JP2010106017A - Pharmaceutical containing fused bicyclic heteroaryl derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a novel pharmaceutical containing a fused bicyclic heteroaryl derivative or a pharmacologically acceptable salt thereof, which has excellent blood sugar lowering effect and is effective in treating diseases of glycogen metabolism and lipid metabolism, or diseases in which peroxisome proliferator activated receptor (PPAR)γ participates and/or in preventing the onset of these diseases. <P>SOLUTION: The pharmaceutical includes a compound shown by general formula (I) or a pharmacologically acceptable salt thereof. In the formula, R<SP>1</SP>is a 1C-6C alkyl group, and a 6C-10C aryl group or the like which is a group selected from a substituent group (a) and in which one to five may be independently substituted; R<SP>2</SP>is a 1C-6C alkyl group; R<SP>3</SP>is a 6C-10C aryl group or the like which is a group selected from the substituent group (a) and in which one or five may be independently substituted; Q is a group shown by formula =CH- or a nitrogen atom; the substituent group (a) consists of a halogen atom, a 1C-6C alkyl group, a 1C-6C hydroxyalkyl group or the like. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a novel condensed bicyclic that prevents the treatment and / or the onset of a pharmaceutical, particularly a blood sugar-lowering effect, or a saccharide and lipid metabolism disease, or a disease mediated by peroxisome activated receptor (PPAR) γ. The present invention relates to a medicament containing a heteroaryl derivative or a pharmacologically acceptable salt thereof as an active ingredient.

  In addition, the present invention provides a sugar / lipid metabolism improving action, an insulin resistance improving action, an anti-inflammatory action, or a cancer cell growth inhibition containing a novel condensed bicyclic heteroaryl derivative or a pharmacologically acceptable salt thereof as an active ingredient. Diabetes (especially type II diabetes), hyperglycemia, hyperlipidemia, obesity, impaired glucose tolerance, insulin resistance, fasting glycemia, cachexia, psoriasis, diabetic complications, arteriosclerosis Disease, atherosclerosis, hypertension, pancreatitis, polycystic ovary syndrome, fatty liver, nonalcoholic cirrhosis (NASH), gestational diabetes, inflammatory disease, cancer, osteoporosis, degenerative osteoporosis, neurodegenerative disease, Alzheimer's disease The present invention relates to a therapeutic and / or prophylactic agent for hyperuricemia, metabolic syndrome and the like.

  In recent years, patients with metabolic syndrome such as type II diabetes, hyperinsulinemia, abnormal lipid metabolism, obesity, hypertension, and arteriosclerotic diseases are increasing all over the world due to changes in lifestyle. Patients with metabolic syndrome have several times the risk of coronary artery disease, cerebral infarction, and cerebral hemorrhage, and further develop chronic complications such as nephropathy, neuropathy, and retinopathy. The increase in the number of patients with complications is a major factor that raises medical costs (Non-patent Document 1).

  Furthermore, in recent studies, ligands that act on PPARγ have been used to prevent or improve pathological conditions called metabolic syndromes such as type II diabetes, hyperinsulinemia, lipid metabolism disorders, obesity, hypertension, arteriosclerotic diseases, and insulin resistance. It has become clear that it is useful (Non-Patent Document 2). Moreover, the ligand which acts on PPARγ suppresses the production of inflammatory cytokines (Non-patent Documents 3 and 4) and induces apoptosis to suppress the proliferation of cancer cells (Non-patent Document 5). It is also useful for the prevention and improvement of diseases and cancer. Specific examples of ligands that activate PPARγ include pioglitazone (Non-patent Document 6) and rosiglitazone (Non-patent Document 7) classified into thiazolidinedione drugs already used in the treatment of type II diabetes. It is done. Since these thiazolidinedione drugs have side effects such as fluid retention, weight gain, and increased risk of heart disease, development of safer pharmaceuticals is desired (Patent Document 1). Currently, many researchers are researching ligands that activate or suppress PPARα, γ, or δ, and research and development of pharmaceuticals aimed at preventing or improving diseases and metabolic syndrome caused by insulin resistance, inflammation, etc. (Non-patent Document 8).

International Publication No. 2004/014308 Pamphlet

Annual Reports in Medicinal Chemistry, 39, 41-56 (2004). Annual Reviews of Medicine, 53, 409-435 (2002). Nature, 391, 79-82 (1998). Nature, 391, 82-86 (1998). Biochemical and Biophysical Research Communications, 270, 400-405 (2000). Chem. Pharm. Bull., 39, 1440-1445 (1991). Bioorganic and Medicinal Chemistry Letter, 4, 1181-1184 (1994). Annual Report in Medicinal Chemistry, 38, 71-80 (2003).

  The present inventors have conducted intensive research for the purpose of developing therapeutic and / or preventive drugs for sugar and lipid metabolic diseases or diseases mediated by peroxisome-activated receptor (PPAR) γ, and have a specific chemical structure. The fused bicyclic heteroaryl derivative has a good blood glucose lowering effect, or the so-called glucose / lipid metabolism improving effect, insulin resistance improving effect, arteriosclerosis, hypertension, cardiovascular disorder, complications derived from these, etc. Since it has an action to improve pathological conditions caused by metabolic syndrome and various types of inflammation, and since this compound is a Ligand that acts on PPARγ, it has been found that it has a cancer cell growth inhibitory action. completed.

  That is, the present invention relates to metabolic syndrome, that is, diabetes (particularly type II diabetes), hyperglycemia, hyperlipidemia, obesity, impaired glucose tolerance (IGT), insulin resistance, fasting blood glucose. Impaired fasting glucose (IFG), hypertension, fatty liver, non-alcoholic cirrhosis (NASH), diabetic complications (eg retinopathy, nephropathy, neuropathy), arteriosclerosis, gestational diabetes mellitus: GDM), diseases such as polycystic ovary syndrome (PCOS), inflammatory diseases (eg osteoarthritis, pain, inflammatory bowel disease, etc.), acne, sunburn, psoriasis, eczema, allergic diseases, asthma, digestive tract Ulcer, ulcerative colitis, Crohn's disease, coronary artery disease, arteriosclerosis, atherosclerosis, diabetic retinopathy, diabetic macular disease, macular edema, diabetic nephropathy, ischemic heart disease, cerebrovascular disorder, peripheral Circulation Harm, autoimmune diseases (eg systemic lupus erythematosus, rheumatoid arthritis, Sjogren's syndrome, systemic scleroderma, mixed connective tissue disease, Hashimoto's disease, Crohn's disease, ulcerative colitis, idiopathic Addison disease, male infertility, Goodpasture syndrome, acute progressive glomerulonephritis, myasthenia gravis, multiple myositis, multiple sclerosis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, Behcet's disease, CREST syndrome, etc.), pancreatitis, evil Fluid, cancer (eg, stomach cancer, lung cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, liver cancer), leukemia, sarcoma (eg, liposarcoma), osteoporosis, degenerative osteoporosis, neurodegenerative disease, Alzheimer's disease, high Provided is a medicament containing a novel condensed bicyclic heteroaryl derivative or a pharmacologically acceptable salt thereof as an active ingredient, which is useful as a therapeutic or prophylactic agent for uricemia and dry eye.

  The present invention relates to (1) general formula (I)

[Where:
R ¹ is selected from a C ₁ -C ₆ alkyl group, a C ₆ -C ₁₀ aryl group that may be independently substituted with a group selected from the substituent group a, and a substituent group a. 1 to independently a group indicates three optionally substituted heterocyclic group, or C ₃ -C ₆ cycloalkyl,
R ² represents a C ₁ -C ₆ alkyl group,
R ³ is independently 1 to 5 C ₆ -C ₁₀ aryl groups which may be independently substituted with a group selected from substituent group a or 1 to 3 groups independently selected from substituent group a And represents an optionally substituted heterocyclic group,
Q represents a group represented by the formula = CH- or a nitrogen atom,
Substituent group a represents a halogen _atom, C 1 -C _{6 alkyl,} C 1 -C ₆ hydroxyalkyl _group, C 1 -C ₆ halogenated alkyl group, a carboxyl group, a carbamoyl _group, C 2 -C ₇ alkylcarbonyl group , _C 2 -C ₇ alkoxycarbonyl group, hydroxy _group, C 1 -C ₆ alkoxy _group, C 1 -C ₆ halogenated alkoxy _group, C 2 -C ₇ alkylcarbonyloxy _group, C 2 -C ₇ alkoxycarbonyloxy group , amino _group, C 2 -C ₇ alkylcarbonylamino _group, C 2 -C ₇ alkoxycarbonylamino _group, C 1 -C ₆ alkylsulfonylamino group, 4-morpholinyl Moto及busy - _(C 1 -C ₆ alkyl) amino A group consisting of groups is shown. Or a pharmacologically acceptable salt thereof as an active ingredient.

In the present invention, preferably,
(2) In (1),
R ¹ is independently a group selected from 1-ethylpropyl group, (halogen atom, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ halogenated alkoxy group and amino group) Or a pharmacologically acceptable salt thereof, which is a phenyl group or 2,3-dihydro-1-benzofuran-6-yl group optionally substituted by 1 to 3 as an active ingredient.

(3) In (1),
R ¹ is 1-ethylpropyl group, 2-fluorophenyl group, 3-fluorophenyl group, 3-chlorophenyl group, 2,5-difluorophenyl group, 4-chloro-3-fluorophenyl group, 3-chloro-4 -Fluorophenyl group, 4-methylphenyl group, 3-ethylphenyl group, 3,4-dimethylphenyl group, 3-trifluoromethoxyphenyl group, 3-methoxyphenyl group, 3-methoxy-4-methylphenyl group, 4 -A pharmaceutical comprising a compound which is an amino-3,5-dimethylphenyl group or a 2,3-dihydro-1-benzofuran-6-yl group or a pharmacologically acceptable salt thereof as an active ingredient.

(4) In (1),
R ¹ is a 2-fluorophenyl group, a 3-fluorophenyl group, a 3-chlorophenyl group, a 2,5-difluorophenyl group, a 4-chloro-3-fluorophenyl group, a 3-chloro-4-fluorophenyl group, 4 -A pharmaceutical comprising a compound which is a methylphenyl group or a 2,3-dihydro-1-benzofuran-6-yl group or a pharmacologically acceptable salt thereof as an active ingredient.

(5) In any one item selected from (1) to (4),
A pharmaceutical comprising, as an active ingredient, a compound wherein R ² is a methyl group and Q is a group represented by the formula = CH- or a pharmacologically acceptable salt thereof.

(6) In any one item selected from (1) to (5),
A pharmaceutical comprising a compound wherein R ³ is a phenyl group substituted with 1 to 3 fluorine atoms and / or a carboxyl group or a pharmacologically acceptable salt thereof as an active ingredient.

(7) In any one item selected from (1) to (5),
R ³ is medicine containing 3-carboxyphenyl group or 3-carboxy-5 compound or a pharmacologically acceptable salt thereof is a fluorophenyl group as an active ingredient.

(8) R ¹ is selected from 1-ethylpropyl group, (halogen atom, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ halogenated alkoxy group and amino group). A phenyl group or a 2,3-dihydro-1-benzofuran-6-yl group which may be independently substituted with 1 to 3 groups independently, R ² is a methyl group, and R ³ is 1 to 3 Containing as an active ingredient a compound or a pharmacologically acceptable salt thereof, which is a phenyl group substituted with one fluorine atom and / or carboxyl group, and Q is a group represented by the formula = CH- or a nitrogen atom Medicine.

(9) R ¹ is 1-ethylpropyl group, 2-fluorophenyl group, 3-fluorophenyl group, 3-chlorophenyl group, 2,5-difluorophenyl group, 4-chloro-3-fluorophenyl group, 3- Chloro-4-fluorophenyl group, 4-methylphenyl group, 3-ethylphenyl group, 3,4-dimethylphenyl group, 3-trifluoromethoxyphenyl group, 3-methoxyphenyl group, 3-methoxy-4-methylphenyl A 4-amino-3,5-dimethylphenyl group or a 2,3-dihydro-1-benzofuran-6-yl group, R ² is a methyl group, and R ³ is a 3-carboxylphenyl group or A compound or a pharmacologically acceptable salt thereof, which is a 3-carboxyl-5-fluorophenyl group and Q is a group represented by the formula = CH- or a nitrogen atom. A medicine containing as an active ingredient.

(10) R ¹ is 2-fluorophenyl group, 3-fluorophenyl group, 3-chlorophenyl group, 2,5-difluorophenyl group, 4-chloro-3-fluorophenyl group, 3-chloro-4-fluorophenyl A 4-methylphenyl group or a 2,3-dihydro-1-benzofuran-6-yl group, R ² is a methyl group, and R ³ is a 3-carboxylphenyl group or 3-carboxyl-5- A pharmaceutical comprising a compound or a pharmacologically acceptable salt thereof as an active ingredient which is a fluorophenyl group and Q is a group represented by the formula = CH-.

(11) A compound having the general formula (I)
3-{[6- (3-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid,
3- [6- (3-chlorophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzoic acid,
3-{[6- (4-chloro-3-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid,
3-{[6- (3-chloro-4-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid,
3-{[6- (4-amino-3,5-dimethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid,
3-{[6- (1-ethylpropoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid,
3-{[6- (2-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid,
3-{[1-methyl-6- (4-methylphenoxy) -1H-benzimidazol-2-yl] methoxy} benzoic acid,
3-{[6- (3-ethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid,
3-{[6- (3-methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid,
3-({1-methyl-6- [3- (trifluoromethoxy) phenoxy] -1H-benzimidazol-2-yl} methoxy) benzoic acid,
3-{[6- (2,5-difluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid,
3-{[6- (3,4-dimethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid,
3-{[6- (3-methoxy-4-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid,
3-{[6- (2,3-dihydro-1-benzofuran-6-yloxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid,
3-{[3-methyl-5- (4-methylphenoxy) -3H-imidazo [4,5-b] pyridin-2-yl] methoxy} benzoic acid,
3-fluoro-5-{[3-methyl-5- (4-methylphenoxy) -3H-imidazo [4,5-b] pyridin-2-yl] methoxy} benzoic acid, or
3-{[5- (3,4-dimethylphenoxy) -3-methyl-3H-imidazo [4,5-b] pyridin-2-yl] methoxy} benzoic acid or a compound thereof according to (1) A pharmaceutical comprising a pharmacologically acceptable salt as an active ingredient.

(12) A compound having the general formula (I)
3-{[6- (3-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid,
3- [6- (3-chlorophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzoic acid,
3-{[6- (4-chloro-3-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid,
3-{[6- (3-chloro-4-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid,
3-{[6- (2-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid,
3-{[1-methyl-6- (4-methylphenoxy) -1H-benzimidazol-2-yl] methoxy} benzoic acid,
3-{[6- (2,5-difluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid, or
3-{[6- (2,3-dihydro-1-benzofuran-6-yloxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid or a compound thereof according to (1) A pharmaceutical comprising a pharmacologically acceptable salt as an active ingredient.

(13) A compound having the general formula (I)
3-{[6- (3-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid,
3- [6- (3-chlorophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzoic acid,
3-{[6- (4-chloro-3-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid,
3-{[6- (3-chloro-4-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid,
3-{[6- (2-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid,
3-{[1-methyl-6- (4-methylphenoxy) -1H-benzimidazol-2-yl] methoxy} benzoic acid,
3-{[6- (2,5-difluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid, or
3-{[6- (2,3-dihydro-1-benzofuran-6-yloxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid is effective as a compound according to (1) Pharmaceuticals contained as an ingredient.

  (14) A pharmaceutical comprising the compound described in any one of (1) to (13) or a pharmacologically acceptable salt thereof as an active ingredient.

  (15) The medicament according to (14), wherein the medicament activates PPARγ.

  (16) The medicament according to (14), wherein the medicament is for treatment and / or prevention of a disease caused by enhanced PPARγ inhibition.

  (17) The medicament according to (14), wherein the medicament is for reducing blood sugar.

  (18) The medicament according to (14), wherein the medicament is for the treatment and / or prevention of diabetes.

  (19) The medicament according to (14), wherein the medicament is for the treatment and / or prevention of type II diabetes.

  (20) The medicament according to (14), wherein the medicament improves sugar / lipid metabolism, improves insulin resistance, suppresses inflammation, or suppresses cancer cell proliferation.

  (21) The medicament according to (14), wherein the medicament is for the treatment and / or prevention of diseases caused by metabolic syndrome.

  (22) The drug is hyperglycemia, hyperlipidemia, obesity, glucose intolerance, insulin resistance, fasting glycemia, hypertension, fatty liver, nonalcoholic cirrhosis, diabetic complications, arteriosclerosis, Atherosclerosis, gestational diabetes mellitus, polycystic ovary syndrome, inflammatory disease, cancer, osteoporosis, regressive osteoporosis, neurodegenerative disease, Alzheimer's disease, hyperuricemia, acne, sunburn, psoriasis, eczema, allergic disease, Asthma, gastrointestinal ulcer, ulcerative colitis, Crohn's disease, coronary artery disease, arteriosclerosis, atherosclerosis, diabetic retinopathy, diabetic macular disease, macular edema, diabetic nephropathy, ischemic heart disease, cerebrovascular The medicament according to (14) for the treatment and / or prevention of disorders, peripheral circulatory disorders, autoimmune diseases, pancreatitis, cachexia, leukemia, sarcoma, or dry eye.

(23) A PPARγ activator / modulator containing the compound described in any one of (1) to (13) or a pharmacologically acceptable salt thereof as an active ingredient.

In the present invention, the “C ₁ -C ₆ alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl , 2-methylpentyl, 1-methylpentyl, or 3,3-dimethylbutyl group, R ¹ is preferably a 1-ethylpropyl group, and in others, preferably 1 to 4 carbon atoms. A linear or branched alkyl group (C ₁ -C ₄ alkyl group), more preferably a methyl group or an ethyl group (C ₁ -C ₂ alkyl group), and even more preferably methyl. It is a group.

In the present invention, the “C ₃ -C ₆ cycloalkyl group” is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, and preferably a cyclopentyl group.

  In the present invention, the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferable is a fluorine atom or a chlorine atom.

In the present invention, the “C ₁ -C ₆ hydroxyalkyl group” is a group in which a hydroxy group is bonded to the “C ₁ -C ₆ alkyl group”. For example, a hydroxymethyl, hydroxyethyl or hydroxypropyl group, preferably a group in which the hydroxy group is bonded to a linear or branched alkyl group having 1 to 4 carbon atoms (C ₁ substituted with a hydroxy group). a -C ₄ alkyl group), more preferably a hydroxymethyl group or a 2-hydroxyethyl group, even more preferably more, a hydroxymethyl group.

In the present invention, the “C ₁ -C ₆ halogenated alkyl group” is a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C ₁ -C ₆ alkyl group”. For example, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl or 2-fluoro An ethyl group, preferably a group (C ₁ -C ₄ halogenated alkyl group) in which the same or different 1 to 5 “halogen atoms” are bonded to the “C ₁ -C ₄ alkyl group”. More preferably, the same or different 1 to 5 “halogen atoms” are groups bonded to the “C ₁ -C ₂ alkyl group” (C ₁ -C ₂ halogenated alkyl group), and more Preferred is a trifluoromethyl group.

In the present invention, the “C ₂ -C ₇ alkylcarbonyl group” is a group in which the “C ₁ -C ₆ alkyl group” is bonded to a carbonyl group. For example, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl or isovaleryl group, preferably a group in which the “C ₁ -C ₄ alkyl group” is bonded to a carbonyl group (C ₂ -C ₅ alkylcarbonyl) a group), more preferably an acetyl group or a propionyl group (C ₂ -C ₃ alkylcarbonyl group), even more preferably more, an acetyl group.

In the present invention, the “C ₁ -C ₆ alkoxy group” is a group in which the “C ₁ -C ₆ alkyl group” is bonded to an oxygen atom, and is a linear or branched alkoxy group having 1 to 6 carbon atoms. It is. For example, a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy or 2-methylbutoxy group, preferably a linear or branched chain having 1 to 4 carbon atoms An alkoxy group (C ₁ -C ₄ alkoxy group), more preferably a methoxy group or an isopropoxy group.

In the present invention, the “C ₂ -C ₇ alkoxycarbonyl group” is a group in which the “C ₁ -C ₆ alkoxy group” is bonded to a carbonyl group. For example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl or pentoxycarbonyl group, preferably the above-mentioned “C ₁ -C ₄ ” An “alkoxy group” is a group bonded to a carbonyl group (C ₂ -C ₅ alkoxycarbonyl group), more preferably a methoxycarbonyl group or an ethoxycarbonyl group (C ₂ -C ₃ alkoxycarbonyl group), and even more A methoxycarbonyl group is preferred.

In the present invention, the “C ₁ -C ₆ halogenated alkoxy group” is a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C ₁ -C ₆ alkoxy group”. For example, a trifluoromethoxy, trichloromethoxy, difluoromethoxy, fluoromethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 2-bromoethoxy, 2-chloroethoxy or 2-fluoroethoxy group Yes, preferably a group (C ₁ -C ₄ halogenated alkoxy group) in which the same or different 1 to 5 “halogen atoms” are bonded to the “C ₁ -C ₄ alkoxy group”, and more preferably Are groups (C ₁ -C ₂ halogenated alkoxy groups) in which the same or different 1 to 5 “halogen atoms” are bonded to the “C ₁ -C ₂ alkoxy group”, and more preferably , A trifluoromethoxy group.

In the present invention, the “C ₂ -C ₇ alkylcarbonyloxy group” is a group in which the “C ₂ -C ₇ alkylcarbonyl group” is bonded to an oxygen atom. For example, an acetoxy, propionyloxy, butyryloxy or isobutyryloxy group, preferably a group in which the “C ₂ -C ₅ alkylcarbonyl group” is bonded to an oxygen atom (C ₂ -C ₅ alkylcarbonyloxy group) And more preferably an acetoxy group or a propionyloxy group (C ₂ -C ₃ alkylcarbonyloxy group), and still more preferably an acetoxy group.

In the present invention, the “C ₂ -C ₇ alkoxycarbonyloxy group” is a group in which the “C ₂ -C ₇ alkoxycarbonyl group” is bonded to an oxygen atom. For example, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, isopropoxycarbonyloxy, butoxycarbonyloxy or isobutoxycarbonyloxy group, preferably the “C ₂ -C ₅ alkoxycarbonyl group” is an oxygen atom. A bonded group (C ₂ -C ₅ alkoxycarbonyloxy group), more preferably a methoxycarbonyloxy group or an ethoxycarbonyloxy group (C ₂ -C ₃ alkoxycarbonyloxy group), and even more preferably. , A methoxycarbonyloxy group.

In the present invention, the “C ₂ -C ₇ alkylcarbonylamino group” is a group in which one carbonyl group bonded to the “C ₁ -C ₆ alkyl group” is bonded to an amino group. For example, an acetamido, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino or butylcarbonylamino group, preferably a carbonyl group to which one of the above “C ₁ -C ₄ alkyl groups” is bonded is bonded to an amino group. a the group _(C 2 -C ₅ alkylcarbonylamino group), more preferably a acetamide group or an ethyl carbonyl amino group _(C 2 -C ₃ alkylcarbonylamino group).

In the present invention, the “C ₂ -C ₇ alkoxycarbonylamino group” is a group in which one carbonyl group bonded to the “C ₁ -C ₆ alkoxy group” is bonded to an amino group. For example, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, isopropoxycarbonylamino, butoxycarbonylamino, isobutoxycarbonylamino or s-butoxycarbonylamino group, preferably the above-mentioned “C ₁ -C ₄ alkoxy group” Is a group (C ₂ -C ₅ alkoxycarbonylamino group) bonded to an amino group, more preferably a methoxycarbonylamino group or an ethoxycarbonylamino group (C ₂ -C ₃ alkoxycarbonyl). Amino group), and more preferably a methoxycarbonylamino group.

In the present invention, the “C ₁ -C ₆ alkylsulfonylamino group” is a group in which one sulfonyl group to which the “C ₁ -C ₆ alkyl group” is bonded is bonded to an amino group. For example, it is a methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino or butylsulfonylamino group, and preferably a sulfonyl group to which one of the aforementioned “C ₁ -C ₄ alkyl groups” is bonded is an amino group. A group bonded to (mono-C ₁ -C ₄ alkylsulfonylamino group), more preferably a methylsulfonylamino group or an ethylsulfonylamino group (mono-C ₁ -C ₂ alkylsulfonylamino group), Even more preferred is a methylsulfonylamino group.

In the present invention, the “di- (C ₁ -C ₆ alkyl) amino group” is a group in which two identical or different “C ₁ -C ₆ alkyl groups” are bonded to an amino group. For example, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, dipentylamino, diisopentylamino, dineopentylamino, dihexylamino, N-ethyl-N-methylamino, N-methyl-N -Propylamino, N-isopropyl-N-methylamino, N-butyl-N-methylamino, N-isobutyl-N-methylamino, N-methyl-N-pentylamino, N-isopentyl-N-methylamino, N -Ethyl-N-propylamino, N-ethyl-N-isopropylamino, N-butyl-N-ethylamino or N-ethyl-N-isopentylamino groups, preferably the same or different two group _"C 1 -C ₄ alkyl group" is bonded to an amino group (di - _{(C 1} C ₄ alkyl) amino group), more preferably, dimethylamino group, diethylamino group or N- ethyl -N- methylamino group (di- - a _(C 1 -C ₂ alkyl) amino group), even more A dimethylamino group is preferred.

In the present invention, the “C ₆ -C ₁₀ aryl group” is an aromatic hydrocarbon group having 6 to 10 carbon atoms. Preferable is a phenyl group or a naphthyl group, and more preferable is a phenyl group.

  In the present invention, the “heterocyclic group” contains 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, and may further contain 1 or 2 nitrogen atoms, and the sulfur atom contains 2 oxygen atoms. A 4- to 7-membered heterocyclic group to which atoms may be bonded. For example, a group such as furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl group `` Aromatic heterocyclic groups '', tetrahydropyranyl, tetrahydrothienyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, pyrazolidinyl, dioxolanyl or dioxanyl groups A partially or fully reduced saturated heterocyclic group ”, and the heterocyclic group may be another ring such as a benzene ring. May be condensed with a group ("fused bicyclic heteroaryl group"), for example, benzothienyl, benzothiazolyl, benzoxazolyl, isobenzofuranyl, 1,3-dihydroisobenzofuranyl, quinolyl, 1,3-benzodioxolanyl, 1,4-benzodioxanyl, indolyl, isoindolyl or indolinyl group, preferably a 6-membered complex containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms A cyclic group or a fused bicyclic heteroaryl group, more preferably a pyridyl group, a morpholinyl group, a tetrahydro-2H-pyran group, a 2,3-dihydro-1-benzofuran group, or a 1,3-benzodioxole group And more preferably 3-pyridyl group, 4-morpholinyl group, tetrahydro-2H-pyran-4-yl group, 2,3-dihydride It is a ro-1-benzofuran-6-yl group or a 1,3-benzodioxol-5-yl group, and particularly preferably a 2,3-dihydro-1-benzofuran-6-yl group.

In the present invention, the “C ₆ -C ₁₀ aryl group optionally substituted with 1 to 5 groups independently selected from the substituent group a” is independently 1 with a group selected from the substituent group a. Or the above-mentioned “C ₆ -C ₁₀ aryl group” which may be substituted. In R ¹ , a group selected from a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ halogenated alkoxy group and an amino group is preferably independently 1 to 3 A phenyl group which may be substituted, more preferably 2-fluorophenyl group, 3-fluorophenyl group, 3-chlorophenyl group, 2,5-difluorophenyl group, 4-chloro-3-fluorophenyl. Group, 3-chloro-4-fluorophenyl group, 4-methylphenyl group, 3-ethylphenyl group, 3,4-dimethylphenyl group, 3-trifluoromethoxyphenyl group, 3-methoxyphenyl group, 3-methoxy- 4-methylphenyl group or 4-amino-3,5-dimethylphenyl group, and even more preferably, 2-fluorophenyl group, 3-fluorophenyl group, Group, 3-chlorophenyl group, a 2,5-difluorophenyl group, 4-chloro-3-fluorophenyl group, 3-chloro-4-fluorophenyl group or a 4-methylphenyl group, in ^{R 3,} suitably Is a phenyl group substituted with 1 to 3 fluorine atoms and / or a carboxyl group, more preferably a 3-carboxylphenyl group or a 3-carboxyl-5-fluorophenyl group.

In the present invention, “a heterocyclic group optionally substituted with 1 to 3 groups independently selected from the substituent group a” is independently substituted with 1 to 3 groups independently selected from the substituent group a. And the above-mentioned “heterocyclic group”. Preferably, a pyridyl group, a pyridyl group, a tetrahydro-2H-pyran-4-yl group, tetrahydrofuran-3, each independently substituted with 1 to 3 groups selected from a halogen atom and a C ₁ -C ₆ alkoxy group. ―Ile group,
2,3-dihydro-1-benzofuran-6-yl group or 1,3-benzodioxol-5-yl group, more preferably 2,3-dihydro-1-benzofuran-6-yl group It is.

In the present invention, R ¹ is preferably a 1-ethylpropyl group (a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ halogenated alkoxy group, or an amino group). R ¹ is a phenyl group or 2,3-dihydro-1-benzofuran-6-yl group which may be independently substituted with 1 to 3 groups independently, and more preferably R ¹ is a 1-ethylpropyl group, 2-fluorophenyl group, 3-fluorophenyl group, 3-chlorophenyl group, 2,5-difluorophenyl group, 4-chloro-3-fluorophenyl group, 3-chloro-4-fluorophenyl group, 4-methylphenyl group 3-ethylphenyl group, 3,4-dimethylphenyl group, 3-trifluoromethoxyphenyl group, 3-methoxyphenyl group, 3-methoxy-4-methylphenyl , 4-amino-3,5-a-dimethylphenyl group or a 2,3-dihydro-1-benzofuran-6-yl group, even more preferred ^{R 1} is 2-fluorophenyl group, 3-fluorophenyl group, 3-chlorophenyl group, 2,5-difluorophenyl group, 4-chloro-3-fluorophenyl group, 3-chloro-4-fluorophenyl group, 4-methylphenyl group or 2,3-dihydro-1-benzofuran-6 -An yl group.

In the present invention, preferred R ² is a methyl group.

In the present invention, preferred R ³ is a phenyl group substituted with 1 to 3 fluorine atoms and / or a carboxyl group, and more preferred R ³ is a 3-carboxylphenyl group or 3-carboxyl-5. -A fluorophenyl group.

  In the present invention, Q is preferably a group represented by the formula = CH-.

  The condensed bicyclic heteroaryl derivative having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may be any isomer (keto-enol isomer, diastereoisomer, optical isomer, rotational isomer). Etc.).

  The condensed bicyclic heteroaryl derivative having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has various isomers since an asymmetric carbon atom is present in the molecule. In the compounds of the present invention, these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Therefore, the present invention includes all of these isomers and a mixture of these isomers in an arbitrary ratio.

  For the stereoisomer as described above, an optically active raw material compound is used, or a compound according to the present invention is synthesized using an asymmetric synthesis or asymmetric induction method, or a synthesized compound according to the present invention is synthesized. If desired, it can be obtained by isolation using a conventional optical resolution method or separation method.

The condensed bicyclic heteroaryl derivative having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof also contains an unnatural proportion of atomic isotopes at one or more of the atoms constituting such a compound. obtain. The atomic isotopes such as deuterium ⁽² H), tritium ⁽³ H), and the like iodine -125 ⁽¹²⁵ I) or carbon -14 ⁽¹⁴ C). In addition, the compound can be radiolabeled with a radioisotope such as tritium ( ³ H), iodine-125 ( ¹²⁵ I) or carbon-14 ( ¹⁴ C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.

  “Pharmaceutically acceptable salt thereof” refers to a salt that has no significant toxicity and can be used as a medicine. When the condensed bicyclic heteroaryl derivative having the general formula (I) of the present invention has a basic group such as an amino group, it is reacted with an acid, and an acidic group such as a carboxyl group is also reacted. When it has, it can be made into a salt by reacting with a base.

  Preferred salts based on basic groups are preferably hydrohalides such as hydrofluorates, hydrochlorides, hydrobromides, hydroiodides; nitrates, perchlorates, sulfuric acids. Inorganic acid salts such as salts and phosphates; alkyl sulfonates such as methane sulfonate and ethane sulfonate; halogenated alkyl sulfonates such as trifluoromethane sulfonate; benzene sulfonate, p- Aryl sulfonates such as toluene sulfonate; or acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate Such organic acid salts can be mentioned.

  On the other hand, the salt based on an acidic group is preferably an alkali metal salt such as sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as calcium salt or magnesium salt; or aluminum salt or iron salt. And metal salts such as

  The condensed bicyclic heteroaryl derivative having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is allowed to stand in the atmosphere, absorbs moisture in a purification or preparation process, and has adsorbed water or water. In some cases, such hydrates are also included in the salts of the present invention.

  The condensed bicyclic heteroaryl derivative having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may absorb a certain other solvent and become a solvate. Japanese salts are also included in the salts of the present invention.

  Specific examples of the compound having the general formula (I) of the present invention include the compounds shown in Table 1 below, but the present invention is not limited to these groups.

In Table 1 below, the meanings of the abbreviations are as follows. That is,
Me represents a methyl group,
Et represents an ethyl group,
1-Et-Pr represents a 1-ethylpropyl group,
Cypent represents a cyclopentyl group,
Ph represents a phenyl group,
_3-CO 2 _H-Ph represents a 3-carboxyphenyl group,
4-Mor represents a 4-morpholinyl group,
_{5-CO 2 H-3-} Py represents a 5-carboxy-3-pyridyl group,
Het (A) represents a tetrahydro-2H-pyran-4-yl group,
Het (B) represents a tetrahydrofuran-3-yl group,
Het (C) represents a 2,3-dihydro-1-benzofuran-6-yl group,
Het (D) represents a 1,3-benzodioxol-5-yl group.

  (Table 1)

――――――――――――――――――――――――――――――
Compound number R ¹ QR ³
――――――――――――――――――――――――――――――
1-1 Et = CH- 2-CO ₂ H-Ph
1-2 Et = CH- 2-CO ₂ Et-Ph
1-3 Et = CH- 3-CO ₂ H-Ph
1-4 Et = CH- 3-CO ₂ Me-Ph
1-5 Et = CH- 4-CO ₂ H-Ph
1-6 Et = CH- 4-CO ₂ Et-Ph
1-7 Et = CH- 5-CO ₂ H-3-Py
1-8 Et = CH- 5-CO ₂ Me-3-Py
_{1-9 Et N 2-CO 2 H} -Ph
1-10 Et N 2-CO ₂ Et-Ph
1-11 Et N 3-CO ₂ H-Ph
1-12 Et N 3-CO ₂ Me-Ph
1-13 Et N 4-CO ₂ H-Ph
1-14 Et N 4-CO ₂ Et-Ph
1-15 Et N 5-CO ₂ H-3-Py
1-16 Et N 5-CO ₂ Me-3-Py
1-17 Ph = CH- 2-CO ₂ H-Ph
1-18 Ph = CH- 2-CO ₂ Et-Ph
_{1-19 Ph = CH- 3-CO 2} H-Ph
1-20 Ph = CH- 3-CO ₂ Me-Ph
1-21 Ph = CH- 4-CO ₂ H-Ph
1-22 Ph = CH- 4-CO ₂ Et-Ph
1-23 Ph = CH-5-CO ₂ H-3-Py
1-24 Ph = CH-5-CO ₂ Me-3-Py
1-25 Ph N 2-CO ₂ H-Ph
1-26 Ph N 2-CO ₂ Et-Ph
1-27 Ph N 3-CO ₂ H-Ph
1-28 Ph N 3-CO ₂ Me-Ph
_{1-29 Ph N 4-CO 2 H} -Ph
1-30 Ph N 4-CO ₂ Et-Ph
1-31 Ph N 5-CO ₂ H-3-Py
1-32 Ph N 5-CO ₂ Me-3-Py
1-33 3-F-Ph = CH- 2-CO ₂ H-Ph
1-34 3-F-Ph = CH- 2-CO ₂ Et-Ph
1-35 3-F-Ph = CH- 3-CO ₂ H-Ph
1-36 3-F-Ph = CH- 3-CO ₂ Me-Ph
1-37 3-F-Ph = CH- 4-CO ₂ H-Ph
1-38 3-F-Ph = CH- 4-CO ₂ Et-Ph
1-39 3-F-Ph = CH-5-CO ₂ H-3-Py
1-40 3-F-Ph = CH-5-CO ₂ Me-3-Py
1-41 3-F-Ph N 2-CO ₂ H-Ph
1-42 3-F-Ph N 2-CO ₂ Et-Ph
1-43 3-F-Ph N 3-CO ₂ H-Ph
1-44 3-F-Ph N 3-CO ₂ Me-Ph
1-45 3-F-Ph N 4-CO ₂ H-Ph
1-46 3-F-Ph N 4-CO ₂ Et-Ph
1-47 3-F-Ph N 5-CO ₂ H-3-Py
1-48 3-F-Ph N 5-CO ₂ Me-3-Py
1-49 3-Cl-Ph = CH- 2-CO ₂ H-Ph
1-50 3-Cl-Ph = CH- 2-CO ₂ Et-Ph
1-51 3-Cl-Ph = CH- 3-CO ₂ H-Ph
1-52 3-Cl-Ph = CH- 3-CO ₂ Me-Ph
1-53 3-Cl-Ph = CH- 4-CO ₂ H-Ph
1-54 3-Cl-Ph = CH- 4-CO ₂ Et-Ph
1-55 3-Cl-Ph = CH-5-CO ₂ H-3-Py
1-56 3-Cl-Ph = CH-5-CO ₂ Me-3-Py
1-57 3-Cl-Ph N 2-CO ₂ H-Ph
1-58 3-Cl-Ph N 2-CO ₂ Et-Ph
1-59 3-Cl-Ph N 3-CO ₂ H-Ph
1-60 3-Cl-Ph N 3-CO ₂ Me-Ph
1-61 3-Cl-Ph N 4-CO ₂ H-Ph
1-62 3-Cl-Ph N 4-CO ₂ Et-Ph
1-63 3-Cl-Ph N 5-CO ₂ H-3-Py
1-64 3-Cl-Ph N 5-CO ₂ Me-3-Py
1-65 3- (4-Mor) -Ph = CH- 2-CO ₂ H-Ph
1-66 3- (4-Mor) -Ph = CH- 2-CO ₂ Et-Ph
1-67 3- (4-Mor) -Ph = CH-3-CO ₂ H-Ph
1-68 3- (4-Mor) -Ph = CH-3-CO ₂ Me-Ph
1-69 3- (4-Mor) -Ph = CH- 4-CO ₂ H-Ph
1-70 3- (4-Mor) -Ph = CH- 4-CO ₂ Et-Ph
1-71 3- (4-Mor) -Ph = CH-5-CO ₂ H-3-Py
1-72 3- (4-Mor) -Ph = CH-5-CO ₂ Me-3-Py
1-73 3- (4-Mor) -Ph N 2-CO ₂ H-Ph
1-74 3- (4-Mor) -Ph N 2-CO ₂ Et-Ph
1-75 3- (4-Mor) -Ph N 3-CO ₂ H-Ph
1-76 3- (4-Mor) -Ph N 3-CO ₂ Me-Ph
1-77 3- (4-Mor) -Ph N 4-CO ₂ H-Ph
1-78 3- (4-Mor) -Ph N 4-CO ₂ Et-Ph
1-79 3- (4-Mor) -Ph N 5-CO ₂ H-3-Py
1-80 3- (4-Mor) -Ph N 5-CO ₂ Me-3-Py
1-81 2,4-Cl ₂ -Ph = CH- 2-CO ₂ H-Ph
1-82 2,4-Cl ₂ -Ph = CH- 2-CO ₂ Et-Ph
1-83 2,4-Cl ₂ -Ph = CH-3-CO ₂ H-Ph
_{1-84 2,4-Cl 2 -Ph = CH-} 3-CO 2 Me-Ph
1-85 2,4-Cl ₂ -Ph = CH-4-CO ₂ H-Ph
1-86 2,4-Cl ₂ -Ph = CH- 4-CO ₂ Et-Ph
1-87 2,4-Cl ₂ -Ph = CH-5-CO ₂ H-3-Py
1-88 2,4-Cl ₂ -Ph = CH-5-CO ₂ Me-3-Py
1-89 2,4-Cl ₂ -Ph N 2-CO ₂ H-Ph
1-90 2,4-Cl ₂ -Ph N 2-CO ₂ Et-Ph
1-91 2,4-Cl ₂ -Ph N 3-CO ₂ H-Ph
1-92 2,4-Cl ₂ -Ph N 3-CO ₂ Me-Ph
1-93 2,4-Cl ₂ -Ph N 4-CO ₂ H-Ph
1-94 2,4-Cl ₂ -Ph N 4-CO ₂ Et-Ph
1-95 2,4-Cl ₂ -Ph N 5-CO ₂ H-3-Py
1-96 2,4-Cl ₂ -Ph N 5-CO ₂ Me-3-Py
1-97 4-Cl-3-F-Ph = CH- 2-CO ₂ H-Ph
1-98 4-Cl-3-F-Ph = CH- 2-CO ₂ Et-Ph
1-99 4-Cl-3-F-Ph = CH- 3-CO ₂ H-Ph
1-100 4-Cl-3-F-Ph = CH-3-CO ₂ Me-Ph
1-101 4-Cl-3-F-Ph = CH- 4-CO ₂ H-Ph
1-102 4-Cl-3-F-Ph = CH- 4-CO ₂ Et-Ph
1-103 4-Cl-3-F-Ph = CH-5-CO ₂ H-3-Py
1-104 4-Cl-3-F-Ph = CH-5-CO ₂ Me-3-Py
1-105 4-Cl-3-F-Ph N 2-CO ₂ H-Ph
1-106 4-Cl-3-F-Ph N 2-CO ₂ Et-Ph
1-107 4-Cl-3-F-Ph N 3-CO ₂ H-Ph
1-108 4-Cl-3-F-Ph N 3-CO ₂ Me-Ph
1-109 4-Cl-3-F-Ph N 4-CO ₂ H-Ph
1-110 4-Cl-3-F-Ph N 4-CO ₂ Et-Ph
1-111 4-Cl-3-F-Ph N 5-CO ₂ H-3-Py
1-112 4-Cl-3-F-Ph N 5-CO ₂ Me-3-Py
1-113 3-Cl-4-F-Ph = CH- 2-CO ₂ H-Ph
1-114 3-Cl-4-F-Ph = CH- 2-CO ₂ Et-Ph
1-115 3-Cl-4-F-Ph = CH- 3-CO ₂ H-Ph
1-116 3-Cl-4-F-Ph = CH-3-CO ₂ Me-Ph
1-117 3-Cl-4-F-Ph = CH- 4-CO ₂ H-Ph
1-118 3-Cl-4-F-Ph = CH- 4-CO ₂ Et-Ph
1-119 3-Cl-4-F-Ph = CH-5-CO ₂ H-3-Py
1-120 3-Cl-4-F-Ph = CH-5-CO ₂ Me-3-Py
1-121 3-Cl-4-F-Ph N 2-CO ₂ H-Ph
1-122 3-Cl-4-F-Ph N 2-CO ₂ Et-Ph
1-123 3-Cl-4-F-Ph N 3-CO ₂ H-Ph
1-124 3-Cl-4-F-Ph N 3-CO ₂ Me-Ph
1-125 3-Cl-4-F-Ph N 4-CO ₂ H-Ph
1-126 3-Cl-4-F-Ph N 4-CO ₂ Et-Ph
1-127 3-Cl-4-F-Ph N 5-CO ₂ H-3-Py
1-128 3-Cl-4-F-Ph N 5-CO ₂ Me-3-Py
1-129 4-NH ₂ -3,5-Me ₂ -Ph = CH- 2-CO ₂ H-Ph
1-130 4-NH ₂ -3,5-Me ₂ -Ph = CH- 2-CO ₂ Et-Ph
1-131 4-NH ₂ -3,5-Me ₂ -Ph = CH-3-CO ₂ H-Ph
1-132 4-NH ₂ -3,5-Me ₂ -Ph = CH-3-CO ₂ Me-Ph
1-133 4-NH ₂ -3,5-Me ₂ -Ph = CH- 4-CO ₂ H-Ph
1-134 4-NH ₂ -3,5-Me ₂ -Ph = CH- 4-CO ₂ Et-Ph
1-135 4-NH ₂ -3,5-Me ₂ -Ph = CH-5-CO ₂ H-3-Py
1-136 4-NH ₂ -3,5-Me ₂ -Ph = CH-5-CO ₂ Me-3-Py
1-137 4-NH ₂ -3,5-Me ₂ -Ph N 2-CO ₂ H-Ph
1-138 4-NH ₂ -3,5-Me ₂ -Ph N 2-CO ₂ Et-Ph
1-139 4-NH ₂ -3,5-Me ₂ -Ph N 3-CO ₂ H-Ph
1-140 4-NH ₂ -3,5-Me ₂ -Ph N 3-CO ₂ Me-Ph
1-141 4-NH ₂ -3,5-Me ₂ -Ph N 4-CO ₂ H-Ph
_{1-142 4-NH 2 -3,5-Me} 2 -Ph N 4-CO 2 Et-Ph
1-143 4-NH ₂ -3,5-Me ₂ -Ph N 5-CO ₂ H-3-Py
1-144 4-NH ₂ -3,5-Me ₂ -Ph N 5-CO ₂ Me-3-Py
1-145 3-Py = CH- 2-CO ₂ H-Ph
1-146 3-Py = CH- 2-CO ₂ Et-Ph
1-147 3-Py = CH- 3-CO ₂ H-Ph
1-148 3-Py = CH- 3-CO ₂ Me-Ph
1-149 3-Py = CH- 4-CO ₂ H-Ph
1-150 3-Py = CH- 4-CO ₂ Et-Ph
1-151 3-Py = CH-5-CO ₂ H-3-Py
1-152 3-Py = CH-5-CO ₂ Me-3-Py
1-153 3-Py N 2-CO ₂ H-Ph
1-154 3-Py N 2-CO ₂ Et-Ph
1-155 3-Py N 3-CO ₂ H-Ph
1-156 3-Py N 3-CO ₂ Me-Ph
1-157 3-Py N 4-CO ₂ H-Ph
1-158 3-Py N 4-CO ₂ Et-Ph
1-159 3-Py N 5-CO ₂ H-3-Py
1-160 3-Py N 5-CO ₂ Me-3-Py
1-161 1-Et-Pr = CH- 3-CO ₂ H-Ph
1-162 Cycpent = CH- 3-CO ₂ H-Ph
1-163 Cychex = CH- 3-CO ₂ H-Ph
1-164 2-F-Ph = CH- 3-CO ₂ H-Ph
1-165 4-F-Ph = CH- 3-CO ₂ H-Ph
1-166 2-Me-Ph = CH- 3-CO ₂ H-Ph
1-167 3-Me-Ph = CH- 3-CO ₂ H-Ph
1-168 4-Me-Ph = CH- 3-CO ₂ H-Ph
1-169 2-Et-Ph = CH- 3-CO ₂ H-Ph
1-170 3-Et-Ph = CH- 3-CO ₂ H-Ph
1-171 4-Et-Ph = CH- 3-CO ₂ H-Ph
1-172 2-OMe-Ph = CH- 3-CO ₂ H-Ph
1-173 3-OMe-Ph = CH- 3-CO ₂ H-Ph
1-174 4-OMe-Ph = CH- 3-CO ₂ H-Ph
1-175 3-CF ₃ -Ph = CH- 3-CO ₂ H-Ph
1-176 3-OCF ₃ -Ph = CH- 3-CO ₂ H-Ph
1-177 3-NMe ₂ -Ph = CH-3-CO ₂ H-Ph
1-178 2,4-F ₂ -Ph = CH-3-CO ₂ H-Ph
1-179 2,5-F ₂ -Ph = CH-3-CO ₂ H-Ph
1-180 3,4-F ₂ -Ph = CH-3-CO ₂ H-Ph
1-181 3,5-F ₂ -Ph = CH-3-CO ₂ H-Ph
1-182 2-F-4-Me-Ph = CH- 3-CO ₂ H-Ph
1-183 4-F-2-Me-Ph = CH-3-CO ₂ H-Ph
1-184 2-F-5-Me-Ph = CH-3-CO ₂ H-Ph
1-185 5-F-2-Me -Ph = CH- 3-CO 2 H-Ph
1-186 3-F-4-Me-Ph = CH- 3-CO ₂ H-Ph
1-187 4-F-3-Me-Ph = CH-3-CO ₂ H-Ph
1-188 3-F-5-Me-Ph = CH-3-CO ₂ H-Ph
1-189 2-F-4-OMe-Ph = CH-3-CO ₂ H-Ph
1-190 4-F-2-OMe-Ph = CH- 3-CO ₂ H-Ph
1-191 2-F-5-OMe-Ph = CH-3-CO ₂ H-Ph
1-192 5-F-2-OMe-Ph = CH-3-CO ₂ H-Ph
1-193 3-F-4-OMe-Ph = CH-3-CO ₂ H-Ph
1-194 4-F-3-OMe-Ph = CH-3-CO ₂ H-Ph
1-195 3-F-5-OMe-Ph = CH-3-CO ₂ H-Ph
1-196 2,4-Me ₂ -Ph = CH-3-CO ₂ H-Ph
1-197 2,5-Me ₂ -Ph = CH-3-CO ₂ H-Ph
1-198 3,4-Me ₂ -Ph = CH-3-CO ₂ H-Ph
1-199 3,5-Me ₂ -Ph = CH-3-CO ₂ H-Ph
1-200 2-OMe-4-Me-Ph = CH- 3-CO ₂ H-Ph
1-201 4-OMe-2-Me-Ph = CH-3-CO ₂ H-Ph
1-202 2-OMe-5-Me-Ph = CH-3-CO ₂ H-Ph
1-203 5-OMe-2-Me-Ph = CH-3-CO ₂ H-Ph
1-204 3-OMe-4-Me-Ph = CH-3-CO ₂ H-Ph
1-205 4-OMe-3-Me-Ph = CH-3-CO ₂ H-Ph
1-206 3-OMe-5-Me-Ph = CH-3-CO ₂ H-Ph
1-207 3-Cl-5-F-Ph = CH-3-CO ₂ H-Ph
1-208 Het (A) = CH- 3-CO ₂ H-Ph
1-209 Het (B) = CH- 3-CO ₂ H-Ph
1-210 Het (C) = CH- 3-CO ₂ H-Ph
1-211 Het (D) = CH- 3-CO ₂ H-Ph
1-212 3-F-Ph = CH- 3-CO ₂ H-5-F-Ph
1-213 4-F-Ph = CH- 3-CO ₂ H-5-F-Ph
1-214 3-Cl-Ph = CH- 3-CO ₂ H-5-F-Ph
1-215 4-Cl-Ph = CH- 3-CO ₂ H-5-F-Ph
1-216 3-Me-Ph = CH- 3-CO ₂ H-5-F-Ph
1-217 4-Me-Ph = CH- 3-CO ₂ H-5-F-Ph
1-218 3-OMe-Ph = CH- 3-CO ₂ H-5-F-Ph
1-219 4-OMe-Ph = CH- 3-CO ₂ H-5-F-Ph
1-220 4-Cl-3-F-Ph = CH-3-CO ₂ H-5-F-Ph
1-221 4-Me-Ph N 3-CO ₂ H-Ph
1-222 4-Me-Ph N 3-CO ₂ H-5-F-Ph
1-223 3,4-Me ₂ -Ph N 3-CO ₂ H-Ph
1-224 3,4-Me ₂ -Ph N 3-CO ₂ H-5-F-Ph
1-225 3,5-Me ₂ -Ph N 3-CO ₂ H-Ph
1-226 3,5-Me ₂ -Ph N 3-CO ₂ H-5-F-Ph
1-227 3-F-4-Me-Ph N 3-CO ₂ H-Ph
1-228 3-F-4-Me-Ph N 3-CO ₂ H-5-F-Ph
――――――――――――――――――――――――――――――

