhos), 2-(dicyclohexyl) Phosphinyl-2'-(dimethylamino)biphenyl (DavePhos), 2-dicyclohexylphosphinyl-2',4',6'-triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphinyl-2',6'-dimethoxybiphenyl (SPhos), 2-di-tert-butylphosphinyl-2',4',6'-triisopropylbiphenyl (tBuXPhos), and 2-(di-tert-butylphosphinyl)biphenyl (JohnPhos).

[0115] Suitable bases include, but are not limited to, sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, tripotassium phosphate, cesium carbonate, potassium carbonate, sodium carbonate, and sodium bicarbonate.

[0116] Examples of suitable solvents or co-solvent mixtures include, but are not limited to, water, dichloromethane, THF, 1,4-dioxane, DMF, DMSO, MeCN, DMA, NMP, and toluene.

[0117] The reaction can be carried out at a temperature of about -20 to 200°C, more preferably at a temperature of about 60 to 130°C. Typically, the reaction time is about 30 minutes to 48 hours, more preferably about 3 hours to 24 hours.

[0118] The molar ratio of compounds of general formula (IV), suitable copper catalysts, suitable ligands and suitable bases is 1:0.01:0.01:1 to 1:5:5:10, but is not limited thereto.

[0119] <Option 4> {Chemical Formula 36} In Scheme 4, compounds of general formula (V) can be prepared by hydroxylation of compounds of general formula (VIII) in the presence of a suitable copper catalyst, a suitable ligand and a suitable base in an inert solvent.

[0120] Examples of suitable copper catalysts include, but are not limited to, copper (0), copper acetate (I), copper bromide (I), copper chloride (I), copper iodide (I), copper oxide (I), copper trifluoromethanesulfonate (II), copper acetate (II), copper bromide (II), copper chloride (II), copper iodide (II), copper oxide (II), copper sulfate (II), copper tetra(acetonitrile)hexafluorophosphate (I), and copper acetylacetonate (II).

[0121] Examples of suitable ligands include, for example, 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, quinoline-8-ol, 1,10-phenanthroline, proline, and oxalyldiamine derivatives such as N1,N2-bis(4-hydroxy-2,6-dimethyl)oxalamide, N1,N2-bis(1-naphthylmethyl)glyoxalamide, N,N′-dibenzyloxalamide, N1,N2 - bis(2,4,6-trimethoxyphenyl)glyoxalamide and N,N′-bis(2-phenylethyl)glyoxalamide, 6-hydroxymethylpyridineamide derivatives such as N-(2,6-xylyl)-6-hydroxymethylpyridineamide, 6-hydroxy-N-(2,4,6-trimethoxyphenyl)methylpyridineamide, 6-hydroxy-N-(2-methylnaphthyl-1-yl)methylpyridineamide, 6-hydroxy-N-(naphthyl-1-yl)methylpyridineamide, N-([1,1'-biphenyl]-2-yl)-6-hydroxymethylpyridineamide, 6-hydroxy-N-(2-( Trifluoromethylphenyl)methylpyridineamide, 6-hydroxy-N-(o-tolyl)methylpyridineamide, 6-hydroxy-N-phenylmethylpyridineamide, 6-hydroxy-N-(thiophen-2-ylmethyl)methylpyridineamide, 6-hydroxy-N-(naphthyl-1-ylmethyl)methylpyridineamide, N-(2,6-diisopropylphenyl)-6-hydroxymethylpyridineamide, N-(2,6-difluorophenyl)-6-hydroxymethylpyridineamide, N-(2,6-dimethoxyphenyl)-6-hydroxymethylpyridineamide and 6-hydroxy-N-(4-hydroxy-2,6-dimethylphenyl) ) methylpyridine amide, 4-hydroxyquinoline-2-carboxyamide derivatives such as 4-hydroxy-N-phenylquinoline-2-carboxyamide and N-(2,6-dimethyl)-4-hydroxyquinoline-2-carboxyamide and 6-hydroxymethylpyridine hydrazide derivatives such as N-(1,3-dimethyl-9H-carbazole-9-yl)-6-hydroxymethylpyridine amide, N-(2,7-dimethyl-9H-carbazole-9-yl)-6-hydroxymethylpyridine amide and N-(2,7-di-tert-butyl-9H-carbazole-9-yl)-6-hydroxymethylpyridine amide, but not limited thereto.

