Treatment and prevention of functional gastrointestinal disorders and xerostomia

Abstract

Provided is a novel prophylactic agent or therapeutic agent for functional gastrointestinal disorders or xerostomia. The present invention is a therapeutic agent or prophylactic agent that is for functional gastrointestinal disorders and that contains, as an active ingredient, an azabenzoimidazole compound represented by formula [1] (in the formula, the symbols are as defined in the description) or a pharmaceutically acceptable salt thereof, or a solvate thereof.

Description

[Technical field]

[0001] The present invention relates to a therapeutic and preventive agent for functional gastrointestinal disorders (FGIDs), and also to a therapeutic and preventive agent for xerostomia (dry mouth).

[0002] According to the Rome IV diagnostic criteria (hereinafter sometimes referred to as "Rome IV"), functional gastrointestinal disorders are also called brain-gut correlation disorders, and are a group of diseases that present with gastrointestinal symptoms related to gastrointestinal motility disorders, visceral hypersensitivity, etc. (Non-Patent Document 1).

[0003] Functional gastrointestinal disorders in adults include functional esophageal disorders, functional gastroduodenal disorders, functional bowel disorders, functional abdominal pain syndrome, functional gallbladder-sphincter of Oddi disorders, and functional anorectal syndrome (Non-Patent Documents 1, 2). For example, functional esophageal disorders include functional heartburn, functional gastroduodenal disorders include functional dyspepsia, and functional bowel disorders include irritable bowel syndrome (IBS), functional constipation, and opioid-induced constipation.

[0004] The onset and pathology of functional gastrointestinal disorders are thought to be closely related to physiological functions such as gastrointestinal motility, perception, and intestinal flora, psychological factors such as stress, and furthermore, genetic factors and living environment (Non-Patent Document 1). Patients with functional gastrointestinal disorders experience chronic or recurrent gastrointestinal symptoms (e.g., stomach upset, stomach pain, diarrhea, constipation, etc.), and their quality of life (QOL) declines due to restrictions on their daily activities.

[0005] Xerostomia is a disease in which the oral cavity becomes dry due to a decrease in the amount of saliva secreted, caused by various factors. When the amount of saliva secreted is decreased, unpleasant subjective symptoms such as mastication disorder, abnormal taste, and dry mouth are observed, as well as objective symptoms such as halitosis, tongue coating, and periodontal disease. When the decrease in saliva secretion is severe, patients are likely to suffer from dental caries, angular cheilitis, and the like. This leads to a decrease in the quality of life of patients with xerostomia (Non-Patent Document 3). [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Rome IV(Functional Gastrointestinal Disorders,4th Edition).2016.Rome Foundation,INC. [Non-Patent Document 2] Gastroenterology,2016,Vol.150,No.6,p.1257-1261 [Non-Patent Document 3] Advances in Clinical Experimental Medicine,2016,Vol.25,No.1,p.199-206 [Non-Patent Document 4] Pharmaceutical Reviews,1998,Vol.50,No.2,p.279-290 [Non-Patent Document 5] British Journal of Pharmacology,2006,Vol.148,No.5,p.565-578 [Non-Patent Document 6] Trends in Pharmacological Sciences,2017,Vol.38,No.9,p.837-847 [Non-Patent Document 7] Nature,2012,Vol.482,pp.552-556 Summary of the Invention [Problem to be solved by the invention]

[0007] As described above, functional gastrointestinal disorders and xerostomia reduce the QOL of patients. For this reason, there is a demand for therapeutic and preventive agents for functional gastrointestinal disorders and xerostomia.

[0008] An object of the present invention is to provide a novel therapeutic or prophylactic agent for functional gastrointestinal disorders. Another object of the present invention is to provide a novel therapeutic or prophylactic agent for xerostomia. [Means for solving the problem]

[0009] As a result of intensive research, the present inventors have found that an azabenzimidazole compound represented by the following formula [1] or a pharma- ceutical acceptable salt thereof, or a solvate thereof (sometimes referred to as the "compound of the present invention" in this specification) is useful for the prevention and treatment of functional gastrointestinal disorders and xerostomia, and have completed the present invention.