  In Table 1, the preferred compounds are compound numbers 1-19, 1-27, 1-35, 1-43, 1-50, 1-59, 1-99, 1-107, 1-115, 1-123. 1-131, 1-139, 1-161, 1-164, 1-168, 1-170, 1-173, 1-175, 1-176, 1-179, 1-188, 1-198, 1-198, -204, 1-210, 1-217, 1-220, 1-221, 1-222, 1-223, 1-224 or 1-227.

More preferred compounds are
3-{[6- (3-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-35),
3- [6- (3-chlorophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzoic acid (Compound No. 1-51),
3-{[6- (4-Chloro-3-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-99),
3-{[6- (3-chloro-4-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-115),
3-{[6- (4-amino-3,5-dimethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-131),
3-{[6- (1-ethylpropoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-161),
3-{[6- (2-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-164),
3-{[1-methyl-6- (4-methylphenoxy) -1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-168),
3-{[6- (3-ethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-170),
3-{[6- (3-methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-173),
3-({1-methyl-6- [3- (trifluoromethoxy) phenoxy] -1H-benzimidazol-2-yl} methoxy) benzoic acid (Compound No. 1-176),
3-{[6- (2,5-difluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-179),
3-{[6- (3,4-dimethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-198),
3-{[6- (3-methoxy-4-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-204),
3-{[6- (2,3-dihydro-1-benzofuran-6-yloxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-210),
3-{[3-methyl-5- (4-methylphenoxy) -3H-imidazo [4,5-b] pyridin-2-yl] methoxy} benzoic acid (Compound No. 1-221),
3-fluoro-5-{[3-methyl-5- (4-methylphenoxy) -3H-imidazo [4,5-b] pyridin-2-yl] methoxy} benzoic acid (Compound No. 1-222), or ,
3-{[5- (3,4-dimethylphenoxy) -3-methyl-3H-imidazo [4,5-b] pyridin-2-yl] methoxy} benzoic acid (Compound No. 1-223).

Even more preferred compounds are
3-{[6- (3-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-35),
3- [6- (3-chlorophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzoic acid (Compound No. 1-51),
3-{[6- (4-Chloro-3-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-99),
3-{[6- (3-chloro-4-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-115),
3-{[6- (2-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-164),
3-{[1-methyl-6- (4-methylphenoxy) -1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-168),
3-{[6- (2,5-difluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-179), or
3-{[6- (2,3-dihydro-1-benzofuran-6-yloxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-210).

  The condensed bicyclic heteroaryl derivative having the above general formula (I) or a pharmacologically acceptable salt thereof according to the present invention has a good blood glucose lowering action, a sugar / lipid metabolism improving action, an insulin resistance improving action, an arteriosclerosis, Since it has an action of improving pathological conditions caused by so-called metabolic syndrome and various types of inflammation such as hypertension, cardiovascular disorder, and complications derived therefrom, and since this compound is Ligand acting on PPARγ, cancer cells It has been found to have an inhibitory effect on growth, and metabolic syndrome, ie, diabetes, hyperglycemia, hyperlipidemia, obesity, impaired glucose tolerance (IGT), insulin resistance, fasting blood glucose Impaired fasting glucose (IFG), hypertension, fatty liver, nonalcoholic cirrhosis (NASH), diabetic complications (eg retinopathy, nephropathy, neuropathy), arteriosclerosis, gestational diabetes (Gestational diabetes mellitus: GDM), diseases such as polycystic ovary syndrome (PCOS), inflammatory diseases (eg osteoarthritis, pain, inflammatory bowel disease), acne, sunburn, psoriasis, eczema, allergic diseases , Asthma, gastrointestinal ulcer, ulcerative colitis, Crohn's disease, coronary artery disease, arteriosclerosis, atherosclerosis, diabetic retinopathy, diabetic macular disease, macular edema, diabetic nephropathy, ischemic heart disease, brain Vascular disorders, peripheral circulatory disorders, autoimmune diseases (eg systemic lupus erythematosus, rheumatoid arthritis, Sjogren's syndrome, systemic scleroderma, mixed connective tissue disease, Hashimoto's disease, Crohn's disease, ulcerative colitis, idiopathic Addison Disease, male infertility, Goodpasture syndrome, acute progressive glomerulonephritis, myasthenia gravis, polymyositis, multiple sclerosis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, beech Etto's disease, CREST syndrome, etc.), pancreatitis, cachexia, cancer (eg, stomach cancer, lung cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, liver cancer), leukemia, sarcoma (eg, liposarcoma), osteoporosis, regression It is useful in the treatment and / or prevention of osteoporosis, neurodegenerative diseases, Alzheimer's disease, hyperuricemia, and dry eye. It can also be used as a medicament for the treatment and / or prevention of the above diseases.

The schematic diagram of a PPARγ expression plasmid cited in Test Example 1. Schematic diagram of PPRE reporter plasmid, cited in Test Example 1. A dose-dependent curve conceptual diagram cited in Test Example 1. FIG.

In FIG. 3, the luciferase activity value of the positive control group is 100%, and the luciferase activity value of the control group is 0%. The maximum value of luciferase activity indicated by the test compound alone is defined as Emax (%), and the maximum value of luciferase activity suppression of the test compound in the presence of Compound A is defined as Imax (%). The drug concentration of the partial agonist showing the value of Emax / 2 is EC ₅₀ , and the drug concentration of the partial antagonist showing the value of (100−Imax) / 2 is IC ₅₀ .
――― indicates the presence of Compound A, ……… indicates the absence of Compound A.

  The compound having the general formula (I) of the present invention can be produced according to the methods A to C described below.

  The solvent used in the reaction of each step of the following methods A to C is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, and is selected from, for example, the following solvent group. Solvents are hydrocarbons such as pentane, hexane, octane, petroleum ether, ligroin, cyclohexane; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methyl Amides such as 2-pyrrolidinone and hexamethylphosphoric triamide; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, i-propanol, n Alcohols such as 2-butanol, 2-butanol, 2-methyl-1-propanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve Sulfoxides such as dimethyl sulfoxide; sulfones such as sulfolane; nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate Esters such as acetone, methyl ethyl ketone, 4-methyl-2-pentanone, methyl isobutyl ketone, isophorone, cyclohexanone, nitro compounds such as nitroethane and nitrobenzene, dichloromethane, 1,2-dichloroethane, chlorobenzene, Halogenated hydrocarbons such as dichlorobenzene, chloroform, and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, and xylene; such as acetic acid, formic acid, propionic acid, butyric acid, and trifluoroacetic acid Such carboxylic acids; water; and it consists of a mixture of these solvents.

  The base used in the reaction of each step of the following methods A to C is, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate; sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydrogen carbonate Alkali metal hydrogen carbonates such as lithium hydride, sodium hydride, alkali metal hydrides such as potassium hydride; alkali metal water such as sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide Oxides; inorganic bases such as alkali metal fluorides such as sodium fluoride and potassium fluoride; sodium methoxide, sodium ethoxide, sodium-t-butoxide, potassium methoxide, potassium ethoxide, potassium-t Alkali metal alkoxides such as butoxide and lithium methoxide Xoxides; alkali metal trialkylsiloxides such as sodium trimethylsiloxide, potassium trimethylsiloxide, lithium trimethylsiloxide; mercaptan alkali metals such as methyl mercaptan sodium and ethyl mercaptan sodium; N-methylmorpholine, triethylamine, Tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabi (B) Organic bases such as [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU); or butyllithium, lithium diisopropylamide, lithium Organometallic bases such as bis (trimethylsilyl) amide.

  In the reaction of each step of the following methods A to C, the reaction temperature varies depending on the solvent, starting material, reagent and the like, and the reaction time varies depending on the solvent, starting material, reagent, reaction temperature and the like.

  In the reaction in each step of the following methods A to C, after completion of the reaction, each target compound is collected from the reaction mixture according to a conventional method. For example, neutralize the reaction mixture as appropriate, or remove insoluble matter by filtration, add water and an immiscible organic solvent such as ethyl acetate, and separate the organic layer containing the target compound, It can be obtained by washing with water, drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, etc., filtering, and then distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., usually using methods commonly used for separation and purification of organic compounds, applying chromatography, and the like. Can be separated and purified. For a target compound insoluble in a solvent, the obtained solid crude product can be purified by washing with a solvent. In addition, the target compound in each step can be directly used in the next reaction without purification.

  The reaction in each step of Method A to Method C will be described below.

  Method A is a method for producing a compound having the general formula (I).

In the present invention, R ¹ , R ² , R ³ and Q are as defined above, and R ^1a and R ^3a are an amino group or a hydroxy group contained as a substituent in the groups R ¹ and R ^3. And / or the carboxyl group represents an amino group, a hydroxy group and / or a carboxyl group which may be protected, and represents the same group as the group in the definition of R ¹ and R ³ .

Step A1 This step is a step of producing a compound having the general formula (IV).

  In this step, in the presence of a base in a solvent, a known compound or a compound having the general formula (II) that is easily obtained in the same manner as a known method using a known compound as a starting material is converted into a known compound or a known compound as a starting material. The reaction is carried out by reacting with a compound having the general formula (III) which is easily obtained in the same manner as in the known method.

  The solvent used in this step is preferably an amide, and more preferably N, N-dimethylformamide or N-methyl-2-pyrrolidone.

  The base used in this step is preferably an alkali metal carbonate or alkali metal hydride, and more preferably cesium carbonate or sodium hydride.

  The reaction temperature in this step is usually 50 ° C. to 150 ° C., preferably 80 ° C. to 120 ° C.

  The reaction time in this step is usually 0.5 to 48 hours, preferably 1 to 30 hours.

Step A2 This step is a step of producing a compound having the general formula (V).

  This step comprises reacting a compound having the general formula (IV) with iron in the presence of ammonium chloride in a solvent or a compound having the general formula (IV) in a solvent in the presence of a palladium catalyst. The reduction is performed in a hydrogen atmosphere.

  The solvent used in this step is preferably ethers, alcohols or water, more preferably tetrahydrofuran, methanol, ethanol or water, and even more preferably ethanol or ethanol and water. It is a mixed solvent.

  The palladium catalyst used in this step is, for example, a divalent palladium catalyst or a zero-valent palladium catalyst, and preferably palladium-activated carbon, palladium (II) acetate, palladium (II) trifluoroacetate, palladium Black, palladium (II) bromide, palladium (II) chloride, palladium (II) iodide, palladium (II) cyanide, palladium (II) nitrate, palladium (II) oxide, palladium (II) sulfate, dichlorobis (acetonitrile) ) Palladium (II), dichlorobis (benzonitrile) palladium (II), dichloro (1,5-cyclooctadiene) palladium (II), acetylacetone palladium (II), palladium sulfide (II), tris (dibenzylideneacetone) di Palladium (0), tetrakis (aceto Nitrile) palladium (II) tetrafluoroborate or arylpalladium chloride dimer, more preferably palladium-activated carbon.

  The reaction temperature in this step is usually −20 ° C. to 120 ° C., preferably 0 ° C. to 100 ° C.

  The reaction time in this step is usually 1 hour to 48 hours, preferably 2 hours to 24 hours.

Step A3 This step is a step of producing a compound having the general formula (VI).

  This step is performed by reacting a compound having the general formula (V) with glycolic acid in a solvent in the presence of hydrochloric acid (preferably 4N hydrochloric acid).

  The solvent used in this step is preferably an ether or water, more preferably dioxane or water, and even more preferably a mixed solvent of dioxane and water.

  The reaction temperature in this step is usually 50 ° C. to 150 ° C., preferably 80 ° C. to 120 ° C.

  The reaction time in this step is usually 0.5 to 48 hours, preferably 1 to 24 hours.

Step A4 This step is a step of producing a compound having the general formula (I).

This step has the general formula (VII) which can be easily obtained in the same manner as in a known method using a known compound or a known compound as a starting material for a compound having the general formula (VI) in the presence of a condensing agent in a solvent. After being carried out by reacting with a compound, it is optionally carried out by removing the protecting group of the amino group, hydroxy group and / or carboxyl group in R ^1a and / or R ^3a .

  The solvent used in this step is preferably an aromatic hydrocarbon, and more preferably toluene.

  The condensing agent used in this step is, for example, a combination of azodicarboxylic acid ester and tertiary phosphine, a combination of azodicarboxylic acid amide and tertiary phosphine, or (trialkylphosphoranylidene) acetonitrile, preferably , A combination of azodicarboxylic amide and tertiary phosphine, and more preferably a combination of tributylphosphine and 1,1 ′-(azodicarbonyl) dipiperidine.

  The reaction temperature in this step is usually −78 ° C. to 120 ° C., preferably 0 ° C. to 50 ° C.

  The reaction time in this step is usually 0.5 to 24 hours, preferably 1 to 12 hours.

  Method B is another method for producing a compound having the general formula (I).

In the present invention, R ¹ , R ² , R ³ , Q, R ^1a and R ^3a have the same meaning as described above.

Step B1 This step is a step of producing a compound having the general formula (IX).

  In this step, in the presence of a condensing agent and a base in a solvent, a compound having the general formula (V) is easily obtained in the same manner as in a known method using a known compound or a known compound as a starting material. It is carried out by reacting with a compound having

  The solvent used in this step is preferably an amide or a halogenated hydrocarbon, and more preferably N, N-dimethylformamide or dichloromethane.

  The condensing agent used in this step is, for example, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HATU), 1-propane. Phosphonic acid cyclic anhydride (T3P), dicyclohexylcarbodiimide (DCCD), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide ( EDAC), isobutyl chloroformate (IBCF), 1,1′-carbonylbis-1H-imidazole (CDI), diethyl cyanophosphonate (DEPC), diphenyl phosphate azide (DPPA), N-hydroxysuccinimide, N— Hydroxy-5-norbornene-2,3-dicarboxyl A de or dipyridyl disulfide, can coexist optionally 1-hydroxybenzotriazole or 1-hydroxybenzotriazole hydrate (HOBt), preferably a EDCI.

  The base used in this step is preferably triethylamine, N-methylmorpholine or 4- (N, N-dimethylamino) pyridine.

  The reaction temperature in this step is usually -50 ° C to 100 ° C, preferably -20 ° C to 60 ° C.

  The reaction time in this step is usually 0.1 hour to 24 hours, preferably 0.5 hour to 10 hours.

Step B2 This step is a step of producing a compound having the general formula (I).

This step is carried out by reacting the compound having the general formula (IX) with hydrochloric acid, and then optionally removing the protective group for the amino group, hydroxy group and / or carboxyl group in R ^1a and / or R ^3a . Is done.

  The reaction temperature in this step is usually −20 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.

  The reaction time in this step is usually 0.5 hours to 150 hours, preferably 1 hour to 72 hours.

  Method C is another method for producing a compound having the general formula (I).

In the present invention, R ¹ , R ² , R ³ , Q, R ^1a and R ^3a have the same meaning as described above.

Step C1 This step is a step of producing a compound having the general formula (XI).

  In this step, in the presence of a base in a solvent, a known compound or a compound having the general formula (X) easily obtained in the same manner as a known method using a known compound as a starting material is converted to a compound having the general formula (III). By reacting with.

  The solvent used in this step is preferably an amide, and more preferably N, N-dimethylformamide or N-methyl-2-pyrrolidone.

  The base used in this step is preferably an alkali metal hydride, and more preferably sodium hydride.

  The reaction temperature in this step is usually −78 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.

  The reaction time in this step is usually 0.5 to 48 hours, preferably 1 to 24 hours.

Step C2 This step is a step of producing a compound having the general formula (XII).

  This step comprises reacting a compound having the general formula (XI) with iron in the presence of ammonium chloride in a solvent or a compound having the general formula (XI) in a solvent in the presence of a palladium catalyst. The reduction is carried out in the same manner as in Step A2 of Method A by reducing in a hydrogen atmosphere.

Step C3 This step is a step of producing a compound having the general formula (XIII).

  This step is performed in the same manner as in Method B1 of Method B above by reacting a compound having the general formula (XII) with a compound having the general formula (VIII) in the presence of a condensing agent and a base in a solvent. .

Step C4 This step is a step of producing a compound having the general formula (I).

This step is carried out in the same manner as in Step B2 of Method B by reacting a compound having the general formula (XIII) with acetic acid, and then, if desired, an amino group in R ^1a and / or R ^3a , hydroxy This is done by removing the protecting group of the group and / or carboxyl group.

  The starting compounds having the general formulas (II), (III), (VII), (VIII) and (X) are known compounds, or can be easily prepared by using known compounds as starting materials according to known methods or similar methods. To be manufactured.

In the above, the protecting groups of “amino group which may be protected”, “hydroxy group which may be protected” and “carboxyl group which may be protected” in the definition of R ^1a and R ^3a are hydrogenolysis, A protecting group that can be cleaved by chemical methods such as hydrolysis, electrolysis, and photolysis, and indicates a protecting group commonly used in organic synthetic chemistry (eg, TW Greene et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999)).

In the above, "protecting group" of the "protected hydroxy group which may be" in the definition of R ^1a and R ^3a is not particularly limited as long as it is a protecting group for a hydroxy group used in the field of organic synthetic chemistry, For example, “a general protecting group for a hydroxy group”, preferably a formyl group, the aforementioned “C ₂ -C ₇ alkylcarbonyl group”, a halogenated group such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl. “Alkylcarbonyl groups” such as alkylcarbonyl groups, alkoxyalkylcarbonyl groups such as methoxyacetyl, acryloyl, propioroyl, methacryloyl, crotonoyl, isocrotonoyl, unsaturated alkylcarbonyl groups such as (E) -2-methyl-2-butenoyl Benzoyl, α-naphthoyl, β-naphtho Arylcarbonyl groups such as methylphenol, 2-bromobenzoyl, 4-chlorobenzoyl halide arylcarbonyl group such as yl, 2,4,6-trimethylbenzoyl, _C 1 -C ₆ alkylation, such as 4-toluoyl ant - Rucarbonyl group, C ₁ -C ₆ alkoxylated arylcarbonyl group like 4-anisoyl, nitrated arylcarbonyl group like 4-nitrobenzoyl, 2-nitrobenzoyl, C like 2- (methoxycarbonyl) benzoyl ₂ -C ₇ alkoxycarbonyl arylcarbonyl group, "arylcarbonyl group" such as arylated arylcarbonyl group such as 4-phenylbenzoyl; the _"C 2 -C ₇ alkoxycarbonyl group", 2,2,2 Ethoxycarbonyl, 2-trimethylsilyl ethoxy Halogen or tri like carbonyl - (C ₁ -C ₆ alkyl) "alkoxycarbonyl group" such as a C ₂ -C ₇ alkoxycarbonyl group substituted with a silyl group; tetrahydropyran-2-yl, 3-bromo-tetrahydropyran “Tetrahydropyranyl or tetrahydrothiopyranyl group” such as 2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl; “Tetrahydrofuranyl or tetrahydrothiofuranyl group” such as 2-yl, tetrahydrothiofuran-2-yl; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilane Lil, birds such as triisopropylsilyl - (C ₁ -C ₆ alkyl) silyl group, diphenylmethyl silyl, diphenyl butylsilyl, diphenyl isopropylsilyl, such as phenyl diisopropylsilyl (C ₁ -C ₆ alkyl) diarylsilyl or “Silyl groups” such as di- (C ₁ -C ₆ alkyl) arylsilyl groups; methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxy (C ₁ -C ₆ alkoxy) methyl groups such as methyl, (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkoxy) methyl groups such as 2-methoxyethoxymethyl, 2,2,2-trichloro (C ₁ such as ethoxymethyl, bis (2-chloroethoxy) methyl -C ₆ "alkoxymethyl group" such as a halogenated alkoxy) methyl; 1-ethoxyethyl, 1- (isopropoxy) _(C 1 -C ₆ alkoxy) ethyl groups such as ethyl, 2,2,2-trichloroethyl A “substituted ethyl group” such as an ethyl halide group such as: 1 to 3 such as benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl; C ₁ -C ₆ alkyl group substituted with 3 aryl groups, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxy Phenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-sia _C 1 -C ₆ alkyl such as _benzyl, C 1 -C ₆ alkoxy, nitro, halogen, a cyano group - Le ring of 1 to 3 substituted ants - _C 1 -C substituted with Le group “Aralkyl groups” such as ₆ alkyl groups; “alkenyloxycarbonyl groups” such as vinyloxycarbonyl and allyloxycarbonyl; benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitro An “aralkyloxycarbonyl group” in which the aryl ring may be substituted with one or two C ₁ -C ₆ alkoxy or nitro groups, such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, and more Preferred is an alkylcarbonyl group, a silyl group, or an aralkyl group.

In the above, the “protecting group” of the “optionally protected carboxyl group” in the definition of R ^1a and R ^3a is not particularly limited as long as it is a protecting group for a carboxyl group used in the field of synthetic organic chemistry. For example, “a general protecting group for a carboxyl group”, preferably the above “C ₁ -C ₆ alkyl group”; “C ₂ -C ₆ alkenyl group” such as ethenyl, 1-propenyl, 2-propenyl ” A “C ₂ -C ₆ alkynyl group” such as ethynyl, 1-propynyl, 2-propynyl; the “C ₁ -C ₆ halogenated alkyl group”; the “C ₁ -C ₆ hydroxyalkyl group”; Such as (C ₂ -C ₇ alkylcarbonyl)-(C ₁ -C ₆ alkyl group); the “aralkyl group”; or the “silyl group”, and more preferably C ₁ -C _{A 6} alkyl group or an aralkyl group;

In the above, the “protecting group” of the “amino group that may be protected” in the definition of R ^1a and R ^3a is not particularly limited as long as it is a protecting group of an amino group used in the field of organic synthetic chemistry. For example, “alkylcarbonyl group”; “arylcarbonyl group”; “alkoxycarbonyl group”; “silyl group”; “aralkyl group”; “alkenyloxycarbonyl group” in “general protecting group for hydroxy group”; A group similar to “aralkyloxycarbonyl group” or N, N-dimethylaminomethylene, benzylidene, 4-methoxybenzylidene, 4-nitrobenzylidene, salicylidene, 5-chlorosalicylidene, diphenylmethylene, (5-chloro Substitutions to form “Schiff bases, such as 2-hydroxyphenyl) phenylmethylene The methylene group ", preferably, an alkylcarbonyl group, an arylcarbonyl group or an alkoxycarbonyl group, more preferably an alkoxycarbonyl group.

  Processes that require protection and deprotection are known methods (for example, the method described in “Protective Groups in Organic Synthesis” (Theodora W. Greene, Peter GMWuts, 1999, published by Wiley-Interscience Publication)). It is done accordingly.

  When the fused bicyclic heteroaryl derivative having the above general formula (I) of the present invention or a pharmacologically acceptable salt thereof is used as a medicine, itself or an appropriate pharmacologically acceptable, It can be mixed with excipients, diluents, etc., and administered orally, for example, orally by tablets, capsules, granules, powders or syrups, or parenterally by injections or suppositories.

  These formulations include excipients (eg sugar derivatives such as lactose, sucrose, sucrose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, alpha starch, dextrin; cellulose derivatives such as crystalline cellulose; Gum arabic; dextran; organic excipients such as pullulan; silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium metasilicate magnesium phosphate; phosphates such as calcium hydrogen phosphate; calcium carbonate And inorganic excipients such as sulfates such as calcium sulfate), lubricants (for example, stearic acid, calcium stearate, metal stearate such as magnesium stearate) Salt; Talc; Colloidal silica; Veegum, Gay wax Such as wax; boric acid; adipic acid; sulfate such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; fatty acid sodium salt; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; And silicic acids such as silicic acid hydrate; and the starch derivatives mentioned above), binders (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and the above excipients) And the like, and disintegrants (for example, cellulose derivatives such as low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally crosslinked sodium carboxymethylcellulose; And chemically modified starches such as carboxymethyl starch and sodium carboxymethyl starch), stabilizers (paraoxybenzoates such as methylparaben and propylparaben; chlorobutanol, benzyl alcohol, phenyl) Alcohols such as ethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.), Flavoring agents (eg, commonly used, Sweeteners, acidulants, flavors, and the like can be given.), And additives such as diluents are used to produce them by a known method.

  The amount used varies depending on the symptoms, age, etc. of the patient (warm-blooded animal, particularly human), but in the case of oral administration, the lower limit per day is 0.0015 mg / kg body weight (preferably 0.008 mg / kg). kg body weight), an upper limit of 70 mg / kg body weight (preferably 7 mg / kg body weight), and in the case of intravenous administration, a lower limit of 0.00015 mg / kg body weight per day (preferably 0.0008 mg / kg kg body weight) and an upper limit of 8.5 mg / kg body weight (preferably 5 mg / kg body weight) are desirably administered to adults 1 to 6 times per day according to symptoms.

  EXAMPLES Examples, test examples, and formulation examples will be shown below to explain the present invention in more detail. However, the scope of the present invention is not limited to these examples.

Elution in the column chromatography of the examples was performed under observation by TLC (Thin Layer Chromatography, thin layer chromatography). In TLC observation, silica gel 60F ₂₅₄ manufactured by Merck was used as a TLC plate, a solvent used as an elution solvent in column chromatography was used as a developing solvent, and a UV detector was used as a detection method. As silica gel for the column, silica gel SK-85 (230-400 mesh), silica gel SK-34 (70-230 mesh) or Fuji Silysia Chemical Chromatorex NH (200-350 mesh) manufactured by Merck Ltd. was used. In addition to ordinary column chromatography, an automated chromatography apparatus (SP-1) manufactured by Biotage was used as appropriate. The abbreviations used in the examples have the following significance.
mg: milligram, g: gram, mL: milliliter, MHz: megahertz.

In the following examples, nuclear magnetic resonance (hereinafter, ¹ H NMR) spectra are described with chemical shift values as δ values (ppm) using tetramethylsilane as a standard substance. The fission pattern is indicated by s for single lines, d for double lines, t for triple lines, q for quadruple lines, quint for quintet lines, and sep for seven-line lines.

  Mass spectrometry (hereinafter, referred to as MS) was performed by FAB (Fast Atom Bombardment) method, EI (Electron Ionization) method, or ESI (Electron Spray Ionization) method.

Example 1 3-{[6- (4-Amino-3,5-dimethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate dihydrochloride (Compound No. 1- 132 dihydrochloride)
(1a) [6- (4-tert-butoxycarbonylamino-3,5-dimethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol
[6- (4-amino-3,5-dimethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol ((13 g, 43.7 mmol) JP 2004-123711), (Boc) ₂ O ( 19 g, 87 mmol) was dissolved in 150 mL of isopropanol and stirred overnight. The mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (10% methanol-ethyl acetate), and the resulting foam was crystallized from ethyl acetate and hexane to obtain the target compound (4.5 g, yield 26%).
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.26 (9H, s), 2.21 (6H, s), 3.75 (3H, s), 4.89 (2H, s), 6.67 (2H, s), 6.93 (1H , D, J = 2 Hz), 6.96 (1H, dd, J = 2, 9 Hz), 7.63 (1H, d, J = 9 Hz).
(1b) 3-{[6- (4-Amino-3,5-dimethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate dihydrochloride {6- [4- ( tert-butyloxycarbonylamino) -3,5-dimethylphenoxy] -1-methyl-1H-benzimidazol-2-yl} methanol (0.40 g, 1.0 mmol), methyl 3-hydroxybenzoate (0.23 g) , 1.5 mmol) in toluene solution was added tri-n-butylphosphine (0.41 g, 2.0 mmol) and 1,1 ′-(azodicarbonyl) dipiperidine (0.50 g, 2.0 mmol) for 10 hours. Stir. After concentrating the reaction solution, purification was performed using silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/2), and then 4N hydrogen chloride / 1,4-dioxane solution (10 mL) was added for 2 hours. Stir. The precipitated solid was collected by filtration and washed with ethyl acetate and ether. The title compound (0.32 g, yield 63%) was obtained by drying under reduced pressure.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 2.25 (6H, s), 3.87 (3H, s), 3.87 (3H, s), 5.60 (2H, s), 6.74 (2H, s), 7.03 (1H, d, J = 8.8 Hz), 7.41 (1H, s), 7.45 (1H, d, J = 8.3 Hz), 7.52 (1H, dd, J = 7.8, 8.3 Hz), 7.63 (1H, d , J = 7.8 Hz), 7.69 (1H, s), 7.72 (1H, d, J = 8.8 Hz).
MS (ESI +) m / z: 432 (M + H) ⁺ .
HRMS (ESI +) m / Z: 432.19037 (M + H) ⁺ , calcd 432.19233 (-1.96 mmu).

Example 2 3-{[6- (4-Amino-3,5-dimethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid dihydrochloride (Compound No. 1-131) Dihydrochloride)
3-{[6- (4-Amino-3,5-dimethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate dihydrochloride (0.22 g) synthesized in Example 1 , 0.4 mmol) in 1,4-dioxane solution was added 1N aqueous sodium hydroxide solution (10 mL, 10 mmol), and the mixture was stirred at 60 ° C. for 2 hours. After treating with concentrated hydrochloric acid (1.5 mL), the reaction mixture was concentrated, and the resulting solid was washed with water and ethyl acetate and dried under reduced pressure to give the title object compound (0.12 g, yield 61). %).
Mp 235-239 ° C,
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 2.30 (6H, s), 3.91 (3H, s), 5.65 (2H, s), 6.78 (2H, s), 7.11 (1H, dd, J = 2.0, 8.8 Hz), 7.43 (1H, d, J = 7.8 Hz), 7.49 (1H, dd, J = 7.8, 7.8 Hz), 7.51 (1H, d, J = 2.0 Hz), 7.63 (1H, d , J = 7.8 Hz), 7.76 (1H, d, J = 8.8 Hz).
MS (ESI +) m / z: 418 (M + H) ⁺ , 440 (M + Na) ⁺ , 462 (M + 2Na-H) ⁺ .
HRMS (ESI +) m / Z: 418.18023 (M + H) ⁺ , calcd 418.17668 (3.55 mmu).

Example 3 4-{[6- (4-Amino-3,5-dimethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} ethyl benzoate dihydrochloride (Compound No. 1- 134 dihydrochloride)
{6- [4- (tert-Butyloxycarbonylamino) -3,5-dimethylphenoxy] -1-methyl-1H-benzimidazol-2-yl} methanol (0.40 g, 1.0 mmol), 4-hydroxy To a toluene solution of ethyl benzoate (0.25 g, 1.5 mmol), tri-n-butylphosphine (0.41 g, 2.0 mmol), 1,1 ′-(azodicarbonyl) dipiperidine (0.50 g, 2. 0 mmol) was added and stirred for 10 hours. After concentrating the reaction solution, purification was performed using silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/2), and then 4N hydrogen chloride / 1,4-dioxane solution (10 mL) was added for 2 hours. Stir. The precipitated solid was collected by filtration and washed with ethyl acetate and ether. The title object compound (0.35 g, yield 67%) was obtained by drying under reduced pressure.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 1.31 (3H, t, J = 7.0 Hz), 2.12 (6H, s), 3.90 (3H, s), 4.29 (2H, q, J = 7.0 Hz), 5.66 (2H, s), 6.71 (2H, s), 7.10 (1H, d, J = 8.8 Hz), 7.29 (2H, d, J = 8.8 Hz), 7.51 (1H, s), 7.75 ( 1H, d, J = 8.8 Hz), 7.98 (2H, d, J = 8.8 Hz).
MS (ESI +) m / z: 446 (M + H) ⁺ .
HRMS (ESI +) m / Z: 446.20801 (M + H) ⁺ , calcd 446.20798 (0.03 mmu).

Example 4 4-{[6- (4-Amino-3,5-dimethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid dihydrochloride (Compound No. 1-133) Dihydrochloride)
4-{[6- (4-Amino-3,5-dimethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} ethyl benzoate dihydrochloride (0.26 g, 0.4 mmol) A 1N aqueous sodium hydroxide solution (10 mL, 10 mmol) was added to the 1,4-dioxane solution, and the mixture was stirred at 60 ° C. for 2 hours. After treatment with concentrated hydrochloric acid (1.5 mL), the reaction mixture was concentrated, and the resulting solid was washed with water and ethyl acetate and dried under reduced pressure to give the title object compound (0.15 g, yield 77). %).
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 2.30 (6H, s), 3.89 (3H, s), 5.64 (2H, s), 6.77 (2H, s), 7.08 (1H, d, J = 8.8 Hz), 7.25 (2H, d, J = 8.8 Hz), 7.49 (1H, s), 7.75 (1H, d, J = 8.8 Hz), 7.95 (2H, d, J = 8.8 Hz).
MS (ESI +) m / z: 418 (M + H) ⁺ .
HRMS (ESI +) m / Z: 418.17523 (M + H) ⁺ , calcd 418.17668 (-1.45 mmu).

Example 5 2-{[6- (4-Amino-3,5-dimethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} ethyl benzoate dihydrochloride (Compound No. 1- 130 dihydrochloride)
{6- [4- (tert-Butyloxycarbonylamino) -3,5-dimethylphenoxy] -1-methyl-1H-benzimidazol-2-yl} methanol (0.40 g, 1.0 mmol), 2-hydroxy To a toluene solution of ethyl benzoate (0.23 g, 1.5 mmol), tri-n-butylphosphine (0.41 g, 2.0 mmol), 1,1 ′-(azodicarbonyl) dipiperidine (0.50 g, 2. 0 mmol) was added and stirred for 10 hours. After concentrating the reaction solution, purification was performed using silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/2), and then 4N hydrogen chloride / 1,4-dioxane solution (10 mL) was added for 2 hours. Stir. The precipitated solid was collected by filtration and washed with ethyl acetate and ether. The title compound (0.34 g, yield 65%) was obtained by drying under reduced pressure.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 1.20 (3H, t, J = 7.2 Hz), 2.33 (6H, s), 3.94 (3H, s), 4.23 (2H, q, J = 7.2 Hz), 5.64 (2H, s), 6.79 (2H, s), 7.11 (1H, d, J = 8.8 Hz), 7.13 (1H, dd, J = 7.3, 7.8 Hz), 7.45 (1H, d, J = 8.4 Hz), 7.55 (1H, s), 7.60 (1H, ddd, J = 1.4, 7.3, 8.4 Hz), 7.72 (1H, dd, J = 1.4, 7.8 Hz), 7.77 (1H, d, J = 8.8 Hz).
MS (ESI +) m / z: 446 (M + H) ⁺ , 468 (M + Na) ⁺ .
HRMS (ESI +) m / Z: 446.21002 (M + H) ⁺ , calcd 446.20798 (2.04 mmu).

Example 6 2-{[6- (4-Amino-3,5-dimethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid dihydrochloride (Compound No. 1-129) Dihydrochloride)
3-{[6- (4-Amino-3,5-dimethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} ethyl benzoate dihydrochloride (0.26 g, 0.4 mmol) A 1N aqueous sodium hydroxide solution (10 mL, 10 mmol) was added to the 1,4-dioxane solution, and the mixture was stirred at 60 ° C. for 2 hours. After treatment with concentrated hydrochloric acid (1.5 mL), the reaction mixture was concentrated, and the resulting solid was washed with water and ethyl acetate and dried under reduced pressure to give the title object compound (0.13 g, yield 66). %).
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 2.30 (6H, s), 3.92 (3H, s), 5.62 (2H, s), 6.87 (2H, s), 7.10 (1H, m), 7.11 (1H, m), 7.43 (1H, d, J = 8.3 Hz), 7.55 (1H, m), 7.58 (1H, s), 7.69 (1H, dd, J = 1.4, 7.6 Hz), 7.75 (1H , d, J = 8.8 Hz).
MS (ESI +) m / z: 418 (M + H) ⁺ .
HRMS (ESI +) m / Z: 418.17421 (M + H) ⁺ , calcd 418.17668 (-2.47 mmu).

Example 7 3-{[6- (3-Fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate hydrochloride (hydrochloride of compound number 1-36)
(7a) tert-butyl [5- (3-fluorophenoxy) -2-nitrophenyl] methylcarbamate 3-fluorophenol (3.53 g, 31.5 mmol), tert-butyl (5-chloro-2-nitrophenyl) To a solution of methyl carbamate (8.60 g, 30.0 mmol) in N, N-dimethylacetamide (15 mL) and tetrahydrofuran (60 mL) was added potassium tert-butoxide (3.93 g, 35.0 mmol) under ice cooling. Stir at 30 ° C. for 30 hours. The reaction mixture was concentrated, extracted with ethyl acetate (200 mL) and water (200 mL), and the organic layer was dried and concentrated to give the title object compound (9.21 g, yield 81%).
(7b) (6-Fluoro-1-methyl-1H-benzimidazol-2-yl) methanol tert-butyl [5- (3-fluorophenoxy) -2-nitrophenyl] methylcarbamate (9.21 g, 25.4 mmol) ), Ammonium chloride (0.80 g, 15.0 mmol) in water (30 mL) and ethanol (120 mL) were added iron powder (7.53 g, 135.0 mmol), and the mixture was stirred at 70 ° C. for 9 hours. The reaction solution was concentrated, 4N hydrochloric acid (90 mL) was added to the obtained brown solid, and the mixture was stirred at 120 ° C. for 30 minutes to obtain a uniform solution. Glycolic acid (6.84 g, 90.0 mmol) was added to this solution and stirred at 120 ° C. for 4 hours. After the reaction solution was concentrated, 2N aqueous sodium hydroxide solution was gradually added to make the solution basic, thereby precipitating a solid. The obtained solid was recrystallized from ethanol to obtain the title object compound (4.90 g, yield 71%).
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 3.80 (3H, s), 4.71 (2H, d, J = 5.5 Hz), 5.59 (1H, t, J = 5.5 Hz), 6.75-6.82 ( 2H, m), 6.87-6.97 (2H, m), 7.33-7.42 (2H, m), 7.62 (1H, d, J = 8.6 Hz).
(7c) 3-{[6- (3-Fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate hydrochloride [6- (3-Fluorophenoxy) -1-methyl- 1H-benzimidazol-2-yl] methanol (0.41 g, 1.5 mmol) and methyl 3-hydroxybenzoate (0.34 g, 2.3 mmol) in tri n-butylphosphine (0.61 g, 3.0 mmol) and 1,1 ′-(azodicarbonyl) dipiperidine (0.76 g, 3.0 mmol) were added and stirred for 10 hours. After concentrating the reaction solution, purification was performed using silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/2), and then 4N hydrogen chloride / 1,4-dioxane solution (10 mL) was added for 2 hours. Stir. The precipitated solid was collected by filtration and washed with ethyl acetate and ether. The title compound (0.43 g, yield 64%) was obtained by drying under reduced pressure.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 3.87 (3H, s), 3.90 (3H, s), 5.62 (2H, s), 6.82 (1H, ddd, J = 0.8, 2.4, 8.2 Hz ), 6.86 (1H, ddd, J = 2.4, 2.4, 8.2 Hz), 6.96 (1H, dddd, J = 0.8, 2.4, 8.4, 8.4 Hz), 7.14 (1H, dd, J = 2.2, 8.8 Hz), 7.41 (1H, ddd, J = 6.9, 8.2, 8.4 Hz), 7.46 (1H, ddd, J = 1.1, 2.6, 8.2 Hz), 7.52 (1H, dd, J = 7.5, 8.2 Hz), 7.59 (1H, d, J = 2.2 Hz), 7.64 (1H, ddd, J = 1.1, 1.5, 7.5 Hz), 7.70 (1H, dd, J = 1.5, 2.6 Hz), 7.78 (1H, d, J = 8.8 Hz).
MS (ESI +) m / z: 407 (M + H) ⁺ , 429 (M + Na) ⁺ .
HRMS (ESI +) m / Z: 407.13957 (M + H) ⁺ , calcd 407.14071 (-1.14 mmu).