[0122] Suitable bases include, but are not limited to, sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, tripotassium phosphate, cesium carbonate, and potassium carbonate.

[0123] Examples of suitable solvents or co-solvent mixtures include, but are not limited to, water, dichloromethane, THF, 1,4-dioxane, DMF, DMSO, MeCN, DMA, NMP, and toluene.

[0124] The reaction can be carried out at a temperature of about -20 to 200°C, more preferably at a temperature of about 60 to 130°C. Typically, the reaction time is about 30 minutes to 48 hours, more preferably about 3 hours to 24 hours.

[0125] The molar ratio of the compound of general 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 thereto.

[0126] Example Throughout this application, the abbreviations used have the following meanings: Ac: Acetyl group Bn: Benzyl DABCO: 1,4-diazabicyclo[2.2.2]octane DBN: 1,5-diazabicyclo[4.3.0]non-5-ene DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DCM: Dichloromethane DMA: N,N-dimethylacetamide DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide ESI: Electroionization EtOAc: Ethyl acetate HPLC: High Performance Liquid Chromatography LC: Liquid Chromatography LG: Detachment from the base MeCN: Acetonitrile MeOH: Methanol MHz: megahertz MS: Mass spectrometry Ms: Methanesulfonyl group Ms2O: Mesylate anhydride NMR: Nuclear Magnetic Resonance NMP: N-methylpyrrolidone rt: room temperature t BuOMe: tert-butyl methyl ether TEA: Triethylamine Tf: Trifluoromethanesulfonyl group TFA: Trifluoroacetic acid Tf2O: Trifluoromethanesulfonic anhydride THF: Tetrafluorofuran Ts: Toluenesulfonyl group UPLC: Ultimate Liquid Chromatography UV: Ultraviolet light Mass spectrometry (ESI) data were obtained using a Waters ACQUITYUPLC H-Class equipped with a QDa mass spectrometer and an ACQUITY PDA detector. NMR data, unless otherwise specified, were determined at 400 MHz (JNM-ECZ400S, JEOLLtd.) using deuterated chloroform (99.8% D) or dimethyl sulfoxide (99.9% D) as solvent and tetramethylsilane (TMS) as an internal standard, in parts per million (ppm), with each peak having an error range of + / - 0.05 ppm. Previous abbreviations used are: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad peak, etc. Chemical symbols have their general meanings: M (mol / L), L (liter), mL (milliliter), g (gram), mg (milligram), mol (molar), mmol (millimole).

[0127] The invention is illustrated in the following non-limiting examples, wherein all reagents are commercially available unless otherwise stated, all operations are performed at room temperature or ambient temperature, i.e., in the range of about 18–25°C; reactions are monitored by LC-MS, and the reaction times given are for illustrative purposes only; the structure and purity of all isolated compounds are determined by at least one of the following techniques: mass spectrometry or NMR. The yields provided are for illustrative purposes only. Column chromatography was performed using Biotage SNAP KP-Sil and Biotage SNAP Isolute NH2. Residual metals in the reaction can be removed as needed using a suitable metal removal agent. The compounds were purified using reverse-phase HPLC under the following apparatus and conditions.

[0128] HPLC: Device: Waters MS-trigger AutoPurification (registered trademark) system Column: Waters XBridge C8, 19mm × 50mm, 5μm particle or Waters XBridge C18, 19mm × 50mm, 5μm particle Mobile phase: (A) 0.05% (v / v) ammonia solution, (B) MeCN Flow rate: 20 mL / min Gradient: A / B (95 / 5) to A / B (5 / 95) within 5 minutes The compounds prepared are usually named according to ChemDraw (version 19.1, PerkinElmer Informatics).

[0129] Synthesis section The present invention will be further described in detail using the following embodiments, but these do not limit the invention.

[0130] Compounds 1, 2, 5 and 6 include all geometric isomers and tautomers.