[0010] That is, the present invention can include the following (Item 1) to (Item 14). (Section 1) The following formula [1] [ka] [In the formula, R 1 is a hydrogen atom or an alkyl group, or two R 1 may be taken together with adjacent carbon atoms to form a 3- to 7-membered cycloalkyl or oxygen-containing non-aromatic heterocycle; R 2 is a hydrogen atom, an alkyl group, a cycloalkyl group, an alkyl group substituted with a cycloalkyl group, or an alkoxyalkyl group; R 3 is a hydrogen atom, alkyl, or alkoxyalkyl; R 4is pyridyl optionally substituted with 1 or 2 groups selected from the group consisting of alkyl, trihaloalkyl, alkoxy, cyano, and cycloalkyl, or phenyl optionally substituted with 1 to 3 groups selected from the group consisting of trihaloalkyl, halogen, alkoxy, and cycloalkyl; A is A-1, A-2, A-3, A-4, or A-5 of the following: [ka] (The left bond of each group is bonded to the 2-position of the azabenzimidazole in formula [1], the right bond is bonded to W in formula [1], and R 11 is a group selected from a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, and a nitro group; W is a bond or the following W-1, W-2, or W-3: [ka] (R 21 is a hydrogen atom or an alkyl group; B is B-1, B-2, B-3, or B-4: [ka] (The left bond of each group is bonded to W in formula [1], the right bond is bonded to Y in formula [1], and U 1 is a nitrogen atom, or CR 41 And U 2 is a nitrogen atom, or CR 42 and R 41 and R 42 are each independently a hydrogen atom, an alkyl group, a halogen atom, or a hydroxyl group; m and n are each 1, 2, or 3; R 31 and R 32 are each independently a hydrogen atom, an alkyl, a halogen, or an alkoxyalkyl, or R 31 and R 32 may, together with adjacent carbon atoms, form an alkylene bridge (R 31 and R 32 is U1 , and U 2 ) and replace it in any position that can be replaced except for . Y is a hydrogen atom or the following Y-1 to Y-4, or Y-11 to Y-16: [ka] (R 51 is alkyl, p is 1, 2, or 3, q ​​is 0, 1, or 2, r is 1, 2, or 3, and T is O, S, SO2, or NR 61 where R 61 is a hydrogen atom or alkyl, s is 0, 1, 2, or 3, and t is 0 or 1.) and is selected from any one of the following (a) to (d): (a) When W is a bond B is B-1 or B-2, and U 2 is a nitrogen atom, Y is Y-1, Y-2, Y-3, or Y-4; B is B-1, B-2, and U 2 CR 42 When (R 42 has the same meaning as above), U 1 is a nitrogen atom, Y is Y-11, Y-12, Y-13, Y-14, Y-15, or Y-16; When B is B-3 or B-4, Y is a hydrogen atom, (b) If W is W-1 B is B-1, U 1 is a nitrogen atom, U 2 is a nitrogen atom, Y is Y-1, Y-2, Y-3, or Y-4; B is B-1, U 1 is a nitrogen atom, ·U 2 CR 42 When (R 42 has the same meaning as above), Y is Y-11, Y-12, Y-13, Y-14, Y-15, or Y-16; (c) If W is W-2 B is B-1 or B-2, U 1 is a nitrogen atom, U 2 is a nitrogen atom, Y is Y-1, Y-2, Y-3, or Y-4; B is B-1 or B-2, U 1 is a nitrogen atom, U 2 CR 42 When (R 42 has the same meaning as above), Y is Y-11, Y-12, Y-13, Y-14, Y-15, or Y-16; When B is B-3 or B-4, Y is a hydrogen atom; (d) If W is a W-3: B is B-1, U 1 is CR 41 (R 41 has the same meaning as above), U 2 When is a nitrogen atom, Y is Y-1, Y-2, Y-3, or Y-4. or a medicament for treating or preventing a functional gastrointestinal disorder, comprising, as an active ingredient, an azabenzimidazole compound represented by the following formula: (Section 2) Item 2. The therapeutic or prophylactic agent according to Item 1, wherein W is a bond. (Section 3) The following cases are met: (1) B is B-1 or B-2, U 2 is a nitrogen atom, Y is Y-1, Y-2, or Y-3; (2) B is B-1 or B-2, U 2 CR 42 and Y is Y-11, Y-12, or Y-15; (3) The therapeutic or prophylactic agent according to item 1 or 2, wherein B is B-4 and Y is a hydrogen atom. (Section 4) R 4 Item 4. The therapeutic or prophylactic agent according to Item 3, wherein is a pyridyl substituted with one group selected from the group consisting of alkyl, trihaloalkyl, alkoxy, cyano, and cycloalkyl, and trihaloalkyl. (Section 5) Item 5. The therapeutic or prophylactic agent according to Item 4, wherein A is A-4. (Section 6) Item 6. The therapeutic or prophylactic agent according to any one of items 1 to 