Example 8 3-{[6- (3-Fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid hydrochloride (hydrochloride of compound number 1-35)
1 of methyl 3-{[6- (3-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid hydrochloride (0.33 g, 0.74 mmol) synthesized in Example 7 To the 1,4-dioxane solution was added 1N aqueous sodium hydroxide solution (15 mL, 15 mmol), and the mixture was stirred at 60 ° C. for 2 hours. After treatment with concentrated hydrochloric acid (2.5 mL), the reaction mixture was concentrated, and the resulting solid was washed with water and ethyl acetate and dried under reduced pressure to give the title object compound (0.22 g, yield 69). %).
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 3.95 (3H, s), 5.70 (2H, s), 6.85 (1H, ddd, J = 0.8, 2.4, 8.2 Hz), 6.89 (1H, ddd , J = 2.3, 2.4, 8.2 Hz), 6.99 (1H, dddd, J = 0.8, 2.3, 8.2, 8.4 Hz), 7.24 (1H, dd, J = 2.2, 8.9 Hz), 7.42 (1H, ddd, J = 6.9, 8.2, 8.2 Hz), 7.45 (1H, ddd, J = 1.1, 2.6, 8.2 Hz), 7.51 (1H, dd, J = 7.5, 8.2 Hz), 7.64 (1H, ddd, J = 1.1, 1.3 , 7.5 Hz), 7.69 (1H, d, J = 2.23 Hz), 7.71 (1H, dd, J = 1.3, 2.6 Hz), 7.84 (1H, d, J = 8.9 Hz).
MS (ESI +) m / z: 393 (M + H) ⁺ , 415 (M + Na) ⁺ , 437 (M + 2Na-H) ⁺ .
HRMS (ESI +) m / Z: 393.12228 (M + H) ⁺ , calcd 393.12506 (-2.78 mmu).

Example 9 3-{[6- (4-Chloro-3-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate hydrochloride (hydrochloric acid of Compound No. 1-100 salt)
(9a) [(4-Chloro-3-fluorophenoxy) -2-nitrophenyl] -methyl-carbamic acid tert-butyl ester
N, N-dimethylformamide of 4-chloro-3-fluorophenol (4.94 g, 30.0 mmol) and (5-chloro-2-nitrophenyl) -methyl-carbamic acid tert-butyl ester (8.60 g, 30.0 mmol) ( To the solution was added sodium hydride (> 56% in oil, 1.31 g, 30.0 mmol) under ice cooling. After gradually warming up to room temperature, it heated up to 80 degree | times and stirred as it was for 8 hours. Furthermore, after leaving still overnight at room temperature, it stirred again at 80 degree | times for 1 hour. After allowing to cool, water and saturated brine were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to obtain the desired product (12.63 g, yield: 100%) as pale yellow needles.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.32 (9H, s), 3.26 (3H, s), 6.85-6.92 (4H, m), 7.43 (1H, t, J = 8.6Hz), 7.93 (1H , t, J = 8.6Hz).
(9b) [6- (4-Chloro-3-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol
[(4-Chloro-3-fluorophenoxy) -2-nitrophenyl] -methyl-carbamic acid tert-butyl ester (12.62 g, 30.0 mmol) dissolved in ethanol (150 mL) and water (75 mL), then iron powder (8.03 g, 150 mmol) and ammonium chloride (803.2 mg, 15.0 mmol) were added, and the mixture was heated to reflux for 4 and a half hours. The reaction mixture was allowed to cool, diluted with water, saturated brine, and ethyl acetate, and filtered through celite. The filtrate was separated, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and [2-amino-5- (4-chloro-3-fluorophenoxy) -phenyl] -methyl-carbamic acid tert -Butyl ester was obtained as a white solid (12.01 g, 100% yield). To this was added glycolic acid (3.42 g, 45.0 mmol) and 4N hydrochloric acid-1,4-dioxane solution (150 mL), and the mixture was heated to reflux for 2 hours. The reaction solution was slowly poured into a saturated aqueous solution of sodium bicarbonate under ice cooling, and further diisopropyl ether was added and stirred. After a few minutes, a pale yellow powder was produced, which was collected by filtration, washed successively with a mixture of ethyl acetate and n-hexane and water, and dried to give the desired product (3.85 g, yield 42%) Obtained as a yellow powder.
H-NMR (CDCl ₃ , 400 MHz) δ: 3.78 (3H, s), 4.88 (2H, s), 6.69 (1H, dd, J = 3.9, 10.1 Hz), 6.73 (1H, dd, J = 3.2, 10.1 Hz), 6.93-6.95 (2H, m), 7.28 (1H, t, J = 8.7Hz), 7.05 (1H, d, J = 8.7Hz).
(9c) 3-{[6- (4-Chloro-3-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate hydrochloride [6- (4-Chloro-3- To a toluene solution of fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol (0.46 g, 1.5 mmol), methyl 3-hydroxybenzoate (0.34 g, 2.3 mmol), tri-n -Butylphosphine (0.61 g, 3.0 mmol) and 1,1 ′-(azodicarbonyl) dipiperidine (0.76 g, 3.0 mmol) were added and stirred for 10 hours. After concentrating the reaction solution, purification was performed using silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/2), and then 4N hydrogen chloride / 1,4-dioxane solution (10 mL) was added for 2 hours. Stir. The precipitated solid was collected by filtration and washed with ethyl acetate and ether. The title compound (0.44 g, 61% yield) was obtained by drying under reduced pressure.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 3.87 (3H, s), 3.92 (3H, s), 5.66 (2H, s), 6.88 (1H, ddd, J = 1.3, 2.8, 8.9 Hz ), 7.15 (1H, dd, J = 2.8, 10.8 Hz), 7.21 (1H, dd, J = 2.2, 8.8 Hz), 7.47 (1H, ddd, J = 1.1, 2.6, 8.3 Hz), 7.53 (1H, dd, J = 7.5, 8.3 Hz), 7.59 (1H, dd, J = 8.8, 8.9 Hz), 7.64 (1H, ddd, J = 1.1, 1.5, 7.5 Hz), 7.65 (1H, d, J = 2.2 Hz ), 7.71 (1H, dd, J = 1.5, 2.6 Hz), 7.81 (1H, d, J = 8.8 Hz).
MS (ESI +) m / z: 441 (M + H) ⁺ , 443 (M + H + 2) ⁺ , 463 (M + Na) ⁺ , 465 (M + Na + 2) ⁺ .
HRMS (ESI +) m / Z : 441.10171 (M + H) +, calcd 441.10174 (-0.03 mmu).

Example 10 3-{[6- (4-Chloro-3-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid hydrochloride (hydrochloride of compound number 1-99) )
3-{[6- (4-Chloro-3-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid methyl hydrochloride synthesized in Example 9 (0.33 g, 0. 1N aqueous sodium hydroxide solution (10 mL, 10 mmol) was added to a 1,4-dioxane solution of 69 mmol), and the mixture was stirred at 60 ° C. for 2 hours. After treating with concentrated hydrochloric acid (1.5 mL), the reaction mixture was concentrated, and the resulting solid was washed with water and ethyl acetate and dried under reduced pressure to give the title object compound (0.23 g, yield 72). %).
Mp 197-201 ° C.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 3.94 (3H, s), 5.68 (2H, s), 6.88 (1H, ddd, J = 1.3, 2.8, 8.9 Hz), 7.16 (1H, dd , J = 2.8, 10.7 Hz), 7.23 (1H, dd, J = 2.2, 8.8 Hz), 7.44 (1H, ddd, J = 1.1, 2.6, 8.3 Hz), 7.50 (1H, dd, J = 7.6, 8.3 Hz), 7.59 (1H, dd, J = 8.8, 8.9 Hz), 7.63 (1H, ddd, J = 1.1, 1.3, 7.6 Hz), 7.68 (1H, d, J = 2.2 Hz), 7.70 (1H, dd , J = 1.3, 2.6 Hz), 7.82 (1H, d, J = 8.8 Hz).
MS (ESI +) m / z: 427 (M + H) ⁺ , 429 (M + H + 2) ⁺ , 449 (M + Na) ⁺ , 451 (M + Na + 2) ⁺ .
HRMS (ESI +) m / Z: 427.08529 (M + H) ⁺ , calcd 427.08609 (-0.80 mmu).

Example 11 3-{[6- (3-Chloro-4-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate hydrochloride (hydrochloric acid of Compound No. 1-116 salt)
(11a) [(3-Chloro-4-fluorophenoxy) -2-nitrophenyl] -methyl-carbamic acid tert-butyl ester
3-chloro-4-fluorophenol (5.97 g, 36.7 mmol) and (5-chloro-2-nitrophenyl) -methyl-carbamic acid tert-butyl ester (10.40 g, 36.3 mmol), sodium hydride (> 56% in oil, 1.58 g, 36.3 mmol) and N, N-dimethylformamide (200 mL) in the same manner as in Example 7a to obtain the desired product (15.50 g, yield 100%) as pale yellow needles.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.32 (9H, s), 3.26 (3H, s), 6.79-6.85 (2H, m), 6.95-6.97 (1H, m), 7.15-7.18 (2H, m), 7.91-7.93 (1H, m).
(11b) [2-Amino-5- (3-chloro-4-fluorophenoxy) -phenyl] -methyl-carbamic acid tert-butyl ester
[(3-Chloro-4-fluorophenoxy) -2-nitrophenyl] -methyl-carbamic acid tert-butyl ester (7.51 g, 18.1 mmol), iron powder (4.84 g, 90.5 mmol), ammonium chloride (0.48 g, 9.05 mmol), ethanol (100 mL), and water (50 mL) were synthesized in the same manner as in Example 7b to obtain the desired product as light brown crystals (6.98 g, yield 93%).
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.58 (9H, s), 3.14 (3H, s), 3.72 (1H, broad), 6.74-6.82 (4H, m), 6.90-6.99 (1H, m) , 7.05 (1H, t, J = 8.8Hz).
(11c) [6- (3-Chloro-4-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol
[2-Amino-5- (3-chloro-4-fluorophenoxy) -phenyl] -methyl-carbamic acid tert-butyl ester (6.89 g, 16.6 mmol), glycolic acid (1.89 g, 24.9 mmol), 4N hydrochloric acid Synthesis was performed in the same manner as in Example 7b from a 1,4-dioxane solution (120 mL) to obtain the desired product as light brown crystals (2.42 g, yield 48%).
H-NMR (CDCl ₃ , 400 MHz) δ: 3.78 (3H, s), 4.89 (2H, s), 6.85-7.00 (4H, m), 7.09 (1H, t, J = 8.6 Hz), 7.05 (1H, d, J = 8.8Hz).
(11d) 3-{[6- (3-Chloro-4-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate hydrochloride [6- (3-Chloro-4- To a toluene solution of fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol (0.46 g, 1.5 mmol), methyl 3-hydroxybenzoate (0.34 g, 2.3 mmol), tri-n -Butylphosphine (0.61 g, 3.0 mmol) and 1,1 ′-(azodicarbonyl) dipiperidine (0.76 g, 3.0 mmol) were added and stirred for 10 hours. After concentrating the reaction solution, purification was performed using silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/2), and then 4N hydrogen chloride / 1,4-dioxane solution (10 mL) was added for 2 hours. Stir. The precipitated solid was collected by filtration and washed with ethyl acetate and ether. The title object compound (0.48 g, yield 67%) was obtained by drying under reduced pressure.
^{1 H-NMR (DMSO-d} 6, 400 MHz) δ: 3.87 (3H, s), 3.92 (3H, s), 5.66 (2H, s), 7.06 (1H, ddd, J = 3.0, 3.9, 9.1 Hz ), 7.19 (1H, dd, J = 2.2, 8.9 Hz), 7.28 (1H, dd, J = 3.0, 6.3 Hz), 7.46 (1H, dd, J = 8.9, 9.1 Hz), 7.47 (1H, ddd, J = 1.1, 2.2, 8.2 Hz), 7.53 (1H, dd, J = 7.6, 8.2 Hz), 7.59 (1H, d, J = 2.2 Hz), 7.65 (1H, ddd, J = 1.1, 1.5, 7.6 Hz) ), 7.71 (1H, dd, J = 1.5, 2.2 Hz), 7.79 (1H, d, J = 8.9 Hz).
MS (ESI +) m / z: 441 (M + H) ⁺ , 443 (M + H + 2) ⁺ , 463 (M + Na) ⁺ , 465 (M + Na + 2) ⁺ .
HRMS (ESI +) m / Z: 441.10182 (M + H) ⁺ , calcd 441.10174 (0.08 mmu).

Example 12 3-{[6- (3-Chloro-4-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid hydrochloride (hydrochloride of compound number 1-115) )
3-{[6- (3-Chloro-4-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid methyl hydrochloride synthesized in Example 11 (0.34 g, 0. 1N aqueous sodium hydroxide solution (10 mL, 10 mmol) was added to a 1,4-dioxane solution of 7 mmol), and the mixture was stirred at 60 ° C. for 2 hours. After treating with concentrated hydrochloric acid (1.5 mL), the reaction mixture was concentrated, and the resulting solid was washed with water and ethyl acetate and dried under reduced pressure to give the title object compound (0.23 g, yield 70). %).
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 3.94 (3H, s), 5.69 (2H, s), 7.07 (1H, ddd, J = 3.0, 3.9, 9.1 Hz), 7.22 (1H, dd , J = 2.2, 8.9 Hz), 7.29 (1H, dd, J = 3.0, 6.2 Hz), 7.44 (1H, ddd, J = 1.1, 2.7, 8.2 Hz), 7.46 (1H, dd, J = 9.1, 9.1 Hz), 7.50 (1H, dd, J = 7.6, 8.2 Hz), 7.63 (1H, d, J = 2.2 Hz), 7.64 (1H, ddd, J = 1.1, 1.3, 7.6 Hz), 7.70 (1H, dd , J = 1.3, 2.7 Hz), 7.82 (1H, d, J = 8.9 Hz).
MS (ESI +) m / z: 427 (M + H) ⁺ , 429 (M + H + 2) ⁺ , 449 (M + Na) ⁺ , 451 (M + Na + 2) ⁺ .
HRMS (ESI +) m / Z: 427.08535 (M + H) ⁺ , calcd 427.08609 (-0.74 mmu).

Example 13 3-[(1-Methyl-6-phenoxy-1H-benzimidazol-2-yl) methoxy] methyl benzoate hydrochloride (hydrochloride of compound number 1-20)
(13a) (6-Phenoxy-1-methyl-1H-benzimidazol-2-yl) methanol
2-Nitro-4-chlorophenyl (methyl) carbamic acid tert-butyl ester (22.5 g, 78.6 mmol) and phenol (7.5 g, 78.6 mmol) were dissolved in tetrahydrofuran (180 mL) and DMF (20 mL) and sodium hydride ( 3.4 g, 78.6 mmol) was added, and the mixture was stirred at 80 ° C. for 10 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. After washing with water and saturated brine and drying over sodium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in 250 mL of ethanol, 10% palladium carbon (8 g) was added, and the mixture was stirred at 60 ° C. for 4 hours under hydrogen. Celite was used to remove the catalyst, and the solvent was distilled off under reduced pressure. The residue was dissolved in 1,4-dioxane (80 mL) and 4N hydrochloric acid-dioxane (80 mL), glycolic acid (8.7 g, 115 mmol) was added, and the mixture was heated to reflux for 2 hours. After cooling, the mixture was neutralized with saturated sodium hydrogen carbonate, and the resulting crystals were filtered and washed with water and ethyl acetate to obtain 14 g (yield 73%) of the target compound.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 3.77 (3H, s), 4.70 (2H, s), 6.85-6.97 (3H, m), 7.05-7.11 (1H, m), 7.23-7.28 (3H, m), 7.58-7.61 (1H, m).
(13b) Methyl 3-[(1-methyl-6-phenoxy-1H-benzimidazol-2-yl) methoxy] benzoate hydrochloride (1-methyl-6-phenoxy-1H-benzimidazol-2-yl) methanol (0.38 g, 1.5 mmol), toluene solution of methyl 3-hydroxybenzoate (0.34 g, 2.3 mmol), tri-n-butylphosphine (0.61 g, 3.0 mmol), 1,1′- (Azodicarbonyl) dipiperidine (0.76 g, 3.0 mmol) was added and stirred for 10 hours. After concentrating the reaction solution, purification was performed using silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/2), and then 4N hydrogen chloride / 1,4-dioxane solution (10 mL) was added for 2 hours. Stir. The precipitated solid was collected by filtration and washed with ethyl acetate and ether. The title compound was obtained by drying under reduced pressure (0.42 g, yield 66%).
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 3.88 (3H, s), 3.93 (3H, s), 5.69 (2H, s), 7.02 (2H, d, J = 8.7 Hz), 7.12 ( 1H, dd, J = 2.2, 8.8 Hz), 7.15 (1H, t, J = 7.5 Hz), 7.41 (2H, dd, J = 7.5, 8.7 Hz), 7.48 (1H, ddd, J = 1.3, 2.6, 8.2 Hz), 7.54 (1H, dd, J = 7.5, 8.2 Hz), 7.59 (1H, d, J = 2.2 Hz), 7.66 (1H, ddd, J = 1.3, 1.5, 7.5 Hz), 7.72 (1H, dd, J = 1.5, 2.6 Hz), 7.80 (1H, d, J = 8.8 Hz).
MS (ESI +) m / z: 389 (M + H) ⁺ , 441 (M + Na) ⁺ .
HRMS (ESI +) m / Z: 389.15176 (M + H) ⁺ , calcd 389.15013 (1.63 mmu).

Example 14 3-[(1-Methyl-6-phenoxy-1H-benzimidazol-2-yl) methoxy] benzoic acid hydrochloride (hydrochloride of compound number 1-19)
1,4-Dioxane solution of methyl 3-[(1-methyl-6-phenoxy-1H-benzimidazol-2-yl) methoxy] benzoate hydrochloride (0.28 g, 0.7 mmol) synthesized in Example 13 To the mixture was added 1N aqueous sodium hydroxide solution (10 mL, 10 mmol), and the mixture was stirred at 60 ° C. for 2 hr. After treating with concentrated hydrochloric acid (1.5 mL), the reaction mixture was concentrated, and the resulting solid was washed with water and ethyl acetate and dried under reduced pressure to give the title object compound (0.19 g, yield 70). %).
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 3.95 (3H, s), 5.72 (2H, s), 7.04 (2H, d, J = 8.8 Hz), 7.16 (1H, t, J = 7.5 Hz), 7.21 (1H, dd, J = 2.4, 8.8 Hz), 7.41 (2H, dd, J = 7.5, 8.8 Hz), 7.46 (1H, ddd, J = 1.1, 2.6, 8.2 Hz), 7.50 (1H , dd, J = 7.5, 8.2 Hz), 7.62 (1H, d, J = 2.2 Hz), 7.64 (1H, ddd, J = 1.1, 1.5, 7.5 Hz), 7.71 (1H, dd, J = 1.5, 2.6 Hz), 7.82 (1H, d, J = 8.8 Hz).
MS (ESI +) m / z: 375 (M + H) ⁺ , 397 (M + Na) ⁺ , 419 (M + 2Na-H) ⁺ .
HRMS (ESI +) m / Z : 375.13441 (M + H) +, calcd 375.13448 (-0.07 mmu).

Example 15 3-[(3-Methyl-5-phenoxy-3H-imidazo [4,5-b] pyridin-2-yl) methoxy] methyl benzoate dihydrochloride (dihydrochloric acid of Compound No. 1-28 salt)
(15a) (3-Methyl-5-phenoxy-3H-imidazo [4,5-b] pyridin-2-yl) methanol phenol (12.08 g, 128 mmol) was dissolved in THF (200 mL) and sodium hydride (60 %, 5.12 g, 128 mmol). Subsequently, 6-chloro-N-methyl-3-nitropyridin-2-amine (20 g, 107 mmol) was added and stirred at 80 degrees for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N potassium hydroxide solution, water and saturated brine, dried and concentrated. The residue was dissolved in THF (50 mL) -ethanol (50 mL), palladium hydroxide (500 mg) was added, and the mixture was stirred overnight under hydrogen. Celite was used to remove the catalyst, and the solvent was distilled off under reduced pressure. The residue was dissolved in 1,4-dioxane (150 mL) and 4N hydrochloric acid-dioxane (150 mL), glycolic acid (24.4 g, 321 mmol) was added, and the mixture was heated to reflux for 10 hours. After cooling, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. After sequentially washing with water and saturated brine and drying, the solvent was distilled off. The resulting crystals were washed thoroughly with diisopropyl ether to obtain 21.8 g (yield 80%) of the target compound.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 3.67 (3H, s, J = 7 Hz), 4.69 (2H, d, J = 5 Hz), 5.61 (1H, t, J = 5 Hz), 6.84 ( 1H, d, J = 8Hz), 7.12-7.23 (3H, m), 7.39-7.45 (2H, m), 8.06 (1H, d, J = 8Hz).
(15b) 3-[(3-Methyl-5-phenoxy-3H-imidazo [4,5-b] pyridin-2-yl) methoxy] methyl benzoate dihydrochloride (3-methyl-5-phenoxy-3H- To a toluene solution of imidazo [4,5-b] pyridin-2-yl) methanol (0.38 g, 1.5 mmol) and methyl 3-hydroxybenzoate (0.34 g, 2.3 mmol) was added tri-n-butylphosphine. (0.61 g, 3.0 mmol) and 1,1 ′-(azodicarbonyl) dipiperidine (0.76 g, 3.0 mmol) were added and stirred for 10 hours. After concentrating the reaction solution, purification was performed using silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/2), and then 4N hydrogen chloride / 1,4-dioxane solution (10 mL) was added for 2 hours. Stir. The precipitated solid was collected by filtration and washed with ethyl acetate and ether. The title compound (0.40 g, yield 58%) was obtained by drying under reduced pressure.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 3.72 (3H, s), 3.86 (3H, s), 5.54 (2H, s), 6.96 (1H, d, J = 8.6 Hz), 7.18 ( 1H, d, J = 7.5 Hz), 7.22 (1H, t, J = 7.3 Hz), 7.43 (2H, m), 7.45 (1H, dd, J = 7.6, 8.2 Hz), 7.61 (1H, dd, J = 1.5, 7.6 Hz), 7.66 (1H, dd, J = 1.5, 2.3 Hz), 8.18 (1H, d, J = 8.6 Hz).
MS (ESI +) m / z: 390 (M + H) ⁺ , 412 (M + Na) ⁺ .
HRMS (ESI +) m / Z: 390.14693 (M + H) ⁺ , calcd 390.14538 (1.55 mmu).

Example 16 3-[(3-Methyl-5-phenoxy-3H-imidazo [4,5-b] pyridin-2-yl) methoxy] benzoic acid dihydrochloride (dihydrochloride of compound number 1-27 )
3-[(3-Methyl-5-phenoxy-3H-imidazo [4,5-b] pyridin-2-yl) methoxy] benzoic acid methyl dihydrochloride (0.25 g, 0.6 mmol) synthesized in Example 15 1N aqueous solution of sodium hydroxide (10 mL, 10 mmol) was added to the 1,4-dioxane solution, and the mixture was stirred at 60 ° C. for 2 hours. After treating with concentrated hydrochloric acid (1.5 mL), the reaction mixture was concentrated, and the resulting solid was washed with water and ethyl acetate and dried under reduced pressure to give the title object compound (0.16 g, yield 65). %).
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 3.73 (3H, s), 5.53 (2H, s), 6.96 (1H, d, J = 8.6 Hz), 7.18 (1H, d, J = 8.7 Hz), 7.22 (1H, t, J = 7.5 Hz), 7.38 (1H, ddd, J = 1.1, 2.6, 8.2 Hz), 7.42 (2H, m), 7.46 (1H, dd, J = 7.6, 8.2 Hz ), 7.59 (1H, ddd, J = 1.1, 1.3, 7.6 Hz), 7.64 (1H, dd, J = 1.3, 2.6 Hz), 8.18 (1H, d, J = 8.6 Hz).
MS (ESI +) m / z: 376 (M + H) ⁺ , 398 (M + Na) ⁺ , 420 (M + 2Na-H) ⁺ .
HRMS (ESI +) m / Z: 376.12947 (M + H) ⁺ , calcd 376.12973 (−0.26 mmu).

Example 17 5-{[6- (4-Amino-3,5-dimethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl nicotinate 5/2 hydrochloride (Compound No. 1-136 5/2 hydrochloride)
{6- [4- (tert-Butyloxycarbonylamino) -3,5-dimethylphenoxy] -1-methyl-1H-benzimidazol-2-yl} methanol (0.60 g, 1.5 mmol), 5-hydroxy To a toluene solution of methyl nicotinate (0.34 g, 2.3 mmol), tri-n-butylphosphine (0.61 g, 3.0 mmol), 1,1 ′-(azodicarbonyl) dipiperidine (0.76 g, 3. 0 mmol) was added and stirred for 10 hours. After concentrating the reaction solution, purification was performed using silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/2), and then 4N hydrogen chloride / 1,4-dioxane solution (10 mL) was added for 2 hours. Stir. The precipitated solid was collected by filtration and washed with ethyl acetate and ether. The title object compound (0.48 g, 61% yield) was obtained by drying under reduced pressure.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 2.34 (6H, s), 3.91 (3H, s), 3.93 (3H, s), 5.80 (2H, s), 6.79 (2H, s), 7.15 (1H, dd, J = 2.0, 8.0 Hz), 7.58 (1H, d, J = 2.0 Hz), 7.78 (1H, d, J = 8.6 Hz), 8.09 (1H, dd, J = 1.6, 2.7 Hz) ), 8.75 (1H, d, J = 2.7 Hz), 8.78 (1H, d, J = 1.6 Hz).
MS (ESI +) m / z : 433 (M + H) +, 455 (M + Na) +.
HRMS (ESI +) m / Z: 433.18576 (M + H) ⁺ , calcd 433.18758 (-1.82 mmu).

Example 18 5-{[6- (4-Amino-3,5-dimethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} nicotinic acid dihydrochloride (Compound No. 1-135) Dihydrochloride)
5-{[6- (4-Amino-3,5-dimethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl nicotinate 5/2 hydrochloride (0.35 g, 0.7 mmol) 1N aqueous solution of sodium hydroxide (10 mL, 10 mmol) was added to the 1,4-dioxane solution, and the mixture was stirred at 60 ° C. for 2 hours. After treating with concentrated hydrochloric acid (1.5 mL), the reaction mixture was concentrated, and the resulting solid was washed with water and ethyl acetate and dried under reduced pressure to give the title object compound (0.17 g, yield 52). %).
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 2.30 (6H, s), 3.89 (3H, s), 5.71 (2H, s), 6.76 (2H, s), 7.05 (1H, dd, J = 2.0, 8.6 Hz), 7.46 (1H, d, J = 2.0 Hz), 7.73 (1H, d, J = 8.6 Hz), 8.04 (1H, dd, J = 1.6, 3.1 Hz), 8.68 (1H, d , J = 3.1 Hz), 8.74 (1H, d, J = 1.6 Hz).
MS (ESI +) m / z: 419 (M + H) ⁺ , 441 (M + Na) ⁺ .
HRMS (ESI +) m / Z: 419.17103 (M + H) ⁺ , calcd 419.17193 (-0.90 mmu).

Example 19 3-{[1-Methyl-6- (3-morpholin-4-ylphenoxy) -1H-benzimidazol-2-yl] methoxy} methyl benzoate dihydrochloride (compound no. 1-68 Dihydrochloride)
(19a) Methyl- [5- (3-morpholin-4-yl-phenoxy) -2-nitro-phenyl] -carbamic acid tert-butyl ester
(5-Chloro-2-nitro-phenyl) -methyl-carbamic acid tert-butyl ester (5.0 g, 17 mmol), sodium hydride (761 mg, 17 mmol), 3-morpholin-4-yl-phenol (3.2 g, 17 mmol) The crude target compound obtained in the same manner as in Example 7a was purified using silica gel column chromatography to obtain the target compound (6.5 g, yield 86%) as a yellow foam.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.32 (9H, s), 3.15-3.22 (4H, m), 3.25 (3H, s), 3.81-3.88 (4H, m), 6.57 (1H, t, J = 7.3Hz), 6.62 (1H, s), 6.79 (1H, d, J = 7.8Hz), 6.82-6.91 (2H, m), 7.24-7.33 (1H, m), 7.92 (1H, d, J = 8.8Hz).
(19b) [2-Amino-5- (3-morpholin-4-yl-phenoxy) -phenyl] -methyl-carbamic acid tert-butyl ester Methyl- [5- (3-morpholine-4 synthesized in Example 19a -Yl-phenoxy) -2-nitro-phenyl] -carbamic acid tert-butyl ester (6.5 g, 15 mmol), palladium-carbon (10%, 1.0 g) suspended in ethyl acetate (100 mL) under a hydrogen atmosphere 2 Stir for hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the desired product (5.8 g, yield 96%) as a pale orange solid.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.38 (9H, s), 3.09-3.16 (7H, m), 3.80-3.84 (4H, m), 6.38 (1H, br s), 6.51 (1H, s ), 6.56 (1H, d, J = 7.4Hz), 6.70-6.80 (3H, m), 7.13 (1H, t, J = 8.0Hz).
(19c) [1-Methyl-6- (3-morpholin-4-yl-phenoxy) -1H-benzimidazol-2-yl] -methanol [2-amino-5- (3-morpholine synthesized in Example 19b] -4-yl-phenoxy) -phenyl] -methyl-carbamic acid tert-butyl ester (5.8 g, 15 mmol) and glycolic acid (1.66 g, 22 mmol) in 4N hydrochloric acid (60 mL), 1,4-dioxane (60 mL) It melt | dissolved in the mixed solvent and heated and refluxed. The organic solvent was distilled off from the reaction solution under reduced pressure, and the remaining aqueous solution was washed with methylene chloride, neutralized with excess sodium bicarbonate, diluted with ethyl acetate and stirred. The resulting solid was filtered to obtain the target compound (2.8 g, yield 57%) as a light brown solid.
^{1 H-NMR (DMSO-d} 6, 400 MHz) δ: 3.03-3.08 (4H, m), 3.67-3.71 (4H, m), 3.76 (3H, s), 4.66-4.69 (2H, m), 6.30 (1H, dd, J = 2.0, 7.8Hz), 6.55 (1H, t, J = 2.35), 6.65 (1H, dd, J = 2.2, 8.0Hz), 6.86 (1H, dd, J = 2.4, 8.6Hz ), 7.14 (1H, t, J = 8.2Hz), 7.22 (1H, d, J = 2.4Hz), 7.55 (1H, d, J = 8.6Hz).
(19d) 3-{[1-Methyl-6- (3-morpholin-4-ylphenoxy) -1H-benzimidazol-2-yl] methoxy} methyl benzoate dihydrochloride [1-Methyl-6- (3 To a toluene solution of -morpholin-4-ylphenoxy) -1H-benzimidazol-2-yl] methanol (0.51 g, 1.5 mmol) and methyl 3-hydroxybenzoate (0.34 g, 2.3 mmol), n-Butylphosphine (0.61 g, 3.0 mmol) and 1,1 ′-(azodicarbonyl) dipiperidine (0.76 g, 3.0 mmol) were added and stirred for 10 hours. After concentrating the reaction solution, purification was performed using silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/2), and then 4N hydrogen chloride / 1,4-dioxane solution (10 mL) was added for 2 hours. Stir. The precipitated solid was collected by filtration and washed with ethyl acetate and ether. The title object compound (0.49 g, yield 60%) was obtained by drying under reduced pressure.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 3.13 (4H, t, J = 4.7 Hz), 3.72 (4H, t, J = 4.7 Hz), 3.87 (3H, s), 3.97 (3H, s), 5.76 (2H, s), 6.42 (1H, dd, J = 2.0, 7.8 Hz), 6.70 (1H, dd, J = 2.0, 2.0 Hz), 6.80 (1H, dd, J = 2.0, 8.2 Hz) ), 7.23 (1H, dd, J = 7.8, 8.2 Hz), 7.23 (1H, dd, J = 2.3, 8.6 Hz), 7.50 (1H, ddd, J = 1.2, 2.4, 8.3 Hz), 7.54 (1H, dd, J = 7.1, 8.3 Hz), 7.64 (1H, d, J = 2.3 Hz), 7.65 (1H, ddd, J = 1.2, 1.6, 7.1 Hz), 7.72 (1H, dd, J = 1.6, 2.4 Hz) ), 7.82 (1H, d, J = 8.6 Hz).
MS (ESI +) m / z: 474 (M + H) ⁺ , 496 (M + Na) ⁺ .
HRMS (ESI +) m / Z: 474.20084 (M + H) ⁺ , calcd 474.20290 (-2.06 mmu).

Example 20 3-{[1-Methyl-6- (3-morpholin-4-ylphenoxy) -1H-benzimidazol-2-yl] methoxy} benzoic acid 1/2 hydrochloride (Compound No. 1-67 Of 1/2 hydrochloride)
3-{[1-Methyl-6- (3-morpholin-4-ylphenoxy) -1H-benzimidazol-2-yl] methoxy} methyl benzoate dihydrochloride (0.34 g, 0.7 mmol) 1, 1-N sodium hydroxide aqueous solution (10 mL, 10 mmol) was added to the 4-dioxane solution, and it stirred at 60 degreeC for 2 hours. After treating with concentrated hydrochloric acid (1.5 mL), the reaction mixture was concentrated, and the resulting solid was washed with water and ethyl acetate and dried under reduced pressure to give the title object compound (0.18 g, yield 59). %).
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 3.69 (4H, t, J = 4.7 Hz), 3.80 (4H, t, J = 4.7 Hz), 5.45 (2H, s), 6.32 (1H, dd, J = 2.0, 8.2 Hz), 6.57 (1H, dd, J = 2.0, 2.4 Hz), 6.66 (1H, dd, J = 2.4, 8.2 Hz), 6.90 (1H, dd, J = 2.4, 8.6 Hz) ), 7.15 (1H, dd, J = 8.2, 8.2 Hz), 7.28 (1H, d, J = 2.4 Hz), 7.36 (1H, ddd, J = 8.2 Hz), 7.43 (1H, dd, J = 7.4, 8.2 Hz), 7.55 (1H, ddd, J = 7.4 Hz), 7.61 (1H, br), 7.62 (1H, d, J = 8.6 Hz).
MS (ESI +) m / z: 460 (M + H) ⁺ , 482 (M + Na) ⁺ .
HRMS (ESI +) m / Z: 460.18678 (M + H) ⁺ , calcd 460.18725 (-0.47 mmu).

Example 21 4-{[1-Methyl-6- (3-morpholin-4-ylphenoxy) -1H-benzimidazol-2-yl] methoxy} ethyl benzoate dihydrochloride (Compound No. 1-70) Dihydrochloride)
[1-Methyl-6- (3-morpholin-4-ylphenoxy) -1H-benzimidazol-2-yl] methanol (0.51 g, 1.5 mmol), ethyl 4-hydroxybenzoate (0.37 g, 2 .3 mmol) in toluene solution was added tri-n-butylphosphine (0.61 g, 3.0 mmol) and 1,1 ′-(azodicarbonyl) dipiperidine (0.76 g, 3.0 mmol) and stirred for 10 hours. . After concentrating the reaction solution, purification was performed using silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/2), and then 4N hydrogen chloride / 1,4-dioxane solution (10 mL) was added for 2 hours. Stir. The precipitated solid was collected by filtration and washed with ethyl acetate and ether. The title object compound (0.55 g, yield 65%) was obtained by drying under reduced pressure.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 1.31 (3H, t, J = 7.0 Hz), 3.11 (4H, t, J = 4.7 Hz), 3.71 (4H, t, J = 4.7 Hz) , 3.94 (3H, s), 4.28 (2H, q, J = 7.04 Hz), 5.73 (2H, s), 6.40 (1H, dd, J = 2.0, 7.8 Hz), 6.66 (1H, dd, J = 2.0 , 2.0 Hz), 6.76 (1H, dd, J = 2.0, 8.2 Hz), 7.18 (1H, dd, J = 2.4, 9.0 Hz), 7.22 (1H, dd, J = 7.8, 8.2 Hz) 7.29 (2H, d, J = 9.0 Hz), 7.59 (1H, d, J = 2.4), 7.78 (1H, d, J = 9.0 Hz), 7.97 (2H, d, J = 9.0 Hz).
MS (ESI +) m / z: 488 (M + H) ⁺ , 510 (M + Na) ⁺ .
HRMS (ESI +) m / Z: 488.21667 (M + H) ⁺ , calcd 488.21855 (-1.87 mmu).

Example 22 4-{[1-Methyl-6- (3-morpholin-4-ylphenoxy) -1H-benzimidazol-2-yl] methoxy} benzoic acid dihydrochloride (compound no. 1-69 Hydrochloride)
4-{[1-Methyl-6- (3-morpholin-4-ylphenoxy) -1H-benzimidazol-2-yl] methoxy} ethyl benzoate dihydrochloride (0.43 g, 0.8 mmol) 1, A 1N aqueous sodium hydroxide solution (10 mL, 10 mmol) was added to the 4-dioxane solution, and the mixture was stirred at 60 ° C. for 2 hours. After treatment with concentrated hydrochloric acid (1.5 mL), the reaction mixture is concentrated, and the resulting solid is washed with water and ethyl acetate and dried under reduced pressure to give the title object compound (0.24 g, yield 59). %).
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 3.11 (4H, t, J = 4.7 Hz), 3.71 (4H, t, J = 4.7 Hz), 3.94 (3H, s), 5.72 (2H, s), 6.39 (1H, dd, J = 2.3, 7.8 Hz), 6.65 (1H, dd, J = 2.0, 2.3 Hz), 6.76 (1H, dd, J = 2.0, 8.2 Hz), 7.18 (1H, dd , J = 2.4, 9.0 Hz), 7.22 (1H, dd, J = 7.8, 8.2 Hz), 7.26 (2H, d, J = 9.0 Hz), 7.58 (1H, d, J = 2.3 Hz), 7.78 (1H , d, J = 9.0 Hz), 7.94 (2H, d, J = 9.0 Hz).
MS (ESI +) m / z: 460 (M + H) ⁺ , 482 (M + Na) ⁺ .
HRMS (ESI +) m / Z: 460.18703 (M + H) ⁺ , calcd 460.18725 (-0.22 mmu).

Example 23: 3-[(6-Ethoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] methyl benzoate hydrochloride (hydrochloride of compound number 1-4)
(23a) (6-Ethoxy-1-methyl-1H-benzimidazol-2-yl) methanol
2-Nitro-4-ethoxy (methyl) carbamic acid tert-butyl ester (4 g, 13.5 mmol) was dissolved in 100 mL of ethanol, 10% palladium carbon (1 g) was added, and the mixture was stirred under hydrogen for 2 hours. Celite was used to remove the catalyst, and the solvent was distilled off under reduced pressure. The residue was dissolved in 1,4-dioxane (30 mL) and 4N hydrochloric acid-dioxane (30 mL), glycolic acid (2.05 g, 27 mmol) was added, and the mixture was heated to reflux for 5.5 hours. After cooling, the mixture was neutralized with saturated sodium hydrogen carbonate, and the resulting crystals were filtered and washed with water and ethyl acetate to obtain 1.51 g (yield 54%) of the target compound.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 1.36 (3H, t, J = 7 Hz), 3.77 (3H, s), 4.07 (2H, q, J = 7 Hz), 4.65 (2H, s) 6.77 (1H, dd, J = 2Hz, 8Hz), 7.05 (1H, d, J = 2Hz), 7.44 (1H, d, J = 8Hz).
(23b) Methyl 3-[(6-ethoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzoate hydrochloride (6-ethoxy-1-methyl-1H-benzimidazol-2-yl) methanol (0.60 g, 2.0 mmol), toluene solution of methyl 3-hydroxybenzoate (0.46 g, 3.0 mmol), tri-n-butylphosphine (0.91 g, 4.5 mmol), 1,1′- (Azodicarbonyl) dipiperidine (1.13 g, 4.5 mmol) was added and stirred for 10 hours. After concentrating the reaction solution, purification was performed using silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/2), and then 4N hydrogen chloride / 1,4-dioxane solution (10 mL) was added for 2 hours. Stir. The precipitated solid was collected by filtration and washed with ethyl acetate and ether. The title object compound (0.49 g, yield 65%) was obtained by drying under reduced pressure.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 1.39 (3H, t, J = 7.1 Hz), 3.88 (3H, s), 3.98 (3H, s), 4.16 (2H, q, J = 7.1 Hz), 5.71 (2H, s), 7.13 (1H, dd, J = 2.2, 8.9 Hz), 7.47 (1H, d, J = 2.2 Hz), 7.49 (1H, ddd, J = 1.3, 2.6, 8.2 Hz ), 7.55 (1H, dd, J = 7.5, 8.2 Hz), 7.67 (1H, dd, J = 1.3, 7.5 Hz), 7.69 (1H, d, J = 8.9 Hz), 7.72 (1H, d, J = 2.6 Hz).
MS (ESI +) m / z: 341 (M + H) ⁺ , 363 (M + Na) ⁺ .
HRMS (ESI +) m / Z: 341.15051 (M + H) ⁺ , calcd 341.15013 (0.37 mmu).

Example 24 3-[(6-Ethoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzoic acid hydrochloride (hydrochloride of compound number 1-3)
To a 1,4-dioxane solution of methyl 3-[(6-ethoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzoate hydrochloride (0.38 g, 1.0 mmol), 1N sodium hydroxide Aqueous solution (10 mL, 10 mmol) was added and stirred at 60 ° C. for 2 hours. After treating with concentrated hydrochloric acid (1.5 mL), the reaction mixture was concentrated, and the resulting solid was washed with water and ethyl acetate and dried under reduced pressure to give the title object compound (0.22 g, yield 61). %).
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 1.40 (3H, t, J = 7.1 Hz), 3.98 (3H, s), 4.16 (2H, q, J = 7.1 Hz), 5.71 (2H, s), 7.13 (1H, dd, J = 2.2, 8.9 Hz), 7.45 (1H, ddd, J = 1.1, 2.6, 8.2 Hz), 7.52 (1H, dd, J = 7.5, 8.2 Hz), 7.65 (1H , ddd, J = 1.1, 1.3, 7.5 Hz), 7.70 (1H, d, J = 8.9 Hz), 7.71 (1H, dd, J = 1.3, 2.6 Hz).
MS (ESI +) m / z: 327 (M + H) ⁺ , 349 (M + Na) ⁺ , 371 (M + 2Na-H) ⁺ .
HRMS (ESI +) m / Z: 327.13292 (M + H) ⁺ , calcd 327.13448 (-1.56 mmu).