[0131] Example 1 (Synthesis of compound 3: benzimidazole intermediate (BI)) Compound 3: 1-Benzyl-4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazol-6-carboxamide {Chemical Formula 37} <Step-1>: Synthesis of 4-((1-(benzylamino)ethylene)amino)-N,N-dimethylbenzamide (Compound 2) {Chemical Formula 38} Tf₂O (8.34 g, 29.6 mmol) was added to a solution of N-benzylacetamide (4.01 g, 26.9 mmol) and pyridine (4.78 mL, 59.1 mmol) in DCM (100 mL) at 0 °C under a nitrogen atmosphere. The mixture was stirred at room temperature for 2 hours. Then, 4-amino-N,N-dimethylbenzamide (4.41 g, 26.9 mmol) and pyridine (4.78 mL, 59.1 mmol) were added to the reaction mixture at room temperature. The mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After the reaction was complete, saturated sodium bicarbonate aqueous solution (150 mL) was added to the mixture, and the mixture was stirred at room temperature for 20 minutes. The organic layer was separated. The aqueous layer was extracted with DCM (50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to obtain compound 2 (10.1 g) as crude oil. This crude oil was used directly in the next step without further purification.

[0132] 1 H-NMR (400MHz, CDCl3) delta 7.40-7.26 (7H,m), 6.79 (2H,d,J=7.8Hz), 4.73 (1H,br s), 4.53 (2H,d,J=4.1Hz), 3.05 (6H,br s), 1.81 (3H,s).

[0133] MS (ESI) m / z: 296.4 (M+H) + .

[0134] <Step-2>: Synthesis of 4-(N'-benzylacetamidine)-3,5-dibromo-N,N-dimethylbenzamide (Compound 1) {Chemical Formula 39} At 0 °C, N-bromosuccinimide (10.05 g, 56.5 mmol) was added to a solution of 4-((1-(benzylamino)ethylene)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). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated. The residual solid was purified by amino gel column chromatography and dissolved in 0-50% EtOAc / hexane. After evaporation of the solvent, heptane (30 mL) was slowly added to the residue in EtOAc (15 mL) at room temperature. A precipitate appeared. The precipitate was collected and dried under vacuum to obtain compound 1 as a solid (7.96 g, 65.3% yield, derived from 4-amino-N,N-dimethylbenzamide).

[0135] 1 H-NMR (400MHz, 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).

[0136] MS (ESI) m / z: 454.1 (M+H) + .

[0137] <Step-3>: Synthesis of 1-benzyl-4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazolium-6-carboxamide (compound 3) {Chemical Formula 40} A mixture of compound 1 (200 mg, 0.441 mmol) in DMSO (0.44 mL), N1,N2-bis(4-hydroxy-2,6-dimethyl)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) was stirred at 110 °C for 13 hours in a sealed tube. After the reaction was complete, a saturated ammonium chloride aqueous solution was added to the mixture. The resulting mixture was extracted with DCM-MeOH (5:1, 3 mL, 3 times). The combined organic layers were concentrated. The resulting residue was purified by silica gel column chromatography and dissolved in 0-5% MeOH / DCM to obtain compound 3 as a solid (51 mg, 37.4% yield).

[0138] 1 H-NMR (400MHz, DMSO-d6) delta 9.99 (1H,s), 7.37-7.24 (3H,m), 7.12 (2H,d,J=7.8Hz), 6.96 (1H,s), 6.55 (1H,s), 5.45 (2H,s), 2.90 (6H,br s), 2.52 (3H, s).

[0139] MS (ESI) m / z: 310.4 (M+H) + .

[0140] Substitution reaction from compound 1 to compound 3 using 6-hydroxy-N-(4-hydroxy-2,6-dimethylphenyl)methylpyridine amide as a ligand Preparation of 6-hydroxy-N-(4-hydroxy-2,6-dimethylphenyl)methylpyridine amide as a ligand At 0 °C, propyl phosphoric anhydride (over 50 wt% in EtOAc, 10.8 mL) was added to a solution of 6-hydroxypyridinecarboxylic acid (2.00 g, 14.38 mmol), 4-amino-3,5-xylenol (2.07 g, 15.10 mmol), and TEA (4.01 mL, 28.80 mmol) in THF (10 mL). The mixture was stirred at room temperature for 2 hours. 2 mol / L NaOH and water were added to the mixture (adjusted to pH 4–6). The mixture was extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was suspended in MeOH-water (30 mL–40 mL). The mixture was stirred at room temperature for 3 days. The precipitate was collected and used… tBuOMe was washed. The solid was vacuum dried to obtain 6-hydroxy-N-(4-hydroxy-2,6-dimethylphenyl)methylpyridine amide as a solid (1.02 g, 27.5% yield).