5, wherein the azabenzimidazole compound is any one of the following compounds (1) to (15): (1) [4-(5-{5-[3-fluoro-5-(trifluoromethyl)phenyl]-7-[{[1-(methoxymethyl)cyclobutyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperazin-1-yl]acetic acid, (2) 4-fluoro-1-(5-{5-[3-fluoro-5-(trifluoromethyl)phenyl]-7-[{[1-(methoxymethyl)cyclobutyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid, (3) 1-(5-{5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclobutyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid, (4) 1-(5-{5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclobutyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid, (5) {[1-(5-{5-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidin-4-yl]oxy}acetic acid, (6) 1-(4-{5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}-3-fluorophenyl)piperidine-4-carboxylic acid, (7) 1-(5-{5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-[(3-methoxy-2,2-dimethylpropyl)(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid, (8) 1-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(ethoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid, (9) 1-(5-{5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid, (10) 3-[4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperazin-1-yl]propanoic acid, (11) [4-(4-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}-3-fluorophenoxy)piperidin-1-yl]acetic acid, (12) 3-[(2S)-4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-2-(methoxymethyl)piperazin-1-yl]propanoic acid, (13) 3-[(3R)-4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(ethoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-3-methylpiperazin-1-yl]propanoic acid, (14) 3-[(3R)-4-(5-{5-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-3-methylpiperazin-1-yl]propanoic acid, (15) 3-[(3R)-4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-3-methylpiperazin-1-yl]propanoic acid. (Section 7) Item 7. The therapeutic or preventive agent according to any one of Items 1 to 6, wherein the functional gastrointestinal disorder is irritable bowel syndrome (IBS). (Section 8) Item 7. The therapeutic or preventive agent according to any one of Items 1 to 6, wherein the functional gastrointestinal disorder is functional constipation. (Section 9) The following formula [1] [ka] [In the formula, R 1 is a hydrogen atom or an alkyl group, or two R 1 may be taken together with adjacent carbon atoms to form a 3- to 7-membered cycloalkyl or oxygen-containing non-aromatic heterocycle; R 2 is a hydrogen atom, an alkyl group, a cycloalkyl group, an alkyl group substituted with a cycloalkyl group, or an alkoxyalkyl group; R 3 is a hydrogen atom, alkyl, or alkoxyalkyl; R 4 is pyridyl optionally substituted with 1 or 2 groups selected from the group consisting of alkyl, trihaloalkyl, alkoxy, cyano, and cycloalkyl, or phenyl optionally substituted with 1 to 3 groups selected from the group consisting of trihaloalkyl, halogen, alkoxy, and cycloalkyl; A is A-1, A-2, A-3, A-4, or A-5 of the following: [ka] (The left bond of each group is bonded to the 2-position of the azabenzimidazole in formula [1], the right bond is bonded to W in formula [1], and R 11 is a group selected from a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, and a nitro group; W is a bond or the following W-1, W-2, or W-3: [ka] (R 21 is a hydrogen atom or an alkyl group; B is B-1, B-2, B-3, or B-4: [ka] (The left bond of each group is bonded to W in formula [1], the right bond is bonded to Y in formula [1], and U 1is a nitrogen atom, or CR 41 And U 2 is a nitrogen atom, or CR 42 and R 41 and R 42 are each independently a hydrogen atom, an alkyl group, a halogen atom, or a hydroxyl group; m and n are each 1, 2, or 3; R 31 and R 32 are each independently a hydrogen atom, an alkyl, a halogen, or an alkoxyalkyl, or R 31 and R 32 may, together with adjacent carbon atoms, form an alkylene bridge (R 31 and R 32 is U 1 , and U 2 ) and replace it in any position that can be replaced except for . Y is a hydrogen atom or the following Y-1 to Y-4, or Y-11 to Y-16: [ka] (R 51 