Example 25 3-{[1-Methyl-6- (pyridin-3-yloxy) -1H-benzimidazol-2-yl] methoxy} methyl benzoate dihydrochloride (dihydrochloride of compound number 1-148) )
(25a) [1-Methyl-6- (pyridin-3-yloxy) -1H-benzimidazol-2-yl] methanol 2-amino-5- (pyridin-3-yloxy) phenyl (methyl) carbamate tert-butyl (7.61 g, 24.1 mmol) [US6432993 B1] in 1,4-dioxane (75 mL) and 4N aqueous hydrochloric acid (75 mL) mixed solution was added glycolic acid (2.75 g, 36.2 mmol) at 50 ° C. After stirring for 30 minutes, the mixture was heated to reflux for 7 hours. The reaction solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / methanol = 5/1) to give the title object compound (4.31 g, 16.9 mmol). Got.
1H-NMR (CDCl ₃ , 400MHz) δ: 3.78 (3H, s), 4.90 (2H, s), 6.96-7.01 (2H, m), 7.25-7.28 (2H, m), 7.65-7.68 (1H, m ), 8.34-8.42 (2H, m).
(25b) 3-{[1-Methyl-6- (pyridin-3-yloxy) -1H-benzimidazol-2-yl] methoxy} methyl benzoate dihydrochloride [1-Methyl-6 synthesized in Example 25a -(Pyridin-3-yloxy) -1H-benzimidazol-2-yl] methanol (1.0 g, 3.92 mmol) was dissolved in toluene (17 mL) and 3-hydroxybenzoic acid methyl ester (895 mg, 5.88 mmol). ), 1,1 ′-(azodicarbonyl) dipiperidine (2.97 g, 9.65 mmol) and n-tributylphosphine (2.90 mL, 11.8 mmol) were added, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate / methanol = 5/1) to give 3-{[1-methyl-6- (pyridine-3 -Iyloxy) -1H-benzimidazol-2-yl] methoxy} benzoic acid methyl ester (1.5 g, 3.85 mmol) was obtained. 3-{[1-Methyl-6- (pyridin-3-yloxy) -1H-benzimidazol-2-yl] methoxy} benzoic acid methyl ester (681 mg, 1.75 mmol) was dissolved in ethyl acetate (15 mL), 4N Hydrochloric acid (1,4 dioxane solution, 5 mL) was added, and the mixture was stirred at room temperature for 10 min. The solid was collected by filtration and recrystallized from ethanol to give the title object compound (627 mg, 1.36 mmol).
Mp 195-208 ° C.
IR (KBr) νmax 1238, 1272, 1489, 1546, 1707.
_{1H-NMR (DMSO-d 6} , 400MHz) δ: 3.88 (3H, s), 3.97 (3H, s), 5.75 (2H, s), 7.36 (1H, dd, J = 8.8, 2.2Hz), 7.50- 7.56 (2H, m), 7.65-7.66 (1H, m), 7.73-7.82 (3H, m), 7.86-7.91 (2H, m), 8.57 (1H, dd, J = 5.1, 1.3Hz), 8.63 ( (1H, d, J = 2.4Hz).
MS (FAB) m / z: 390 (M + H) ⁺ .
_{Anal.calcd for C 22 H 19 N 3} O 4 + 2HCl:. C, 57.15; H, 4.58; Cl, 15.34; N, 9.09 Found C, 53.52; H, 4.99; Cl, 14.73; N, 8.48.

Example 26 3-{[1-Methyl-6- (pyridin-3-yloxy) -1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-147)
1 of intermediate 3-{[1-methyl-6- (pyridin-3-yloxy) -1H-benzimidazol-2-yl] methoxy} benzoic acid methyl ester synthesized in Example 25b (800 mg, 2.05 mmol) 1,4-dioxane (5 mL) solution was added with 1N aqueous sodium hydroxide solution (2.26 mL, 2.26 mmol), and the mixture was stirred at 70 ° C. for 1 hour. 1N aqueous hydrochloric acid was added to the reaction solution to adjust the pH to 7, and the precipitated solid was collected by filtration and washed with ethyl acetate to obtain the title object compound (332 mg, 0.885 mmol).
Mp 240-245 ° C.
IR (KBr) νmax 1219, 1290, 1421, 1478, 1586, 1697.
_{1H-NMR (DMSO-d 6} , 400 MHz) δ: 3.83 (3H, s), 5.48 (2H, s), 7.00 (1H, dd, J = 8.6, 2.4Hz), 7.34-7.47 (5H, m) , 7.57-7.59 (1H, m), 7.63-7.70 (2H, m), 8.32 (1H, dd, J = 4.0, 1.5Hz), 8.38 (1H, dd, J = 2.8, 0.9Hz).
MS (FAB) m / z: 376 (M + H) ⁺ .
Anal.calcd for C ₂₁ H ₁₇ N ₃ O ₄ : C, 67.19; H, 4.56; N, 11.19. Found C, 67.14; H, 4.71; N, 11.04.

Example 27 3-{[6- (4-Fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-165)
(27a) [5- (4-Fluorophenoxy) -2-nitrophenyl] methylcarbamic acid tert-butyl ester 4-fluorophenol (1.1 g, 10 mmol) and (5-chloro-2-nitrophenyl) methylcarbamic acid tert- Synthesis as in Example (28a) using butyl ester (2.9 g, 10 mmol), sodium hydride (> 56% in oil, 0.38 g, 10 mmol), N, N-dimethylformamide (40 mL), Crystallization from hexane gave the title material (3.2 g, 88% yield) as a yellow solid.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.33 (6H, s), 1.50 (3H, s), 3.26 (3H, s), 6.81 (1H, dd, J = 2.7, 9.0 Hz), 6.85 (1H , br s), 7.07-7.17 (4H, m), 7.93-7.97 (1H, m).
(27b) [2-Amino-5- (4-fluorophenoxy) phenyl] methylcarbamic acid tert-butyl ester [5- (4-fluorophenoxy) -2-nitrophenyl] methylcarbamic acid tert prepared in Example (27a) -Examples using butyl ester (3.2 g, 8.8 mmol) and iron powder (2.4 g, 12 mmol), ammonium chloride (0.24 g, 1.2 mmol), ethanol (40 mL), water (20 mL). It was synthesized in the same manner as in 28b), and the obtained oil was directly used in the next reaction.
(27c) [6- (4-Fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol [2-amino-5- (4-fluorophenoxy) phenyl] prepared in Example (27b) Synthesis in the same manner as in Example (28c) from methyl carbamic acid tert-butyl ester (2.9 g, 8.8 mmol) and glycolic acid (1.0 g, 13 mmol), 4N hydrochloric acid-1,4-dioxane solution (40 mL) The resulting dark brown oil was used as such for the next reaction.
(27d) 3-{[6- (4-Fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate [6- (4-Fluorophenoxy) prepared in Example (27c) ) -1-Methyl-1H-benzimidazol-2-yl] methanol (0.30 g, 1.1 mmol), methyl 3-hydroxybenzoate (0.25 g, 1.7 mmol), tri-n-butylphosphine (0. 55 mL, 2.2 mmol), 1,1 ′-(azodicarbonyl) dipiperidine (0.56 g, 2.2 mmol), dichloromethane (6.0 mL) and the reaction and workup according to Example (28d). By performing, the target compound (0.36 g, yield 81%) was obtained.
¹ H-NMR (CDCl _3, 500 MHz) δ: 3.82 (3H, s), 3.92 (3H, s), 5.39 (2H, s), 6.94-7.05 (5H, m), 7.29 (1H, br s) , 7.38 (1H, t, J = 7.8 Hz), 7.69 (1H, d, J = 7.8 Hz), 7.71-7.74 (2H, m).
MS (FAB) m / z: 407 (M + H) ⁺ .
(27e) 3-{[6- (4-Fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid 3-{[6- (4- Fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate (0.34 g, 0.84 mmol), 1N aqueous sodium hydroxide solution (1.3 mL, 1.3 mmol), 1, The target compound (0.10 g, yield 37%) as a white solid was obtained by performing the reaction and post-treatment according to Example (28e) using 4-dioxane.
¹ H-NMR (DMSO-d ₆ , 500 MHz) δ: 3.81 (3H, s), 5.46 (2H, s), 6.93 (1H, dd, J = 2.4, 8.8 Hz), 7.01-7.04 (2H, m ), 7.19 (2H, t, J = 8.8 Hz), 7.30 (1H, d, J = 2.4 Hz), 7.37-7.39 (1H, m), 7.45 (1H, t, J = 7.8 Hz), 7.57 (2H , d, J = 7.8 Hz), 7.66 (1H, d, J = 8.8 Hz), 7.63 (1H, s), 13.03 (1H, br.s).
MS (FAB) m / z: 393 (M + H) ⁺ .
Anal.calcd for C ₂₂ H ₁₇ FN ₂ O ₄ + 0.14H ₂ O: C, 66.91; H, 4.41; N, 7.09; F, 4.81. Found C, 66.85; H, 4.46; N, 7.21; F, 4.81 .

Example 28 3-{[6- (2-Fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-164)
(28a) [5- (2-Fluorophenoxy) -2-nitrophenyl] methylcarbamic acid tert-butyl ester 2-fluorophenol (0.16 mL, 1.7 mmol) in N, N-dimethylformamide (10 mL) under a nitrogen atmosphere (5-chloro-2-nitrophenyl) methylcarbamic acid tert-butyl ester (500 mg, 1.7 mmol), sodium hydride (> 56% in oil, 0.84 g, 1.9 mmol) and 80 Stir for 7 hours. The reaction mixture was concentrated, aqueous sodium bicarbonate was added, and the mixture was extracted twice with diethyl ether, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting yellow oil was used as such for the next reaction.
(28b) [2-Amino-5- (2-fluorophenoxy) phenyl] methylcarbamic acid tert-butyl ester [5- (2-fluorophenoxy) -2-nitrophenyl] methylcarbamic acid tert prepared in Example (28a) -A mixture of butyl ester (0.74 g, 1.7 mmol), ethanol (8.0 mL) and water (4.0 mL) was mixed with iron powder (0.47 g, 8.8 mmol), ammonium chloride (0.047 g, 0 .88 mmol) was added and heated to reflux for 2 hours. Insoluble material was filtered off using Celite, water was added to the concentrated filtrate, and the mixture was extracted twice with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting oil was used as such for the next reaction.
(28c) [6- (2-Fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol [2-amino-5- (2-fluorophenoxy) phenyl] prepared in Example (28b) Methylcarbamic acid tert-butyl ester (0.58 g, 1.749 mmol) was dissolved in 4N hydrochloric acid-1,4-dioxane solution (10 mL), and glycolic acid (0.20 g, 2.6 mmol) was added to add 1.5. The mixture was heated to reflux for a day. The reaction mixture was concentrated, aqueous sodium bicarbonate was added, and the mixture was extracted twice with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was simply purified using silica gel column chromatography (elution solvent: hexane / ethyl acetate = 5/1 only ethyl acetate-methanol / dichloromethane = 1/5). . The solvent was distilled off under reduced pressure, and the resulting dark brown oil was used as such for the next reaction.
(28d) 3-{[6- (2-Fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate [6- (2-Fluorophenoxy) prepared in Example (28c) ) -1-Methyl-1H-benzimidazol-2-yl] methanol (0.20 g, 0.7 mmol), methyl 3-hydroxybenzoate (0.16 g, 1.1 mmol) in dichloromethane solution and tri-n-butyl. Phosphine (0.36 mL, 1.4 mmol) and 1,1 ′-(azodicarbonyl) dipiperidine (0.36 g, 1.4 mmol) were added and stirred for 12 hours. The reaction solution was concentrated, suspended in a mixed solvent of hexane / ethyl acetate (= 3/2), subjected to ultrasonic waves, and the precipitated solid was separated by filtration. The filtrate was concentrated and purified using silica gel column chromatography (eluent: hexane / ethyl acetate = 5/1 to 1/1). The target compound (0.16 g, yield 58%) was obtained by drying under reduced pressure.
¹ H-NMR (CDCl _3, 400 MHz) δ: 3.81 (3H, s), 3.92 (3H, s), 5.39 (2H, s), 6.96 (1H, s), 7.00-7.05 (2H, m), 7.07-7.13 (2H, m), 7.20 (1H, t, J = 9.5 Hz), 7.29 (1H, d, J = 7.3 Hz), 7.37 (1H, t, J = 7.3 Hz), 7.69 (1H, d , J = 7.8 Hz), 7.70-7.74 (2H, m).
MS (FAB) m / z: 407 (M + H) ⁺ .
(28e) 3-{[6- (2-Fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid 3-{[6- (2- To a 1,4-dioxane solution of methyl (fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoate (0.16 g, 0.36 mmol), 1N aqueous sodium hydroxide solution (0.54 mL) , 0.54 mmol) and stirred at 70 ° C. for 1.5 hours. The reaction mixture was concentrated, water was added, and 1N aqueous hydrochloric acid was added dropwise to neutralize. The precipitated solid was collected by filtration to obtain the target compound (0.096 g, yield 68%) as a white solid.
¹ H-NMR (DMSO-d _6, 400 MHz) δ: 3.81 (3H, s), 5.47 (2H, s), 6.94 (1H, dd, J = 2.5, 8.8 Hz), 7.04-7.09 (1H, m ), 7.18 (2H, ddd, J = 3.1, 3.3, 6.1 Hz), 7.30 (1H, d, J = 2.4 Hz), 7.35-7.42 (2H, m), 7.45 (1H, t, J = 7.8 Hz) , 7.58 (1H, d, J = 7.4 Hz), 7.66 (1H, d, J = 8.6 Hz), 7.63 (1H, s), 13.03 (1H, br.s).
MS (FAB) m / z: 393 (M + H) ⁺ .
Anal.calcd for C ₂₂ H ₁₇ FN ₂ O ₄ + 0.14H ₂ O: C, 66.91; H, 4.41; N, 7.09; F, 4.81.Found C, 66.86; H, 4.48; N, 7.08; F, 4.80 .

Example 29 3-{[6- (3-Methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-173)
(29a) [5- (3-Methoxyphenoxy) -2-nitrophenyl] methylcarbamic acid tert-butyl ester 3-methoxyphenol (0.19 mL, 1.7 mmol) and (5-chloro-2-nitrophenyl) methylcarbamic acid Example (28a) using tert-butyl ester (0.50 g, 1.7 mmol), sodium hydride (> 56% in oil, 0.84 g, 1.9 mmol), N, N-dimethylformamide (10 mL) The yellow oil obtained was used in the next reaction as it was.
(29b) [2-Amino-5- (3-methoxyphenoxy) phenyl] methylcarbamic acid tert-butyl ester [5- (3-methoxyphenoxy) -2-nitrophenyl] methylcarbamic acid tert prepared in Example (29a) -Butyl ester (0.65 g, 1.7 mmol) and iron powder (0.47 g, 8.7 mmol), ammonium chloride (0.047 g, 0.87 mmol), ethanol (8.0 mL), water (4.0 mL) Was synthesized in the same manner as in Example (28b), and the obtained oil was used as such in the next reaction.
(29c) [6- (3-Methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol [2-amino-5- (3-methoxyphenoxy) phenyl] prepared in Example (29b) Methylcarbamic acid tert-butyl ester (0.60 g, 1.7 mmol) and glycolic acid (0.20 g, 2.6 mmol), 4N hydrochloric acid-1,4-dioxane solution (10 mL), as in Example (28c) The obtained dark brown oil was used as such for the next reaction.
(29d) 3-{[6- (3-Methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate [6- (3-methoxyphenoxy) prepared in Example (29c) ) -1-Methyl-1H-benzimidazol-2-yl] methanol (0.24 g, 0.85 mmol), methyl 3-hydroxybenzoate (0.20 g, 1.3 mmol), tri-n-butylphosphine (0. 43 mL, 1.7 mmol), 1,1 ′-(azodicarbonyl) dipiperidine (0.43 g, 1.7 mmol), dichloromethane (6.0 mL) and the reaction and workup according to Example (28d). By performing, the target compound (0.23 g, yield 65%) was obtained.
¹ H-NMR (CDCl _3, 400 MHz) δ: 3.77 (3H, s), 3.89 (3H, s), 5.57 (2H, s), 6.55-6.58 (2H, m), 6.61-6.69 (1H, m ), 7.00-7.07 (2H, m), 7.19-7.25 (2H, m), 7.38 (1H, t, J = 7.8 Hz), 7.84 (1H, d, J = 8.6 Hz), 7.78 (1H, d, J = 7.4 Hz), 8.03 (1H, s).
(29e) 3-{[6- (3-Methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid 3-{[6- (3- Methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate (0.23 g, 0.56 mmol), 1N aqueous sodium hydroxide solution (0.83 mL, 0.83 mmol), 1, The target compound (0.20 g, yield 89%) as a white solid was obtained by performing the reaction and post-treatment according to Example (28e) using 4-dioxane.
¹ H-NMR (CDCl _3, 400 MHz) δ: 3.77 (3H, s), 3.89 (3H, s), 5.57 (2H, s), 6.55-6.58 (2H, m), 6.61-6.69 (1H, m ), 7.00-7.07 (2H, m), 7.19-7.25 (2H, m), 7.38 (1H, t, J = 7.8 Hz), 7.84 (1H, d, J = 8.6 Hz), 7.78 (1H, d, J = 7.4 Hz), 8.03 (1H, s).
MS (FAB) m / z: 405 (M + H) ⁺ .
_{. Anal calcd for C 23 H 20} N 2 O 5 + 0.33H 2 O:. C, 67.31; H, 5.08; N, 6.83 Found C, 67.47; H, 4.94; N, 6.92.

Example 30 3-{[6- (4-Methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-174)
(30a) [5- (4-Methoxyphenoxy) -2-nitrophenyl] methylcarbamic acid tert-butyl ester 4-methoxyphenol (0.20 g, 1.7 mmol) and (5-chloro-2-nitrophenyl) methylcarbamic acid Example (28a) using tert-butyl ester (0.50 g, 1.7 mmol), sodium hydride (> 56% in oil, 0.84 g, 1.9 mmol), N, N-dimethylformamide (10 mL) The yellow oil obtained was used in the next reaction as it was.
(30b) [2-Amino-5- (4-methoxyphenoxy) phenyl] methylcarbamic acid tert-butyl ester [5- (4-methoxyphenoxy) -2-nitrophenyl] methylcarbamic acid tert prepared in Example (30a) -Butyl ester (0.65 g, 1.7 mmol) and iron powder (0.47 g, 8.7 mmol), ammonium chloride (0.047 g, 0.87 mmol), ethanol (8.0 mL), water (4.0 mL) Was synthesized in the same manner as in Example (28b), and the obtained oil was used as such in the next reaction.
(30c) [6- (4-Methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol [2-amino-5- (4-methoxyphenoxy) phenyl] prepared in Example (30b) Similar to Example (28c) from methylcarbamic acid tert-butyl ester (0.60 g, 1.7 mmol) and glycolic acid (0.40 g, 5.2 mmol), 4N hydrochloric acid-1,4-dioxane solution (20 mL) The obtained dark brown oil was used as such for the next reaction.
(30d) 3-{[6- (4-Methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate [6- (4-methoxyphenoxy) prepared in Example (30c) ) -1-Methyl-1H-benzimidazol-2-yl] methanol (0.23 g, 0.79 mmol), methyl 3-hydroxybenzoate (0.18 g, 1.2 mmol), tri-n-butylphosphine (0. 40 mL, 2.0 mmol), 1,1 ′-(azodicarbonyl) dipiperidine (0.39 g, 2.0 mmol), dichloromethane (4.0 mL) and the reaction and workup according to Example (28d). As a result, a light brown oily target compound (0.25 g, yield 75%) was obtained.
¹ H-NMR (CDCl _3, 400 MHz) δ: 3.79 (3H, s), 3.81 (3H, s), 3.92 (3H, s), 5.38 (2H, s), 6.88-6.91 (3H, m), 6.97-7.01 (3H, m), 7.27-7.31 (1H, m), 7.37 (1H, t, J = 7.8 Hz), 7.66-7.73 (3H, m).
(30e) 3-{[6- (4-Methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid 3-{[6- (4- Methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate (0.25 g, 0.59 mmol), 1N aqueous sodium hydroxide solution (0.89 mL, 0.89 mmol), 1, The target compound (0.21 g, yield 86%) as a white solid was obtained by performing the reaction and post-treatment according to Example (28e) using 4-dioxane.
¹ H-NMR (CDCl _3, 500 MHz) δ: 3.79 (3H, s), 3.81 (3H, s), 5.36 (2H, br.s.), 6.87-6.93 (3H, m) 6.98 (3H, d , J = 8.3 Hz), 7.20-7.29 (1H, m), 7.36 (1H, s), 7.65-7.76 (3H, m).
MS (FAB) m / z: 405 (M + H) ⁺ .
_{. Anal calcd for C 23 H 20} N 2 O 5 + 1.5H 2 O:. C, 64.03; H, 5.37; N, 6.49 Found C, 63.96; H, 5.30; N, 6.52.

Example 31 3- [6- (3-Chlorophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzoic acid hydrochloride (hydrochloride of compound number 1-51)
(31a) tert-butyl [5- (3-chlorophenoxy) -2-nitrophenyl] methylcarbamate 3-chlorophenol (1.29 g, 10 mmol) and tert-butyl 5-chloro-2-nitrophenyl) methylcarbamate ( To a solution of 2.87 g, 10 mmol) of N, N-dimethylformamide (20 mL) was added sodium hydride (56%, 0.38 g, 10 mmol) under ice cooling. The reaction mixture was stirred at 80 ° C. for 6 hours. After allowing to cool, water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed twice with water (100 mL) and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (hexane: ethyl acetate, 6: 1) to obtain the title compound (3.79 g, yield 99%) as a yellow oil.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.33 (6H, s), 1.50 (3H, s), 3.27 (3H, s), 6.87 (1H, dd, J = 2.7, 8.6 Hz), 6.89 ( 1H, br s), 7.01 (1H, d, J = 8.1 Hz), 7.12 (1H, t, J = 2.0 Hz), 7.24-7.26 (1H, m), 7.38 (1H, t, J = 8.2 Hz) , 7.96 (1H, d, J = 9.0 Hz).
(31b) tert-butyl [2-amino-5- (3-chlorophenoxy) phenyl] methylcarbamate tert-butyl [5- (3-chlorophenoxy) -2-nitrophenyl] obtained in Example (31a) A solution of methyl carbamate (3.79 g, 10 mmol), ammonium chloride (0.27 g, 5.0 mmol) and iron powder (2.79 g, 50 mmol) in ethanol (50 mL) and water (25 mL) was stirred with heating under reflux for 1 hour. . After allowing to cool, the reaction mixture was filtered through Celite. The filtrate was concentrated, water (100 mL) was added, the mixture was extracted with ethyl acetate (100 mL), and the organic layer was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (hexane: ethyl acetate, 5: 1) to obtain the title compound (3.49 g, yield 99%) as a yellow oil.
_{^{1 H-NMR (CDCl 3,}} 400 MHz) δ: 1.41 (9H, s), 3.16 (3H, s), 3.70 (2H, br s), 6.77 (1H, d, J = 8.6 Hz), 6.82-6.90 (4H, m), 6.99-7.01 (1H, m), 7.20 (1H, t, J = 8.2 Hz).
(31c) [6- (3-Chlorophenoxy) -1-methyl-1H-benzimidazol-2-ylmethanol tert-butyl [2-amino-5- (3-chlorophenoxy) obtained in Example (31b) ) Phenyl] methylcarbamate (3.49 g, 10 mmol) and glycolic acid (1.52 g, 20 mmol) in 4M dioxane hydrochloride (10 mL) were stirred for 9 hours under reflux. After allowing to cool, the reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution (100 mL), extracted with ethyl acetate (100 mL), and the organic layer was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (methylene chloride: methanol, 95: 5) to obtain the title compound (0.66 g, yield 23%) as a light brown powder.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 3.79 (3H, s), 4.91 (2H, s), 6.88 (1H, d, J = 8.6 Hz), 6.95 (1H, s), 6.98-7.01 ( 2H, m), 7.05 (1H, d, J = 8.2 Hz), 7.24 (1H, d, J = 8.2 Hz), 7.69 (1H, d, J = 9.4 Hz).
(31d) 3-{[6- (3-Chlorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate [6- (3-Chloro] obtained in Example (31c) Phenoxy) -1-methyl-1H-benzimidazol-2-ylmethanol (660 mg, 2.3 mmol), methyl 3-hydroxybenzoate (522 mg, 3.4 mmol), tri-n-butylphosphine (925 mg, 4.6 mmol) Then, a solution of 1,1 ′-(azodicarbonyl) dipiperidine (1.15 g, 4.6 mmol) in methylene chloride (5 mL) was stirred for 3 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (hexane: ethyl acetate, 2: 1) to give the title compound (935 mg, yield 97%) as a white amorphous.
_{^{1 H-NMR (CDCl 3,}} 400 MHz) δ: 3.85 (3H, s), 3.93 (3H, s), 5.41 (2H, s), 6.89 (1H, ddd, J = 0.8, 3.1, 8.2 Hz), 6.97 (1H, t, J = 2.0 Hz), 7.01-7.07 (3H, m), 7.24 (1H, d, J = 8.2 Hz), 7.29-7.32 (1H, m), 7.39 (1H, t, J = 7.8 Hz), 7.70 (1H, dt, J = 1.1, 7.4 Hz), 7.73-7.74 (1H, m), 7.77 (1H, d, J = 9.4 Hz).
(31e) 3- [6- (3-Chlorophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzoic acid hydrochloride 3-{[6- (3- Chlorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoate methyl (933 mg, 2.21 mmol) in 2M aqueous sodium hydroxide (5 mL) and dioxane (10 mL) was heated under reflux for 2 hours. Stir. After allowing to cool, 5M hydrochloric acid (20 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration to give the title compound (829 mg, yield 84%) as a white powder.
¹ H-NMR (DMSO-d ₆ , 400 MH) δ: 3.91 (3H, s), 5.62 (2H, s), 6.98 (1H, dd, J = 3.1, 9.0 Hz), 7.04 (1H, t, J = 2.0 Hz), 7.17 (1H, dd, J = 2.4, 9.0 Hz), 7.18-7.20 (1H, m), 7.40 (1H, d, J = 8.2 Hz), 7.42-7.44 (1H, m), 7.49 (1H, t, J = 7.8 Hz), 7.61 (1H, s), 7.62 (1H, d, J = 7.4 Hz), 7.69 (1H, s), 7.79 (1H, d, J = 9.0 Hz).
MS (FAB +) m / z: 409 (M + H) ⁺ .
Mp: 218-222 ° C.

Example 32 3-{[1-Methyl-6- (3-methylphenoxy) -1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-167)
(32a) Methyl [5- (3-methylphenoxy) -2-nitrophenyl] carbamic acid tert-butyl ester m-cresol (0.36 mL, 3.5 mmol) and (5-chloro-2-nitrophenyl) -methyl Examples using carbamic acid tert-butyl ester (1.0 g, 3.5 mmol), sodium hydride (> 56% in oil, 0.17 g, 3.8 mmol), N, N-dimethylformamide (20 mL) It was synthesized in the same manner as (28a), and the obtained yellow oil was used as it was in the next reaction.
(32b) [2-Amino-5- (3-methylphenoxy) phenyl] methylcarbamic acid tert-butyl ester Methyl [5- (3-methylphenoxy) -2-nitrophenyl] -carbamine prepared in Example (32a) Acid tert-butyl ester (1.2 g, 3.5 mmol) and iron powder (0.93 g, 17 mmol), ammonium chloride (0.093 g, 1.7 mmol), ethanol (16 mL), water (8.0 mL) were used. In the same manner as in Example (28b), the obtained oil was directly used in the next reaction.
(32c) [1-Methyl-6- (3-methylphenoxy) -1H-benzimidazol-2-yl] methanol [2-amino-5- (3-methylphenoxy) phenyl] prepared in Example (32b) Methylcarbamic acid tert-butyl ester (1.1 g, 3.5 mmol) was dissolved in 4N hydrochloric acid-1,4-dioxane solution (20 mL), glycolic acid (0.80 g, 10 mmol) was added, and the mixture was heated to reflux overnight. . After evaporating the solvent under reduced pressure, aqueous sodium bicarbonate (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The obtained organic layer was washed with saturated brine (80 mL) and then dried over anhydrous magnesium sulfate. The solid obtained by distilling off the solvent under reduced pressure was washed with diisopropyl ether to obtain the target compound (0.59 g, yield 63%).
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 2.32 (3H, s), 3.75 (3H, s), 4.90 (2H, s), 6.80 (2H, s), 6.90 (1H, d, J = 7.4 Hz), 6.94-7.02 (2H, m), 7.21 (1H, t, J = 7.8 Hz), 7.65 (1H, d, J = 8.6 Hz).
(32d) 3-{[1-Methyl-6- (3-methylphenoxy) -1H-benzimidazol-2-yl] methoxy} methyl benzoate [1-Methyl-6- (prepared in Example (32c)] 3-methylphenoxy) -1H-benzimidazol-2-yl] methanol (0.24 g, 0.89 mmol), methyl 3-hydroxybenzoate (0.20 g, 1.3 mmol), tri-n-butylphosphine (0. 45 mL, 1.8 mmol), 1,1 ′-(azodicarbonyl) dipiperidine (0.45 g, 1.8 mmol), dichloromethane (6.0 mL) and the reaction and workup according to Example (28d). As a result, a target compound (0.31 g, yield 85%) was obtained as a white solid.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 3.81 (3H, br s), 3.92 (3H, s), 5.39 (2H, s), 6.78-6.83 (2H, m), 6.91 (1H, d, J = 7.8 Hz), 6.97-7.04 (2H, m), 7.21 (1H, t, J = 8.0 Hz), 7.27-7.32 (1H, m), 7.38 (1H, t, J = 7.8 Hz), 7.69 ( 1H, td, J = 1.2, 1.4, 7.6 Hz), 7.71-7.75 (2H, m).
MS (FAB) m / z: 403 (M + H) ⁺ .
(32e) 3-{[1-Methyl-6- (3-methylphenoxy) -1H-benzimidazol-2-yl] methoxy} benzoic acid 3-{[1-Methyl-6] prepared in Example (32d) -(3-Methylphenoxy) -1H-benzimidazol-2-yl] methoxy} methyl benzoate (0.29 g, 0.72 mmol), 1N aqueous sodium hydroxide solution (1.1 mL, 1.1 mmol), 1, The target compound (0.17 g, yield 60%) as a white solid was obtained by performing the reaction and post-treatment according to Example (28e) using 4-dioxane (1.0 mL).
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 2.27 (3H, s), 3.81 (3H, s), 5.47 (2H, s), 6.74-6.83 (2H, m), 6.87-6.97 (2H, m), 7.32 (1H, d, J = 2.4 Hz), 7.36-7.41 (1H, m), 7.45 (1H, t, J = 8.0 Hz), 7.58 (1H, dt, J = 1.2, 1.4, 7.6 Hz ), 7.62-7.68 (2H, m).
MS (FAB) m / z: 389 (M + H) ⁺ .
_{. Anal calcd for C 23 H 20} N 2 O 4 + 0.33H 2 O:. C, 70.04; H, 5.28; N, 7.10 Found C, 69.99; H, 5.16; N, 7.15.

Example 33 3-({1-Methyl-6- [3- (trifluoromethoxy) phenoxy] -1H-benzimidazol-2-yl} methoxy] benzoic acid (Compound No. 1-176)
(33a) tert-butyl methyl {2-nitro-5- [3- (trifluoromethoxy) phenoxy] phenyl} carbamate 3-trifluoromethoxyphenol (1.78 g, 10 mmol), tert-butyl 5-chloro-2- According to the method described in Example (31a) using nitrophenyl) methylcarbamate (2.87 g, 10 mmol) and sodium hydride (56%, 0.38 g, 10 mmol), 99% yield) was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.33 (6H, s), 1.50 (3H, s), 3.27 (3H, s), 6.89-6.91 (2H, m), 6.99 (1H, s.) , 7.05 (1H, d, J = 8.6 Hz), 7.13 (1H, d, J = 7.8 Hz), 7.47 (1H, t, J = 8.2 Hz), 7.97 (1H, d, J = 8.6 Hz).
(33b) tert-butyl {2-amino-5- [3- (trifluoromethoxy) phenoxy] phenyl} methylcarbamate tert-butyl methyl {2-nitro-5- [3- (Trifluoromethoxy) phenoxy] phenyl} carbamate (2.87 g, 10 mmol) and iron powder (2.79 g, 50 mmol) were used according to the method described in Example (31b) and the title compound (3.98 g). Yield 99%) as a yellow oil.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.41 (9H, brs), 3.15 (3H, s), 3.72 (2H, br s), 6.76-6.89 (5H, m), 7.26-7.30 (2H, m).
(33c) {1-methyl-6- [3- (trifluoromethoxy) phenoxy] -1H-benzimidazol-2-yl} methanol tert-butyl obtained in Example (33b) {2-amino-5- [3- (Trifluoromethoxy) phenoxy] phenyl} methyl carbamate (3.98 g, 10 mmol) and glycolic acid (1.52 g, 20 mmol) according to the method described in Example (31c) (3.08 g, 91% yield) was obtained as a light brown powder.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 3.79 (3H, s), 4.91 (2H, s), 6.85 (1H, s), 6.89 (1H, dd, J = 2.4, 8.6 Hz), 6.92- 6.95 (1H, m), 6.98-7.01 (2H, m), 7.32 (1H, t, J = 8.2 Hz), 7.67 (1H, d, J = 9.0 Hz).
(33d) Methyl 3-({1-methyl-6- [3- (trifluoromethoxy) phenoxy] -1H-benzimidazol-2-yl} methoxy) benzoate {1- Methyl-6- [3- (trifluoromethoxy) phenoxy] -1H-benzimidazol-2-yl} methanol (3.08 g, 9.1 mmol), methyl 3-hydroxybenzoate (2.08 g, 13.7 mmol) , Tri-n-butylphosphine (3.68 g, 18.2 mmol) and 1,1 ′-(azodicarbonyl) dipiperidine (4.59 g, 18.2 mmol). The title compound (3.52 g, yield 91%) was obtained as a white powder.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 3.85 (3H, s), 3.93 (3H, s), 5.42 (2H, s), 6.86 (1H, s), 6.91 (1H, dd, J = 2.4 , 7.4 Hz), 6.93-6.96 (1H, m), 7.02-7.06 (2H, m), 7.29-7.34 (2H, m), 7.39 (1H, t, J = 7.4 Hz), 7.69-7.74 (2H, m), 7.77 (1H, d, J = 8.2 Hz).
(33e) 3-({1-Methyl-6- [3- (trifluoromethoxy) phenoxy] -1H-benzimidazol-2-yl} methoxy] benzoic acid 3-({obtained in Example (33d) 1-methyl-6- [3- (trifluoromethoxy) phenoxy] -1H-benzimidazol-2-yl} methoxy) methyl benzoate (3.52 g, 7.45 mmol) in 2M aqueous sodium hydroxide (20 mL) and The dioxane (40 mL) solution was stirred with heating under reflux for 2 hours, and after standing to cool, 1 M hydrochloric acid (50 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration, and this solid was dissolved in 1 M aqueous sodium hydroxide solution (50 mL). 1M hydrochloric acid (50 mL) was added, and the precipitated solid was collected by filtration to give the title compound (2.75 g, yield 81%) as a white powder.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 3.83 (3H, s), 5.48 (2H, s), 6.95-6.97 (2H, m), 7.00 (1H, dd, J = 2.4, 8.6 Hz ), 7.07-7.09 (1H, m), 7.36-7.39 (1H, m), 7.43-7.49 (3H, m), 7.58 (1H, dt, J = 1.2, 7.8 Hz), 7.64 (1H, dd, J = 1.2, 2.4 Hz), 7.71 (1H, d, J = 8.2 Hz), 13.08 (1H, br s).
MS (FAB +) m / z: 459 (M + H) ⁺ .
Mp: 221-227 ° C.

Example 34 3-{[6- (4-Fluoro-3-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-187)
(34a) [5- (4-Fluoro-3-methylphenoxy) -2-nitrophenyl] methylcarbamic acid tert-butyl ester 4-fluoro-3-methylphenol (0.78 mL, 7.0 mmol) and (5-chloro -2-Nitrophenyl) methylcarbamic acid tert-butyl ester (2.0 g, 7.0 mmol), sodium hydride (> 56% in oil, 0.28 g, 7.0 mmol), N, N-dimethylformamide (20 mL) Was used in the same manner as in Example (28a), and the resulting yellow oil was used as such in the next reaction.
(34b) [2-Amino-5- (4-fluoro-3-methylphenoxy) phenyl] methylcarbamic acid tert-butyl ester [5- (4-fluoro-3-methylphenoxy)-prepared in Example (34a) 2-Nitrophenyl] methylcarbamic acid tert-butyl ester (2.6 g, 7.0 mmol) and iron powder (1.9 g, 35 mmol), ammonium chloride (0.19 g, 3.5 mmol), ethanol (20 mL), water ( 10 mL) was used in the same manner as in Example (28b), and the obtained oil was used as such for the next reaction.
(34c) [6- (4-Fluoro-3-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol [2-amino-5- (4-fluoro] prepared in Example (34b) -3-methylphenoxy) phenyl] methylcarbamic acid tert-butyl ester (2.4 g, 7.0 mmol) was dissolved in 5N hydrochloric acid (20 mL), 1,4-dioxane (20 mL), and glycolic acid (0.80 g, 10 mmol) was added and heated to reflux overnight. The mixture was cooled to room temperature, sodium bicarbonate water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The obtained organic layer was washed with saturated brine (80 mL) and then dried over anhydrous magnesium sulfate. The solid obtained by distilling off the solvent under reduced pressure was washed with diisopropyl ether to obtain the target compound (1.5 g, yield 77%) as a light reddish brown solid.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 2.25 (3H, d, J = 2.0 Hz), 3.78 (3H, s), 4.05 (1H, br s), 4.91 (2H, s), 6.75-6.81 (1H, m), 6.83 (2H, dd, J = 2.9, 6.1 Hz), 6.87 (1H, d, J = 2.0 Hz), 6.96 (2H, d, J = 8.6 Hz), 7.60 (1H, d, J = 8.6 Hz).
(34d) 3-{[6- (4-Fluoro-3-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate [6- (prepared in Example (34c)] 4-fluoro-3-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol (0.25 g, 0.88 mmol) and methyl 3-hydroxybenzoate (0.20 g, 1.3 mmol), Using tri-n-butylphosphine (0.44 mL, 1.8 mmol), 1,1 ′-(azodicarbonyl) dipiperidine (0.44 g, 1.8 mmol), dichloromethane (4 mL), according to Example (28d) The target compound (0.30 g, yield 80%) was obtained as a white solid by performing the reaction and post-treatment.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 2.25 (3H, d, J = 2.0 Hz), 3.81 (3H, s), 3.92 (3H, s), 5.39 (2H, s), 6.76-6.86 ( 2H, m), 6.92-7.00 (3H, m), 7.27-7.31 (1H, m), 7.38 (1H, t, J = 8.0 Hz), 7.71 (3H, d, J = 8.6 Hz).
(34e) 3-{[6- (4-Fluoro-3-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid 3-{[6 prepared in Example (34d) -(4-Fluoro-3-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate (0.31 g, 0.72 mmol), 1 N aqueous sodium hydroxide solution (1.2 mL) 1.2 mmol), 1,4-dioxane (1.0 mL), and the reaction and post-treatment according to Example (28e) gave the target compound (0.24 g, yield 81% as a white solid). )
¹ H-NMR (DMSO-d ₆ , 500 MHz) δ: 2.20 (3H, s), 3.81 (3H, s), 5.46 (2H, s), 6.80-6.87 (1 H, m), 6.89-6.95 (2H , m), 7.12 (1H, t, J = 9.0 Hz), 7.28 (1H, d, J = 2.0 Hz), 7.36-7.41 (1H, m), 7.45 (1H, t, J = 7.8 Hz), 7.57 (1H, d, J = 7.8 Hz), 7.62-7.67 (2H, m), 13.03 (1H, br s).
MS (FAB) m / z: 407 (M + H) ⁺ .
_{. Anal calcd for C 23 H 19} FN 2 O 4 + 0.10HCl:. C, 67.37; H, 4.69; F, 4.63; N, 6.83; Cl, 0.86 Found C, 67.24; H, 4.70; F, 4.56; N , 7.00; Cl, 0.64.

Example 35 3-{[6- (3,4-Difluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-180)
(35a) [5- (3,4-Difluorophenoxy) -2-nitrophenyl] methylcarbamic acid tert-butyl ester 3,4-difluorophenol (0.95 g, 7.0 mmol) and (5-chloro-2-nitro Performed with phenyl) methylcarbamic acid tert-butyl ester (2.0 g, 7.0 mmol), sodium hydride (> 56% in oil, 0.28 g, 7.0 mmol), N, N-dimethylformamide (20 mL) Synthesis was performed in the same manner as in Example (28a), and the obtained yellow solid was directly used in the next reaction.
(35b) [2-Amino-5- (3,4-difluorophenoxy) phenyl] methylcarbamic acid tert-butyl ester [5- (3,4-difluorophenoxy) -2-nitrophenyl prepared in Example (35a) ] Using methylcarbamic acid tert-butyl ester (2.7 g, 7.0 mmol), iron powder (1.9 g, 35 mmol), ammonium chloride (0.19 g, 3.5 mmol), ethanol (20 mL), and water (10 mL) In the same manner as in Example (28b), the obtained oil was directly used in the next reaction.
(35c) [6- (3,4-Difluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol [2-amino-5- (3,4-difluoro) prepared in Example (35b) Phenoxy) phenyl] methylcarbamic acid tert-butyl ester (2.4 g, 7.0 mmol) and glycolic acid (0.80 g, 10 mmol), 5N aqueous hydrochloric acid (20 mL), 1,4-dioxane (20 mL) The target compound (1.5 g, yield 76%) as a light brown solid was obtained by carrying out the reaction and post-treatment according to Example (34c).
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 3.78 (3H, s), 4.90 (2H, s), 6.67-6.74 (1H, m), 6.77-6.85 (1H, m), 6.97 (2H, s ), 7.11 (1H, q, J = 9.3 Hz), 7.67 (1H, d, J = 8.2 Hz).
(35d) 3-{[6- (3,4-Difluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate [6- (3,3) prepared in Example (35c) 4-Difluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol (0.25 g, 0.88 mmol) and methyl 3-hydroxybenzoate (0.20 g, 1.3 mmol), tri-n-butyl Reaction according to Example (28d) using phosphine (0.44 mL, 1.8 mmol), 1,1 ′-(azodicarbonyl) dipiperidine (0.44 g, 1.8 mmol), dichloromethane (4.0 mL) And the target compound (0.30 g, yield 80%) of white solid was obtained by performing a post-process.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 3.84 (3H, s), 3.94 (3H, s), 5.40 (2H, s), 5.41 (10H, br s), 6.69-6.75 (1H, m) , 6.79-6.85 (1H, m), 6.97-7.02 (2H, m), 7.07-7.15 (1H, m), 7.28-7.32 (1H, m), 7.38 (1H, t, J = 8.1 Hz), 7.67 -7.71 (1H, m), 7.74 (2H, s).
MS (FAB) m / z: 425 (M + H) ⁺ .
(35e) 3-{[6- (3,4-Difluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid 3-{[6- (prepared in Example (35d)] 3,4-difluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate (0.31 g, 0.72 mmol), 1N aqueous sodium hydroxide solution (1.2 mL, 1.2 mmol) ), 1,4-dioxane (1.0 mL), and the reaction and post-treatment were performed according to Example (28e) to give the target compound (0.25 g, yield 82%) as a white solid. .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 3.82 (3H, s), 5.47 (2H, s), 6.77-6.84 (1H, m), 6.97 (1H, dd, J = 2.4, 8.6 Hz) , 7.10-7.18 (1H, m), 7.35-7.48 (4H, m), 7.55-7.70 (3H, m).
MS (FAB) m / z: 411 (M + H) ⁺ .
Anal.calcd for C ₂₂ H ₁₆ F ₂ N ₂ O ₄ + 0.10HCl: C, 67.37; H, 4.69; F, 4.63; N, 6.83; Cl, 0.86. Found C, 67.24; H, 4.70; F, 4.56 N, 7.00; Cl, 0.64.