[0141] 1 H-NMR (400MHz, DMSO-d6) delta 11.12 (1H,brs), 9.57 (1H,s), 9.25 (1H,s), 7.72 (1H,t,J=7.3Hz), 7.29 (1H,s), 6.75 (1H,d,J=8.2Hz), 6.51 (2H,s), 2.07 (6H,s).

[0142] MS (ESI) m / z: 259.3 (M+H) + .

[0143] A mixture of compound 1 (5.00 g, 11.03 mmol), 6-hydroxy-N-(4-hydroxy-2,6-dimethylphenyl)methylpyridineamide (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) was degassed three times with nitrogen. The mixture was stirred at 80 °C for one day under a nitrogen atmosphere. Separately, 6-hydroxy-N-(4-hydroxy-2,6-dimethylphenyl)methylpyridineamide (285 mg, 1.10 mmol) and CuI (105 mg, 0.552 mmol) were added to the reaction mixture at room temperature. The mixture was stirred at 80 °C for 7.5 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature and poured into a saturated aqueous solution of ammonium chloride (150 mL). A precipitate formed. The resulting mixture was stirred at room temperature for one day. The precipitate was collected and dried under vacuum. The solid (3.80 g) was suspended in DCM (38 mL). The mixture was filtered using a diatomaceous earth pad, and the filter cake was washed with DCM (100 mL). The filtrate was concentrated to give a brown solid (3.42 g). The solid (3.42 g) was suspended in EtOAc (34 mL) and stirred at 80 °C for 3 hours. After cooling to room temperature, the solid was collected and dried to give compound 3 as a solid (2.65 g, 78.0% yield).

[0144] 1H-NMR (400MHz, DMSO-d6) delta 9.94 (1H, brs ),7.38-7.21(3H,m),7.12(2H,d,J=7.3Hz),6.96(1H,s),6.53(1H,s),5.44(2H,s),2.90(6H,s),2.51(3H,s).

[0145] MS (ESI) m / z: 310.2 (M+H) + .

[0146] Example 2 (Benzimidazole intermediate (BI): Synthesis of compound 4) Compound 4: 1-Benzyl-4-bromo-N,N,2-trimethyl-1H-benzo[d]imidazol-6-carboxamide {Chemical Formula 41} A mixture of compound 1 (300 mg, 0.662 mmol) in DMSO (0.66 mL), 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) was stirred at 110 °C for 1 day in a sealed tube. After the reaction was complete, 10% ammonia (3 mL) was added to the mixture. The resulting mixture was extracted with EtOAc (3 mL, twice). The combined organic layers were concentrated. The resulting residue was purified by silica gel column chromatography and dissolved in 50% EtOAc / DCM to obtain compound 4 (205 mg, 83% yield) as a gel.

[0147] 1 H-NMR (400MHz, CDCl3) delta 7.50 (1H,d,J=1.4Hz), 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).

[0148] MS (ESI) m / z: 372.3 (M+H) + .

[0149] Example 3 (Synthesis of benzimidazole intermediate (BI): Compound 7) Compound 7: 1-Benzyl-4-hydroxy-2-methyl-1H-benzo[d]imidazol-6-carboxylic acid {Chemical Formula 42} <Step-1>: Synthesis of methyl 4-((1-(benzylamino)ethylene)amino)benzoate (compound 6) {Chemical Formula 43} Tf₂O (3.12 g, 11.06 mmol) was added to a solution of N-benzylacetamide (1.50 g, 10.05 mmol) and 2,6-dimethylpyridine (2.34 mL, 20.11 mmol) in DCM (30 mL) at 0 °C under a nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour. Then, methyl 4-aminobenzoate (1.67 g, 11.06 mmol) was added to the reaction mixture at room temperature. The mixture was stirred at room temperature for 1 day under a nitrogen atmosphere. After the reaction was complete, a saturated aqueous solution of sodium bicarbonate was added to the mixture and stirred at room temperature for 20 minutes. The organic layer was separated. The aqueous layer was extracted with DCM. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to obtain compound 6 (5.21 g) as crude oil. This crude oil was used directly in the next step without further purification.