is alkyl, p is 1, 2, or 3, q ​​is 0, 1, or 2, r is 1, 2, or 3, and T is O, S, SO2, or NR 61 where R 61 is a hydrogen atom or alkyl, s is 0, 1, 2, or 3, and t is 0 or 1.) and is selected from any one of the following (a) to (d): (a) When W is a bond B is B-1 or B-2, and U 2 is a nitrogen atom, Y is Y-1, Y-2, Y-3, or Y-4; B is B-1, B-2, and U 2 CR 42 When (R 42 has the same meaning as above), U 1 is a nitrogen atom, Y is Y-11, Y-12, Y-13, Y-14, Y-15, or Y-16; When B is B-3 or B-4, Y is a hydrogen atom, (b) If W is W-1 B is B-1, U 1 is a nitrogen atom, U 2 is a nitrogen atom, Y is Y-1, Y-2, Y-3, or Y-4; B is B-1, U 1 is a nitrogen atom, ·U 2 CR 42 When (R 42 has the same meaning as above), Y is Y-11, Y-12, Y-13, Y-14, Y-15, or Y-16; (c) If W is W-2 B is B-1 or B-2, U 1 is a nitrogen atom, U 2 is a nitrogen atom, Y is Y-1, Y-2, Y-3, or Y-4; B is B-1 or B-2, U 1 is a nitrogen atom, U 2 CR 42 When (R 42 has the same meaning as above), Y is Y-11, Y-12, Y-13, Y-14, Y-15, or Y-16; When B is B-3 or B-4, Y is a hydrogen atom; (d) If W is a W-3: B is B-1, U 1 is CR 41 (R 41 has the same meaning as above), U 2 When is a nitrogen atom, Y is Y-1, Y-2, Y-3, or Y-4. or a medicament for treating or preventing xerostomia, comprising as an active ingredient an azabenzimidazole compound represented by the following formula: (Section 10) Item 10. The therapeutic or prophylactic agent according to Item 9, wherein W is a bond. (Section 11) The following cases are met: (1) B is B-1 or B-2, U 2 is a nitrogen atom, Y is Y-1, Y-2, or Y-3; (2) B is B-1 or B-2, U 2 CR 42 and Y is Y-11, Y-12, or Y-15; (3) The therapeutic or prophylactic agent according to item 9 or 10, wherein B is B-4 and Y is a hydrogen atom. (Section 12) R 4 Item 12. The therapeutic or prophylactic agent according to Item 11, wherein is pyridyl substituted with one group selected from the group consisting of alkyl, trihaloalkyl, alkoxy, cyano, and cycloalkyl, and trihaloalkyl. (Section 13) Item 13. The therapeutic or prophylactic agent according to Item 12, wherein A is A-4. (Section 14) Item 14. The therapeutic or prophylactic agent according to any one of items 9 to 13, wherein the azabenzimidazole compound is any one of the following compounds (1) to (15): (1) [4-(5-{5-[3-fluoro-5-(trifluoromethyl)phenyl]-7-[{[1-(methoxymethyl)cyclobutyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperazin-1-yl]acetic acid, (2) 4-fluoro-1-(5-{5-[3-fluoro-5-(trifluoromethyl)phenyl]-7-[{[1-(methoxymethyl)cyclobutyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid, (3) 1-(5-{5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclobutyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid, (4) 1-(5-{5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclobutyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid, (5) {[1-(5-{5-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidin-4-yl]oxy}acetic acid, (6) 1-(4-{5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}-3-fluorophenyl)piperidine-4-carboxylic acid, (7) 1-(5-{5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-[(3-methoxy-2,2-dimethylpropyl)(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid, (8) 1-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(ethoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid, (9) 1-(5-{5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid, (10) 3-[4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperazin-1-yl]propanoic acid, (11) [4-(4-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}-3-fluorophenoxy)piperidin-1-yl]acetic acid, (12) 3-[(2S)-4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-2-(methoxymethyl)piperazin-1-yl]propanoic acid, (13) 3-[(3R)-4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(ethoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-3-methylpiperazin-1-yl]propanoic acid, (14) 3-[(3R)-4-(5-{5-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-3-methylpiperazin-1-yl]propanoic acid, (15) 3-[(3R)-4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-3-methylpiperazin-1-yl]propanoic acid. Effect of the Invention