Example 36 3-({1-Methyl-6- [3- (trifluoromethyl) phenoxy] -1H-benzimidazol-2-yl} methoxy) benzoic acid (Compound No. 1-175)
(36a) Methyl {2-nitro-5- [3- (trifluoromethyl) phenoxy] phenyl} carbamic acid tert-butyl ester 3- (trifluoromethyl) phenol (0.87 mL, 7.0 mmol) and (5- Chloro-2-nitrophenyl) methylcarbamic acid tert-butyl ester (2.00 g, 7.0 mmol), sodium hydride (> 56% in oil, 0.28 g, 7.0 mmol), N, N-dimethylformamide (20 mL) ) Was used in the same manner as in Example (28a), and the obtained yellow solid was directly used in the next reaction.
(36b) {2-Amino-5- [3- (trifluoromethyl) phenoxy] phenyl} methylcarbamic acid tert-butyl ester Methyl {2-nitro-5- [3- (trifluoro) prepared in Example (36a) Methyl) phenoxy] phenyl} carbamic acid tert-butyl ester (2.9 g, 7.0 mmol) and iron powder (1.9 g, 35 mmol), ammonium chloride (0.19 g, 3.5 mmol), ethanol (20 mL), water (10 mL) was used in the same manner as in Example (28b), and the obtained oil was directly used in the next reaction.
(36c) {1-Methyl-6- [3- (trifluoromethyl) phenoxy] -1H-benzimidazol-2-yl} methanol {2-amino-5- [3- (prepared in Example (36b)] Trifluoromethyl) phenoxy] phenyl} methylcarbamic acid tert-butyl ester (2.4 g, 7.0 mmol) and glycolic acid (0.80 g, 10 mmol), 5N aqueous hydrochloric acid (20 mL), 1,4-dioxane (20 mL) Was used for the reaction and post-treatment according to Example (34c) to obtain the target compound (1.3 g, yield 57%) as a light brown solid.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 3.78 (3H, s), 4.93 (2H, s), 6.97-7.04 (2H, m), 7.09-7.18 (1H, m), 7.21 (1H, s ), 7.33 (1H, d, J = 8.6 Hz), 7.43 (1H, t, J = 7.8 Hz), 7.71 (1H, d, J = 8.2 Hz).
(36d) 3-({1-Methyl-6- [3- (trifluoromethyl) phenoxy] -1H-benzimidazol-2-yl} methoxy) methyl benzoate {1-Methyl prepared in Example (36c) -6- [3- (trifluoromethyl) phenoxy] -1H-benzimidazol-2-yl} methanol (0.25 g, 0.88 mmol) and methyl 3-hydroxybenzoate (0.20 g, 1.3 mmol), Using tri-n-butylphosphine (0.44 mL, 1.8 mmol), 1,1 ′-(azodicarbonyl) dipiperidine (0.44 g, 1.8 mmol), dichloromethane (4.0 mL), Example (28d) The target compound (0.33 g, yield 81%) as a white solid was obtained by carrying out the reaction and post-treatment according to the above.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 3.85 (3H, s), 3.93 (3H, s), 5.41 (8H, s), 5.41 (2H, s), 7.00-7.06 (2H, m), 7.15 (1H, dd, J = 2.4, 8.2 Hz), 7.23 (1H, s), 7.28-7.46 (4H, m), 7.68-7.79 (3H, m).
MS (FAB) m / z: 457 (M + H) ⁺ .
(36e) 3-({1-Methyl-6- [3- (trifluoromethyl) phenoxy] -1H-benzimidazol-2-yl} methoxy) benzoic acid 3-({1 prepared in Example (36d) -Methyl-6- [3- (trifluoromethyl) phenoxy] -1H-benzimidazol-2-yl} methoxy) methyl benzoate (0.33 g, 0.72 mmol), 1 N aqueous sodium hydroxide solution (1.1 mL) 1.1 mmol), 1,4-dioxane (1.0 mL), and the reaction and post-treatment according to Example (28e) gave the target compound (0.28 g, yield 89%) as a white solid. )
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 3.84 (3H, s), 5.48 (2H, s), 7.01 (1H, dd, J = 2.2, 8.8 Hz), 7.22-7.28 (2H, m) , 7.32-7.50 (4H, m), 7.60 (3H, s), 7.72 (1H, d, J = 8.6 Hz).
MS (FAB) m / z: 443 (M + H) ⁺ .
Anal.calcd for C ₂₃ H ₁₇ F ₃ N ₂ O ₄ + 0.10HCl: C, 61.93; H, 3.86; F, 12.78; N, 6.28; Cl, 0.79. Found C, 61.78; H, 3.85; F, 12.55 N, 6.37; Cl, 0.83.

Example 37 3-{[6- (3-Fluoro-4-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-186)
(37a) [5- (3-Fluoro-4-methylphenoxy) -2-nitrophenyl] methylcarbamic acid tert-butyl ester 3-fluoro-4-methylphenol (0.93 g, 7.4 mmol) and (5-chloro -2-Nitrophenyl) methylcarbamic acid tert-butyl ester (2.0 g, 7.0 mmol), sodium hydride (> 56% in oil, 0.29 g, 7.4 mmol), N, N-dimethylformamide (20 mL) Was used in the same manner as in Example (28a), and the resulting yellow oil was used as such in the next reaction.
(37b) [2-Amino-5- (3-fluoro-4-methylphenoxy) phenyl] methylcarbamic acid tert-butyl ester [5- (3-fluoro-4-methylphenoxy)-prepared in Example (37a) 2-Nitrophenyl] methylcarbamic acid tert-butyl ester (2.6 g, 7.0 mmol) and iron powder (1.9 g, 35 mmol), ammonium chloride (0.19 g, 3.5 mmol), ethanol (20 mL), water ( 10 mL) was used in the same manner as in Example (28b), and the obtained oil was used as such for the next reaction.
(37c) [6- (3-Fluoro-4-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol [2-amino-5- (3-fluoro] prepared in Example (37b) -4-methylphenoxy) phenyl] methylcarbamic acid tert-butyl ester (2.4 g, 7.0 mmol) and glycolic acid (0.80 g, 10 mmol), 5N aqueous hydrochloric acid (20 mL), 1,4-dioxane (20 mL) Was used to carry out the reaction and post-treatment according to Example (34c) to give the target compound (1.6 g, yield 81%) as a light brown solid.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 2.24 (3H, d, J = 2.0 Hz), 3.76 (3H, s), 4.90 (2H, s), 6.63-6.72 (2H, m), 6.92- 7.01 (2H, m), 7.11 (1H, t, J = 9.0 Hz), 7.65 (1H, d, J = 8.6 Hz).
(37d) 3-{[6- (3-Fluoro-4-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate [6- (prepared in Example (37c)] 3-fluoro-4-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol (0.25 g, 0.88 mmol) and methyl 3-hydroxybenzoate (0.20 g, 1.3 mmol), Using tri-n-butylphosphine (0.44 mL, 1.8 mmol), 1,1 ′-(azodicarbonyl) dipiperidine (0.44 g, 1.8 mmol), dichloromethane (4 mL), according to Example (28d) The target compound (0.30 g, yield 82%) was obtained as a white solid by performing the reaction and post-treatment.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 2.24 (3H, d, J = 1.6 Hz), 3.82 (3H, s), 3.92 (3H, s), 5.40 (2H, s), 6.66-6.71 ( 2H, m), 6.98-7.04 (2H, m), 7.11 (1H, t, J = 9.0 Hz), 7.27-7.32 (1H, m), 7.38 (1H, t, J = 8.0 Hz), 7.67-7.70 (1H, m), 7.71-7.75 (2H, m).
MS (FAB) m / z: 421 (M + H) ⁺ .
(37e) 3-{[6- (3-Fluoro-4-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid 3-{[6 prepared in Example (37d) -(3-Fluoro-4-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate (0.30 g, 0.72 mmol), 1 N aqueous sodium hydroxide solution (1.1 mL) 1.1 mmol), 1,4-dioxane (1.0 mL), and the reaction and workup according to Example (28e) gave the target compound (0.27 g, 94% yield) as a white solid. )
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 2.18 (3H, s), 3.82 (3H, s), 5.47 (2H, s), 6.72 (6H, dd, J = 2.4, 8.6 Hz), 6.80 (6H, dd, J = 2.5, 11.1 Hz), 6.95 (6H, dd, J = 2.4, 8.6 Hz), 7.25 (6H, t, J = 8.6 Hz), 7.35-7.40 (2H, m), 7.36 ( 1H, d, J = 2.4 Hz), 7.45 (1H, t, J = 7.8 Hz), 7.58 (1H, d, J = 7.8 Hz), 7.67 (1H, d, J = 8.6 Hz), 7.63-7.69 ( 1H, m), 13.08 (1H, br s).
MS (FAB) m / z: 407 (M + H) ⁺ .
_{. Anal calcd for C 23 H 19} FN 2 O 4:. C, 67.97; H, 4.71; F, 4.67; N, 6.89 Found C, 67.58; H, 4.63; F, 4.67; N, 6.91.

Example 38 3-{[6- (3-Chloro-5-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-207)
(38a) tert-butyl [5- (3-chloro-5-fluorophenoxy) -2-nitrophenyl] methylcarbamate 3-chloro-5-fluorophenol (2.93 g, 20 mmol), tert-butyl 5-chloro- According to the method described in Example (31a) using 2-nitrophenyl) methylcarbamate (5.73 g, 20 mmol) and sodium hydride (56%, 0.76 g, 20 mmol), the title compound (7. 94 g, 99% yield) was obtained as a yellow powder.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.33 (6H, s), 1.51 (3H, s), 3.28 (3H, s), 6.74 (1H, dt, J = 2.4, 9.0 Hz), 6.90- 6.93 (3H, m), 7.00 (1H, d, J = 7.8 Hz), 7.98 (1H, d, J = 8.6 Hz).
(38b) tert-butyl [2-amino-5- (3-chloro-5-fluorophenoxy) phenyl] methylcarbamate tert-butyl obtained in Example (38a) [5- (3-chloro-5-fluoro Phenoxy) -2-nitrophenyl] methylcarbamate (7.94 g, 20 mmol) and iron powder (5.59 g, 100 mmol) and according to the method described in Example (31b), the title compound (7.34 g) Yield 99%) as a brown oil.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.42 (9H, s), 3.15 (3H, s), 3.74 (2H, br s), 6.53 (1H, d, J = 9.8 Hz), 6.68-6.82 (4H, m), 7.04 (1H, dd, J = 2.0, 8.6 Hz).
(38c) [6- (3-Chloro-5-fluorophenoxy) -1-methyl-1H-benzimidazol-2-ylmethanol tert-butyl obtained in Example (38b) [2-amino-5- ( 3-Chloro-5-fluorophenoxy) phenyl] methylcarbamate (7.34 g, 20 mmol) and glycolic acid (3.04 g, 40 mmol) according to the method described in Example (31c) and the title compound ( 2.99 g, 49% yield) was obtained as a white powder.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 3.80 (3H, s), 4.91 (2H, s), 6.58 (1H, dt, J = 2.4, 10.2 Hz), 6.98-7.02 (2H, m), 7.23 (1H, dd, J = 2.0, 9.4 Hz), 7.32 (1H, d, J = 2.0 Hz), 7.70 (1H, d, J = 8.6 Hz).
(38d) 3-{[6- (3-Chloro-5-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate obtained in Example (38c) [6- (3-chloro-5-fluorophenoxy) -1-methyl-1H-benzimidazol-2-ylmethanol (2.99 g, 9.75 mmol), methyl 3-hydroxybenzoate (2.22 g, 14.6 mmol), Follow the procedure described in Example (31d) using tri-n-butylphosphine (3.94 g, 19.5 mmol) and 1,1 ′-(azodicarbonyl) dipiperidine (4.92 g, 19.5 mmol). The title compound (1.30 g, yield 32%) was obtained as a white powder.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 3.87 (3H, s), 3.93 (3H, s), 5.42 (2H, s), 6.59 (1H, dt, J = 2.4, 9.8 Hz), 6.75 ( 1H, s) 6.80 (1H, dt, J = 2.4, 7.8 Hz), 7.03 (1H, dd, J = 2.0, 8.6 Hz), 7.07 (1H, d, J = 2.4 Hz), 7.31 (1H, ddd, J = 1.2, 2.7, 8.2 Hz), 7.39 (1H, t, J = 7.8 Hz), 7.70 (1H, dd, J = 1.2, 7.8 Hz), 7.74 (1H, s), 7.79 (1H, d, J = 8.6 Hz).
(38e) 3- [6- (3-Chloro-5-fluorophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzoic acid 3-{[6- ( 3-Chloro-5-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate (1.30 g, 2.95 mmol) was used as described in Example (33e). According to the method, the title object compound (1.26 g, yield 86%) was obtained as a white powder.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 3.84 (3H, s), 5.48 (2H, s), 6.83-6.86 (2H, m), 7.02 (1H, dd, J = 2.4, 9.0 Hz ), 7.15 (1H, dt, J = 2.0, 8.6 Hz), 7.39 (1H, ddd, J = 1.2, 2.4, 8.2 Hz), 7.45 (1H, t, J = 7.4 Hz), 7.49 (1H, d, J = 2.4 Hz), 7.58 (1H, dt, J = 1.2, 7.4 Hz), 7.65 (1H, dd, J = 1.2, 2.4 Hz), 7.72 (1H, d, J = 8.6 Hz), 13.04 (1H, s).
MS (FAB +) m / z: 427 (M + H) ⁺ .
Mp: 209-213 ° C.

Example 39 3-{[6- (3,5-Difluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-181)
(39a) [5- (3,5-Difluorophenoxy) -2-nitrophenyl] methylcarbamic acid tert-butyl ester 3,5-difluorophenol (2.9 g, 22 mmol) and (5-chloro-2-nitrophenyl) Similar to Example (28a) using methylcarbamic acid tert-butyl ester (6.0 g, 21 mmol), sodium hydride (> 56% in oil, 0.88 g, 22 mmol), N, N-dimethylformamide (30 mL). The yellow solid obtained was used in the next reaction as it was.
(39b) [2-Amino-5- (3,5-difluorophenoxy) phenyl] methylcarbamic acid tert-butyl ester [5- (3,5-difluorophenoxy) -2-nitrophenyl prepared in Example (39a) ] Examples using methylcarbamic acid tert-butyl ester (8.4 g, 22 mmol), iron powder (5.9 g, 110 mmol), ammonium chloride (0.59 g, 11 mmol), ethanol (30 mL), water (15 mL) The compound was synthesized in the same manner as in 28b), and the obtained reddish brown solid was directly used in the next reaction.
(39c) [6- (3,5-Difluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol [2-amino-5- (3,5-difluoro) prepared in Example (39b) Phenoxy) phenyl] methylcarbamic acid tert-butyl ester (7.7 g, 22 mmol) and glycolic acid (2.5 g, 33 mmol), 5N aqueous hydrochloric acid (40 mL), 1,4-dioxane (40 mL) were used in Examples ( The target compound (4.5 g, yield 69%) as a light gray solid was obtained by performing the reaction and post-treatment according to 34c).
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 3.80 (3H, s), 4.92 (2H, s), 6.42-6.55 (3H, m), 7.00 (1H, dd, J = 2.4, 8.6 Hz), 7.04 (1H, d, J = 2.4 Hz), 7.71 (1H, d, J = 8.6 Hz).
(39d) 3-{[6- (3,5-Difluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate [6- (3,3) prepared in Example (39c) 5-Difluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol (0.25 g, 0.88 mmol) and methyl 3-hydroxybenzoate (0.20 g, 1.3 mmol), tri-n-butyl Reaction according to Example (28d) using phosphine (0.44 mL, 1.8 mmol), 1,1 ′-(azodicarbonyl) dipiperidine (0.44 g, 1.8 mmol), dichloromethane (4.0 mL) And the target compound (0.32 g, yield 86%) of white solid was obtained by performing a post-process.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 3.86 (3H, s), 3.92 (3H, s), 3.93 (9H, s), 5.41 (2H, s), 6.44-6.55 (2H, m), 7.03 (1H, dd, J = 2.2, 8.8 Hz), 7.07 (1H, d, J = 2.4 Hz), 7.27-7.33 (2H, m), 7.39 (1H, t, J = 7.8 Hz), 7.67-7.71 (1H, m), 7.73 (1H, dd, J = 1.4, 2.5 Hz), 7.78 (1H, d, J = 8.6 Hz).
(39e) 3-{[6- (3,5-Difluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid 3-{[6- (prepared in Example (39d)] 3,5-difluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate (0.32 g, 0.75 mmol), 1N aqueous sodium hydroxide solution (1.9 mL, 1.9 mmol) ), 1,4-dioxane (1.5 mL), and the reaction and post-treatment were performed according to Example (28e) to give the target compound (0.23 g, yield 76%) as a white solid. .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 3.85 (3H, s), 5.47 (2H, s), 6.69 (2H, dd, J = 2.2, 8.8 Hz), 6.95 (1H, tt, J = 2.2, 9.3 Hz), 7.02 (1H, dd, J = 2.4, 8.6 Hz), 7.30-7.36 (1H, m), 7.42 (1H, t, J = 7.8 Hz), 7.48 (1H, d, J = 2.4 Hz), 7.57 (1H, d, J = 7.4 Hz), 7.63 (1H, dd, J = 1.6, 2.4 Hz), 7.72 (1H, d, J = 8.6 Hz).
MS (FAB) m / z: 411 (M + H) ⁺ .
Anal.calcd for C ₂₂ H ₁₆ F ₂ N ₂ O ₄ + 1.00H ₂ O: C, 61.68; H, 4.24; F, 8.87; N, 6.54. Found C, 61.58; H, 3.95; F, 9.06; N , 6.51.

Example 40 3-{[6- (3-Fluoro-5-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-188)
(40a) 1-fluoro-3-methoxy-5-methylbenzene 3-bromo-5-fluoroanisole (2.05 g, 10 mmol), trimethylboroxine (50% THF solution, 2.51 g, 20 mmol), PdCl ₂ ( A mixed solution of dppf) (0.82 g, 1.0 mmol) and cesium carbonate (6.52 g, 20 mmol) in dioxane (100 mL) and water (50 mL) was stirred with heating under reflux for 10 hours. After allowing to cool, water (100 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (200 mL). The organic layer was washed twice with water (100 mL) and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (hexane: ethyl acetate, 6: 1) to obtain the title compound (1.40 g, yield 66%) as a yellow oil.
_{^{1 H-NMR (CDCl 3,}} 400 MHz) δ: 1.78 (3H, s), 6.44 (1H, dd, J = 2.0, 11.0 Hz), 6.50 (1H, d, J = 11.0 Hz), 6.51 (1H, s).
(40b) 3-Fluoro-5-methylphenol 1-fluoro-3-methoxy-5-methylbenzene (0.92 g, 6.56 mmol) obtained in Example (40a), boron tribromide (1.0 M) A methylene chloride solution (8.53 mL, 8.53 mmol) in methylene chloride (20 mL) was stirred at 0 ° C. for 10 hours. Water (100 mL) was added to the reaction solution, followed by extraction with methylene chloride (100 mL), and then the organic layer was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (hexane: ethyl acetate, 1: 1) to obtain the title compound (0.83 g, yield 99%) as a yellow oil.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 2.06 (3H, s), 4.97 (1H, s), 6.37 (1H, dt, J = 2.4, 10.2 Hz), 6.44 (1H, s), 6.48 ( (1H, d, J = 8.6 Hz).
(40c) tert-butyl [5- (3-fluoro-5-methylphenoxy) -2-nitrophenyl] methylcarbamate 3-fluoro-5-methylphenol (0.83 g, 6) obtained in Example (40b) .56 mmol), tert-butyl 5-chloro-2-nitrophenyl) methylcarbamate (1.88 g, 6.56 mmol) and sodium hydride (56%, 0.25 g, 6.56 mmol). According to the method described in (31a), the title object compound (1.71 g, yield 69%) was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 1.33 (6H, s), 1.51 (3H, s), 2.38 (3H, s), 3.27 (3H, s), 6.63 (1H, dt, J = 2.4 , 9.4 Hz), 6.71 (1H, s), 6.80 (1H, d, J = 8.6 Hz), 6.86-6.88 (2H, m), 7.95 (1H, d, J = 8.2 Hz).
(40d) tert-butyl [2-amino-5- (3-fluoro-5-methylphenoxy) phenyl] methylcarbamate tert-butyl [5- (3-fluoro-5-methyl) obtained in Example (40c) Phenoxy) -2-nitrophenyl] methylcarbamate (1.71 g, 4.54 mmol) and iron powder (1.27 g, 22.7 mmol) and according to the method described in Example (31b), title compound (1.38 g, 88% yield) was obtained as a yellow oil.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.41 (9H, s), 2.29 (3H, s), 3.15 (3H, s), 3.70 (2H, br s), 6.42-6.56 (3H, m) , 6.75-6.83 (3H, m).
(40e) [6- (3-Fluoro-5-methylphenoxy) -1-methyl-1H-benzimidazol-2-ylmethanol tert-butyl obtained in Example (40d) [2-amino-5- ( 3-Fluoro-5-methylphenoxy) phenyl] methylcarbamate (1.38 g, 3.98 mmol) and glycolic acid (0.61 g, 7.97 mmol) according to the method described in Example (31c) The title object compound (0.76 g, yield 67%) was obtained as a light brown oil.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 2.31 (3H, s), 3.78 (3H, s), 4.92 (2H, s), 6.49 (1H, dt, J = 2.0, 10.2 Hz), 6.58 ( 1H, s), 6.61 (1H, d, J = 11.0 Hz), 6.99-7.01 (2H, m), 7.69 (1H, d, J = 9.4 Hz).
(40f) 3-{[6- (3-Fluoro-5-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate obtained in Example (40e) [6- (3-Fluoro-5-methylphenoxy) -1-methyl-1H-benzimidazol-2-ylmethanol (0.76 g, 2.65 mmol), methyl 3-hydroxybenzoate (0.61 g, 3.98 mmol), Follow the procedure described in Example (31d) using tri-n-butylphosphine (1.07 g, 5.31 mmol) and 1,1 ′-(azodicarbonyl) dipiperidine (1.34 g, 5.31 mmol). The title compound (0.82 g, yield 74%) was obtained as a white powder.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 2.30 (3H, s), 3.84 (3H, s), 3.93 (3H, s), 5.40 (2H, s), 6.49 (1H, dt, J = 2.4 , 10.2 Hz), 6.58 (1H, s), 6.60 (1H, d, J = 10.6 Hz), 7.00-7.03 (2H, m), 7.28-7.31 (1H, m), 7.38 (1H, t, J = 7.8 Hz), 7.68 (1H, dt, J = 1.6, 8.6 Hz), 7.72-7.76 (2H, m).
(40 g) 3-{[6- (3-Fluoro-5-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid 3-{[obtained in Example (40f) 6- (3-Fluoro-5-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate (0.82 g, 1.86 mmol) was used for Example (33e) To give the title compound (0.55 g, yield 73%) as a white powder.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 2.25 (3H, s), 3.83 (3H, s), 5.47 (2H, s), 6.58-6.60 (2H, m), 6.75 (1H, d , J = 10.6 Hz), 6.96 (1H, dd, J = 2.4, 8.6 Hz), 7.37-7.39 (2H, m), 7.45 (1H, t, J = 7.4 Hz), 7.57 (1H, dt, J = 1.2, 7.8 Hz), 7.64 (1H, dd, J = 1.2, 2.4 Hz), 7.68 (1H, d, J = 8.6 Hz), 13.03 (1H, s).
MS (FAB +) m / z: 407 (M + H) ⁺ .
Mp: 224-226 ° C.

Example 41 3-{[6- (2,5-Difluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-179)
(41a) [5- (2,5-Difluorophenoxy) -2-nitrophenyl] methylcarbamic acid tert-butyl ester 2,5-difluorophenol (5.1 g, 38 mmol) and (5-chloro-2-nitrophenyl) Using methyl carbamic acid tert-butyl ester (9.8 g, 34 mmol), sodium hydride (> 56% in oil, 1.5 g, 38 mmol), N, N-dimethylformamide (90 mL), according to Example (28a) The target compound (12 g, yield 92%) was obtained as a yellow solid by carrying out the reaction and post-treatment.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.32 (6H, s), 1.50 (3H, br.s.), 3.28 (3H, s), 6.81-7.07 (4H, m), 7.17-7.26 ( 1H, m), 7.96 (1 H, d, J = 9.0 Hz).
(41b) [2-Amino-5- (2,5-difluorophenoxy) phenyl] methylcarbamic acid tert-butyl ester [5- (2,5-difluorophenoxy) -2-nitrophenyl prepared in Example (41a) ] Example (28b) using methylcarbamic acid tert-butyl ester (12 g, 31 mmol) and iron powder (8.4 g, 160 mmol), ammonium chloride (0.84 g, 16 mmol), ethanol (30 mL), and water (15 mL) The obtained reddish brown solid was used in the next reaction as it was.
(41c) [6- (2,5-Difluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol [2-amino-5- (2,5-difluoro) prepared in Example (41b) Phenoxy) phenyl] methylcarbamic acid tert-butyl ester (11 g, 31 mmol) and glycolic acid (3.6 g, 47 mmol), 5N aqueous hydrochloric acid (40 mL), 1,4-dioxane (40 mL), and Example (34c) The target compound (7.6 g, yield 83%) was obtained as a light brown solid by performing the reaction and post-treatment according to the above.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 3.77 (3H, s), 4.91 (2H, s), 6.60-6.71 (1H, m), 6.71-6.82 (1H, m), 6.97-7.06 (2 H, m), 7.09-7.21 (1H, m), 7.68 (1H, d, J = 9.0 Hz).
(41d) 3-{[6- (2,5-Difluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate [6- (2, 5-Difluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol (0.25 g, 0.86 mmol) and methyl 3-hydroxybenzoate (0.20 g, 1.3 mmol), tri-n-butyl Reaction according to Example (28d) using phosphine (0.43 mL, 1.7 mmol), 1,1 ′-(azodicarbonyl) dipiperidine (0.43 g, 1.7 mmol), dichloromethane (4.0 mL) And the target compound (0.28 g, yield 78%) of white solid was obtained by performing a post-process.
¹ H-NMR (CDCl ₃ , 400 MHz): δ ppm: 3.84 (3 H, s), 3.92 (3 H, s), 5.40 (2 H, s), 6.65-6.71 (1 H, m), 6.73 -6.80 (1 H, m), 7.01-7.05 (2 H, m), 7.11-7.18 (1 H, m), 7.29 (1 H, dd, J = 2.7, 8.2 Hz), 7.38 (1 H, t , J = 8.0 Hz), 7.67-7.77 (3 H, m).
(41e) 3-{[6- (2,5-Difluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid 3-{[6- (produced in Example (41d)] 2,5-difluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate (0.28 g, 0.67 mmol), 1N aqueous sodium hydroxide (1.0 mL, 1.0 mmol) ), 1,4-dioxane (1.0 mL), and the reaction and post-treatment were performed according to Example (28e) to give the desired compound (0.25 g, yield 91%) as a white solid. .
¹ H-NMR (DMSO-d ₆ , 500 MHz) δ: 3.83 (3H, s), 5.47 (2H, s), 6.88-6.95 (1H, m), 6.98-7.05 (2H, m), 7.38 (2H, s), 7.41-7.48 (2H, m), 7.58 (1H, d, J = 7.3 Hz), 7.63 (1H, s), 7.68 (1H, d, J = 8.8 Hz), 13.03 (1H, br s) .
MS (FAB) m / z: 411 (M + H) ⁺ .
Anal.calcd for C ₂₂ H ₁₆ F ₂ N ₂ O ₄ + 0.25H ₂ O: C, 63.69; H, 4.01; F, 9.16; N, 6.75. Found C, 63.84; H, 4.05; F, 9.22; N , 6.83.

Example 42 3-{[6- (3-Ethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-170)
(42a) tert-butyl [5- (3-ethylphenoxy) -2-nitrophenyl] methylcarbamate 3-ethylphenol (6.72 g, 55 mmol), tert-butyl 5-chloro-2-nitrophenyl) methylcarbamate ( 14.19 g, 49.5 mmol) and sodium hydride (56%, 2.10 g, 55.0 mmol) and according to the method described in Example (31a), the title compound (20.5 g, yield) 97%) as a yellow oil.
¹ H-NMR (CD Cl ₃ , 400 MHz) δ: 1.27 (3H, t, J = 7.4 Hz), 1.33 (6H, s), 1.50 (3H, s), 2.69 (2H, q, J = 7.4 Hz ), 3.26 (3H, s), 6.82-6.94 (4H, m), 7.11 (1H, d, J = 7.0 Hz), 7.35 (1H, t, J = 7.4 Hz), 7.94 (1H, d, J = (8.6 Hz).
(42b) tert-butyl [2-amino-5- (3-ethylphenoxy) phenyl] methylcarbamate tert-butyl [5- (3-ethylphenoxy) -2-nitrophenyl] obtained in Example (42a) The title compound (18.2 g, 99% yield) was prepared according to the method described in Example (31b) using methyl carbamate (19.8 g, 53.2 mmol) and iron powder (14.9 g, 266 mmol). Was obtained as a light brown oil.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.22 (3H, t, J = 7.4 Hz), 1.56 (9H, s), 2.61 (2H, q, J = 7.4 Hz), 3.15 (3H, s) , 3.66 (2H, br s), 6.73-6.84 (5H, m), 6.88 (1H, d, J = 7.4 Hz), 7.19 (1H, t, J = 7.8 Hz).
(42c) [6- (3-Ethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol tert-butyl [2-amino-5- (3-ethyl) obtained in Example (42b) Phenoxy) phenyl] methylcarbamate (18.2 g, 53.2 mmol) and glycolic acid (8.09 g, 106 mmol) were used according to the method described in Example (31c) to give the title compound (15.0 g, yield). 83%) was obtained as a brown powder.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.23 (3H, t, J = 7.8 Hz), 2.63 (2H, q, J = 7.4 Hz), 3.77 (3H, s), 4.08 (2H, s) , 6.80 (1H, dd, J = 2.0, 8.2 Hz), 6.86 (1H, s), 6.94-6.95 (2H, m), 6.98 (1H, dd, J = 2.4, 9.0 Hz), 7.24 (1H, t , J = 7.8 Hz), 7.62 (1H, d, J = 8.6 Hz).
(42d) 3-{[6- [3-Ethylphenoxy] -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate [6- (3-ethyl) obtained in Example (42c) Phenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol (12.5 g, 44.3 mmol), methyl 3-hydroxybenzoate (10.1 g, 66.5 mmol), tri-n-butylphosphine (17 9g, 88.7 mmol) and 1,1 ′-(azodicarbonyl) dipiperidine (22.4 g, 88.7 mmol) according to the method described in Example (31d) and the title compound (18. 5 g, yield 80%) was obtained as a pale yellow oil.
¹ H-NMR (CDCl ₃ , 400 MHz,) δ: 1.23 (3H, t, J = 7.8 Hz), 2.63 (2H, q, J = 7.4 Hz), 3.82 (3H, s), 3.93 (3H, s ), 5.40 (2H, s), 6.82 (1H, dd, J = 2.4, 8.2 Hz), 6.87 (1H, s), 6.95 (1H, d, J = 7.0 Hz), 7.01 (1H, d, J = 2.4 Hz), 7.03 (1H, dd, J = 2.4, 8.6 Hz), 7.23 (1H, d, J = 7.8 Hz), 7.29-7.32 (1H, m), 7.38 (1H, t, J = 7.4 Hz) , 7.70 (1H, d, J = 7.4 Hz), 7.72-7.74 (2H, m).
(42e) 3-{[6- (3-Ethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid 3-{[6- [3 obtained in Example (42d) -Ethylphenoxy] -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate (14.7 g, 35.3 mmol) according to the method described in Example (33e) The compound (14.2 g, yield 83%) was obtained as a white powder.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 1.15 (3H, t, J = 7.4 Hz), 2.57 (2H, q, J = 7.4 Hz), 3.81 (3H, s), 5.47 (2H, s), 6.76 (1H, dd, J = 2.4, 8.2 Hz), 6.84 (1H, s), 6.92-9.95 (2H, m), 7.25 (1H, t, J = 7.8 Hz), 7.32 (1H, d , J = 2.4 Hz), 7.37-7.40 (1H, m), 7.45 (1H, t, J = 7.8 Hz), 7.58 (1H, d, J = 7.4 Hz), 7.63-7.65 (1H, m), 7.66 (1H, d, J = 8.6 Hz), 13.03 (1H, br s).
MS (FAB +) m / z: 403 (M + H) ⁺ .
Mp: 204-208 ° C.

Example 43 3-{[6- (2,4-Difluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-178)
(43a) 5- (2,4-Difluorophenoxy) -N-methyl-2-nitroaniline 2,4-difluorophenol (5.2 g, 38 mmol) and 5-chloro-N-methylnitroaniline (6.5 g, 35 mmol), sodium hydride (> 56% in oil, 1.8 g, 46 mmol), N, N-dimethylformamide (80 mL), and synthesized in the same manner as in Example (28a). Used for next reaction.
(43b) 4- (2,4-difluorophenoxy) -2-N-methylaminoaniline 5- (2,4-difluorophenoxy) -N-methyl-2-nitroaniline prepared in Example (43a) (9 .8 g, 35 mmol) and iron powder (9.3 g, 170 mmol), ammonium chloride (0.93 g, 17 mmol), ethanol (30 mL), water (15 mL) and synthesized in the same manner as in Example (28b). The resulting reddish brown oil was used as such for the next reaction.
(43c) [6- (2,4-Difluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol 4- (2,4-difluorophenoxy) -2-prepared in Example (43b) N-methylaminoaniline (2.4 g, 7.0 mmol), glycolic acid (3.1 g, 41 mmol), 5N aqueous hydrochloric acid (40 mL) and 1,4-dioxane (40 mL) were used in Example (34c). The target compound (7.7 g, yield 76%) was obtained as a grey-red solid by performing the reaction and post-treatment in the same manner.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 3.74 (3H, s), 4.58 (1H, br s), 4.87 (2H, s), 6.79-6.90 (2H, m), 6.90-7.07 (3H, m), 7.61 (1H, d, J = 8.6 Hz).
(43d) 3-{[6- (2,4-Difluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate [6- (2, 4-Difluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol (0.25 g, 0.86 mmol) and methyl 3-hydroxybenzoate (0.20 g, 1.3 mmol), tri-n-butyl Reaction according to Example (28d) using phosphine (0.43 mL, 1.7 mmol), 1,1 ′-(azodicarbonyl) dipiperidine (0.43 g, 1.7 mmol), dichloromethane (4.0 mL) And the target compound (0.31 g, yield 84%) as a white solid was obtained by performing post-treatment.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 3.81 (3H, s), 3.92 (3H, s), 5.39 (2H, s), 6.81-6.88 (1H, m), 6.90 (1H, d, J = 2.4 Hz), 6.94-7.07 (3H, m), 7.29 (1H, d, J = 1.6 Hz), 7.37 (1H, t, J = 8.2 Hz), 7.66-7.76 (3H, m).
MS (FAB) m / z: 425 (M + H) ⁺ .
(43e) 3-{[6- (2,4-Difluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid 3-{[6- (prepared in Example (43d)] 2,4-difluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate (0.31 g, 0.73 mmol), 1N aqueous sodium hydroxide (1.2 mL, 1.2 mmol) ), 1,4-dioxane (1.0 mL), and the reaction and post-treatment were performed according to Example (28e) to give the target compound (0.14 g, yield 48%) as a white solid. .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 3.80 (3H, s), 5.45 (2H, s), 6.93 (1H, dd, J = 2.5, 8.8 Hz), 7.05-7.12 (1H, m) , 7.19 (1H, dt, J = 5.9, 9.2 Hz), 7.25 (1H, d, J = 2.4 Hz), 7.32-7.37 (1H, m), 7.43 (1H, t, J = 7.82 Hz), 7.44- 7.51 (1H, m), 7.54-7.59 (1H, m), 7.62 (1H, dd, J = 1.4, 2.5 Hz), 7.64 (1H, d, J = 8.6 Hz).
MS (FAB) m / z: 411 (M + H) ⁺ .
Anal.calcd for C ₂₂ H ₁₆ F ₂ N ₂ O ₄ + 0.50H ₂ O: C, 63.01; H, 4.09; F, 9.06; N, 6.68. Found C, 63.13; H, 3.86; F, 9.20; N , 6.70.

Example 44 3-{[1-Methyl-6- (2-methylphenoxy) -1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-166)
(44a) tert-butyl methyl [5- (2-methylphenoxy) -2-nitrophenyl] carbamate 2-methylphenol (4.53 g, 41.9 mmol), 5-chloro-2-nitrophenyl) methylcarbamic acid tert -Crude product of the title object compound according to the method described in Example (28a) using butyl (10.0 g, 34.9 mmol) and sodium hydride (63%, 1.59 g, 41.9 mmol). Was obtained as a brown oil. This was used as such for the next reaction.
(44b) tert-Butyl [2-amino-5- (2-methylphenoxy) phenyl] methylcarbamate Methyl [5- (2-methylphenoxy) -2-nitrophenyl] carbamic acid obtained in Example (44a) According to the method described in Example (28b) using tert-butyl (12.5 g, 34.9 mmol), iron powder (9.74 g, 174 mmol) and ammonium chloride (0.933 g, 17.4 mmol) A crude product of the title object compound was obtained as a brown oil. This was used as such for the next reaction.
(44c) [1-Methyl-6- (2-methylphenoxy) -1H-benzimidazol-2-yl] methanol [2-amino-5- (2-methylphenoxy) phenyl obtained in Example (44b) The title target compound (6.71 g) was prepared according to the method described in Example (28c) using tert-butyl methylcarbamate (11.5 g, 34.9 mmol) and glycolic acid (3.98 g, 52.3 mmol). Yield 72%) as a brown powder.
¹ H NMR (CDCl ₃ , 400 MHz) δ: 2.28 (3H, s), 3.73 (3H, s), 4.86 (2H, s), 6.80 (1H, d, J = 2.0 Hz), 6.83-6.87 (1H, m), 6.91 (1H, dd, J = 2.0, 8.6 Hz), 7.03-7.08 (1H, m), 7.12-7.18 (1H, m), 7.24-7.29 (1H, m), 7.59 (1H, d, J = 8.6 Hz).
(44d) 3-{[1-Methyl-6- (2-methylphenoxy) -1H-benzimidazol-2-yl] methoxy} methyl benzoate [1-methyl-6- 6] obtained in Example (44c) (2-Methylphenoxy) -1H-benzimidazol-2-yl] methanol (6.00 g, 22.4 mmol), methyl 3-hydroxybenzoate (4.08 g, 26.8 mmol), tri-n-butylphosphine (8 .38 mL, 33.5 mmol) and 1,1 ′-(azodicarbonyl) dipiperidine (8.46 g, 33.5 mmol) and according to the method described in Example (28d), the title compound (7. 33 g, 81% yield) was obtained as a white powder.
¹ H NMR (CDCl ₃ , 400 MHz) δ: 2.29 (3H, s), 3.79 (3H, s), 3.92 (3H, s), 5.38 (2H, s), 6.84 (1H, d, J = 2.3 Hz) , 6.88 (1H, d, J = 8.2 Hz), 6.97 (1 H, dd, J = 2.3, 9.0 Hz), 7.04-7.10 (1H, m), 7.13-7.19 (1H, m), 7.25-7.32 ( 2H, m), 7.37 (1H, t, J = 7.8 Hz), 7.66-7.73 (3H, m).
(44e) 3-{[1-Methyl-6- (2-methylphenoxy) -1H-benzimidazol-2-yl] methoxy} benzoic acid 3-{[1-methyl-] obtained in Example (44d) 6- (2-Methylphenoxy) -1H-benzimidazol-2-yl] methoxy} methyl benzoate (6.50 g, 16.2 mmol) and 1 N aqueous sodium hydroxide (24.2 mL, 24.2 mmol) were used. Then, according to the method described in Example (28e), the title object compound (6.13 g, yield 98%) was obtained as a white powder.
¹ H NMR (DMSO-d ₆ , 500 MHz) δ: 2.25 (3H, s), 3.79 (3H, s), 5.45 (2H, s), 6.81 (1H, d, J = 7.8 Hz), 6.86 (1H, dd, J = 2.4, 8.8 Hz), 7.06 (1H, t, J = 7.3 Hz), 7.14-7.21 (2H, m), 7.32 (1H, d, J = 7.3 Hz), 7.36-7.41 (1H, m ), 7.45 (1H, t, J = 8.1 Hz), 7.57 (1H, d, J = 7.3 Hz), 7.63 (2H, d, J = 8.3 Hz), 13.03 (1H, s).
MS (FAB) m / z: 389 (M + H) ⁺ .

Example 45 3-{[6- (2-Fluoro-5-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-184)
(45a) [5- (2-Fluoro-5-methylphenoxy) -2-nitrophenyl] methylcarbamic acid tert-butyl ester 2-fluoro-5-methylphenol (5.1 g, 40 mmol) and (5-chloro-2 -Nitrophenyl) methylcarbamic acid tert-butyl ester (10 g, 36 mmol), sodium hydride (> 56% in oil, 1.6 g, 40 mmol), N, N-dimethylformamide (70 mL), Example (28a) The yellow oil obtained was used in the next reaction as it was.
(45b) [2-Amino-5- (2-fluoro-5-methylphenoxy) phenyl] methylcarbamic acid tert-butyl ester [5- (2-fluoro-5-methylphenoxy)-prepared in Example (45a) 2-Nitrophenyl] methylcarbamic acid tert-butyl ester (15 g, 40 mmol) and iron powder (11 g, 200 mmol), ammonium chloride (1.1 g, 20 mmol), ethanol (30 mL), water (15 mL) and the examples ( It was synthesized in the same manner as in 28b), and the obtained oil was directly used in the next reaction.
(45c) [6- (2-Fluoro-5-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol [2-amino-5- (2-fluoro] prepared in Example (45b) -5-methylphenoxy) phenyl] methylcarbamic acid tert-butyl ester (15 g, 40 mmol) and glycolic acid (4.0 g, 52 mmol), 5N aqueous hydrochloric acid (30 mL), 1,4-dioxane (30 mL) The target compound (8.0 g, yield 70%) as a light brown solid was obtained by carrying out the reaction and post-treatment according to Example (34c).
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 2.27 (3H, s), 3.75 (3H, s), 4.89 (2H, s), 6.78-6.84 (1H, m), 6.85-6.91 (1H, m ), 6.92 (1H, d, J = 2.4 Hz), 6.98 (1H, dd, J = 2.2, 8.8 Hz), 7.07 (1H, dd, J = 8.6, 10.6 Hz), 7.64 (1H, d, J = 9.0 Hz).
(45d) 3-{[6- (2-Fluoro-5-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate [6- (prepared in Example (45c)] 2-fluoro-5-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol (0.25 g, 0.94 mmol) and methyl 3-hydroxybenzoate (0.16 g, 1.0 mmol), Using tri-n-butylphosphine (0.47 mL, 1.9 mmol), 1,1 ′-(azodicarbonyl) dipiperidine (0.47 g, 1.9 mmol) and dichloromethane (4 mL), according to Example (28d) The target compound (0.20 g, yield 49%) was obtained as a white solid by carrying out the reaction and post-treatment.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 2.27 (3H, s), 3.82 (3H, s), 3.92 (3H, s), 5.39 (2H, s), 6.82 (1H, s), 6.86- 6.92 (1H, m), 6.95 (1H, d, J = 2.4 Hz), 7.01 (1H, dd, J = 2.4, 9.0 Hz), 7.07 (1H, dd, J = 8.2, 10.6 Hz), 7.28-7.31 (1H, m), 7.38 (1H, t, J = 7.8 Hz), 7.67-7.73 (3H, m).
MS (FAB) m / z: 421 (M + H) ⁺ .
(45e) 3-{[6- (2-Fluoro-5-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid 3-{[6 prepared in Example (45d) -(2-Fluoro-5-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate (0.20 g, 0.46 mmol), 1 N aqueous sodium hydroxide (0.70 mL) , 0.70 mmol), 1,4-dioxane (1.0 mL), and the reaction and workup according to Example (28e) gave the target compound (0.18 g, 95% yield) as a white solid. )
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 2.23 (3H, s), 3.81 (3H, s), 5.46 (2H, s), 6.87 (1H, s), 6.93 (1H, dd, J = 2.4, 9.0 Hz), 6.94-6.99 (1H, m), 7.22-7.31 (2H, m), 7.39 (1H, s), 7.45 (1H, t, J = 7.8 Hz), 7.58 (1H, d, J = 7.4 Hz), 7.62-7.68 (2H, m).
MS (FAB) m / z: 407 (M + H) ⁺ .
Anal.calcd for C ₂₃ H ₁₉ FN ₂ O ₄ + 0.20H ₂ O: C, 67.38; H, 4.77; F, 4.63; N, 6.83. Found C, 67.43; H, 4.71; F, 4.80; N, 6.87 .

Example 46 3-{[6- (4-Fluoro-2-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-183)
(46a) tert-Butyl [5- (4-fluoro-2-methylphenoxy) -2-nitrophenyl] methylcarbamate 4-fluoro-2-methylphenol (5.28 g, 41.9 mmol), 5-chloro-2- According to the method described in Example (28a) using tert-butyl nitrophenyl) methylcarbamate (10.0 g, 34.9 mmol) and sodium hydride (63%, 1.59 g, 41.9 mmol) The crude product of the target compound was obtained as a brown oil. This was used as such for the next reaction.
(46b) tert-Butyl [2-amino-5- (4-fluoro-2-methylphenoxy) phenyl] methylcarbamate [5- (4-Fluoro-2-methylphenoxy)-obtained in Example (46a) Tert-butyl 2-nitrophenyl] methylcarbamate (13.1 g, 34.9 mmol), iron powder (9.74 g, 174 mmol) and ammonium chloride (0.933 g, 17.4 mmol) were used for the examples (28b The crude product of the title object compound was obtained as a brown powder. This was used as such for the next reaction.
(46c) [6- (4-Fluoro-2-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol [2-amino-5- (4-) obtained in Example (46b) Fluoro-2-methylphenoxy) phenyl] tert-butyl methylcarbamate (12.1 g, 34.9 mmol) and glycolic acid (3.98 g, 52.3 mmol) according to the method described in Example (28c). The title compound (8.62 g, yield 86%) was obtained as a brown powder.
¹ H NMR (CDCl ₃ , 400 MHz) δ: 2.25 (3H, s), 3.73 (3H, s), 4.86 (2H, s), 6.73 (1H, d, J = 2.3 Hz), 6.84-6.90 (3H, m), 6.96-7.00 (1H, m), 7.59 (1H, d, J = 8.6 Hz).
(46d) Methyl 3-{[6- (4-fluoro-2-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoate [6- (4-Fluoro-2-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol (7.50 g, 26.2 mmol), methyl 3-hydroxybenzoate (4.78 g, 31.4 mmol) , Tri-n-butylphosphine (7.85 mL, 31.4 mmol) and 1,1 ′-(azodicarbonyl) dipiperidine (7.93 g, 31.4 mmol) using the method described in Example (28d). To give the title object compound (8.49 g, yield 77%) as a white powder.
¹ H NMR (CDCl ₃ , 400 MHz) δ: 2.25 (3H, s), 3.79 (3H, s), 3.92 (3H, s), 5.38 (2H, s), 6.77 (1H, d, J = 2.3 Hz) , 6.84-7.02 (4H, m), 7.25-7.33 (1H, m), 7.37 (1H, t, J = 8.0 Hz), 7.66-7.74 (3H, m).
(46e) 3-{[6- (4-Fluoro-2-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid 3-{[obtained in Example (46d) 6- (4-Fluoro-2-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate (7.50 g, 17.8 mmol) and 1N aqueous sodium hydroxide (26. 8 mL, 26.8 mmol) was used to give the title object compound (6.48 g, yield 89%) as a white powder according to the method described in Example (28e).
¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 2.22 (3H, s), 3.78 (3H, s), 5.45 (2H, s), 6.82-6.91 (2H, m), 6.98-7.05 (1H, m ), 7.12 (1H, d, J = 2.3 Hz), 7.20 (1H, dd, J = 3.1, 9.4 Hz), 7.35-7.40 (1H, m), 7.45 (1H, t, J = 7.8 Hz), 7.55 -7.59 (1H, m), 7.60-7.65 (2H, m), 13.03 (1H, s).
MS (FAB) m / z: 407 (M + H) ^<+> .