[0150] MS (ESI) m / z: 283.3 (M+H) + .

[0151] <Step-2>: Synthesis of methyl 4-(N'-benzylacetamidine)-3,5-dibromobenzoate (compound 5) {Chemical Formula 44} At room temperature, N-bromosuccinimide (7.16 g, 40.2 mmol) was added to a solution of methyl 4-((1-(benzylamino)ethylene)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). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated. The residual solid was purified by silica gel column chromatography and dissolved in 0-15% EtOAc / hexane. After evaporation of the solvent, the residual solid was suspended in diisopropyl ether. The precipitate was collected and dried under vacuum to obtain compound 5 as a solid (1.12 g, 25.3% yield, derived from methyl 4-aminobenzoate).

[0152] 1H-NMR (400MHz, CDCl3) delta 8.19(2H,s),7.45(2H,d,J=7.3Hz),7.37(2H,t,J=7.3Hz),7.31(1H,d,J=7.3Hz),4.66(2H,d,J=4.6Hz),3.90(3H,s),2.91(1H,br s),1.77(3H,br s).

[0153] MS (ESI) m / z: 441.1 (M+H) + .

[0154] <Step-3>: Synthesis of 1-benzyl-4-hydroxy-2-methyl-1H-benzo[d]imidazolium-6-carboxylic acid (compound 7) {Chemical Formula 45} A mixture of compound 5 (50 mg, 0.114 mmol) in DMSO (0.23 mL), N1,N2-bis(4-hydroxy-2,6-xylyl)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) was stirred at 110 °C for 5 hours in a sealed tube. After the reaction was complete, 10% citric acid aqueous solution was added to the mixture. The precipitate was collected. The solid was purified by reverse-phase HPLC to obtain compound 7 as a solid (4.1 mg, 12.8% yield).

[0155] 1 ¹H-NMR (400MHz, 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 = 7.3Hz), 5.49 (²H, s), 2.54 (³H, s). (No proton signal observed for -COOH) MS (ESI) m / z: 283.3 (M+H) + .

[0156] Example 4 (Proportional scaling synthesis of compound 3 (BI)) Compound 3: 1-Benzyl-4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazol-6-carboxamide {Chemical Formula 46} <Step-1>: Synthesis of 4-((1-(benzylamino)ethylene)amino)-N,N-dimethylbenzamide (Compound 2) {Chemical Formula 47} Tf₂O (22.0 mL, 134 mmol) was added to a solution of N-benzylacetamide (18.2 g, 122 mmol) and pyridine (21.7 mL, 268 mmol) in DCM (200 mL) over 10 minutes at 0 °C under a nitrogen atmosphere. The mixture was stirred at room temperature for 2 hours. Then, 4-amino-N,N-dimethylbenzamide (20.0 g, 122 mmol) and pyridine (21.7 mL, 268 mmol) were added to the reaction mixture at 0 °C. The mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After the reaction was complete, a saturated aqueous solution of sodium bicarbonate (200 mL) was added to the mixture and stirred at room temperature for 20 minutes. The organic layer was separated. The aqueous layer was extracted with DCM (50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to obtain compound 2 (58.7 g) as crude oil. This crude oil was used directly in the next step without further purification.

[0157] 1 H-NMR (400MHz, CDCl3) delta 7.30-7.26 (7H,m), 7.04 (2H,t,J=7.8Hz), 4.72 (1H,br s), 4.57 (2H,br s), 3.11-2.96 (6H,m), 2.13 (3H,s).

[0158] MS (ESI) m / z: 296.4 (M+H) + .

[0159] <Step-2>: Synthesis of 4-(N'-benzylacetamidine)-3,5-dibromo-N,N-dimethylbenzamide (Compound 1) {Chemical Formula 48} At 0 °C, 1,3-dibromo-5,5-dimethylallantoin (36.6 g, 128 mmol) was added to a solution of 4-((1-(benzylamino)ethylene)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). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated. 2 mol / L NaOH aqueous solution (150 mL) and... tBuOMe / EtOAc / MeCN (1:1:1, 660 mL). The organic layer was separated. The aqueous layer was then... t Extraction was performed using BuOMe (110 mL). The combined organic layers were washed with brine (110 mL). The organic layers were dried with sodium sulfate, filtered, and concentrated to obtain crude oil (58.9 g). The crude oil (58.9 g) was passed through an amino gel (Chromatorex: registered trademark) pad (75 g, dissolved in EtOAc (1250 mL)). The filtrate was concentrated. The residue was dissolved in EtOAc (100 mL). Heptane (400 mL) was slowly added to the solution at room temperature. A precipitate appeared. The suspension was stirred at room temperature for 1 day. The precipitate was collected, washed with 20% EtOAc in heptane (100 mL), and dried under vacuum to obtain compound 1 as a solid (42.7 g, 77.0% yield, derived from 4-amino-N,N-dimethylbenzamide).