[0011] According to the present invention, there is provided a novel therapeutic or prophylactic agent for functional gastrointestinal disorders or xerostomia, which comprises, as an active ingredient, an azabenzimidazole compound represented by the above formula [1] or a pharma- ceutical acceptable salt thereof, or a solvate thereof. [Brief description of the drawings]

[0012] [Figure 1] FIG. 1 shows the number of feces in constipated model mice administered with the compounds of Examples 1 to 4. [Diagram 2] FIG. 2 shows the number of feces in the constipated model mice to which the compounds of Examples 6 and 7 were administered. [Diagram 3] FIG. 3 shows the number of feces in constipated model mice administered with the compounds of Examples 8 to 11. [Figure 4] FIG. 4 shows the number of feces in constipated model mice administered with the compounds of Examples 12 to 15. [Diagram 5] FIG. 5 shows the fecal dry weight in FIG. [Figure 6] FIG. 6 shows the fecal dry weight in FIG. [Figure 7] FIG. 7 shows the fecal dry weight in FIG. [Figure 8] FIG. 8 shows the fecal dry weight in FIG. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The meaning of each term used in this specification will be explained below. Unless otherwise specified, each term has the same meaning whether it is used alone or in combination with other terms.

[0014] "Halogen" refers to fluorine, chlorine, bromine, and iodine atoms.

[0015] Examples of the "alkyl" include linear or branched alkyl having 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, and more preferably 1 to 6 carbon atoms. Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 1,2-dimethylpropyl, tert-pentyl, 2-methylbutyl, isopentyl, neopentyl, n-hexyl, sec-hexyl, 1-ethylbutyl, isohexyl, neohexyl, 1,1-dimethylbutyl, thexyl, 2-ethylbutyl, 1,2,2-trimethylpropyl, 2,2-dimethylbutyl, n-heptyl, isoheptyl, n-octyl, and isooctyl.

[0016] The alkyl portion of the "alkoxyalkyl" and "alkyl substituted with cycloalkyl" can be the same as the "alkyl" defined above.

[0017] The term "trihaloalkyl" refers to the above "alkyl" substituted with three of the above "halogens." Specific examples include trifluoromethyl, trichloromethyl, and trifluoroethyl.

[0018] "Alkoxy" refers to a group in which the above-mentioned "alkyl" is bonded to an oxygen atom. For example, a straight or branched alkoxy having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, can be mentioned. Specific examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, and n-octyloxy.

[0019] The alkoxy portion of "alkoxyalkyl" can be the same as "alkoxy" as defined above.

[0020] The term "alkylene" includes alkylene having a straight or branched divalent hydrocarbon group having 1 to 6 carbon atoms. Specific examples include methylene, ethylene, and propylene.

[0021] Examples of "cycloalkyl" include saturated hydrocarbon groups having 3 to 10 carbon atoms and 1 to 3 rings. A monocyclic cycloalkyl having 3 to 6 carbon atoms is preferred. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.1.0]pentyl, bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl.

[0022] The cycloalkyl portion of the "alkyl substituted with cycloalkyl" can be the same as the "cycloalkyl" mentioned above.

[0023] Examples of the "non-aromatic heterocyclic group containing oxygen" include a 3- to 8-membered non-aromatic heterocyclic group, more preferably a 5- to 7-membered non-aromatic heterocyclic group, containing an oxygen atom as a ring-constituting atom other than carbon atoms. Specific examples include oxolanyl (1-oxolanyl, 2-oxolanyl), oxanyl (1-oxanyl, 2-oxanyl, 3-oxanyl), and oxepanyl (1-oxepanyl, 2-oxepanyl, 3-oxepanyl).