Example 47 3-{[6- (3-Fluoro-5-methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-195)
(47a) [5- (3-Fluoro-5-methoxyphenoxy) -2-nitrophenyl] methylcarbamic acid tert-butyl ester 3-fluoro-5-methoxyphenol (4.5 g, 32 mmol) of known [WO2005037763] and ( 5-chloro-2-nitrophenyl) methylcarbamic acid tert-butyl ester (7.7 g, 27 mmol), sodium hydride (> 56% in oil, 1.3 g, 32 mmol), N, N-dimethylformamide (60 mL). The target compound (3.7 g, yield 57%) was obtained by carrying out the reaction and post-treatment according to Example (27a).
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.32 (6H, s), 1.50 (3H, s), 3.27 (3H, s), 3.81 (3H, s), 6.37-6.46 (2H, m), 6.52 (1H, d, J = 11.0 Hz), 6.86-6.96 (2H, m), 7.91-8.03 (1H, m).
(47b) [2-Amino-5- (3-fluoro-5-methoxyphenoxy) phenyl] methylcarbamic acid tert-butyl ester [5- (3-Fluoro-5-methoxyphenoxy)-prepared in Example (47a) 2-Nitrophenyl] methylcarbamic acid tert-butyl ester (3.7 g, 9.5 mmol), iron powder (2.5 g, 47 mmol), ammonium chloride (0.25 g, 4.7 mmol), ethanol (30 mL), water ( 15 mL) was used in the same manner as in Example (28b), and the resulting light brown oil was used as such for the next reaction.
(47c) [6- (3-Fluoro-5-methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol [2-amino-5- (3-fluoro] prepared in Example (47b) -5-methoxyphenoxy) phenyl] methylcarbamic acid tert-butyl ester (3.1 g, 8.7 mmol) and glycolic acid (0.86 g, 11 mmol), 5N aqueous hydrochloric acid (10 mL), 1,4-dioxane (10 mL) Was used to carry out the reaction and post-treatment according to Example (34c) to give the target compound (2.0 g, yield 75%) as a light brown solid.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 3.72 (3H, s), 3.75 (3H, s), 4.90 (2H, d, J = 5.5 Hz), 6.54 (1H, dd, J = 2.9, 6.8 Hz), 6.57-6.63 (1H, m), 6.95 (1H, d, J = 2.4 Hz), 7.00 (1H, dd, J = 2.2, 8.8 Hz), 7.10 (1H, dd, J = 9.0, 10.6 Hz) ), 7.66 (1H, d, J = 8.6 Hz).
(47d) 3-{[6- (3-Fluoro-5-methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate [6- ( 3-fluoro-5-methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol (0.35 g, 1.2 mmol) and methyl 3-hydroxybenzoate (0.19 g, 1.3 mmol), Using tri-n-butylphosphine (0.58 mL, 2.3 mmol), 1,1 ′-(azodicarbonyl) dipiperidine (0.58 g, 2.3 mmol) and dichloromethane (4 mL), according to Example (28d) The target compound (0.31 g, yield 60%) was obtained as a white solid by performing the reaction and post-treatment.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 3.75 (3H, s), 3.84 (3H, s), 3.93 (3H, s), 5.41 (2H, s), 6.27 (1H, ddd, J = 2.0 , 2.2, 10.0 Hz), 6.32-6.37 (2H, m), 6.98-7.09 (2H, m), 7.30 (1H, dd, J = 2.7, 8.2 Hz), 7.38 (1H, t, J = 7.8 Hz) , 7.69 (1H, dt, J = 1.3, 7.5 Hz), 7.73 (1H, dd, J = 1.4, 2.5 Hz), 7.75 (1H, dd, J = 1.2, 8.2 Hz).
MS (FAB) m / z: 437 (M + H) ⁺ .
(47e) 3-{[6- (3-Fluoro-5-methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid 3-{[6 prepared in Example (47d) -(3-Fluoro-5-methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate (0.31 g, 0.70 mmol), 1 N aqueous sodium hydroxide solution (1.1 mL) 1.1 mmol), 1,4-dioxane (1.0 mL), and the reaction and post-treatment according to Example (28e) gave the target compound (0.20 g, yield 67% as a white solid). )
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 3.73 (3H, s), 3.84 (3H, s), 5.47 (2H, s), 6.38 (1H, s), 6.33 (1H, dt, J = 2.3, 10.3 Hz), 6.56 (1H, dt, J = 2.4, 11.0 Hz), 6.98 (1H, dd, J = 2.4, 8.6 Hz), 7.37-7.48 (3H, m), 7.58 (1H, d, J = 7.4 Hz), 7.64 (1H, s), 7.69 (1H, d, J = 8.6 Hz), 13.03 (1H, br s).
MS (FAB) m / z: 423 (M + H) ⁺ .
_{. Anal calcd for C 23 H 19} FN 2 O 5 + 0.20H 2 O:. C, 64.85; H, 4.59; F, 4.46; N, 6.58 Found C, 64.77; H, 4.50; F, 4.58; N, 6.65 .

Example 48 3-{[6- (2-Fluoro-4-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-182)
(48a) [5- (2-Fluoro-4-methylphenoxy) -2-nitrophenyl] methylcarbamic acid tert-butyl ester 2-fluoro-4-methylphenol (5.0 g, 40 mmol) and (5-chloro-2 -Nitrophenyl) methylcarbamic acid tert-butyl ester (10 g, 36 mmol), sodium hydride (> 56% in oil, 1.6 g, 40 mmol), N, N-dimethylformamide (50 mL), Example (28a) The yellow oil obtained was used in the next reaction as it was.
(48b) [2-Amino-5- (2-fluoro-4-methylphenoxy) phenyl] methylcarbamic acid tert-butyl ester [5- (2-fluoro-4-methylphenoxy)-prepared in Example (48a) 2-nitrophenyl] methylcarbamic acid tert-butyl ester (14 g, 36 mmol), iron powder (10 g, 180 mmol), ammonium chloride (0.96 g, 18 mmol), ethanol (30 mL), water (15 mL) It was synthesized in the same manner as in 28b), and the obtained brown oil was used as it was in the next reaction.
(48c) [6- (2-Fluoro-4-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol [2-amino-5- (2-fluoro] prepared in Example (48b) -4-methylphenoxy) phenyl] methylcarbamic acid tert-butyl ester (13 g, 36 mmol) and glycolic acid (3.0 g, 47 mmol), 5N aqueous hydrochloric acid (30 mL), 1,4-dioxane (30 mL) The target compound (9.0 g, yield 87%) as a light brown solid was used in the next reaction as it was by performing the reaction and post-treatment according to Example (34c).
(48d) 3-{[6- (2-Fluoro-4-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate [6- (prepared in Example (48c)] 2-fluoro-4-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol (0.35 g, 1.2 mmol) and methyl 3-hydroxybenzoate (0.19 g, 1.3 mmol), Using tri-n-butylphosphine (0.58 mL, 2.3 mmol), 1,1 ′-(azodicarbonyl) dipiperidine (0.58 g, 2.3 mmol) and dichloromethane (4 mL), according to Example (28d) The target compound (0.38 g, yield 78%) as a white solid was obtained by carrying out the reaction and post-treatment.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 2.36 (3H, s), 3.80 (3H, s), 3.92 (3H, s), 5.38 (2H, s), 6.88-7.04 (5H, m), 7.29 (1H, s), 7.37 (1H, t, J = 8.0 Hz), 7.65-7.75 (3H, m).
MS (FAB) m / z: 421 (M + H) ⁺ .
(48e) 3-{[6- (2-Fluoro-4-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid 3-{[6 prepared in Example (48d) -(2-Fluoro-4-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate (0.38 g, 0.90 mmol), 1 N aqueous sodium hydroxide solution (1.4 mL 1.4 mmol), 1,4-dioxane (1.5 mL), and the reaction and post-treatment according to Example (28e) gave the target compound (0.41 g, yield 100%) as a white solid. )
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 2.31 (3H, s), 3.79 (3H, s), 5.45 (2H, s), 6.90 (1H, dd, J = 2.4, 9.0 Hz), 6.99 -7.02 (2H, m), 7.21 (1H, t, J = 6.7 Hz), 7.21 (1H, s), 7.35-7.40 (1H, m), 7.45 (1H, t, J = 7.8 Hz), 7.55- 7.59 (1 H, m), 7.63 (1H, d, J = 8.6 Hz), 7.63 (1H, dd, J = 1.6, 2.4 Hz), 13.03 (1H, br s).
MS (FAB) m / z: 407 (M + H) ⁺ .
Anal.calcd for C ₂₃ H ₁₉ FN ₂ O ₄ + 0.20H ₂ O: C, 67.38; H, 4.77; F, 4.63; N, 6.83. Found C, 67.46; H, 4.72; F, 4.75; N, 6.89 .

Example 49 3-{[1-Methyl-6- (4-methylphenoxy) -1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-168)
(49a) tert-butyl methyl [5- (4-methylphenoxy) -2-nitrophenyl] carbamate 4-methylphenol (4.53 g, 41.9 mmol), 5-chloro-2-nitrophenyl) methylcarbamic acid tert -Crude product of the title object compound according to the method described in Example (28a) using butyl (10.0 g, 34.9 mmol) and sodium hydride (63%, 1.59 g, 41.9 mmol). Was obtained as a yellow powder. This was used as such for the next reaction.
(49b) tert-Butyl [2-amino-5- (4-methylphenoxy) phenyl] methylcarbamate Methyl [5- (4-methylphenoxy) -2-nitrophenyl] carbamic acid obtained in Example (49a) According to the method described in Example (28b) using tert-butyl (12.5 g, 34.9 mmol), iron powder (9.74 g, 174 mmol) and ammonium chloride (0.933 g, 17.4 mmol) A crude product of the title target compound was obtained as a brown powder. This was used as such for the next reaction.
(49c) [1-Methyl-6- (4-methylphenoxy) -1H-benzimidazol-2-yl] methanol [2-amino-5- (4-methylphenoxy) phenyl obtained in Example (49b) The title target compound (8.31 g) was prepared according to the method described in Example (28c) using tert-butyl methylcarbamate (11.5 g, 34.9 mmol) and glycolic acid (3.98 g, 52.3 mmol). Yield 89%) as a brown powder.
¹ H NMR (CDCl ₃ , 400 MHz) δ: 2.34 (3H, s), 3.74 (3H, s), 4.86 (2H, s), 6.87-6.92 (3H, m), 6.95 (1H, dd, J = 2.3 , 8.6 Hz), 7.14 (2H, d, J = 7.8 Hz), 7.59 (1H, d, J = 8.6 Hz).
(49d) 3-{[1-Methyl-6- (4-methylphenoxy) -1H-benzimidazol-2-yl] methoxy} methyl benzoate [1-Methyl-6-] obtained in Example (49c) (4-Methylphenoxy) -1H-benzimidazol-2-yl] methanol (7.50 g, 28.0 mmol), methyl 3-hydroxybenzoate (5.10 g, 33.5 mmol), tri-n-butylphosphine (8 .38 mL, 33.5 mmol) and 1,1 ′-(azodicarbonyl) dipiperidine (8.46 g, 33.5 mmol) and according to the method described in Example (28d), the title compound (9. 40 g, yield 83%) was obtained as a white brown powder.
¹ H NMR (CDCl ₃ , 500 MHz) δ: 2.34 (3H, s), 3.80 (3H, s), 3.92 (3H, s), 5.39 (2H, s), 6.89-6.97 (3H, m), 7.01 ( 1H, dd, J = 2.4, 8.8 Hz), 7.14 (2H, d, J = 8.3 Hz), 7.27-7.31 (1H, m), 7.37 (1H, t, J = 8.1 Hz), 7.66-7.74 (3H , m).
(49e) 3-{[1-Methyl-6- (4-methylphenoxy) -1H-benzimidazol-2-yl] methoxy} benzoic acid 3-{[1-Methyl-] obtained in Example (49d) 6- (4-Methylphenoxy) -1H-benzimidazol-2-yl] methoxy} methyl benzoate (9.00 g, 22.4 mmol) and 1 N aqueous sodium hydroxide (33.6 mL, 33.6 mmol) were used. Then, according to the method described in Example (28e), the title object compound (5.91 g, yield 68%) was obtained as a white powder.
¹ H NMR (DMSO-d ₆ , 400 MHz): δ 2.28 (3H, s), 3.80 (3H, s), 5.46 (2H, s), 6.87-6.94 (3H, m), 7.17 (2H, d, J = 9.0 Hz), 7.26 (1H, d, J = 2.3 Hz), 7.36-7.41 (1H, m), 7.45 (1H, t, J = 8.0 Hz), 7.58 (1H, d, J = 7.8 Hz), 7.62-7.67 (2H, m), 13.05 (1H, s).
MS (FAB) m / z: 389 (M + H) ⁺ .

Example 50 3-{[6- (5-Fluoro-2-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-185)
(50a) tert-butyl [5- (5-fluoro-2-methylphenoxy) -2-nitrophenyl] methylcarbamate 5-fluoro-2-methylphenol (5.28 g, 41.9 mmol), 5-chloro-2 -Nitrophenyl) tert-butyl methylcarbamate (10.0 g, 34.9 mmol) and sodium hydride (63%, 1.59 g, 41.9 mmol) according to the method described in example (28a) A crude product of the title object compound was obtained as a brown oil. This was used as such for the next reaction.
(50b) [2-Amino-5- (5-fluoro-2-methylphenoxy) phenyl] tert-butyl methylcarbamate [5- (5-fluoro-2-methylphenoxy)-obtained in Example (50a) Tert-butyl 2-nitrophenyl] methylcarbamate (13.1 g, 34.9 mmol), iron powder (9.74 g, 174 mmol) and ammonium chloride (0.933 g, 17.4 mmol) were used for the examples (28b ) To give a crude product of the title object compound as a brown oil. This was used as such for the next reaction.
(50c) [6- (5-Fluoro-2-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol [2-amino-5- (5- Fluoro-2-methylphenoxy) phenyl] tert-butyl methylcarbamate (12.1 g, 34.9 mmol) and glycolic acid (3.98 g, 52.3 mmol) according to the method described in Example (28c). The title compound (8.52 g, yield 85%) was obtained as a brown powder.
¹ H NMR (CDCl ₃ , 500 MHz) δ: 2.26 (3H, s), 3.77 (3H, s), 4.88 (2H, s), 6.50 (1H, dd, J = 2.4, 10.3 Hz), 6.73 (1H, dt, J = 2.4, 8.3 Hz), 6.87 (1H, d, J = 2.4 Hz), 6.93 (1H, dd, J = 2.4, 8.8 Hz), 7.16-7.20 (1H, m), 7.63 (1H, d , J = 8.8 Hz).
(50d) 3-{[6- (5-Fluoro-2-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate obtained in Example (50c) [6- (5-Fluoro-2-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol (7.50 g, 26.2 mmol), methyl 3-hydroxybenzoate (4.78 g, 31.4 mmol) , Tri-n-butylphosphine (7.85 mL, 31.4 mmol) and 1,1 ′-(azodicarbonyl) dipiperidine (7.93 g, 31.4 mmol) using the method described in Example (28d). To give the title object compound (7.15 g, yield 65%) as a white powder.
¹ H NMR (CDCl ₃ , 400 MHz) δ: 2.27 (3H, s), 3.82 (3H, s), 3.92 (3H, s), 5.40 (2H, s), 6.53 (1H, dd, J = 2.7, 9.8 Hz), 6.74 (1H, dt, J = 2.7, 8.2 Hz), 6.91 (1H, d, J = 2.0 Hz), 6.98 (1H, dd, J = 2.0, 8.6 Hz), 7.17-7.22 (1H, m ), 7.27-7.32 (1H, m), 7.38 (1H, t, J = 8.2 Hz), 7.67-7.76 (3H, m).
(50e) 3-{[6- (5-Fluoro-2-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid 3-{[obtained in Example (50d) 6- (5-Fluoro-2-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate (7.00 g, 16.7 mmol) and 1 N aqueous sodium hydroxide (25. The title object compound (6.29 g, yield 93%) was obtained as a white powder according to the method described in Example (28e) using 0 mL, 25.0 mmol).
¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 2.24 (3H, s), 3.82 (3H, s), 5.47 (2H, s), 6.57 (1H, dd, J = 2.5, 10.4 Hz), 6.85- 6.95 (2H, m), 7.29 (1H, d, J = 2.3 Hz), 7.31-7.41 (2H, m), 7.46 (1H, t, J = 7.8 Hz), 7.58 (1H, d, J = 7.8 Hz) ), 7.63-7.66 (1H, m), 7.67 (1H, d, J = 8.6 Hz), 13.04 (1H, s).
MS (FAB) m / z: 407 (M + H) ^<+> .

Example 51 3-{[6- (2-Fluoro-5-methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-191)
(51a) [5- (2-Fluoro-5-methoxyphenoxy) -2-nitrophenyl] methylcarbamic acid tert-butyl ester known [Can. J. et al. Chem. 1988, 66, p. 1479-1482] 2-fluoro-5-methoxyphenol (4.6 g, 32 mmol) and (5-chloro-2-nitrophenyl) methylcarbamic acid tert-butyl ester (7 g, 36 mmol), sodium hydride (> 56% in oil, 1.3 g, 32 mmol), N, N-dimethylformamide (60 mL), and the reaction and workup according to Example (27a) gave the target compound (5.5 g, yield) as a yellow oil. 57%) was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.32 (6H, s), 1.50 (3H, s), 3.26 (3H, s), 3.80 (3H, s), 6.67-6.92 (4H, m), 7.15 (1H, t, J = 9.4 Hz), 7.94 (1H, d, J = 8.6 Hz).
(51b) [2-Amino-5- (2-fluoro-5-methoxyphenoxy) phenyl] methylcarbamic acid tert-butyl ester [5- (2-fluoro-5-methoxyphenoxy)-prepared in Example (51a) 2-Nitrophenyl] methylcarbamic acid tert-butyl ester (5.5 g, 14 mmol), iron powder (6.5 g, 120 mmol), ammonium chloride (0.65 g, 12 mmol), ethanol (30 mL), water (15 mL) In the same manner as in Example (28b), the obtained oil was directly used in the next reaction.
(51c) [6- (2-Fluoro-5-methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol [2-amino-5- (2-fluoro] prepared in Example (51b) -5-methoxyphenoxy) phenyl] methylcarbamic acid tert-butyl ester (5.0 g, 14 mmol) and glycolic acid (1.4 g, 18 mmol), 5N aqueous hydrochloric acid (30 mL), 1,4-dioxane (30 mL) The target compound (2.3 g, yield 64%) was obtained as a pale brown solid by performing the reaction and post-treatment according to Example (34c).
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 3.72 (3H, s), 3.75 (3H, s), 4.90 (2H, d, J = 5.5 Hz), 6.54 (1H, dd, J = 2.9, 6.8 Hz), 6.57-6.63 (1H, m), 6.95 (1H, d, J = 2.4 Hz), 7.00 (1H, dd, J = 2.2, 8.8 Hz), 7.10 (1H, dd, J = 9.0, 10.6 Hz) ), 7.66 (1H, d, J = 8.6 Hz).
(51d) 3-{[6- (2-Fluoro-5-methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate [6- (prepared in Example (51c)] 2-fluoro-5-methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol (2.7 g, 8.8 mmol) and methyl 3-hydroxybenzoate (1.3 g, 8.8 mmol), Tri n-Butylphosphine (4.4 mL, 18 mmol), 1,1 ′-(azodicarbonyl) dipiperidine (4.5 g, 18 mmol), dichloromethane (4 mL) were used for the reaction according to Example (28d). By performing the treatment, the target compound (3.7 g, yield 95%) was obtained as a white solid.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 3.72 (3H, s), 3.82 (3H, s), 3.92 (3H, s), 5.39 (2H, s), 6.55 (1H, dd, J = 3.1 , 6.7 Hz), 6.61 (1H, dt, J = 3.3, 9.0 Hz), 6.97 (1H, d, J = 2.4 Hz), 7.03 (1H, dd, J = 2.4, 8.6 Hz), 7.10 (1H, dd , J = 9.0, 10.2 Hz), 7.29 (1H, dd, J = 2.5, 9.2 Hz), 7.37 (1H, t, J = 8.0 Hz), 7.67-7.70 (1 H, m), 7.70-7.74 (2H , m).
MS (FAB) m / z: 437 (M + H) ⁺ .
(51e) 3-{[6- (2-Fluoro-5-methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid 3-{[6 prepared in Example (51d) -(2-Fluoro-5-methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate (3.7 g, 8.4 mmol), 1 N aqueous sodium hydroxide solution (13 mL, 13 mmol) ), 1,4-dioxane (10 mL), and the reaction and post-treatment were performed according to Example (28e) to give the target compound (2.9 g, yield 81%) as a white solid.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 3.68 (4H, s), 3.81 (3H, s), 5.43 (2H, s), 6.61 (1H, dd, J = 2.9, 6.8 Hz), 6.73 (1H, dt, J = 3.3, 9.1 Hz), 6.94 (1H, dd, J = 2.5, 8.8 Hz), 7.24-7.40 (4H, m), 7.54 (1 H, d, J = 7.4 Hz), 7.61 (1 H, br.s.), 7.65 (1 H, d, J = 9.0 Hz).
MS (FAB) m / z: 423 (M + H) ⁺ .
Anal.calcd for C ₂₃ H ₁₉ FN ₂ O ₅ + 0.20H ₂ O: C, 64.85; H, 4.59; F, 4.46; N, 6.58. Found C, 64.74; H, 4.38; F, 4.63; N, 6.51 .

Example 52 3-({6- [3- (Dimethylamino) phenoxy] -1-methyl-1H-benzimidazol-2-yl} methoxy) benzoic acid (Compound No. 1-177)
(52a) Methyl 3-({6- [3- (dimethylamino) phenoxy] -1-methyl-1H-benzimidazol-2-yl} methoxy) benzoate {6- [3- ( Dimethylamino) phenoxy] -1-methyl-1H-benzimidazol-2-yl} methanol (0.30 g, 1.0 mmol), methyl 3-hydroxybenzoate (0.15 g, 1.0 mmol), tri-n-butyl Reaction according to Example (28d) using phosphine (0.50 mL, 2.0 mmol), 1,1 ′-(azodicarbonyl) dipiperidine (0.51 g, 2.0 mmol), dichloromethane (3.0 mL) And the target compound (0.37 g, yield 84%) as a colorless oil was obtained by performing post-treatment.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 2.93 (6H, s), 3.81 (3H, s), 3.92 (3H, s), 5.39 (2H, s), 6.27-6.35 (1H, m), 6.43 (1H, t, J = 2.4 Hz), 6.4-6.51 (1 H, m), 7.00 (1H, d, J = 1.6 Hz), 7.04 (1H, dd, J = 2.4, 8.6 Hz), 7.17 ( 1H, t, J = 8.2 Hz), 7.29 (1H, dd, J = 3.3, 8.8 Hz), 7.37 (1H, t, J = 7.8 Hz), 7.66-7.75 (3 H, m).
MS (FAB) m / z: 432 (M + H) ⁺ .
(52b) 3-({6- [3- (Dimethylamino) phenoxy] -1-methyl-1H-benzimidazol-2-yl} methoxy) benzoic acid 3-({6- [3- (Dimethylamino) phenoxy] -1-methyl-1H-benzimidazol-2-yl} methoxy) methyl benzoate (0.44 g, 1.0 mmol), 1N aqueous sodium hydroxide solution (1.5 mL, 1 0.5 mmol), 1,4-dioxane (1.0 mL), and the reaction and post-treatment were performed according to Example (28e) to give the target compound (0.33 g, yield 79%) as a white solid. Obtained.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 2.87 (6H, s), 3.81 (3 H, s), 5.46 (2H, s), 6.18 (1H, dd, J = 2.4, 7.4 Hz), 6.36 (1H, t, J = 2.4 Hz), 6.46 (1H, dd, J = 2.4, 7.8 Hz), 6.92 (1H, dd, J = 2.4, 9.0 Hz), 7.12 (1H, t, J = 8.2 Hz ), 7.27 (1H, d, J = 2.0 Hz), 7.39 (1H, dd, J = 1.2, 2.7 Hz), 7.45 (1H, t, J = 8.0 Hz), 7.56-7.60 (1H, m), 7.62 -7.65 (2H, m), 13.03 (1H, br s).
MS (FAB) m / z: 418 (M + H) ⁺ .
_{. Anal calcd for C 24 H 23} N 3 O 4 + 0.20H 2 O:. C, 68.46; H, 5.60; N, 9.98 Found C, 68.33; H, 5.52; N, 9.98.

Example 53 3-{[6- (3-Methoxy-5-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-206)
(53a) [5- (3-Methoxy-5-methylphenoxy) -2-nitrophenyl] methylcarbamic acid tert-butyl ester 3-methoxy-5-methylphenol (4.9 g, 35 mmol) and (5-chloro-2 -Nitrophenyl) methylcarbamic acid tert-butyl ester (8.1 g, 1.7 mmol), sodium hydride (> 56% in oil, 1.7 g, 42 mmol), performed with N, N-dimethylformamide (50 mL) The compound was synthesized in the same manner as in Example (28a), and the obtained yellow oil was directly used in the next reaction.
(53b) [2-Amino-5- (3-methoxy-5-methylphenoxy) phenyl] methylcarbamic acid tert-butyl ester [5- (3-methoxy-5-methylphenoxy)-prepared in Example (53a) 2-Nitrophenyl] methylcarbamic acid tert-butyl ester (11 g, 28 mmol) and iron powder (7.6 g, 140 mmol), ammonium chloride (0.75 g, 14 mmol), ethanol (40 mL), water (10 mL) Synthesis was performed in the same manner as in Example (28b), and the obtained oil was directly used in the next reaction.
(53c) [6- (3-Methoxy-5-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol [2-amino-5- (3-methoxy] prepared in Example (53b) -5-methylphenoxy) phenyl] methylcarbamic acid tert-butyl ester (10 g, 28 mmol) and glycolic acid (2.8 g, 37 mmol), 5N aqueous hydrochloric acid (20 mL), 1,4-dioxane (20 mL), Examples Synthesis was performed in the same manner as in (34c), and the obtained light brown solid was directly used in the next reaction.
(53d) 3-{[6- (3-Methoxy-5-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate [6- (manufactured in Example (53c)] 3-methoxy-5-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol (5.1 g, 17 mmol) and methyl 3-hydroxybenzoate (2.6 g, 17 mmol), tri-n-butyl Synthesis was performed in the same manner as in Example (28d) using phosphine (8.6 mL, 34 mmol), 1,1 ′-(azodicarbonyl) dipiperidine (8.6 g, 34 mmol), and dichloromethane (50 mL), and the resulting light The brown solid was used as such for the next reaction.
(53e) 3-{[6- (3-Methoxy-5-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid 3-{[6 prepared in Example (53d) -(3-methoxy-5-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate (7.4 g, 17 mmol), 1 N aqueous sodium hydroxide solution (26 mL, 26 mmol), The target compound (5.2 g, yield 70%) as a white solid was obtained by performing reaction and post-treatment according to Example (28e) using 1,4-dioxane (25 mL).
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 2.22 (3H, s), 3.70 (3H, s), 3.82 (3H, s), 5.47 (2H, s), 6.32 (1H, s), 6.36 (1H, t, J = 2.4 Hz), 6.50 (1H, s), 6.93 (1H, dd, J = 2.4, 8.6 Hz), 7.32 (1H, d, J = 2.4 Hz), 7.36-7.42 (1H, m), 7.45 (1H, t, J = 7.8 Hz), 7.55-7.61 (1H, m), 7.66 (2H, d, J = 9.0 Hz), 13.04 (1H, s).
MS (FAB) m / z: 419 (M + H) ⁺ .
Anal. Calcd for C ₂₄ H ₂₂ N ₂ O ₅ : C, 68.89; H, 5.30; N, 6.69. Found C, 68.64; H, 5.26; N, 6.59.

Example 54 3-{[6- (3-Methoxy-4-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-204)
(54a) tert-Butyl [5- (3-methoxy-4-methylphenoxy) -2-nitrophenyl] methylcarbamate 5-fluoro-2-methylphenol (5.78 g, 41.9 mmol), 5-chloro-2 -Nitrophenyl) tert-butyl methylcarbamate (10.0 g, 34.9 mmol) and sodium hydride (63%, 1.59 g, 41.9 mmol) according to the method described in example (28a) A crude product of the title object compound was obtained as a brown oil. This was used as such for the next reaction.
(54b) [2-Amino-5- (3-methoxy-4-methylphenoxy) phenyl] tert-butyl methylcarbamate [5- (3-methoxy-4-methylphenoxy)-obtained in Example (54a) Tert-butyl 2-nitrophenyl] methylcarbamate (13.6 g, 34.9 mmol), iron powder (9.74 g, 174 mmol) and ammonium chloride (0.933 g, 17.4 mmol) were used for the examples (28b ) To give a crude product of the title object compound as a brown oil. This was used as such for the next reaction.
(54c) [6- (3-Methoxy-4-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol [2-amino-5- (3- Methoxy-4-methylphenoxy) phenyl] tert-butyl methylcarbamate (12.5 g, 34.9 mmol) and glycolic acid (3.98 g, 52.3 mmol) according to the method described in Example (28c). The title compound (8.93 g, yield 86%) was obtained as a brown powder.
¹ H NMR (CDCl ₃ , 400 MHz) δ: 2.19 (3H, s), 3.75 (3H, s), 3.77 (3H, s), 4.87 (2H, s), 5.10 (1H, s), 6.45 (1H, dd, J = 2.3, 8.2 Hz), 6.57 (1H, d, J = 2.3 Hz), 6.90 (1H, d, J = 2.0 Hz), 6.97 (1H, dd, J = 2.0, 8.6 Hz), 7.03- 7.07 (1H, m), 7.60 (1H, d, J = 8.6 Hz).
(54d) 3-{[6- (3-Methoxy-4-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate [6- (3-Methoxy-4-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol (8.00 g, 26.8 mmol), methyl 3-hydroxybenzoate (4.90 g, 32.2 mmol) , Tri-n-butylphosphine (8.04 mL, 32.2 mmol) and 1,1 ′-(azodicarbonyl) dipiperidine (8.12 g, 32.2 mmol) using the method described in Example (28d). The title compound (8.26 g, yield 71%) was obtained as a white powder.
¹ H NMR (CDCl ₃ , 500 MHz) δ: 2.19 (3H, s), 3.77 (3H, s), 3.81 (3H, s), 3.92 (3H, s), 5.39 (2H, s), 6.47 (1H, dd, J = 2.4, 8.3 Hz), 6.58 (1H, d, J = 2.4 Hz), 6.96 (1H, d, J = 2.4 Hz), 7.02 (1H, dd, J = 2.0, 8.8 Hz), 7.05 ( 1H, d, J = 8.3 Hz), 7.27-7.31 (1H, m), 7.37 (1H, t, J = 7.8 Hz), 7.67-7.73 (3H, m).
(54e) 3-{[6- (3-Methoxy-4-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid 3-{[obtained in Example (54d) 6- (3-Methoxy-4-methylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate (8.00 g, 18.5 mmol) and 1 N aqueous sodium hydroxide (27. 8 mL, 27.8 mmol) was used to give the title object compound (7.44 g, yield 96%) as a white powder according to the method described in Example (28e).
¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 2.11 (3H, s), 3.74 (3H, s), 3.81 (3H, s), 5.46 (2H, s), 6.40 (1H, dd, J = 2.3 , 7.8 Hz), 6.67 (1H, d, J = 2.3 Hz), 6.94 (1H, dd, J = 2.3, 8.6 Hz), 7.08 (1H, d, J = 8.2 Hz), 7.27 (1H, d, J = 2.3 Hz), 7.36-7.42 (1H, m), 7.46 (1H, t, J = 8.0 Hz), 7.56-7.61 (1H, m), 7.65 (1H, d, J = 8.6 Hz), 7.63-7.65 (1H, m).
MS (EI) m / z: 418 M ⁺ .

Example 55 3-{[6- (3,4-Dimethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-198)
(55a) tert-Butyl [5- (3,4-dimethylphenoxy) -2-nitrophenyl] methylcarbamate 3,4-dimethylphenol (5.11 g, 41.9 mmol), 5-chloro-2-nitrophenyl) According to the method described in Example (28a) using tert-butyl methylcarbamate (10.0 g, 34.9 mmol) and sodium hydride (63%, 1.59 g, 41.9 mmol) The crude product was obtained as a brown powder. This was used as such for the next reaction.
(55b) tert-butyl [2-amino-5- (3,4-dimethylphenoxy) phenyl] methylcarbamate [5- (3,4-dimethylphenoxy) -2-nitrophenyl obtained in Example (55a) Described in Example (28b) using tert-butyl methylcarbamate (13.0 g, 34.9 mmol), iron powder (9.74 g, 174 mmol) and ammonium chloride (0.933 g, 17.4 mmol). According to the method, a crude product of the title object compound was obtained as a brown oil. This was used as such for the next reaction.
(55c) [6- (3,4-Dimethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol [2-amino-5- (3, 4-) obtained in Example (55b) Title target compound according to the method described in Example (28c) using tert-butyl (dimethylphenoxy) phenyl] methylcarbamate (11.9 g, 34.9 mmol) and glycolic acid (3.98 g, 52.3 mmol). (7.98 g, 81% yield) was obtained as a brown powder.
¹ H NMR (CDCl ₃ , 400 MHz) δ: 2.23 (3H, s), 2.24 (3H, s), 3.74 (3H, s), 4.86 (2H, s), 4.94 (1H, s), 6.74 (1H, dd, J = 8.2, 2.3 Hz), 6.81 (1H, d, J = 2.3 Hz), 6.89 (1H, d, J = 2.3 Hz), 6.96 (1H, dd, J = 8.6, 2.3 Hz), 7.08 ( 1H, d, J = 8.2 Hz), 7.60 (1H, d, J = 8.6 Hz).
(55d) 3-{[6- (3,4-Dimethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate [6- (3 , 4-dimethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol (7.00 g, 24.8 mmol), methyl 3-hydroxybenzoate (4.53 g, 29.8 mmol), tri-n- Following the procedure described in Example (28d) using butylphosphine (7.43 mL, 29.8 mmol) and 1,1 ′-(azodicarbonyl) dipiperidine (7.51 g, 29.8 mmol), the title purpose The compound (8.36 g, yield 81%) was obtained as a white powder.
_{^{1 H NMR (CDCl 3, 500MHz}} ) δ: 2.23 (3H, s), 2.24 (3H, s), 3.80 (3H, s), 3.92 (3H, s), 5.38 (2H, s), 6.75 (1H, dd, J = 2.4, 8.3 Hz), 6.81 (1H, d, J = 2.4 Hz), 6.95 (1H, d, J = 2.4 Hz), 7.00 (1H, dd, J = 2.4, 8.8 Hz), 7.08 ( 1H, d, J = 8.3 Hz), 7.27-7.31 (1H, m), 7.37 (1H, t, J = 8.3 Hz), 7.66-7.73 (3H, m).
(55e) 3-{[6- (3,4-Dimethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid 3-{[6-] obtained in Example (55d) (3,4-Dimethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate (8.00 g, 19.2 mmol) and 1 N aqueous sodium hydroxide solution (28.8 mL, 28. 8 mmol) was used to give the title object compound (6.21 g, yield 80%) as a white powder according to the method described in Example (28e).
¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 2.18 (3H, s), 2.18 (3H, s), 3.80 (3H, s), 5.46 (2H, s), 6.71 (1 H, dd, J = 2.7, 7.8 Hz), 6.80 (1H, d, J = 2.7 Hz), 6.90 (1H, dd, J = 2.2, 8.8 Hz), 7.11 (1H, d, J = 8.2 Hz), 7.25 (1H, d, J = 2.3 Hz), 7.36-7.41 (1H, m), 7.45 (1H, t, J = 7.8 Hz), 7.56-7.60 (1H, m), 7.61-7.65 (2H, m).
MS (FAB) m / z: 402 M ⁺ .

Example 56 3-{[6- (4-Ethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-171)
(56a) [5- (4-Ethylphenoxy) -2-nitrophenyl] methylcarbamic acid tert-butyl ester 4-ethylphenol (4.0 g, 33 mmol) and (5-chloro-2-nitrophenyl) methylcarbamic acid tert- Synthesized as in Example (28a) using butyl ester (7.5 g, 26 mmol), sodium hydride (> 56% in oil, 2.0 g, 51 mmol), N, N-dimethylformamide (50 mL), The resulting yellow oil was used as such for the next reaction.
(56b) [2-Amino-5- (4-ethylphenoxy) phenyl] methylcarbamic acid tert-butyl ester [5- (4-ethylphenoxy) -2-nitrophenyl] methylcarbamic acid tert prepared in Example (56a) -Synthesis as in Example (28b) using butyl ester (11 g, 26 mmol) and iron powder (7.0 g, 130 mmol), ammonium chloride (0.70 g, 13 mmol), ethanol (30 mL), water (15 mL). The resulting red oil was used as such for the next reaction.
(56c) [6- (4-Ethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol [2-amino-5- (4-ethylphenoxy) phenyl] prepared in Example (56b) Methylcarbamic acid tert-butyl ester (9.0 g, 26 mmol) and glycolic acid (2.6 g, 34 mmol), 5N hydrochloric acid aqueous solution (20 mL), 1,4-dioxane (20 mL) were used according to Example (34c). The target compound (5.8 g, yield 78%) obtained as a light brown solid was used in the next reaction as it was by performing the reaction and post-treatment.
(56d) 3-{[6- (4-Ethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate [6- (4-ethylphenoxy) prepared in Example (56c) ) -1-Methyl-1H-benzimidazol-2-yl] methanol (5.3 g, 19 mmol), methyl 3-hydroxybenzoate (2.8 g, 19 mmol), tri-n-butylphosphine (9.3 mL, 37 mmol) , 1,1 ′-(azodicarbonyl) dipiperidine (9.4 g, 37 mmol), dichloromethane (50 mL), and the reaction and post-treatment according to Example (28d) gave the target compound as a pale red solid (5.6 g, yield 72%) was obtained.
MS (FAB) m / z: 417 (M + H) ⁺ .
(56e) 3-{[6- (4-Ethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid 3-{[6- (4- Ethylphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate (5.6 g, 14 mmol), 1N aqueous sodium hydroxide solution (20 mL, 20 mmol), 1,4-dioxane (25 mL) The target compound (5.1 g, yield 94%) as a white solid was obtained by carrying out the reaction and post-treatment according to Example (28e).
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 1.17 (3H, t, J = 7.6 Hz), 2.58 (2H, q, J = 7.3 Hz), 3.80 (3H, s), 5.46 (2H, s ), 6.87-6.94 (3H, m), 7.19 (2H, d, J = 8.3 Hz), 7.28 (1H, d, J = 2.4 Hz), 7.38 (1H, dd, J = 2.7, 8.1 Hz), 7.45 (1H, t, J = 7.8 Hz), 7.58 (1H, d, J = 7.8 Hz), 7.62-7.67 (2H, m), 13.03 (1H, br s).
MS (FAB) m / z: 403 (M + H) ⁺ .
_{. Anal calcd for C 24 H 22} N 2 O 4 + 0.20H 2 O:. C, 70.99; H, 5.56; N, 6.90 Found C, 70.82; H, 5.32; N, 6.88.

Example 57 3-{[6- (2,3-Dihydro-1-benzofuran-6-yloxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-210 )
(57a) [5- (2,3-Dihydro-1-benzofuran-6-yloxy) -2-nitrophenyl] methylcarbamic acid tert-butyl ester known [J. Am. Chem. Soc. 1948, 70, p. 3619] 2,3-dihydro-1-benzofuran-6-ol (2.2 g, 16 mmol) and (5-chloro-2-nitrophenyl) methylcarbamic acid tert-butyl ester (4.0 g, 14 mmol), hydrogenated Synthesis was performed in the same manner as in Example (28a) using sodium (> 56% in oil, 0.66 g, 16 mmol) and N-methylpyrrolidinone (30 mL), and the resulting yellow oil was used as it was in the next reaction. .
(57b) [2-Amino-5- (2,3-dihydro-1-benzofuran-6-yloxy) phenyl] methylcarbamic acid tert-butyl ester prepared in Example (57a) [5- (2,3-dihydro -1-benzofuran-6-yloxy) -2-nitrophenyl] methylcarbamic acid tert-butyl ester (5.4 g, 14 mmol) and iron powder (3.7 g, 70 mmol), ammonium chloride (0.37 g, 7.0 mmol) , Ethanol (40 mL), and water (20 mL) were synthesized in the same manner as in Example (28b), and the obtained oil was used as such in the next reaction.
(57c) 3- [2-({2-[(tert-Butoxycarbonyl) (methyl) amino] -4- (2,3-dihydro-1-benzofuran-6-yloxy) phenyl} amino) -2-oxo [Ethoxy] methyl benzoate [2-amino-5- (2,3-dihydro-1-benzofuran-6-yloxy) phenyl] methylcarbamic acid tert-butyl ester (5.0 g, 14 mmol) prepared in Example (57b) And [3- (methoxycarbonyl) phenoxy] acetic acid (2.9 g, 14 mmol) were dissolved in dichloromethane (100 mL) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (3.2 g, 17 mmol) was dissolved. And stirred at room temperature for 2.2 hours. Sodium bicarbonate water was added, and the mixture was extracted twice with dichloromethane, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting solid was directly used for the next reaction.
(57d) 3-{[6- (2,3-Dihydro-1-benzofuran-6-yloxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate monohydrochloride Example (57c) 3- [2-({2-[(tert-butoxycarbonyl) (methyl) amino] -4- (2,3-dihydro-1-benzofuran-6-yloxy) phenyl} amino) -2- Oxoethoxy] methyl benzoate (7.7 g, 14 mmol) was dissolved in 5N hydrochloric acid-ethyl acetate solution (50 mL) and heated to reflux for 2 hours. After cooling to room temperature, the precipitated light red solid was collected by filtration to obtain the target compound (7.9 g, yield 100%).
¹ H-NMR (DMSO-d ₆ , 500MHz) δ: 3.15 (2H, t, J = 8.8 Hz), 3.88 (3H, s), 3.93 (3H, s), 4.57 (2H, t, J = 8.8 Hz) ), 5.69 (2H, s), 6.47 (2H, s), 7.16 (1H, d, J = 8.8 Hz), 7.21 (1H, d, J = 7.8 Hz), 7.47-7.56 (3H, m), 7.66 (1H, d, J = 8.3 Hz), 7.72 (1H, s), 7.78 (1H, d, J = 9.3 Hz).
MS (FAB) m / z: 431 (M + H) ⁺ .
(57e) 3-{[6- (2,3-Dihydro-1-benzofuran-6-yloxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid Prepared in Example (57d). 3-{[6- (2,3-Dihydro-1-benzofuran-6-yloxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate monohydrochloride (6.5 g, 14 mmol) By subjecting 1N aqueous sodium hydroxide solution (56 mL, 56 mmol) and 1,4-dioxane (60 mL) to reaction and post-treatment according to Example (28e), the target compound (4.3 g) as a white solid was obtained. Yield 74%).
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 3.13 (2H, t, J = 8.4 Hz), 3.81 (3H, s), 4.55 (2H, t, J = 8.6 Hz), 5.46 (2H, s ), 6.39-6.44 (2H, m), 6.91 (1H, dd, J = 2.4, 8.6 Hz), 7.16 (1H, d, J = 7.8 Hz), 7.28 (1H, d, J = 2.4 Hz), 7.36 -7.40 (1H, m), 7.45 (1H, t, J = 7.8 Hz), 7.58 (1H, dt, J = 1.2, 1.4, 7.6 Hz), 7.62-7.66 (2H, m), 13.04 (1H, br s).
MS (FAB) m / z: 417 (M + H) ⁺ .
Anal. Calcd for C ₂₄ H ₂₀ N ₂ O ₅ + 0.33H ₂ O: C, 68.24; H, 4.93; N, 6.63. Found C, 68.34; H, 4.84; N, 6.79.