[0160] 1 H-NMR (400MHz, CDCl3) delta 7.59 (2H,s), 7.45 (2H,d,J=7.3Hz), 7.36 (2H,t,J=7.3Hz), 7.30 (1H,d,J=7.3Hz), 4.89 (1H,br s), 4.66 (2H, d, J = 4.6Hz), 3.05 (6H, br s), 1.76 (3H, s).

[0161] MS (ESI) m / z: 454.1 (M+H) + .

[0162] <Step-3>: Synthesis of 1-benzyl-4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazolium-6-carboxamide (compound 3) {Chemical Formula 49} A mixture of compound 1 (20.00 g, 44.1 mmol), N1,N2-bis(4-hydroxy-2,6-dimethyl)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) was degassed five times with nitrogen. The mixture was stirred at 120 °C for 3 hours under a nitrogen atmosphere. After the reaction was complete, 10 mL of a 2 mol / L NaOH aqueous solution was added to the mixture, which had cooled to room temperature. The mixture was then... tBuOMe was washed (50 mL, 3 times). The aqueous layer was poured into a saturated ammonium chloride solution (800 mL) and water (100 mL). A precipitate appeared. The resulting mixture was stirred at room temperature for 3 days. The precipitate was collected and dried under vacuum. The solid (13.17 g) was suspended in DCM (86 mL). The mixture was filtered using a diatomaceous earth pad, and the filter cake was washed with DCM (100 mL). The filtrate was concentrated to give a brown solid (11.12 g). The solid (11.12 g) was suspended in EtOAc (111 mL) and stirred at 80 °C for 2 hours. After cooling to room temperature, the solid was collected and dried to give compound 3 as a solid (8.01 g, 58.7% yield).

[0163] 1 H-NMR (400MHz, DMSO-d6) delta 9.94 (1H, brs ),7.38-7.20(3H,m),7.12(2H,d,J=6.9Hz),7.01(1H,brs),6.50(1H,brs),5.46(2H,s),2.90(6H,s),2.50(3H,s).

[0164] MS (ESI) m / z: 310.2 (M+H) + .

[0165] All publications cited in this application, including but not limited to published patents, patent applications, and journal articles, are incorporated herein by reference in their entirety. The invention has been described above with reference to the disclosed embodiments; however, those skilled in the art will readily understand that the detailed embodiments described are merely illustrative. It should be understood that various modifications can be made without departing from the spirit of the invention. Therefore, the invention is limited only to the scope of the following claims.

[0166] Industrial availability This invention relates to a method for preparing a benzimidazole derivative, a method for preparing an intermediate used in the method, and a novel intermediate. The benzimidazole derivative can be used as a pharmaceutical product, particularly as an acid secretion inhibitor. In particular, this invention relates to a method for preparing tegorazone.

Claims

1. A method for preparing a compound represented by general formula (IX) or a pharmaceutically acceptable salt thereof, comprising the following steps: (1) Reacting a compound represented by general formula (I) with a compound represented by general formula (II) to obtain a compound represented by general formula (III); (2) Halogenating a compound represented by general formula (III) to obtain a compound represented by general formula (IV); (3) Cycling a compound represented by general formula (IV) to obtain a compound represented by general formula (V); and (4) Reacting a compound represented by general formula (V) with a compound represented by general formula (VI) to obtain a compound represented by general formula (VII); in, R 1 -N (C 1-6 alkyl) (C 1-6 Alkyl groups), of which 2 (C 1-6 Alkyl groups can form 4-6 membered heterocyclic groups, -OC 1-6 Alkyl or hydroxyl; R 2 C 1-6 Alkyl; R 3 and R 4 Independently for C 1-6 Alkyl or halogen; and Prot. is a protecting group. {Chemical Formula 1} ， {Chemical Formula 2} ， {Chemical Formula 3} ， {Chemical Formula 4} ， {Chemical Formula 5} ， {Chemical Formula 6} ， {Chemical Formula 7} ， {Chemical Formula 8} 。 2. A method for preparing a compound represented by general formula (III) or a salt thereof, {Chemical Formula 9} ， It includes the step of reacting a compound represented by general formula (I) with a compound represented by general formula (II) to obtain a compound represented by general formula (III) or a salt thereof. in, R 1 and R 2 As specified in claim 1; and Prot. is a protecting base.