[0024] Each symbol in formula [1] will be explained below.

[0025] R in Equation [1] 1 is a hydrogen atom or an alkyl group, or two R 1 may be joined together with the adjacent carbon atom to form a 3- to 7-membered cycloalkyl or oxygen-containing non-aromatic heterocycle.

[0026] R 1 As the "alkyl" in this case, methyl, ethyl, n-propyl and n-butyl are preferable, and methyl and ethyl are more preferable.

[0027] R 1 The "cycloalkyl" is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, more preferably cyclobutyl, cyclopentyl, or cyclohexyl.

[0028] R 1 The "non-aromatic heterocyclic group containing oxygen" is preferably 1-oxanyl, 2-oxanyl or 3-oxanyl, more preferably 3-oxanyl.

[0029] R in Equation [1] 2 is a hydrogen atom, alkyl, cycloalkyl, alkyl substituted with cycloalkyl, or alkoxyalkyl.

[0030] R 2 As the "alkyl" in this case, methyl, ethyl, n-propyl, n-butyl and n-pentyl are preferable, and methyl, ethyl, n-propyl and n-butyl are more preferable.

[0031] R 2 As the "cycloalkyl", cyclopropyl and cyclobutyl are preferred.

[0032] R 2 The cycloalkyl of the "alkyl substituted with cycloalkyl" is preferably cyclobutyl or cyclopentyl, more preferably cyclobutyl.

[0033] R 2 The alkyl of the "alkyl substituted with cycloalkyl" is preferably methyl or ethyl, and more preferably methyl.

[0034] R 2 The alkoxy of the "alkoxyalkyl" is preferably methoxy, ethoxy, n-propoxy or isopropoxy, more preferably methoxy or ethoxy.

[0035] R 2The alkyl of the "alkoxyalkyl" is preferably methyl, ethyl or propyl, more preferably methyl or ethyl.

[0036] R in Equation [1] 3 is a hydrogen atom, alkyl, cycloalkyl, alkyl substituted with cycloalkyl, or alkoxyalkyl.

[0037] R 3 As the "alkyl", methyl, ethyl and n-propyl are preferable, and methyl and ethyl are more preferable.

[0038] R 3 The alkoxy of the "alkoxyalkyl" is preferably methoxy or ethoxy, and more preferably methoxy.

[0039] R in Equation [1] 4 is pyridyl which may be substituted with 1 or 2 groups selected from the group consisting of alkyl, trihaloalkyl, alkoxy, cyano, and cycloalkyl, or phenyl which may be substituted with 1 to 3 groups selected from the group consisting of trihaloalkyl, halogen, alkoxy, and cycloalkyl.

[0040] R 4 As the "alkyl" in the pyridyl which may be substituted by one or two alkyl groups, methyl, ethyl and n-propyl are preferred.

[0041] R 4 As the "trihaloalkyl" in the pyridyl which may be substituted with one or two alkyl groups, trifluoromethyl is preferable.

[0042] R 4 As the "alkoxy" in the pyridyl which may be substituted by one or two alkoxy groups, methoxy, ethoxy, n-propoxy, and n-butoxy are preferable, and ethoxy is more preferable.

[0043] R 4 As the "cycloalkyl" in the pyridyl which may be substituted by one or two cycloalkyl groups, cyclopropyl and cyclobutyl are preferred, and cyclopropyl is more preferred.

[0044] R 4 As the "trihaloalkyl" in the phenyl which may be substituted with 1 to 3 trihaloalkyl, trifluoromethyl is preferable.

[0045] R 4 As the "halogen" in the phenyl which may be substituted with 1 to 3 halogens, a chlorine atom, a bromine atom or a fluorine atom is preferable, and a fluorine atom is more preferable.

[0046] R 4 As the "alkoxy" in the phenyl which may be substituted by 1 to 3 alkoxy groups, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy are preferred, and methoxy and ethoxy are more preferred.

[0047] R 4 The "cycloalkyl" which may be substituted on the phenyl is preferably cyclopropyl or cyclobutyl, more preferably cyclopropyl.