Example 58 3-{[6- (1,3-Benzodioxol-5-yloxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-211)
(58a) [5- (1,3-Benzodioxol-5-yloxy) -2-nitrophenyl] methylcarbamic acid tert-butyl ester sesamol (2.9 g, 21 mmol) and (5-chloro-2-nitrophenyl) ) Similar to Example (28a) using methylcarbamic acid tert-butyl ester (5.0 g, 17 mmol), sodium hydride (> 56% in oil, 0.82 g, 21 mmol), N-methylpyrrolidinone (50 mL). The synthesized brown oil was used for the next reaction as it was.
(58b) [2-Amino-5- (1,3-benzodioxol-5-yloxy) phenyl] methylcarbamic acid tert-butyl ester [5- (1,3-benzodio] prepared in Example (58a) Xol-5-yloxy) -2-nitrophenyl] methylcarbamic acid tert-butyl ester (6.8 g, 17 mmol) and iron powder (4.7 g, 87 mmol), ammonium chloride (0.47 g, 8.7 mmol), ethanol (40 mL) and water (20 mL) were used in the same manner as in Example (28b), and the resulting brown oil was used as such for the next reaction.
(58c) 3- [2-({4- (1,3-Benzodioxol-5-yloxy) -2-[(tert-butoxycarbonyl) (methyl) amino] phenyl} amino) -2-oxoethoxy Methyl benzoate [2-amino-5- (1,3-benzodioxol-5-yloxy) phenyl] methylcarbamic acid tert-butyl ester (6.7 g, 17 mmol) prepared in Example (58b) and [ Examples using 3- (methoxycarbonyl) phenoxy] acetic acid (3.7 g, 17 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (4.0 g, 21 mmol), dichloromethane (70 mL) By performing the reaction and post-treatment according to (57c), the obtained solid was directly used in the next reaction.
(58d) 3-{[6- (1,3-Benzodioxol-5-yloxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate monohydrochloride Example (58c) 3- [2-({4- (1,3-benzodioxol-5-yloxy) -2-[(tert-butoxycarbonyl) (methyl) amino] phenyl} amino) -2-oxoethoxy prepared in By subjecting the reaction and workup to methyl benzoate (9.6 g, 17 mmol), 5N hydrochloric acid-ethyl acetate solution (50 mL) according to Example (57d), the target compound (7. 3 g, yield 89%).
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 3.11 (3H, br.s.), 3.93 (3H, s), 4.68 (2H, s), 5.99 (2H, s), 6.49 (1H, dd, J = 2.4, 8.2 Hz), 6.58 (1H, d, J = 2.4 Hz), 6.76 (1H, d, J = 8.2 Hz), 6.82 (1H, br s), 6.86-6.93 (1H, m), 7.20 ( 1H, dd, J = 2.2, 8.0 Hz), 7.42 (1H, t, J = 8.0 Hz), 7.63 (1H, br.s.), 7.74 (1H, d, J = 7.8 Hz).
(58e) 3-{[6- (1,3-Benzodioxol-5-yloxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid 3 prepared in Example (58d) -{[6- (1,3-benzodioxol-5-yloxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate monohydrochloride (7.3 g, 15 mmol), 2 By carrying out the reaction and post-treatment according to Example (28e) using normal sodium hydroxide aqueous solution (31 mL, 62 mmol) and 1,4-dioxane (60 mL), the target compound (6.3 g, yield) was obtained as a white solid. 98%) was obtained.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 3.80 (3H, s), 5.46 (2H, s), 6.03 (2H, s), 6.45 (1H, dd, J = 2.5, 8.4 Hz), 6.71 (1H, d, J = 2.4 Hz), 6.86-6.93 (2H, m), 7.23 (1H, d, J = 2.0 Hz), 7.36-7.41 (1H, m), 7.45 (1H, t, J = 7.8 Hz), 7.56-7.60 (1H, m), 7.61-7.66 (2H, m), 13.07 (1H, br s).
MS (FAB) m / z: 419 (M + H) ⁺ .
_{. Anal calcd for C 23 H 18} N 2 O 6 + 0.25H 2 O:. C, 65.32; H, 4.41; N, 6.62 Found C, 65.54; H, 4.71; N, 6.65.

Example 59 3-{[6- (4-Chloro-3-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} -5-fluorobenzoic acid (Compound No. 1-220)
(59a) 3-{[6- (4-Chloro-3-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} -5-fluorobenzoic acid methyl obtained in Example (9b) [6- (4-Chloro-3-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol (300 mg, 0.978 mmol), methyl 5-fluoro-3-hydroxybenzoate (200 mg, 1.17 mmol), tri-n-butylphosphine (0.366 mL, 1.47 mmol) and 1,1 ′-(azodicarbonyl) dipiperidine (370 mg, 1.47 mmol) as described in Example (28d). According to the above method, the title object compound (362 mg, yield 81%) was obtained as a white powder.
¹ H NMR (CDCl ₃ , 400 MHz) δ: 3.84 (3H, s), 3.93 (3H, s), 5.40 (2H, s), 6.71-6.76 (1H, m), 6.78 (1H, dd, J = 2.7 , 10.2 Hz), 7.00-7.06 (3H, m), 7.31 (1H, dd, J = 8.6, 8.6 Hz), 7.36-7.41 (1H, m), 7.53-7.56 (1H, m), 7.77 (1H, dd, J = 0.6, 8.6 Hz).
(59b) 3-{[6- (4-Chloro-3-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} -5-fluorobenzoic acid obtained in Example (59a) 3-{[6- (4-Chloro-3-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} -5-fluorobenzoate (354 mg, 0.772 mmol) and 1 N water The title object compound (292 mg, yield 85%) was obtained as a white powder according to the method described in Example (28e) using aqueous sodium oxide solution (1.16 mL, 1.16 mmol).
¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 3.83 (3H, s), 5.52 (2H, s), 6.83 (1H, ddd, J = 1.2, 2.7, 9.0 Hz), 7.01 (1H, dd, J = 2.3, 8.6 Hz), 7.09 (1H, dd, J = 2.7, 10.6 Hz), 7.28-7.33 (1H, m), 7.35 (1H, ddd, J = 2.3, 2.3, 10.6 Hz), 7.45 (1H, d, J = 2.0 Hz), 7.47-7.51 (1H, m), 7.54 (1H, dd, J = 8.6, 8.6 Hz), 7.71 (1H, d, J = 8.6 Hz).
MS (FAB) m / z: 445 (M + H) ^<+> .

Example 60 3-Fluoro-5-{[6- (3-methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-218)
(60a) 3-Fluoro-5-{[6- (3-methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate [6- (3-Methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol (300 mg, 1.06 mmol), methyl 5-fluoro-3-hydroxybenzoate (197 mg, 1.16 mmol), tri-n- Using butylphosphine (0.395 mL, 1.58 mmol) and 1,1 ′-(azodicarbonyl) dipiperidine (399 mg, 1.58 mmol) according to the method described in Example (28d), the title compound ( 387 mg, 84% yield) was obtained as a white powder.
¹ H NMR (CDCl ₃ , 400 MHz) δ: 3.78 (3H, s), 3.81 (3H, s), 3.93 (3H, s), 5.39 (2H, s), 6.56-6.60 (2H, m), 6.63- 6.67 (1H, m), 7.00-7.07 (3H, m), 7.19-7.26 (1H, m), 7.36-7.40 (1H, m), 7.53-7.56 (1H, m), 7.74 (1H, d, J = 9.0 Hz).
(60b) 3-Fluoro-5-{[6- (3-methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid 3-Fluoro- obtained in Example (60a) 5-{[6- (3-methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate (376 mg, 0.862 mmol) and 1 N aqueous sodium hydroxide (1.29 mL, 1.29 mmol) was used to give the title object compound (303 mg, 83% yield) as a white powder according to the method described in Example (28e).
¹ H NMR (DMSO-d ₆ , 500 MHz) δ: 3.72 (3H, s), 3.82 (3H, s), 5.50 (2H, s), 6.51 (1H, dd, J = 2.2, 8.1 Hz), 6.56 ( 1H, t, J = 2.2 Hz), 6.68 (1H, dd, J = 2.4, 8.3 Hz), 6.95 (1H, dd, J = 2.4, 8.8 Hz), 7.25 (1H, t, J = 8.3 Hz), 7.28-7.33 (1H, m), 7.33-7.38 (2H, m), 7.48-7.51 (1H, m), 7.67 (1H, d, J = 8.8 Hz).
MS (FAB) m / z: 423 (M + H) ^<+> .

Example 61 3-Fluoro-5-{[6- (3-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-212)
(61a) 3-Fluoro-5-{[6- (3-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate [6- (3-Fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol (300 mg, 1.10 mmol), methyl 5-fluoro-3-hydroxybenzoate (206 mg, 1.21 mmol), tri-n- According to the method described in Example (28d) using butylphosphine (0.413 mL, 1.65 mmol) and 1,1 ′-(azodicarbonyl) dipiperidine (417 mg, 1.65 mmol), the title target compound ( 426 mg, 91% yield) was obtained as a pink powder.
¹ H NMR (CDCl ₃ , 400 MHz) δ: 3.84 (3H, s), 3.93 (3H, s), 5.40 (2H, s), 6.66-6.72 (1H, m), 6.75-6.81 (2H, m), 7.01-7.06 (3H, m), 7.23-7.30 (1H, m), 7.36-7.40 (1H, m), 7.54-7.56 (1H, m), 7.75-7.78 (1H, m).
(61b) 3-Fluoro-5-{[6- (3-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid 3-Fluoro- obtained in Example (61a) 5-{[6- (3-Fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate (395 mg, 0.931 mmol) and 1 N aqueous sodium hydroxide (1.40 mL, 1.40 mmol) was used to give the title object compound (304 mg, 80% yield) as a white powder according to the method described in Example (28e).
¹ H NMR (DMSO-d ₆ , 500 MHz) δ: 3.83 (3H, s), 5.52 (2H, s), 6.77-6.85 (2H, m), 6.89-6.95 (1H, m), 6.99 (1H, dd , J = 2.4, 8.8 Hz), 7.28-7.44 (4H, m), 7.49 (1H, s), 7.70 (1H, d, J = 8.3 Hz), 13.37 (1H, s).
MS (FAB) m / z: 411 (M + H) ^<+> .

Example 62 3-Fluoro-5-{[6- (4-methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-219)
(62a) Methyl 3-fluoro-5-{[6- (4-methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate [6- (4-Methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol (300 mg, 1.06 mmol), methyl 5-fluoro-3-hydroxybenzoate (197 mg, 1.16 mmol), tri-n- Using butylphosphine (0.395 mL, 1.58 mmol) and 1,1 ′-(azodicarbonyl) dipiperidine (399 mg, 1.58 mmol) according to the method described in Example (28d), the title compound ( (432 mg, 94% yield) was obtained as a yellow oil.
¹ H NMR (CDCl ₃ , 400 MHz) δ: 3.79 (3H, s), 3.82 (3H, s), 3.93 (3H, s), 5.37 (2H, s), 6.87-6.93 (3H, m), 6.97- 7.05 (4H, m), 7.35-7.40 (1H, m), 7.52-7.55 (1H, m), 7.70 (1H, d, J = 8.6 Hz).
(62b) 3-Fluoro-5-{[6- (4-methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid 3-Fluoro- obtained in Example (62a) 5-{[6- (4-Methoxyphenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate (420 mg, 0.962 mmol) and 1 N aqueous sodium hydroxide (1.44 mL, 1.44 mmol) was used to give the title object compound (332 mg, 82% yield) as a white powder according to the method described in Example (28e).
¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 3.74 (3H, s), 3.79 (3H, s), 5.49 (2H, s), 6.89 (1H, dd, J = 2.3, 8.6 Hz), 6.92- 7.01 (4H, m), 7.20 (1H, d, J = 2.3 Hz), 7.27-7.37 (2H, m), 7.47-7.50 (1H, m), 7.63 (1H, d, J = 8.6 Hz), 13.37 (1H, s).
MS (FAB) m / z: 423 (M + H) ^<+> .

Example 63 3-Fluoro-5-{[6- (4-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-213)
(63a) Methyl 3-fluoro-5-{[6- (4-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoate [6- (4-Fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methanol (300 mg, 1.10 mmol), methyl 5-fluoro-3-hydroxybenzoate (206 mg, 1.21 mmol), tri-n- According to the method described in Example (28d) using butylphosphine (0.413 mL, 1.65 mmol) and 1,1 ′-(azodicarbonyl) dipiperidine (417 mg, 1.65 mmol), the title compound ( 263 mg, yield 56%) was obtained as a yellow powder.
¹ H NMR (CDCl ₃ , 400 MHz) δ: 3.81 (3H, s), 3.93 (3H, s), 5.38 (2H, s), 6.92-7.09 (7H, m), 7.35-7.41 (1H, m), 7.52-7.56 (1H, m), 7.73 (1H, d, J = 9.0 Hz).
(63b) 3-Fluoro-5-{[6- (4-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid 3-Fluoro- obtained in Example (63a) 5-{[6- (4-Fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate (255 mg, 0.601 mmol) and 1 N aqueous sodium hydroxide (0.900 mL, 0.900 mmol) was used to give the title object compound (197 mg, 80% yield) as a white powder according to the method described in Example (28e).
¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 3.81 (3H, s), 5.50 (2H, s), 6.94 (1H, dd, J = 2.3, 8.6 Hz), 7.00-7.06 (2H, m), 7.16-7.24 (2H, m), 7.28-7.32 (2H, m), 7.35 (1H, dd, J = 2.3, 10.6 Hz), 7.47-7.50 (1H, m), 7.67 (1H, d, J = 9.0 Hz), 13.37 (1H, s).
MS (FAB) m / z: 411 (M + H) ^<+> .

Example 64 3-{[1-Methyl- (6-tetrahydro-2H-pyran-4-yloxy) -1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-208)
(64a) [5- (Tetrahydro-2H-pyran-4-yloxy) -2-nitrophenyl] methylcarbamic acid tert-butyl ester tetrahydro-4-pyranol (780 mg, 7.5 mmol) and (5-chloro-2-nitro Phenyl) methylcarbamic acid tert-butyl ester (2.15 g, 7.5 mmol), sodium hydride (> 56% in oil, 290 mg, 7.5 mmol), N, N-dimethylformamide (30 mL). The title compound (1.59 g, 60% yield) was obtained as a yellow oily substance by synthesis in the same manner as in No. 28a) and purification using an automatic purifier (Isco, 15% ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.33 (6H, s), 1.50 (3H, s), 3.26 (3H, s), 6.81 (1H, dd, J = 2.7, 9.0 Hz), 6.85 (1H , br s), 7.07-7.17 (4H, m), 7.93-7.97 (1H, m).
(64b) [2-Amino-5- (6-tetrahydro-2H-pyran-4-yloxy) phenyl] methylcarbamic acid tert-butyl ester [5- (6-tetrahydro-2H-pyran] prepared in Example (64a) -4-yloxy) -2-nitrophenyl] methylcarbamic acid tert-butyl ester (3.2 g, 8.8 mmol), iron powder (2.4 g, 12 mmol), ammonium chloride (0.24 g, 1.2 mmol), ethanol (40 mL) and water (20 mL) were used in the same manner as in Example (28b), and the resulting oil was used in the next reaction as it was.
(64c) [6- (6-Tetrahydro-2H-pyran-4-yloxy) -1-methyl-1H-benzimidazol-2-yl] methanol [2-amino-5- (prepared in Example (64b)] 6-tetrahydro-2H-pyran-4-yloxy) phenyl] methylcarbamic acid tert-butyl ester (2.9 g, 8.8 mmol) and glycolic acid (1.0 g, 13 mmol), 4N hydrochloric acid-1,4-dioxane solution (40 mL) was synthesized in the same manner as in Example (28c), and the obtained dark brown oil was directly used in the next reaction.
(64d) 3-{[1-Methyl- (6-tetrahydro-2H-pyran-4-yloxy) -1H-benzimidazol-2-yl] methoxy} methyl benzoate Prepared in Example (64c) [6- (6-Tetrahydro-2H-pyran-4-yloxy) -1-methyl-1H-benzimidazol-2-yl] methanol (0.30 g, 1.1 mmol) and methyl 3-hydroxybenzoate (0.25 g, 1 0.7 mmol), tri-n-butylphosphine (0.55 mL, 2.2 mmol), 1,1 ′-(azodicarbonyl) dipiperidine (0.56 g, 2.2 mmol), dichloromethane (6.0 mL) The target compound (0.36 g, yield 81%) was obtained by carrying out the reaction and post-treatment according to Example (28d).
¹ H-NMR (CDCl ₃ , 500 MHz) δ: 3.82 (3H, s), 3.92 (3H, s), 5.39 (2H, s), 6.94-7.05 (5H, m), 7.29 (1H, br s) , 7.38 (1 H, t, J = 7.82 Hz), 7.69 (1H, d, J = 7.82 Hz), 7.71-7.74 (2H, m).
MS (FAB) m / z: 407 (M + H) ⁺ .
(64e) 3-{[1-Methyl- (6-tetrahydro-2H-pyran-4-yloxy) -1H-benzimidazol-2-yl] methoxy} benzoic acid 3-{[prepared in Example (64d) 1-methyl- (6-tetrahydro-2H-pyran-4-yloxy) -1H-benzimidazol-2-yl] methoxy} methyl benzoate (0.34 g, 0.84 mmol), 1 N aqueous sodium hydroxide solution (1 .3 mL, 1.3 mmol) and 1,4-dioxane were used for the reaction and post-treatment according to Example (28e) to obtain the target compound (0.10 g, yield 37%) as a white solid. It was.
¹ H-NMR (DMSO-d ₆ , 500 MHz) δ: 3.81 (3H, s), 5.46 (2H, s), 6.93 (1H, dd, J = 2.44, 8.79 Hz), 7.01-7.04 (2H, m) , 7.19 (2H, t, J = 8.79 Hz), 7.30 (1H, d, J = 2.44 Hz), 7.37-7.39 (1H, m), 7.45 (1H, t, J = 7.81 Hz), 7.57 (2H, d, J = 7.81 Hz), 7.66 (1H, d, J = 8.79 Hz), 7.63 (1H, s), 13.03 (1H, br.s).
MS (FAB) m / z: 393 (M + H) ⁺ .
Anal.calcd for C ₂₄ H ₂₂ N ₂ O ₅ + 0.14H ₂ O: C, 66.91; H, 4.41; N, 7.09; F, 4.81. Found C, 66.85; H, 4.46; N, 7.21; F, 4.81 .

Example 65 3-[(6-Cyclopentyloxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzoic acid (Compound No. 1-162)
(65a) (5-Cyclopentyloxy-2-nitrophenyl] methylcarbamic acid tert-butyl ester cyclopentanol (861 mg, 10 mmol) and (5-chloro-2-nitrophenyl) methylcarbamic acid tert-butyl ester (2.87 g, 10 mmol), sodium hydride (> 56% in oil, 380 mg, 10 mmol), N, N-dimethylformamide (40 mL) and the oily product (3.28 g) obtained in the same manner as in Example (28a). ) Was used as such for the next reaction.
(65b) [2-Amino-5- (cyclopentyloxy) phenyl] methylcarbamic acid tert-butyl ester (5-cyclopentyloxy-2-nitrophenyl) methylcarbamic acid tert-butyl ester prepared in Example (65a) (3. 27 g, 9.7 mmol) and iron powder (2.6 g, 49 mmol), ammonium chloride (0.26 g, 4.9 mmol), ethanol (50 mL), water (25 mL) and synthesized in the same manner as in Example (28b). The obtained oil (2.98 g) was used as such for the next reaction.
(65c) [6- (Cyclopentyloxy) -1-methyl-1H-benzimidazol-2-yl] methanol [2-amino-5- (cyclopentyloxy) phenyl] methylcarbamic acid prepared in Example (65b) tert- Butyl ester (2.98 g, 9.7 mmol), glycolic acid (1.1 g, 14.6 mmol), 5N aqueous hydrochloric acid (25 ml) and dioxane (25 mL) were heated to reflux for 19 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the filtrate was evaporated under reduced pressure. The obtained crude product was washed with diisopropyl ether to obtain the target compound (0.75 g, yield of 3 steps 31%).
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.76-1.92 (8H, m), 3.73 (3H, s), 4.76-4.81 (1H, m), 4.83 (2H, s), 6.69-6.72 (1H, m), 6.81-6.85 (1H, m), 7.51-7.54 (1H, m).
(65d) 3-[(6-Cyclopentyloxy-1-methyl-1H-benzimidazol-2-yl) methoxy] methyl benzoate [6- (cyclopentyloxy) -1-methyl- prepared in Example (65c) 1H-benzimidazol-2-yl] methanol (0.75 g, 3.1 mmol), methyl 3-hydroxybenzoate (0.70 g, 6.1 mmol), tri-n-butylphosphine (1.5 mL, 6.1 mmol) , 1,1 ′-(azodicarbonyl) dipiperidine (1.54 g, 2.2 mmol) and dichloromethane (30 mL) were reacted and worked up according to Example (28d) to give the target compound (0 .70 g, 60% yield) as a yellow solid.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.63-1.71 (2H, m), 1.81-2.00 (6H, m), 3.85 (3H, s), 3.95 (3H, s), 4.84-4.87 (1H, m), 5.40 (2H, s), 6.80-6.83 (1H, m), 6.90-6.94 (1H, m), 7.30-7.34 (1H, m), 7.37-7.41 (1H, m), 7.65-7.68 ( 1H, m), 7.69-7.72 (1H, m), 7.73-7.75 (1H, m).
MS (ESI) m / z: 381 (M + H) ⁺ .
(65e) 3-[(6-Cyclopentyloxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzoic acid 3-[(6-Cyclopentyloxy-1-methyl-) prepared in Example (65d) 1H-benzimidazol-2-yl) methoxy] methyl benzoate (0.69 g, 1.83 mmol), 1N aqueous sodium hydroxide solution (2.75 mL, 2.75 mmol), 1,4-dioxane (2.75 mL) The target compound (0.21 g, yield 31%) as a colorless solid was obtained by carrying out the reaction and post-treatment according to Example (28e).
¹ H-NMR (DMSO-D ₆ , 400 MHz) δ: 1.50-1.61 (2H, m), 1.62-1.75 (4H, m), 1.84-1.95 (2H, m), 3.77 (3H, s), 4.82- 4.88 (1H, m), 5.38 (2H, s), 6.73-6.77 (1H, m), 7.03-7.05 (1H, m), 7.31-7.35 (1H, m), 7.38-7.43 (1H, m), 7.44-7.47 (1H, m), 7.51-7.54 (1H, m), 7.57-7.59 (1H, m), 13.00 (1H, br s).
MS (FAB) m / z: 389 (M + Na) ⁺ .
_{. Anal calcd for C 21 H 22} N 2 O 4 + 0.2H 2 O:. C, 68.17; H, 6.10; N, 7.57 Found C, 68.34; H, 6.10; N, 7.54.

Example 66 3-{[1-Methyl- (6-tetrahydrofuran-3-yloxy) -1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-209)
(66a) [5- (Tetrahydrofuran-3-yloxy) -2-nitrophenyl] methylcarbamic acid tert-butyl ester 3-hydroxytetrahydrofuran (881 mg, 10 mmol) and tert-butyl (5-chloro-2-nitrophenyl) methylcarbamic acid Synthesis was carried out in the same manner as in Example (28a) using ester (2.87 g, 10 mmol), sodium hydride (> 56% in oil, 380 mg, 10 mmol) and N, N-dimethylformamide (40 mL). The oil (2.93 g) was used as such for the next reaction.
(66b) [2-Amino-5- (tetrahydrofuran-3-yloxy) phenyl] methylcarbamic acid tert-butyl ester [5- (tetrahydrofuran-3-yloxy) -2-nitrophenyl] methylcarbamine prepared in Example (66a) Performed with acid tert-butyl ester (2.93 g, 8.7 mmol) and iron powder (2.3 g, 43 mmol), ammonium chloride (0.23 g, 4.3 mmol), ethanol (40 mL), water (20 mL) Synthesis was performed in the same manner as in Example (28b), and the obtained oil (2.67 g) was used in the next reaction as it was.
(66c) [6- (Tetrahydrofuran-3-yloxy) -1-methyl-1H-benzimidazol-2-yl] methanol [2-amino-5- (tetrahydrofuran-3-yloxy) prepared in Example (66b) Phenyl] methylcarbamic acid tert-butyl ester (2.67 g, 8.7 mmol) and glycolic acid (1.0 g, 13.0 mmol), 5N aqueous hydrochloric acid (25 ml) and dioxane (25 mL) were used in Example (28c). The oily substance obtained (1.39 g, yield 65%) was used in the next reaction as it was.
(66d) 3-{[6- (Tetrahydrofuran-3-yloxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate [6- (Tetrahydrofuran-3] prepared in Example (66c) -Yloxy) -1-methyl-1H-benzimidazol-2-yl] methanol (1.39 g, 5.6 mmol), methyl 3-hydroxybenzoate (2.83 g, 11.2 mmol), tri-n-butylphosphine ( 2.8 mL, 11.2 mmol), 1,1 ′-(azodicarbonyl) dipiperidine (2.83 g, 11.2 mmol), dichloromethane (56 mL), and reaction and workup according to Example (28d). By performing, the target compound (1.28 g, yield 60%) was obtained as a colorless solid.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 2.23-2.27 (2H, m), 3.86 (3H, s), 3.94-3.98 (1H, m), 3.95 (3H, s), 4.03-4.08 (3H , m), 5.01-5.05 (1H, m), 5.41 (2H, s), 6.80-6.82 (1H, m), 6.91-6.94 (1H, m), 7.30-7.34 (3H, m), 7.38-7.42 (1H, m), 7.68-7.72 (2H, m), 7.73-7.75 (1H, m).
MS (EI) m / z: 383 (M + H) ⁺ .
(66e) 3-{[6- (Tetrahydrofuran-3-yloxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid 3-{[6- (Tetrahydrofuran) prepared in Example (66d) -3-yloxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate (1.28 g, 3.35 mmol), 1 N aqueous sodium hydroxide solution (5.0 mL, 5.0 mmol), The target compound (0.55 g, yield 45%) as a colorless solid was obtained by carrying out the reaction and post-treatment according to Example (28e) using 1,4-dioxane (5.0 mL).
¹ H-NMR (DMSO-D ₆ , 400 MHz) δ: 1.92-2.01 (1H, m), 2.16-2.25 (1H, m), 3.71-3.91 (4H, m), 3.78 (3H, s), 5.03 -5.08 (1H, m), 5.38 (2H, s), 6.76-6.81 (1H, m), 7.07-7.10 (1H, m), 7.31-7.36 (1H, m), 7.38-7.43 (1H, m) , 7.47-7.53 (2H, m), 7.57-7.60 (1H, m), 13.00 (1H, br s).
MS (FAB) m / z: 391 (M + Na) ⁺ .
_{. Anal calcd for C 20 H 20} N 2 O 5 + 0.2H 2 O:. C, 64.58; H, 5.53; N, 7.53 Found C, 64.55; H, 5.43; N, 7.43.

Example 67 3-{[6- (1-Ethylpropoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid (Compound No. 1-161)
(67a) [5- (1-Ethylpropoxy) -2-nitrophenyl] methylcarbamic acid tert-butyl ester 3-pentanol (4.23 g, 48 mmol) and (5-chloro-2-nitrophenyl) methylcarbamic acid tert- Synthesized as in Example (28a) using butyl ester (11.47 g, 40 mmol), sodium hydride (> 56% in oil, 1.83 g, 48 mmol), N, N-dimethylformamide (200 mL), The oil obtained was used as such for the next reaction.
(67b) [2-Amino-5- (1-ethylpropoxy) phenyl] methylcarbamic acid tert-butyl ester [5- (1-ethylpropoxy) -2-nitrophenyl] methylcarbamic acid tert prepared in Example (67a) -Synthesized in the same manner as (28b) using butyl ester (13.54 g, 40 mmol), iron powder (10.71 g, 200 mmol), ammonium chloride (1.07 g, 20 mmol), ethanol (100 mL), water (100 mL). The obtained oil was used as it was in the next reaction.
(67c) Methyl 3- [2-({1-ethylpropoxy) -2-[(tert-butoxycarbonyl) (methyl) amino] phenyl} amino) -2-oxoethoxy] benzoate Prepared in Example (67b) [2-amino-5- (1-ethoxypropoxy) phenyl] methylcarbamic acid tert-butyl ester (12.34 g, 40 mmol) and [3- (methoxycarbonyl) phenoxy] acetic acid (8.41 g, 40 mmol), 1- Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (8.43 g, 44 mmol), 1-hydroxybenzotriazole (5.95 g, 44 mmol) and dichloromethane (100 mL) were used according to Example (68d). By performing the reaction and post-treatment, the obtained solid is used as it is in the next reaction. It was.
(67d) 3-{[6- (1-Ethylpropoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate 3- [2-({1 -Methyl ethylpropoxy) -2-[(tert-butoxycarbonyl) (methyl) amino] phenyl} amino) -2-oxoethoxy] benzoate was dissolved in 4N hydrochloric acid-dioxane and heated to reflux for 10 minutes. After cooling to room temperature, the reaction solution was distilled off under reduced pressure. Dichloromethane was added to the resulting residue, washed with a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate, and the filtrate after filtration was distilled off under reduced pressure. The obtained residue was purified using an automatic purification apparatus (30% ethyl acetate-hexane) manufactured by Isco, and washed with diisopropyl ether-hexane to give the target compound as a colorless solid (7.7 g, yield in 4 steps). 61%).
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 0.95 (5H, t, J = 7.4 Hz), 1.63-1.72 (4H, m), 3.79 (3H, s), 3.88 (3H, s), 4.08-4.16 (1H, m), 5.33 (2H, s), 6.77-6.80 (1H, m), 6.86-6.91 (1H, m), 7.22-7.26 (2H, m), 7.31-7.35 (1H, m), 7.57 -7.70 (3H, m).
MS (EI) m / z: 369 (M + H) ⁺ .
(67e) 3-{[6- (1-Ethylpropoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid 3-{[6- (1- (Ethylpropoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} methyl benzoate (7.69 g, 20.11 mmol), 1 N aqueous sodium hydroxide solution (30.16 mL, 30.16 mmol), tetrahydrofuran ( The target compound (6.8 g, yield 92%) as a colorless solid was obtained by performing the reaction and post-treatment according to Example (28e) using 100 mL).
¹ H-NMR (DMSO-D ₆ , 400 MHz) δ: 0.89 (6H, t, J = 7.4 Hz), 1.53-1.65 (4H, m), 3.77 (3H, s), 4.26 (1H, s), 5.38 (2H, s), 6.77-6.81 (1H, m), 7.07-7.10 (1H, m), 7.31-7.36 (1H, m), 7.38-7.44 (1H, m), 7.44-7.48 (1H, m) , 7.51-7.55 (1H, m), 7.57-7.61 (1H, m), 12.99 (1H, s).
MS (FAB) m / z: 391 (M + Na) ⁺ .
Anal. Calcd for C ₂₁ H ₂₄ N ₂ O ₄ : C, 68.46; H, 6.57; N, 7.60. Found C, 68.20; H, 6.52; N, 7.58.

Example 68 3-{[5- (3-Fluoro-4-methylphenoxy) -3-methyl-3H-imidazo [4,5-b] pyridin-2-yl] methoxy} benzoic acid (Compound No. 1 -227)
(68a) 6- (3-Fluoro-4-methylphenoxy) -N-methyl-3-nitropyridin-2-amine 6-chloro-N-methyl-3-nitropyridin-2-amine (J. Med. Chem) , 43, 3052, 2000, 1.88 g, 10 mmol) and 3-fluoro-4-methylphenol (1.51 g, 12 mmol) and sodium hydride (56%, 0.46 g, 12.0 mmol). According to the method described in Example (31a), the title object compound (1.94 g, yield 70%) was obtained as a yellow powder.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 2.25 (3H, s), 2.76 (3H, d, J = 4.7 Hz), 6.30 (1H, d, J = 9.0 Hz), 7.02 (1H, dd, J = 2.4, 8.6 Hz), 7.18 (1H, dd, J = 2.0, 10.6 Hz), 7.35 (1H, t, J = 8.6 Hz), 8.44 (1H, d, J = 9.0 Hz), 8.75 ( 1H, br s).
(68b) 6- (3-Fluoro-4-methylphenoxy) -N ² -methylpyridine-2,3-diamine 6- (3-Fluoro-4-methylphenoxy) -N obtained in Example (68a) -According to the method described in Example (31b) using methyl-3-nitropyridin-2-amine (1.94 g, 7.0 mmol) and iron powder (1.95 g, 35.0 mmol). The compound (1.73 g, 99% yield) was obtained as a brown oil.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 2.24 (3H, s), 2.96 (3H, d, J = 4.7 Hz), 4.41 (1H, brs), 5.95 (1H, d, J = 7.8 Hz) , 6.80 (1H, s), 6.82 (1H, s), 6.88 (1H, d, J = 7.8 Hz), 7.11 (1H, t, J = 8.2 Hz).
(68c) [3- (Methoxycarbonyl) phenoxy] acetic acid of t-butyl bromoacetate (506 g, 2.6 mol), methyl 3-hydroxybenzoate (395 g, 2.60 mol) and potassium carbonate (789 g, 5.71 mol) The DMF (2 L) solution was stirred for 4 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (2 L) was added. This mixture was washed twice with water (1 L), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude [3- (methoxycarbonyl) phenoxy] acetic acid t-butyl. Anisole (100 mL) and trifluoroacetic acid (680 mL) were added to a methylene chloride (1 L) solution of this ester, and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from diisopropyl ether to obtain the title compound (476 g, 87%) as a white solid.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 3.93 (3H, s), 4.76 (2H, s), 7.18 (1H, dd, J = 2.7, 8.2 Hz), 7.40 (1H, t, J = 8.2 Hz), 7.58 (1H, dd, J = 1.6, 2.7 Hz), 7.73 (1H, d, J = 7.4 Hz).
(68d) 3- (2-{[6- (3-Fluoro-4-methylphenoxy) -2- (methylamino) pyridin-3-yl] amino} -2-oxoethoxy) methyl benzoate Example (68b) 6- (3-Fluoro-4-methylphenoxy) -N ² -methylpyridine-2,3-diamine (1.11 g, 4.49 mmol) obtained in Example) (68c) [3 -(Methoxycarbonyl) phenoxy] acetic acid (0.94 g, 4.49 mmol), WSC.HCl (0.86 g, 4.49 mmol) and HOBt (0.61 g, 4.49 mmol) in methylene chloride (100 mL) It stirred at room temperature on the day. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate, 1: 1) to give the title compound (1.97 g, yield 79%) as a brown oil.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 2.27 (3H, d, J = 2.0 Hz), 2.86 (3H, s), 3.95 (3H, s), 4.53 (1H, br s), 4.73 (2H , s), 6.05 (1H, d, J = 8.2 Hz), 6.85-6.90 (2H, m), 7.15 (1H, t, J = 9.0 Hz), 7.21 (1H, ddd, J = 0.8, 2.7, 8.2 Hz), 7.36 (1H, d, J = 7.8 Hz), 7.46 (1H, t, J = 7.8 Hz), 7.67 (1H, dd, J = 1.1, 2.4 Hz), 7.74 (1H, s), 7.78 ( (1H, dt, J = 1.1, 7.8 Hz).
(68e) Methyl 3-{[5- (3-fluoro-4-methylphenoxy) -3-methyl-3H-imidazo [4,5-b] pyridin-2-yl] methoxy} benzoate Example (68d) 3- (2-{[6- (3-Fluoro-4-methylphenoxy) -2- (methylamino) pyridin-3-yl] amino} -2-oxoethoxy) benzoic acid methyl (1. 56 g, 3.55 mmol) and acetic acid (20 mL) were stirred at 80 ° C. for 1 day. After allowing to cool, water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed twice with saturated sodium bicarbonate (100 mL) and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (hexane: ethyl acetate, 1: 1) to obtain the title compound (1.13 g, yield 76%) as a white solid.
¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.29 (3H, d, J = 1.6 Hz), 3.84 (3H, s), 3.93 (3H, s), 5.38 (2H, s), 6.83 (1H, d, J = 8.6 Hz), 6.86-6.91 (2H, m), 7.18 (1H, t, J = 8.6 Hz), 7.26-7.29 (1H, m), 7.38 (1H, t, J = 7.8 Hz), 7.69-7.72 (2H, m), 8.03 (1H, d, J = 8.6 Hz).
(68f) 3-{[5- (3-Fluoro-4-methylphenoxy) -3-methyl-3H-imidazo [4,5-b] pyridin-2-yl] methoxy} benzoic acid In Example (68e) The resulting methyl 3-{[5- (3-fluoro-4-methylphenoxy) -3-methyl-3H-imidazo [4,5-b] pyridin-2-yl] methoxy} benzoate (1.13 g, The title object compound (0.79 g, yield 72%) was obtained as a white powder according to the method described in Example (33e) using 2.68 mmol).
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 2.23 (3H, s), 3.70 (3H, s), 5.41 (2H, s), 6.91 (1H, d, J = 8.2 Hz), 6.91- .6.94 (1H, m), 7.05 (1H, dd, J = 2.4, 11.0 Hz), 7.15 (1H, d, J = 9.0 Hz), 7.28 (1H, d, J = 7.8 Hz), 7.32 (1H, d, J = 8.2 Hz), 7.51 (1H, d, J = 7.4 Hz), 7.57 (1H, dd, J = 1.2, 2.4 Hz), 8.14 (1H, d, J = 8.6 Hz).
MS (FAB +) m / z: 408 (M + H) ⁺ .
Mp: 205-207 ° C.

Example 69 3-{[3-Methyl-5- (4-methylphenoxy) -3H-imidazo [4,5-b] pyridin-2-yl] methoxy} benzoic acid (Compound No. 1-221)
(69a) N-methyl-6- (4-methylphenoxy) -3-nitropyridin-2-amine 4-methylphenol (5.0 g, 46 mmol) and 6-chloro-N-methyl-3-nitropyridine-2 -Synthesized as in Example (28a) using amine (7.4 g, 39 mmol), sodium hydride (> 56% in oil, 2.0 g, 51 mmol), N, N-dimethylformamide (50 mL), The resulting dark brown solid was used as such for the next reaction.
(69b) 3-Amino-2-N-methylamino-6- (4-methylphenoxy) pyridine N-methyl-6- (4-methylphenoxy) -3-nitropyridine-2 prepared in Example (69a) Synthesis was performed in the same manner as in Example (28b) using amine (10 g, 39 mmol), iron powder (11 g, 200 mmol), ammonium chloride (1.1 g, 20 mmol), ethanol (30 mL), and water (15 mL). The resulting oil was purified using silica gel column chromatography (eluent: hexane / ethyl acetate = 6/1 to 3/2). By drying under reduced pressure, the target compound (2.2 g, yield 25%) as a dark brown oil was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 2.33 (3H, s), 2.91 (2H, br s), 2.97 (3H, d, J = 5.1 Hz), 4.41 (1H, br.s.), 5.84 (1H, d, J = 7.8 Hz), 6.85 (1H, d, J = 7.8 Hz), 7.01 (2H, d, J = 8.6 Hz), 7.13 (2H, d, J = 8.2 Hz).
(69c) Methyl 3- (2-{[2- (methylamino) -6- (4-methylphenoxy) pyridin-3-yl] amino} -2-oxoethoxy) benzoate Prepared in Example (69b) 3-amino-2-N-methylamino-6- (4-methylphenoxy) pyridine (2.2 g, 9.7 mmol) and [3- (methoxycarbonyl) phenoxy] acetic acid (2.0 g, 9.7 mmol), Examples using 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.2 g, 12 mmol), 1-hydroxybenzotriazole monohydrate (1.8 g, 12 mmol), dichloromethane (40 mL) (28c) was synthesized and the obtained crude product was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3/1 to 6/5). And purified. By drying under reduced pressure, the target compound (3.7 g, yield 90%) as a dark green oil was obtained.
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 2.35 (3H, s), 2.88 (3H, s), 3.94 (3H, s), 4.72 (2H, s), 5.96 (1H, d, J = 8.2 Hz), 7.02-7.08 (2H, m), 7.16 (2H, d, J = 8.2 Hz), 7.20 (1H, ddd, J = 1.2, 2.7, 8.2 Hz), 7.32 (1H, d, J = 8.2 Hz ), 7.45 (1H, t, J = 8.0 Hz), 7.66 (1H, dd, J = 1.4, 2.5 Hz), 7.73 (1H, s), 7.77 (1H, dt, J = 1.0, 1.2, 7.6 Hz) .
MS (FAB) m / z: 422 (M + H) ⁺ .
(69d) 3-{[6- (4-Methylphenoxy) -1-methyl-3H-imidazo [4,5-b] pyridin-2-yl] methoxy} methyl benzoate 3 prepared in Example (69c) Methyl-(2-{[2- (methylamino) -6- (4-methylphenoxy) pyridin-3-yl] amino} -2-oxoethoxy) benzoate (3.7 g, 8.7 mmol) was added to acetic acid ( 40 mL) and heated to reflux for 3.5 hours. After cooling to room temperature, sodium bicarbonate water (100 mL) was added to the concentrated reaction mixture, and the mixture was extracted with ethyl acetate (120 mL × 2). The obtained organic layer was washed with water (100 mL) and saturated brine (80 mL), and dried over anhydrous magnesium sulfate. The pale brown oil obtained by distilling off the solvent under reduced pressure was directly used in the next reaction.
(69e) 3-{[3-Methyl-5- (4-methylphenoxy) -3H-imidazo [4,5-b] pyridin-2-yl] methoxy} benzoic acid 3- prepared in Example (69d) {[6- (4-Methylphenoxy) -1-methyl-3H-imidazo [4,5-b] pyridin-2-yl] methoxy} methyl benzoate (3.5 g, 8.3 mmol), 1N hydroxylation The target compound (2.8 g, yield 82%) as a white solid was obtained by performing reaction and post-treatment according to Example (28e) using aqueous sodium solution (18 mL, 18 mmol) and 1,4-dioxane (20 mL). )
^{1 H-NMR (DMSO-d} 6, 400MHz) δ: 2.32 (3H, s), 3.70 (3H, s), 5.47 (2H, s), 6.86 (1H, d, J = 8.6 Hz), 7.06 (2H , d, J = 8.2 Hz), 7.22 (2H, d, J = 7.8 Hz), 7.35-7.39 (1H, m), 7.45 (1H, t, J = 7.8 Hz), 7.62 (1H, dd, J = 1.4, 2.5 Hz), 7.58 (1H, dt, J = 1.3, 7.5 Hz), 8.12 (1H, d, J = 8.6 Hz), 13.05 (1H, br s).
MS (FAB) m / z: 389 (M + H) ⁺ .
Anal. Calcd for C ₂₂ H ₁₉ N ₃ O ₄ : C, 67.86; H, 4.92; N, 10.79. Found C, 67.69; H, 4.71; N, 10.72.