3. A method for preparing a compound represented by general formula (IV) or a salt thereof, comprising the step of halogenating a compound represented by general formula (III) to obtain a compound represented by general formula (IV), in, R 1 and R 2 As specified in claim 1; and Prot. is a protecting base, {Chemical Formula 10} 。 4. A method for preparing a compound represented by general formula (V) or a salt thereof, comprising the step of cyclizing a compound represented by general formula (IV) to obtain a compound represented by general formula (V), in, R 1 and R 2 As specified in claim 1; and Prot. is a protecting base, {Chemical Formula 11} 。 5. A method for preparing a compound represented by general formula (IX) or a pharmaceutically acceptable salt thereof, comprising one or two of the following steps: (1) To react a compound represented by general formula (I) with a compound represented by general formula (II) to obtain a compound represented by general formula (III); and (3) Cyclate the compound represented by general formula (IV) to obtain the compound represented by general formula (V); in, R 1 and R 2 As specified in claim 1; and Prot. is a protecting base.

6. A method for preparing a compound represented by general formula (IX) or a pharmaceutically acceptable salt thereof, comprising the following steps: (1) Reacting a compound represented by general formula (I) with a compound represented by general formula (II) to obtain a compound represented by general formula (III); (2) Halogenating a compound represented by general formula (III) to obtain a compound represented by general formula (IV); (3a) Cyclate the compound represented by general formula (IV) to obtain the compound represented by general formula (VIII); and (4a) Reacting a compound represented by general formula (VIII) with a compound represented by general formula (VI) to obtain a compound represented by general formula (VII); Among them, R 1 -N (C 1-6 alkyl) (C 1-6 Alkyl groups), of which 2 (C 1-6 Alkyl groups can form 4-6 membered heterocyclic groups, -OC 1-6 Alkyl or hydroxyl; R 2 C 1-6 Alkyl; R 3 and R 4 Independently for C 1-6 Alkyl or halogen; and Prot. is a protecting group. {Chemical Formula 12} 。 7. A method for preparing a compound represented by general formula (VIII) or a salt thereof, comprising the step of cyclizing a compound represented by general formula (IV) to obtain a compound represented by general formula (VIII); in, R 1 and R 2 As specified in claim 6; and Prot. is a protecting base, {Chemical Formula 13} 。 8. A method for preparing a compound or a salt thereof represented by general formula (IX), comprising the following steps: (3a) Cyclate the compound represented by general formula (IV) to obtain the compound represented by general formula (VIII); in, R 1 -N (C 1-6 alkyl) (C 1-6 Alkyl groups), of which 2 (C 1-6 Alkyl groups can form 4-6 membered heterocyclic groups, -OC 1-6 Alkyl, C 1-6 Alkyl or hydroxyl; R 2 C 1-6 Alkyl; R 3 and R 4 Independently for C 1-6 Alkyl or halogen; and Prot. is a protecting group. {Chemical Formula 14} ， {Chemical Formula 15} 。 9. The method according to any one of claims 1 to 8, wherein, R 1 It is -N(methyl)2 and R 2 It is a methyl group.

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, dimethylbenzyl, 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, R 3 and R 4 It is fluorine.

12. The method according to any one of claims 1 to 8, wherein, Cyclization occurs in the presence of a metal catalyst and ligands.