[0048] R 4 As the alkyl group, a group selected from the group consisting of alkyl, trihaloalkyl, alkoxy, cyano, and cycloalkyl, as well as pyridyl substituted with trihaloalkyl are preferred.

[0049] In the formula [1], A is a group represented by the following A-1, A-2, A-3, A-4, or A-5. [ka]

[0050] R in Equation [1] 11is a group selected from a hydrogen atom, halogen, alkyl, alkoxy, and nitro.

[0051] R 11 The "halogen" is preferably a chlorine atom, a bromine atom or a fluorine atom, more preferably a chlorine atom or a fluorine atom.

[0052] R 11 As the "alkyl", methyl, ethyl and n-propyl are preferable, and methyl and ethyl are more preferable.

[0053] R 11 As the "alkoxy", methoxy and ethoxy are preferable, and methoxy is more preferable.

[0054] As A in the formula [1], A-4 is preferable.

[0055] W in formula [1] is a bond or is selected from the following W-1, W-2, or W-3. [ka]

[0056] R in W-1 21 is a group selected from a hydrogen atom and alkyl.

[0057] R 21 As the "alkyl", methyl and ethyl are preferable, and methyl is more preferable.

[0058] W in the formula [1] is preferably a bond.

[0059] B is selected from the following B-1, B-2, B-3, or B-4.

[0060] [ka] (The left bond of each of B-1 to B-4 is bonded to W in formula [1], and the right bond is bonded to Y in formula [1].)

[0061] U 1 is a nitrogen atom, or CR 41 represents U 2 is a nitrogen atom, or CR 42 Represents.

[0062] R 41 , and R 42 each independently represents a hydrogen atom, an alkyl group, a halogen atom, or a hydroxyl group.

[0063] m and n are 1, 2, or 3, respectively.

[0064] R 31 and R 32 are each independently a hydrogen atom, an alkyl, a halogen, or an alkoxyalkyl, or R 31 and R 32 may be taken together with adjacent carbon atoms to form an alkylene bridge. R 31 , and R 32 is U 1 , and U 2 Substitute in any position that can be substituted except for .

[0065] R 31 , and R 32 As the "alkyl", methyl and ethyl are preferable, and methyl is more preferable.

[0066] R 31 , and R 32 The "halogen" is preferably a fluorine atom.

[0067] R 31 , and R 32 The "alkyl" in the "alkoxyalkyl" is preferably methyl, ethyl or n-propyl, more preferably methyl or ethyl.

[0068] R 31 , and R32 The alkoxy of the "alkoxyalkyl" is preferably methoxy or ethoxy, and more preferably methoxy.

[0069] R 31 and R 32 The alkylene bridge formed by combining these is preferably a linear alkylene bridge having 1 to 3 carbon atoms, and more preferably a methylene bridge or an ethylene bridge.

[0070] As B in the formula [1], B-1, B-2 and B-4 are preferable, B-1 and B-4 are more preferable, and B-1 is further preferable.

[0071] Y is a hydrogen atom, or selected from the following Y-1 to Y-4, or Y-11 to Y-16. [ka]

[0072] R 51 is alkyl, p is 1, 2, or 3, q ​​is 0, 1, or 2, r is 1, 2, or 3, and T is O, S, SO2, or NR 61 where R 61 is a hydrogen atom or alkyl; s is 0, 1, 2, or 3; and t is 0 or 1.

[0073] R 51 , and R 61 As the "alkyl", methyl, ethyl and n-propyl are preferable, and methyl and ethyl are more preferable.

[0074] As Y in the formula [1], Y-1, Y-2, Y-3, Y-11, Y-12 and Y-15 are preferable.