Example 70 3-{[5- (3,4-Dimethylphenoxy) -3-methyl-3H-imidazo [4,5-b] pyridin-2-yl] methoxy} benzoic acid (Compound No. 1-223 )
(70a) 6- (3,4-Dimethylphenoxy) -N-methyl-3-nitropyridin-2-amine 3,4-dimethylphenol (5.47 g, 44.8 mmol), 6-chloro-N-methyl- Follow the procedure described in Example (28a) using 3-nitropyridin-2-amine (7.00 g, 37.3 mmol) and sodium hydride (63%, 1.71 g, 44.8 mmol). A crude product of the target compound was obtained as a yellow powder. This was used as such for the next reaction.
(70b) 6- (3,4-dimethylphenoxy) -N ² -methylpyridine-2,3-diamine 6- (3,4-dimethylphenoxy) -N-methyl-3 obtained in Example (70a) -Described in Example (28b) using nitropyridin-2-amine (10.2 g, 37.3 mmol), iron powder (10.4 g, 187 mmol) and ammonium chloride (1.00 g, 18.7 mmol). According to the above method, the title object compound (2.83 g, yield 31%) was obtained as a brown oil.
_{^{1 H NMR (CDCl 3, 400MHz}} ) δ: 2.05 (3H, s), 2.23 (3H, s), 2.98 (3H, d, J = 5.1 Hz), 5.82 (1H, d, J = 7.8 Hz), 6.84 (2H, s), 6.90 (1H, d, J = 2.7 Hz), 7.07 (1H, d, J = 8.2 Hz).
(70c) methyl 3- (2-{[6- (3,4-dimethylphenoxy) -2- (methylamino) pyridin-3-yl] amino} -2-oxoethoxy) benzoate in Example (70b) The obtained 6- (3,4-dimethylphenoxy) -N ² -methylpyridine-2,3-diamine (2.83 g, 11.6 mmol), [3- (methoxycarbonyl) phenoxy] acetic acid (2.44 g, 11.6 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.23 g, 11.6 mmol) and 1-hydroxybenzotriazole monohydrate (1.57 g, 11.6 mmol). Was used to give the title object compound (4.45 g, yield 88%) as a brown powder according to the method described in Example (28c).
¹ H NMR (CDCl ₃ , 400 MHz) δ: 2.25 (3H, s), 2.25 (3H, s), 2.89 (3H, s), 3.94 (3H, s), 4.72 (2H, s), 5.93 (1H, d, J = 8.2 Hz), 6.89 (1H, dd, J = 2.7, 8.2 Hz), 6.94 (1H, d, J = 2.3 Hz), 7.11 (1H, d, J = 7.8 Hz), 7.19 (1H, dd, J = 2.7, 8.2 Hz), 7.31 (1H, d, J = 8.2 Hz), 7.44 (1H, t, J = 8.0 Hz), 7.64-7.67 (1H, m), 7.73-7.80 (2H, m ).
(70d) 3-{[5- (3,4-Dimethylphenoxy) -3-methyl-3H-imidazo [4,5-b] pyridin-2-yl] methoxy} methyl benzoate Obtained in Example (70c) 3- (2-{[6- (3,4-dimethylphenoxy) -2- (methylamino) pyridin-3-yl] amino} -2-oxoethoxy) benzoic acid methyl (4.45 g, 10. The title object compound (3.21 g, yield 75%) was obtained as a white powder according to the method described in Example (28d) using 2 mmol) and acetic acid (51.0 mL).
¹ H NMR (CDCl ₃ , 400 MHz) δ: 2.27 (3H, s), 2.27 (3H, s), 3.85 (3H, s), 3.92 (3H, s), 5.37 (2H, s), 6.75 (1H, d, J = 8.6 Hz), 6.90 (1H, dd, J = 2.3, 7.8 Hz), 6.95 (1H, d, J = 2.3 Hz), 7.14 (1H, d, J = 8.6 Hz), 7.25-7.29 ( 2H, m), 7.38 (1H, t, J = 7.8 Hz), 7.67-7.73 (2H, m).
(70e) 3-{[5- (3,4-Dimethylphenoxy) -3-methyl-3H-imidazo [4,5-b] pyridin-2-yl] methoxy} benzoic acid obtained in Example (70d) 3-{[5- (3,4-dimethylphenoxy) -3-methyl-3H-imidazo [4,5-b] pyridin-2-yl] methoxy} methyl benzoate (3.16 g, 7.57 mmol) And the 1N aqueous sodium hydroxide solution (11.4 mL, 11.4 mmol) were used to give the title object compound (2.90 g, yield 95%) as a white powder according to the method described in Example (28e). It was.
¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 2.22 (3H, s), 2.22 (3H, s), 3.71 (3H, s), 5.47 (2H, s), 6.82 (1H, d, J = 8.6 Hz), 6.88 (1H, dd, J = 2.7, 8.2 Hz), 6.96 (1H, d, J = 2.7 Hz), 7.16 (1H, d, J = 7.8 Hz), 7.37 (1H, ddd, J = 1.2 , 2.7, 8.2 Hz), 7.45 (1H, t, J = 7.8 Hz), 7.56-7.59 (1H, m), 7.62-7.64 (1H, m), 8.10 (1H, d, J = 8.2 Hz), 13.03 (1H, s).
MS (FAB) m / z: 404 (M + H) ^<+> .

Example 71 3-{[5- (3,5-Dimethylphenoxy) -3-methyl-3H-imidazo [4,5-b] pyridin-2-yl] methoxy} benzoic acid (Compound No. 1-225 )
(71a) 6- (3,5-Dimethylphenoxy) -N-methyl-3-nitropyridin-2-amine 3,5-dimethylphenol (5.0 g, 45 mmol) and 6-chloro-N-methyl-3- Similar to Example (28a) using nitropyridin-2-amine (7.1 g, 38 mmol), sodium hydride (> 56% in oil, 2.0 g, 49 mmol), N, N-dimethylformamide (50 mL). The yellow solid obtained was used in the next reaction as it was.
(71b) 3-Amino-6- (3,5-dimethylphenoxy) -2-N-methylaminopyridine 6- (3,5-dimethylphenoxy) -N-methyl-3-prepared in Example (71a) Nitropyridin-2-amine (10 g, 37 mmol) was dissolved in ethanol (100 mL) under a nitrogen atmosphere, 10% palladium / carbon (2.0 g) was added, and the mixture was replaced with hydrogen and stirred vigorously at room temperature for 1.2 hours. . After resubstitution with nitrogen, the catalyst was filtered off using Celite, and the target compound as a red-purple oil obtained by drying the filtrate under reduced pressure was used in the next reaction as it was.
(71c) methyl 3- (2-{[6- (3,5-dimethylphenoxy) -2- (methylamino) pyridin-3-yl] amino} -2-oxoethoxy) benzoate in Example (71b) Prepared 3-amino-6- (3,5-dimethylphenoxy) -2-N-methylaminopyridine (12 g, 37 mmol) and [3- (methoxycarbonyl) phenoxy] acetic acid (7.7 g, 37 mmol), 1- Synthesis was performed in the same manner as in Example (57c) using ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (8.4 g, 44 mmol) and dichloromethane (150 mL), and the obtained gray amorphous target compound was used as it was. Used for next reaction.
(71d) 3-{[5- (3,5-Dimethylphenoxy) -3-methyl-3H-imidazo [4,5-b] pyridin-2-yl] methoxy} methyl benzoate monohydrochloride Example (71c) ) Methyl 3- (2-{[6- (3,5-dimethylphenoxy) -2- (methylamino) pyridin-3-yl] amino} -2-oxoethoxy) benzoate (16 g, 37 mmol) Was dissolved in acetic acid (150 mL) and heated to reflux for 2.5 hours. The reaction mixture was concentrated, ethyl acetate (5 mL) and aqueous sodium bicarbonate were added, and sonicated. The precipitated light brown solid was collected by filtration to obtain the target compound (13 g, yield 86%).
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 2.32 (6H, s), 3.86 (3H, s), 3.93 (3H, s), 5.38 (2H, s), 6.71-6.81 (3H, m) , 6.84 (1H, s), 7.29 (1H, dd, J = 1.0, 2.5 Hz), 7.38 (1H, t, J = 7.8 Hz), 7.67-7.71 (1H, m), 7.72 (1H, dd, J = 1.4, 2.5 Hz), 7.99 (1H, d, J = 8.6 Hz).
MS (FAB) m / z: 418 (M + H) ⁺ .
(71e) 3-{[5- (3,5-Dimethylphenoxy) -3-methyl-3H-imidazo [4,5-b] pyridin-2-yl] methoxy} benzoic acid Prepared in Example (71d) Methyl 3-{[5- (3,5-dimethylphenoxy) -3-methyl-3H-imidazo [4,5-b] pyridin-2-yl] methoxy} benzoate (13 g, 32 mmol), 1N hydroxylation The target compound (11 g, yield 85%) as a white solid was obtained by performing reaction and post-treatment according to Example (28e) using aqueous sodium solution (47 mL, 47 mmol) and 1,4-dioxane (50 mL). Obtained.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 2.27 (6H, s), 3.72 (3H, s), 5.48 (2H, s), 6.75 (2H, s), 6.84 (2H, s), 7.34 -7.41 (1H, m), 7.45 (1H, t, J = 7.8 Hz), 7.58 (1H, d, J = 7.4 Hz), 7.63 (1H, s), 8.12 (1H, d, J = 8.6 Hz) .
MS (FAB) m / z: 404 (M + H) ⁺ .
_{. Anal calcd for C 23 H 21} N 3 O 4 + 0.33H 2 O:. C, 67.47; H, 5.33; N, 10.26 Found C, 67.69; H, 5.30; N, 10.28.

Example 72 3-Fluoro-5-{[3-methyl-5- (4-methylphenoxy) -3H-imidazo [4,5-b] pyridin-2-yl] methoxy} benzoic acid (Compound No. 1 -222)
(72a) Methyl 3-fluoro-5- (2-{[2- (methylamino) -6- (4-methylphenoxy) pyridin-3-yl] amino} -2-oxoethoxy) methyl benzoate Example (69b) ) 6 obtained in (4-methylphenoxy) -N ² - methylpyridine-2,3-diamine (1.88g, 8.22mmol), [3- fluoro-5- (methoxycarbonyl) phenoxy] acetic acid ( 1.88 g, 8.22 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.58 g, 8.22 mmol) and 1-hydroxybenzotriazole monohydrate (1.11 g, 8 .22 mmol) was used to give the title object compound (2.65 g, yield 73%) as a brown powder according to the method described in Example (68d).
¹ H NMR (CDCl ₃ , 400 MHz) δ: 2.36 (3H, s), 2.90 (3H, s), 3.94 (3H, s), 4.71 (2H, s), 5.96 (1H, d, J = 8.2 Hz) , 6.93 (1H, td, J = 2.3, 9.4 Hz), 7.05 (2H, d, J = 8.6 Hz), 7.17 (2H, d, J = 8.6 Hz), 7.31 (1H, d, J = 8.2 Hz) , 7.44-7.49 (2H, m), 7.71 (1H, s).
(72b) 3-Fluoro-5-{[3-methyl-5- (4-methylphenoxy) -3H-imidazo [4,5-b] pyridin-2-yl] methoxy} methyl benzoate Example (72a) 3-Fluoro-5- (2-{[2- (methylamino) -6- (4-methylphenoxy) pyridin-3-yl] amino} -2-oxoethoxy) benzoic acid methyl (2. The title compound (2.17 g, yield 85%) was obtained as a white powder according to the method described in Example (68e) using 65 g, 6.09 mmol) and acetic acid (30.0 mL).
¹ H NMR (CDCl ₃ , 500 MHz) δ: 2.37 (3H, s), 3.82 (3H, s), 3.92 (3H, s), 5.36 (2H, s), 6.78 (1H, d, J = 8.8 Hz) , 6.98-7.03 (1H, m), 7.06 (2H, d, J = 8.3 Hz), 7.19 (2H, d, J = 8.8 Hz), 7.36-7.40 (1H, m), 7.51-7.54 (1H, m ), 7.99 (1H, d, J = 8.3 Hz).
(72c) 3-Fluoro-5-{[3-methyl-5- (4-methylphenoxy) -3H-imidazo [4,5-b] pyridin-2-yl] methoxy} benzoic acid In Example (72b) The resulting methyl 3-fluoro-5-{[3-methyl-5- (4-methylphenoxy) -3H-imidazo [4,5-b] pyridin-2-yl] methoxy} benzoate (2.17 g, 5.15 mmol) and 1N aqueous sodium hydroxide solution (7.72 mL, 7.72 mmol) were used to give the title object compound (1.52 g, yield 72%) according to the method described in Example (28e). Obtained as a white powder.
¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 2.32 (3H, s), 3.69 (3H, s), 5.50 (2H, s), 6.86 (1H, d, J = 8.6 Hz), 7.03-7.09 ( 2H, m), 7.20-7.25 (2H, m), 7.28-7.36 (2H, m), 7.46-7.49 (1H, m), 8.12 (1H, d, J = 8.6 Hz), 13.38 (1H, s) .
MS (FAB) m / z: 408 (M + H) ^<+> .

Test Example 1: Hypoglycemic Action Male KK mice (purchased from Nippon Claire) were purchased at 6 weeks of age and then raised to 15-20 weeks of age to develop diabetes. Mice were individually housed during the habituation period and the test period, with free access to water and feed (FR2, Funabashi Farm).

  At the start of the experiment, after measuring body weight, blood was collected from a mouse tail vein using a heparin-coated glass tube, and after centrifugation, plasma was separated. The plasma glucose concentration was measured using Glucodaro GXT (A & T), and individuals with a blood glucose level of about 350 mg / dl or more were selected. Three to four animals were used in the experiment, and the groups were divided so that the average body weight and the average blood glucose level were approximate. In the compound administration group, each compound was mixed with the feed so as to contain 0.03%. Separately, a group fed only with feed was used as a control group.

  The experimental period (drug administration period) was 3 days. The day of grouping was taken as day 0, and body weight was measured and blood was collected from the tail vein on day 3, and blood glucose levels were measured.

The blood glucose lowering rate was calculated from the following formula.
Blood glucose reduction rate = [(control group blood glucose level−compound administration group blood glucose level) / control group blood glucose level] × 100
The obtained results are shown in Table 2.
(Table 2)
――――――――――――――
Example Blood glucose reduction rate (%)
――――――――――――――
2 37
8 29
10 35
12 30
14 33
16 60
28 61
29 60
31 47
33 42
41 51
42 29
49 48
54 32
55 44
59 47
67 50
69 43
70 38
72 42
――――――――――――――.

  From Table 2, it was found that the compound of the present invention has an excellent blood glucose lowering effect. Therefore, the compound of the present invention is considered to be useful as a therapeutic agent for diabetes (particularly, a therapeutic agent for type II diabetes).

  In the following Test Examples 2 to 5, unless otherwise specified, each operation is described in the literature (Sambrook, J., Fritsch, EF and Maniatis, T., “Molecular Cloning”, Cold Spring Harbor Laboratory Press, 1989). The method was performed. Commercially available reagents and kits were used according to the attached instructions.

Test Example 2: Evaluation of PPARγ modulator activity (Procedure 1) Chemical synthesis of a DNA oligomer as a polymerase chain reaction primer In designing a polymerase chain reaction (hereinafter referred to as “PCR”) primer, a human PPARγ2 gene sequence (GenBANK accession No. D83233) was used. ). A recognition sequence by the restriction enzyme BglII necessary for insertion into the restriction enzyme site BamHI of the expression plasmid pSG5 (Stratagene) of the gene is added to the upstream region and downstream region of the gene encoding human PPARγ2 protein, and PCR primers Two types of polynucleotides shown in SEQ ID NOS: 1 and 2 in the sequence listing below (hereinafter referred to as “S1” and “AS1”, respectively) were used.

(Procedure 2) Chemical synthesis of DNA oligomer containing PPARγ-responsive gene sequence
In order to construct a reporter plasmid having a PPAR responsive element for the purpose of measuring the ability to activate transcription via PPARγ, two polynucleotides shown in SEQ ID NOs: 3 and 4 in the following sequence listing (hereinafter “ S2 ”and“ AS2 ”). The DNA fragment to be inserted was designed based on the gene sequence of the promoter region of acyl Co-A oxidase in rats (JD Tugwood, EMBO J, 1992, 11, 2, p.433-439) . In order to insert into the reporter plasmid pGV-P2 (Toyo Ink Co., Ltd.), a recognition sequence by restriction enzyme NheI was added to S2 and XhoI was added to AS2.

(Procedure 3) Construction of human PPARγ expression plasmid FIG. 1 shows a schematic diagram of a PPARγ expression plasmid.

  Using a cDNA library derived from human adipose tissue (Clontech) as a template, DNA oligomers S1 and AS1 as PCR primers obtained in step 1, and PCR using heat-resistant DNA polymerase Ex-Taq (Takara Shuzo) As a result, a DNA fragment of about 1500 base pairs (hereinafter referred to as bp) was amplified. Each cycle consists of 30 cycles of incubation at 94 ° C for 1 minute, 55 ° C for 30 seconds, 72 ° C for 30 seconds. The obtained approximately 1500 bp DNA fragment was partially cleaved with the restriction enzyme BglII and inserted into the restriction enzyme site BamHI of pSG5 to obtain a human PPARγ expression plasmid pSG5-hPPARγ. The inserted DNA fragment was confirmed to be human PPARγ2 by the dideoxynucleotide chain termination method.

(Procedure 4) Construction of Reporter Plasmid FIG. 2 shows a schematic diagram of the PPRE reporter plasmid.

  A digested vector pGV-P2 digested with restriction enzymes NheI and XhoI and purified by 1.0% agarose gel electrophoresis was prepared. The DNA oligomers S2 and AS2 obtained in Procedure 2 were mixed and incubated in a 94 ° C. water bath for 1 minute, and then incubated at 25 ° C. for 1 hour to form double-stranded DNA in which S2 and AS2 were annealed. Then, after phosphorylating the end using DNA polynucleotide kinase (Toyobo Co., Ltd.), ligated with the previously prepared pGV-P2 digest and restriction enzyme sites NheI and XhoI, and a reporter plasmid having a PPAR response element pGV-P2-PPRE was obtained.

(Procedure 5) Gene Introduction into Animal Cells Using the plasmids obtained in Procedure 3 and Procedure 4, Escherichia coli HB-101 strain was transformed by a conventional method. HB-101 strain carrying the plasmid in L-broth medium (10 g tryptone (Difco), 5 g yeast extract (Difco), 5 g sodium chloride each in 1 L aqueous solution) containing 37 μg / ml of ampicillin at 37 ° C. Culture was performed for 17 hours. Thereafter, each plasmid was purified by the alkaline SDS method and used for gene transfer into animal cells. According to the manual attached to LipofectAMINE reagent, pSG5-hPPARγ, pGV-P2-PPRE, LipofectAMINE reagent (Invitrogen Cat.No.18324-020) were mixed and transiently introduced into human osteosarcoma cell line MG63 Thereafter, the cells were collected. The collected cells are 10% fetal bovine serum (MOREGATE BATCH: 474030) 10% (v / v), Penicillin-Streptomycin, Liquid (GIBCO BRL Cat.No.15140-122) is 1% (v / v) Using a mixed α-MEM medium (GIBCO BRL Cat.No.12571-048) (hereinafter abbreviated as 10% α-MEM), add 30000 to 40000 cells / well in a 96-well plate (COSTAR 3917). the seeded into each well, 37 ° C. using a CO ₂ incubator (NAPCO), and cultured for 24 hours under conditions of _{5% CO 2, 95% -RH} .

(Procedure 6) Reagent addition method for evaluating transcription activation promoting action The medium was removed from the culture plate prepared in Procedure 5. To the control group, 10% α-MEM was added by 95 μl / well. For the positive control group, the following compound A prepared in a 10 μM DMSO solution (compound A is shown as an example, but not limited to PPARγ agonists) is diluted to 1 / 1,000 with 10% α-MEM. This was added in an amount of 95 μl / well. Thereafter, DMSO diluted 20-fold with 10% α-MEM was added to the control group and the positive control group by 5 μl / well. To the test compound addition group, 10% α-MEM was added by 95 μl / well. Thereafter, the test compound diluted to various concentrations with DMSO was diluted 20-fold with 10% α-MEM, and this was added at 5 μl / well.

(Compound A and production method thereof)
Compound A: N- [4- [2- [4- (2,4-Dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] phenyl] benzamide
5- [4- [6- (4-Aminophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione dihydrochloride 400 mg anhydrous N, N-dimethylformamide To an 8 ml solution, 0.36 ml of triethylamine and 0.10 ml of benzoyl chloride were added dropwise. After stirring this reaction solution at room temperature for 1 hour, the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1 → 2: 1 → 3: 1 → 4: 1) to obtain 247 mg of the target compound as a white powder. Obtained.

  Melting point: 200-204 ° C.

(Procedure 7) Reagent addition method for evaluating transcription activation inhibitory action The medium was removed from the culture plate prepared in Procedure 5. To the control group, 10% α-MEM was added by 95 μl / well. In the positive control group, the above-mentioned compound A prepared in 10 μM DMSO solution was diluted to 1 / 1,000 with 10% α-MEM, and 95 μl / well was added. Thereafter, DMSO was diluted 20-fold with 10% α-MEM, and 5 μl / well was added to the control group and the positive control group. To the test compound addition group, 95 μl / well of Compound A prepared in 10 μM DMSO solution diluted to 1 / 1,000 with 10% α-MEM was added. Thereafter, the test compound diluted to various concentrations with DMSO was diluted 20-fold with 10% α-MEM, and this was added at 5 μl / well.

(Procedure 8) Measuring method of luciferase activity After culturing the cells prepared in Procedure 6 and Procedure 24 for 24 hours, the medium is removed, and the amount is equivalent to luciferase luminescent substrate LT2.0 (Wako Pure Chemical Industries, Ltd. Cat. No. 309-05884). Add 50 μl / well of Dulbecco's Phosphate-Buffered Saline (GIBCO BRL Cat. No. 14040-117 or SIGMA CHEMICAL CO. Cat. The mixture was stirred at E-36). Using Analyst (Molecular Devices), luciferase activity was measured and a dose-dependent curve was drawn.

(Procedure 9) Calculation method of IC ₅₀ and EC _{50 In} determining IC ₅₀ , Imax, EC ₅₀ and Emax of a test compound, these values are defined as follows. FIG. 3 shows a conceptual diagram.

When the luciferase activity value of the positive control group is 100% and the luciferase activity value of the control group is 0%, the maximum value of the luciferase activity indicated by the test compound alone is Emax (%), which is suppressed by the test compound when Compound A is present. The maximum suppression value of luciferase activity is defined as Imax (%). Then, to calculate the concentration of test compound showing the value of Emax / 2 as EC _50. Further, the concentration of the test compound showing a value of (100−Imax) / 2 is calculated as IC ₅₀ . IC ₅₀ and EC ₅₀ calculated in this way were used for evaluation of PPARγ modulator activity.

Table 3 shows the measurement results.
(Table 3)
____________________________________________
Example EC ₅₀ (M) Emax (%) IC ₅₀ (M) Imax (%)
____________________________________________
2 3.28x10 ^-9 70 5.61x10 ^-8 -44
8 7.72x10 ^-9 39 7.33x10 ^-8 -34
10 2.06x10 ^-9 42 3.32x10 ^-8 -50
12 2.34x10 ^-9 42 4.04x10 ^-8 -43
14 5.17 × 10 ⁻⁸ 54 6.37 × 10 ⁻⁸ −35
16 2.64 × 10 ⁻⁸ 46 4.02 × 10 ⁻⁷ −44
____________________________________________

  As shown in Table 3, the compound of the present invention has a PPARγ modulator activity and is a therapeutic agent for diseases based on abnormal lipid metabolism, arteriosclerosis, hyperlipidemia, diabetes, degenerative osteoporosis, obesity, cancer, etc. Or it is useful as a preventive agent.

Test Example 3: Adipocyte Differentiation Inhibition Test Rat white adipocytes were subjected to experiments using cells contained in a white adipocyte culture kit purchased from Primary Cell. As the growth medium and differentiation induction medium, the medium contained in the white adipocyte culture kit purchased from Primary Cell was used. All cell cultures in this experiment were performed in a CO ₂ incubator (37 ° C., 95% humidity, 5% CO ₂ ).

Immediately after arrival, the purchased cells were extracted from the entire transport medium, added with 5 ml of growth medium (/ 25 cm ² -flask), and cultured for 1 day. After that, 83,000cells / mL cell suspension is prepared using growth medium so that it becomes 5,000-6,000cells / well (60μL / well) in 96-well type I collagen coated microplate (Becton Dickinson). The cell suspension was dispensed. As a blank group, each plate was provided with wells (blank wells) in which only growth medium containing no cells was dispensed.

  On the next day, all of the growth medium was removed and 147 μL / well of differentiation induction medium was added. 1) In the test compound addition group, a 100 μM DMSO solution of the test compound diluted 20-fold with a medium for differentiation induction was 3 μL / well (final test compound concentration: 100 nM, final DMSO concentration: 0.1% (v / v) ) And Compound A at a final concentration of 3.3 nM (DMSO at this time has a final concentration of 0.01%, so it can be ignored), 2) In the positive control group, DMSO diluted 20 times with differentiation-inducing medium 3 μL / well (DMSO final concentration: 0.1% (v / v)) and Compound A final concentration 3.3 nM, 3) In the negative control group, DMSO diluted 20 times with differentiation-inducing medium 3 μL / well (DMSO final concentration: 0.1% (v / v)), cells were added to seeded wells.

  After culturing for 5 days, the whole medium for differentiation induction in each well was removed, 60 μL of 10% (v / v) formaldehyde aqueous solution (fixing solution) was added to each well, and the cells were allowed to stand at room temperature for 20 minutes. The total amount of the fixative was removed, and a 0.2% (v / v) Triton X-100 (Sigma) aqueous solution was dispensed in 60 μL of each well and allowed to stand at room temperature for 5 minutes. Remove all Triton X-100 aqueous solution, and distribute 60 μL of fat staining solution in which Oil Red O (Sigma) is dissolved to 0.3% (w / v) in 60% (v / v) isopropanol aqueous solution to each well. Poured and left at room temperature for 10 minutes. After removing the whole amount of the fat staining solution, each well was washed twice by dispensing and removing 60 μL of 60% (v / v) aqueous isopropanol solution. Thereafter, 100 μL of DMSO was added to each well and stirred at room temperature for 5 minutes. Using a multi-plate reader (BIO-TEK INSTRUMENTS INC.) Or the like, the absorbance at 550 nm (ABS550) was measured, and the amount stained with Oil Red O was measured. The adipocyte differentiation degree (%) of the test compound addition group was calculated with the ABS550 measurement value of the positive control group being 100% and the ABS550 measurement value of the negative control group being 0.

The results are shown in Table 4. Note that N. D. Indicates that calculation is not possible.
(Table 4)
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Example IC ₅₀ (M) Imax (%)
___________________
2 1.2x10 ^-8 -33
8 5.3 × 10 ⁻⁸ −29
10 4.5 × 10 ⁻⁸ −29
12 N.R. D. N. D.
14 N.R. D. N. D.
16 N.R. D. N. D.
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  As shown in Table 4, the compound of the present invention suppresses differentiation into adipocytes and is useful as an anti-obesity agent.

Test Example 4: Adipocyte Differentiation Promotion Test Rat white adipocytes were subjected to experiments using cells contained in a white adipocyte culture kit purchased from Primary Cell. As the growth medium and differentiation induction medium, the medium contained in the white adipocyte culture kit purchased from Primary Cell was used. All cell cultures in this experiment were performed in a CO ₂ incubator (37 ° C., 95% humidity, 5% CO ₂ ).

Immediately after arrival, the purchased cells were extracted from the entire transport medium, added with 5 ml of growth medium (/ 25 cm ² -flask), and cultured for 1 day. After that, 83,000cells / mL cell suspension is prepared using growth medium, and suspended in a 96-well type I collagen coated microplate (SUMITOMO BAKELITE) at 5,000cells / well (60μL / well). The suspension was dispensed. As a blank group, each plate was provided with wells (blank wells) in which only growth medium containing no cells was dispensed.

  On the next day, all of the growth medium was removed and 147 μL / well of differentiation induction medium was added. 1) In the test compound addition group, a 100 μM DMSO solution of the test compound diluted 20-fold with a medium for differentiation induction was 3 μL / well (final test compound concentration: 100 nM, final DMSO concentration: 0.1% (v / v) 2) In the positive control group, DMSO 20-fold diluted with differentiation-inducing medium 3 μL / well (DMSO final concentration: 0.1% (v / v)) and Compound A final concentration 3.3 nM (in this case) DMSO will be negligible because the final concentration will be 0.01%) 3) In the negative control group, DMSO diluted 20-fold with differentiation-inducing medium 3 μL / well (DMSO final concentration: 0.1% (v / v)), cells were added to seeded wells.

  After culturing for 5 days, the whole medium for differentiation induction in each well was removed, 60 μL of 10% (v / v) formaldehyde aqueous solution (fixing solution) was added to each well, and the cells were allowed to stand at room temperature for 20 minutes. The total amount of the fixative was removed, and a 0.2% (v / v) Triton X-100 (Sigma) aqueous solution was dispensed in 60 μL of each well and allowed to stand at room temperature for 5 minutes. Remove all the Triton X-100 aqueous solution, and distribute 60 μL of fat staining solution in which Oil Red O (Sigma) is dissolved to 0.3% (w / v) in 60% (v / v) isopropanol aqueous solution to each well. Poured and left at room temperature for 10 minutes. After removing the whole amount of the fat staining solution, each well was washed twice by dispensing and removing 60 μL of 60% (v / v) aqueous isopropanol solution. Thereafter, 100 μL of DMSO was added to each well and stirred at room temperature for 5 minutes. Using a multiplate reader (BIO-TEK INSTRUMENTS INC.), The absorbance at 550 nm (ABS550) was measured, and the amount stained with Oil Red O was measured. The adipocyte differentiation degree (%) of the test compound addition group was calculated with the ABS550 measurement value of the positive control group as 100% and the ABS550 measurement value of the negative control group as 0.

The results are shown in Table 5.
(Table 5)
___________________
Example EC ₅₀ (M) Emax (%)
___________________
2 4.2 × 10 ⁻⁹ 73
8 7.4x10 ^-9 75
10 6.6x10 ^-9 78
12 5.2 × 10 ⁻⁹ 82
14 2.0 × 10 ⁻⁸ 56
16 6.4x10 ^-8 71
__________________.

  As shown in Table 5, it is considered that the compound of the present invention partially promoted differentiation into adipocytes as a result of enhancing insulin sensitivity, and is useful as an antidiabetic drug.

Test Example 5: Measurement of PPARγ activating action / modulator activity Rosiglitazone used in the examples is a commercially available PPARγ activator, which is a compound described in US Pat. No. 5,002,953, It can be manufactured according to the method.

  A report by Kliewer et al. (Journal of Biological Chemistry, 1995, vol.270 (22), p.12953-12956) is a method for measuring the ability of a compound to activate PPARγ (hereinafter referred to as PPARγ activation / modulator activity). The test by the reporter assay method was conducted with reference to. Details are shown below.

(1) Preparation of GAL4-PPARγ chimeric receptor expression plasmid
Referring to the report of Kliewer et al., The GAL4-ligand binding region (corresponding to about 300 amino acids at the carboxy terminus) of human PPARγ was bound to the DNA binding region of the yeast transcription factor GAL4 (corresponding to the amino terminal region of 147 amino acids). A gene expressing PPARγ receptor was prepared.

  The base sequence of the human PPARγ gene is described in the gene database GenBank with Accession No. X90563.

(1-1) Acquisition of total RNA from cell line HepG2 Cell line HepG2 (American Type Culture Collection HB-8065) was purchased from Dainippon Pharmaceutical Co., Ltd., and a tissue culture flask (BD) with a culture area of 75 square centimeters (BD (Manufactured by Biosciences). As the medium, Dulbecco's modified Eagle medium (Gibco D-MEM, manufactured by Invitrogen), fetal bovine serum (manufactured by Hycron), 10% volume ratio, antibiotic solution [Antibiotic Antimycotic Solution, stabilized (100x), manufactured by Sigma ] Were added at a volume ratio of 1%, respectively.

  Cultivate in a carbon dioxide incubator at 37 ° C under 95% carbon dioxide for 3 days. When grown to approximately semi-confluent, remove the medium in the flask by aspiration and keep ice-cooled phosphate buffered saline. 10 ml of water (Gibco Dulbecco's Phosphate-Buffered Saline, manufactured by Invitrogen) was added to wash the cells, and then the saline was removed by aspiration. Thereafter, 7.5 ml of Trizol reagent (Gibco TRIZOL reagent, manufactured by Invitrogen) was added to the cells in the flask, and pipetting was repeated, and the cells were allowed to stand at room temperature for about 5 minutes to lyse the cells.

  The cell lysate was subjected to isopropyl alcohol precipitation or the like according to the instructions for the Trizol reagent to obtain RNA precipitates, which were dissolved in pure water and stored in a freezer at about minus 20 ° C. The RNA solution at this time was 0.22 ml, and the absorbance at 260 nm of a sample that was partially diluted 100-fold with pure water was 0.562. It was calculated that 39.5 μg / ml RNA was present at an absorbance of 1, and the total RNA yield was 0.562 × 100 × 39.5 × 0.22 = 488 μg.

(1-2) Cloning of cDNA of PPARγ ligand binding region
The following two deoxyoligonucleotides designed based on the human PPARγ gene sequence as primers for amplification of the cDNA in the PPARγ ligand binding region by reverse transcriptase polymerase chain reaction (RT-PCR). (Primer No. 3 and Primer No. 4) were chemically synthesized using Beckman Oligo 1000 (manufactured by Beckman).

  RT-PCR using Ready-To-Go RT-PCR Beads (manufactured by Amersham Pharmacia Biotech Co., Ltd.) using the previously obtained HepG2 total RNA as a template and the above primers No. 3 and No. 4 as primers. The PPARγ cDNA was amplified by this method. The reaction product was subjected to 1.5% agarose electrophoresis, the amplified band of about 900 base pairs was excised and purified, and cloned into plasmid pCRII (Invitrogen). The amplified DNA fragment contains a human PPARγ ligand-binding region, that is, a sequence encoding 175 to 475, and a restriction enzyme BamHI cleavage site and a restriction enzyme HindIII site on the 5 ′ side and 3 ′ side, respectively. It was considered that it had the added nucleotide sequence shown in SEQ ID NO: 7 in the sequence listing. The nucleotide sequence was confirmed, and a plasmid clone that correctly contained the sequence shown in SEQ ID NO: 7 was selected.

(1-3) Acquisition of Plasmid pM-PPARγ Next, the selected plasmid was treated with restriction enzymes BamHI and HindIII to obtain an approximately 900 base pair fragment containing the gene of the PPARγ ligand binding region. This was cloned by inserting it into the BamHI-HindIII site of a plasmid pM (manufactured by CLONTECH Laboratories, Inc.) having a gene for the DNA binding region of the yeast transcription factor GAL4.

  The plasmid pM-PPARγ obtained by the above operation contains the nucleotide sequence shown in SEQ ID NO: 8 in the sequence listing, and amino acid numbers 1 to 147 of the yeast transcription factor GAL4 at the amino terminal portion. A GAL4-PPARγ chimeric receptor comprising the amino acid sequence shown in SEQ ID NO: 9 in the Sequence Listing, which contains and contains human PPARγ at positions 175 to 475 and a stop codon at the carboxy terminus, can be expressed in mammalian cells It is a gene.

(2) Measurement of PPARγ activation ability The previously obtained plasmid pM-PPARγ and the plasmid pFR-Luc purchased from Stratagene Cloning Systems are each removed to a concentration of 1 mg / mL. Dissolved in brine.

  Monkey kidney-derived cell line COS-7 (American Type Culture Collection CRL-1651) is seeded in a 75 square centimeter culture flask, and Dulbecco's modified Eagle medium (hereinafter, medium) containing 10% fetal bovine serum is used. The cells were cultured under conditions of 37 ° C. and 5% carbon dioxide until reaching 80% confluence.

  COS-7 cells were transfected overnight using Lipofectamine 2000 transfection reagent (Invitrogen) with 4.8 micrograms of plasmid pM-PPARγ and 19.2 μg of plasmid pFR-Luc per flask. Cultured.

  The next day, cells were trypsinized and recovered, suspended in phenol red-free Dulbecco's modified Eagle's medium containing 75 mL of 10% fetal bovine serum, and a white 96-well plate (manufactured by Coster) was prepared, with 95 μL per well. Seeded with medium in volume and cultured overnight.

  The test compound was dissolved in dimethyl sulfoxide at a concentration of 30 mM. Diluted stepwise 6 times with dimethyl sulfoxide to prepare compound solutions of various concentrations up to 18 nM. Dimethylsulfoxide dissolved in dimethyl sulfoxide at a concentration of 30 mM was prepared for the control group and dimethyl sulfoxide for the positive control group. These were diluted 150-fold with the medium, and 5 μL thereof was added to the wells in which the cells were growing. The range of treatment concentration of the test compound to the cells is from 10 μM concentration to 0.006 nM concentration. After the addition, the cells were cultured overnight.

  The next day, the medium was removed, and Luc Lite (Perkin Elmer) was prepared according to the package insert, and 50 microliters was added to each well. The mixture was stirred for about 30 minutes, subjected to Analyst (manufactured by Molecular Devices), the amount of luminescence in each well was measured for 0.5 seconds, and was defined as luciferase activity.

  When the luciferase activity value of the positive control group is 100% and the luciferase activity value of the control group is 0%, the maximum value of the luciferase activity shown by the test compound alone is Emax (%), and the test compound showing the value of Emax / 2 Concentration was calculated as EC50.

The results obtained are shown in Table 6.
(Table 6)
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Example EC ₅₀ (microM) Emax (%)
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2 0.2987 73.3
8 4.7426 91.0
10 0.0670 46.5
12 0.0397 60.2
14 0.8446 89.6
16 0.5497 60.9
______________________.

  As shown in Table 6, the compounds of the present invention have PPARγ activating action / modulator activity, diseases based on abnormal lipid metabolism, arteriosclerosis, hyperlipidemia, diabetes, regression stage osteoporosis, obesity, cancer, etc. It is useful as a therapeutic or prophylactic agent.

Formulation Example 1: Capsules Example 16 Compound 50 mg
Lactose 128mg
Corn starch 70mg
Magnesium stearate 2mg
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Total amount 250mg
After mixing the powder of the above formulation and passing through a 60 mesh sieve, this powder is put into a 250 mg gelatin capsule to form a capsule.

Formulation Example 2: Tablet Example 16 Compound 50 mg
Lactose 126mg
Corn starch 23mg
Magnesium stearate 1mg
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Total amount 200mg
The powder of the above formulation is mixed, granulated and dried using corn starch paste, and then tableted by a tableting machine to make one tablet of 200 mg. This tablet can be sugar-coated if necessary.

  The fused bicyclic heteroaryl derivative having the above general formula (I) of the present invention or a pharmacologically acceptable salt thereof has a good hypoglycemic action, and is a metabolic syndrome, that is, diabetes, hyperglycemia, high Lipemia, obesity, impaired glucose tolerance (IGT), insulin resistance, impaired fasting glucose (IFG), hypertension, fatty liver, nonalcoholic cirrhosis (NASH), diabetes Diseases such as retinopathy (eg retinopathy, nephropathy, neuropathy), arteriosclerosis, gestational diabetes mellitus (GDM), polycystic ovary syndrome (PCOS), inflammatory diseases (eg osteoarthritis) Pain, inflammatory bowel disease, etc.), acne, sunburn, psoriasis, eczema, allergic disease, asthma, gastrointestinal ulcer, ulcerative colitis, Crohn's disease, coronary artery disease, arteriosclerosis, atherosclerosis, diabetic retina Disease , Diabetic macular disease, macular edema, diabetic nephropathy, ischemic heart disease, cerebrovascular disorder, peripheral circulatory disorder, autoimmune disease (eg systemic lupus erythematosus, rheumatoid arthritis, Sjogren's syndrome, systemic scleroderma, mixed Type connective tissue disease, Hashimoto disease, Crohn's disease, ulcerative colitis, idiopathic Addison disease, male infertility, Goodpasture syndrome, acute progressive glomerulonephritis, myasthenia gravis, multiple myositis, multiple sclerosis, self Immune hemolytic anemia, idiopathic thrombocytopenic purpura, Behcet's disease, CREST syndrome, etc.), pancreatitis, cachexia, cancer (eg, stomach cancer, lung cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, liver cancer) , Leukemia, sarcoma (eg, liposarcoma), osteoporosis, degenerative osteoporosis, neurodegenerative disease, Alzheimer's disease, hyperuricemia, and dry eye treatment and / or prevention agent.

SEQ ID NO: 1: PCR primer S1
Sequence number 2: PCR primer AS1
Sequence number 3: PCR primer S2
Sequence number 4: PCR primer AS2
SEQ ID NO: 5: PCR sense primer SEQ ID NO: 6: PCR antisense primer SEQ ID NO: 7: nucleotide sequence of synthetic human PPARγ cDNA SEQ ID NO: 8: nucleotide sequence of GAL4 chimeric PPARγ receptor gene SEQ ID NO: 9: GAL4 chimeric PPARγ receptor Amino acid sequence

Claims (15)

Formula (I)

[Where:
R ¹ is selected from a C ₁ -C ₆ alkyl group, a C ₆ -C ₁₀ aryl group that may be independently substituted with a group selected from the substituent group a, and a substituent group a. 1 to independently a group indicates three optionally substituted heterocyclic group, or C ₃ -C ₆ cycloalkyl,
R ² represents a C ₁ -C ₆ alkyl group,
R ³ is independently 1 to 5 C ₆ -C ₁₀ aryl groups which may be independently substituted with a group selected from substituent group a or 1 to 3 groups independently selected from substituent group a And represents an optionally substituted heterocyclic group,
Q represents a group represented by the formula = CH- or a nitrogen atom,
Substituent group a represents a halogen _atom, C 1 -C _{6 alkyl,} C 1 -C ₆ hydroxyalkyl _group, C 1 -C ₆ halogenated alkyl group, a carboxyl group, a carbamoyl _group, C 2 -C ₇ alkylcarbonyl group , _C 2 -C ₇ alkoxycarbonyl group, hydroxy _group, C 1 -C ₆ alkoxy _group, C 1 -C ₆ halogenated alkoxy _group, C 2 -C ₇ alkylcarbonyloxy _group, C 2 -C ₇ alkoxycarbonyloxy group , amino _group, C 2 -C ₇ alkylcarbonylamino _group, C 2 -C ₇ alkoxycarbonylamino _group, C 1 -C ₆ alkylsulfonylamino group, 4-morpholinyl Moto及busy - _(C 1 -C ₆ alkyl) amino A group consisting of groups is shown. Or a pharmacologically acceptable salt thereof as an active ingredient. Selection according to claim 1, ^{R 1} is 1-ethylpropyl group, a (halogen _atom, C 1 -C _{6 alkyl,} C 1 -C ₆ alkoxy _group, C 1 -C ₆ halogenated alkoxy group and an amino group) A compound which is a phenyl group or a 2,3-dihydro-1-benzofuran-6-yl group which may be independently substituted with 1 to 3 groups or a pharmacologically acceptable salt thereof as an active ingredient Medicine. In Claim 1, R ¹ is 2-fluorophenyl group, 3-fluorophenyl group, 3-chlorophenyl group, 2,5-difluorophenyl group, 4-chloro-3-fluorophenyl group, 3-chloro-4- A pharmaceutical comprising a compound which is a fluorophenyl group, a 4-methylphenyl group or a 2,3-dihydro-1-benzofuran-6-yl group or a pharmacologically acceptable salt thereof as an active ingredient. The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 3 wherein R ² is a methyl group and Q is a group represented by the formula = CH- as an active ingredient. Contains medicines. 5. The compound according to claim 1, wherein R ³ is a 3-carboxylphenyl group or a 3-carboxyl-5-fluorophenyl group, or a pharmacologically acceptable salt thereof as an active ingredient. Medicine to do. A compound having the general formula (I)
3-{[6- (3-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid,
3- [6- (3-chlorophenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy] benzoic acid,
3-{[6- (4-chloro-3-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid,
3-{[6- (3-chloro-4-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid,
3-{[6- (2-fluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid,
3-{[1-methyl-6- (4-methylphenoxy) -1H-benzimidazol-2-yl] methoxy} benzoic acid,
3-{[6- (2,5-difluorophenoxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid, or
The compound according to claim 1, which is 3-{[6- (2,3-dihydro-1-benzofuran-6-yloxy) -1-methyl-1H-benzimidazol-2-yl] methoxy} benzoic acid, or a compound thereof A pharmaceutical comprising a pharmacologically acceptable salt as an active ingredient.   A medicament comprising as an active ingredient the compound according to any one of claims 1 to 6 or a pharmacologically acceptable salt thereof.   The medicament according to claim 7 for activating PPARγ.   The medicament according to claim 7, for treating and / or preventing a disease caused by enhanced PPARγ inhibition.   The medicine according to claim 7 for reducing blood sugar.   The medicament according to claim 7 for treating and / or preventing diabetes.   The medicament according to claim 7, which is for improving sugar / lipid metabolism, improving insulin resistance, suppressing inflammation, or suppressing cancer cell proliferation.   The medicament according to claim 7, for treating and / or preventing a disease caused by metabolic syndrome.   The drug is hyperglycemia, hyperlipidemia, obesity, glucose intolerance, insulin resistance, fasting glycemia, hypertension, fatty liver, nonalcoholic cirrhosis, diabetic complications, arteriosclerosis, atherosclerosis Sclerosis, gestational diabetes, polycystic ovary syndrome, inflammatory disease, cancer, osteoporosis, degenerative osteoporosis, neurodegenerative disease, Alzheimer's disease, hyperuricemia, acne, sunburn, psoriasis, eczema, allergic disease, asthma, digestion Duct ulcer, ulcerative colitis, Crohn's disease, coronary artery disease, arteriosclerosis, atherosclerosis, diabetic retinopathy, diabetic macular disease, macular edema, diabetic nephropathy, ischemic heart disease, cerebrovascular disorder, peripheral The medicament according to claim 7, for the treatment and / or prevention of sexual circulatory disorder, autoimmune disease, pancreatitis, cachexia, leukemia, sarcoma, or dry eye.   A PPARγ activator / modulator comprising, as an active ingredient, the compound according to any one of claims 1 to 6 or a pharmacologically acceptable salt thereof.

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