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

14. The method according to claim 12, wherein, The ligand is selected from the following: 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, quinoline-8-ol, 1,10-phenanthroline, proline, and oxalyldiamine derivatives such as N1,N2-bis(4-hydroxy-2,6-dimethyl)oxalamide, N1,N2-bis(1-naphthylmethyl)glyoxalamide, N,N′-dibenzyloxalamide, N1,N2-bis(4-hydroxy-2,6-dimethyl) ... (2,4,6-Trimethoxyphenyl)glyoxalamide and N,N′-bis(2-phenylethyl)glyoxalamide, 6-hydroxymethylpyridineamide derivatives such as N-(2,6-xylyl)-6-hydroxymethylpyridineamide, 6-hydroxy-N-(2,4,6-trimethoxyphenyl)methylpyridineamide, 6-hydroxy-N-(2-methylnaphth-1-yl)methylpyridineamide, 6-hydroxy-N-(naphth-1-yl)methylpyridineamide, N-([1,1'-biphenyl]-2-yl)-6-hydroxymethylpyridineamide, 6-hydroxy-N-(2-(trifluoro) Methylphenyl)methylpyridine amide, 6-hydroxy-N-(o-tolyl)methylpyridine amide, 6-hydroxy-N-phenylmethylpyridine amide, 6-hydroxy-N-(thiophen-2-ylmethyl)methylpyridine amide, 6-hydroxy-N-(naphth-1-ylmethyl)methylpyridine amide, N-(2,6-diisopropylphenyl)-6-hydroxymethylpyridine amide, N-(2,6-difluorophenyl)-6-hydroxymethylpyridine amide, N-(2,6-dimethoxyphenyl)-6-hydroxymethylpyridine amide and 6-hydroxy-N-(4-hydroxy-2,6-xylyl) One or more of the following groups: methylpyridine amide, 4-hydroxyquinoline-2-carboxyamide derivatives such as 4-hydroxy-N-phenylquinoline-2-carboxyamide and N-(2,6-dimethyl)-4-hydroxyquinoline-2-carboxyamide and 6-hydroxymethylpyridine hydrazide derivatives such as N-(1,3-dimethyl-9H-carbazole-9-yl)-6-hydroxymethylpyridine amide, N-(2,7-dimethyl-9H-carbazole-9-yl)-6-hydroxymethylpyridine amide and N-(2,7-di-tert-butyl-9H-carbazole-9-yl)-6-hydroxymethylpyridine amide.

15. The method according to any one of claims 1, 5, 6, 8, 9, and 10, wherein, The general formula (IX) is a (S)-chiral compound represented by the general formula (X). {Chemical Formula 16} 。 16. The method according to claim 15, wherein, The chiral compound represented by the general formula (X) is tegorazan; wherein R 1 -N(methyl)2; R 2 It is methyl; and R 3 and R 4 It is fluorine.

17. A compound represented by general formula (III) or a geometrical isomer, tautomer, or salt thereof: {Chemical Formula 17} ， in, R 1 -N (C 1-6 alkyl) (C 1-6 Alkyl groups), of which 2 (C 1-6 Alkyl groups can form 4-6 membered heterocyclic groups, -OC 1-6 Alkyl, C 1-6 Alkyl or hydroxyl; R 2 C 1-6 Alkyl group; and Prot. is a protecting group.

18. A compound represented by general formula (IV), its geometric isomers, tautomers, or salts: {Chemical Formula 18} ， in, R 1 -N (C 1-6 alkyl) (C 1-6 Alkyl groups), of which 2 (C 1-6 Alkyl groups can form 4-6 membered heterocyclic groups, -OC 1-6 Alkyl, C 1-6 Alkyl or hydroxyl; R 2 C 1-6 Alkyl group; and Prot. is a protecting group.

19. Use of a compound represented by general formula (III), a compound represented by general formula (IV), or a pharmaceutically acceptable salt thereof as an intermediate compound in the preparation of a compound represented by general formula (IX): {Chemical Formula 19} ， {Chemical Formula 20} ， {Chemical Formula 21} ， in, R 1 -N (C 1-6 alkyl) (C 1-6 Alkyl groups), of which 2 (C 1-6 Alkyl groups can form 4-6 membered heterocyclic groups, -OC 1-6 Alkyl, C 1-6 Alkyl or hydroxyl; R 2 C 1-6 Alkyl; R 3 and R 4 Independently for C 1-6 Alkyl or halogen; and Prot. is a protecting group.

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

21. A preparation process for a pharmaceutical composition, wherein, The process includes mixing the compound of claim 17 or 18 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

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