[0075] The combination of W, B, and Y in formula [1] is as follows: (a) When W is a bond B is B-1 or B-2, and U 2 is a nitrogen atom, Y is Y-1, Y-2, Y-3, or Y-4, with Y-1, Y-2, and Y-3 being preferred. B is B-1, B-2, and U 2 CR 42 When (R 42 has the same meaning as above), U 1 is a nitrogen atom, Y is Y-11, Y-12, Y-13, Y-14, Y-15, or Y-16, and Y-11, Y-12, and Y-15 are preferred. When B is B-3 or B-4, Y is a hydrogen atom, (b) If W is W-1 B is B-1, U 1 is a nitrogen atom, U 2 is a nitrogen atom, Y is Y-1, Y-2, Y-3 or Y-4, with Y-1, Y-2 and Y-3 being preferred. B is B-1, U 1 is a nitrogen atom, U 2 CR 42 When (R 42 has the same meaning as above), and Y is Y-11, Y-12, Y-13, Y-14, Y-15, or Y-16, with Y-11, Y-12, and Y-15 being preferred. (c) If W is W-2 B is B-1 or B-2, U 1 is a nitrogen atom, U 2 is a nitrogen atom, Y is Y-1, Y-2, Y-3 or Y-4, with Y-1, Y-2 and Y-3 being preferred. B is B-1 or B-2, U 1 is a nitrogen atom, U 2 CR 42 When (R 42 has the same meaning as above), and Y is Y-11, Y-12, Y-13, Y-14, Y-15, or Y-16, with Y-11, Y-12, and Y-15 being preferred. When B is B-3 or B-4, Y is a hydrogen atom, (d) If W is a W-3: B is B-1, U 1 is CR 41 (R 41 has the same meaning as above), U 2 is a nitrogen atom, Y is Y-1, Y-2, Y-3, or Y-4, with Y-1, Y-2, and Y-3 being preferred.

[0076] The compound of the present invention can be produced from a known compound or an intermediate that can be easily synthesized, for example, by the method described below, the Examples described below, or a known method. In the production of the compound of the present invention, when the raw material has a substituent that affects the reaction, the raw material is generally protected with an appropriate protecting group by a known method beforehand, and then the reaction is carried out. The protecting group can be removed by a known method after the reaction.

[0077] The azabenzimidazole compound of the present invention can be used as a medicine as it is, but can also be used in the form of a pharma- ceutically acceptable salt, solvate, or solvate of a salt by a known method. Examples of pharma-ceutically acceptable salts include salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, salts of organic acids such as acetic acid, malic acid, lactic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid, and salts of organic bases such as salts of alkali metals such as lithium, potassium, and sodium, salts of alkaline earth metals such as magnesium and calcium, and ammonium salts. These salts can be formed by a commonly used method.

[0078] For example, when the compound of the present invention is a hydrochloride salt, the azabenzimidazole compound of the present invention can be obtained by dissolving the compound in an alcohol solution of hydrogen chloride, an ethyl acetate solution of hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, a cyclopentyl methyl ether solution of hydrogen chloride, or a diethyl ether solution of hydrogen chloride.

[0079] Of the compounds of the present invention, those having an asymmetric carbon atom are included in the present invention in both stereoisomers and mixtures thereof. Stereoisomers can be produced, for example, by optical resolution of a racemate using an optically active acid (tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.) by a known method utilizing its basicity, or by using a previously prepared optically active compound as a raw material. In addition, they can also be produced by optical resolution using a chiral column or asymmetric synthesis.

[0080] The formula [1] in the present invention is not limited to a specific isomer, but includes all possible isomers and racemates, for example, as shown below, including tautomers [1Eq] and stereoisomers. [ka] (In the formula, each symbol has the same meaning as defined above.)

[0081] Acetylcholine (ACh) is a neurotransmitter that is released from the terminals of parasympathetic nerves and motor nerves and transmits nerve stimuli by binding to acetylcholine receptors (AChR). Acetylcholine receptors are broadly classified into G protein-coupled muscarinic receptors and ion channel-type nicotinic receptors. Muscarinic receptors are classified into five subtypes, M1 to M5. Subtype M3 muscarinic receptors (hereinafter sometimes referred to as "M3 receptors") are mainly expressed in the bladder, digestive tract, pupils, salivary glands, lacrimal glands, etc., and have been reported to be involved in contraction of the bladder, digestive tract, and pupils, and secretion of saliva and tears, etc. (see Non-Patent Documents 4 and 5).

[0082] In G protein-coupled receptors, many structures of allosteric sites different from the orthosteric site where endogenous agonists bind have been reported, and in recent years, this allosteric site has attracted a lot of attention (see Non-Patent Document 6). Depending on the ligand that binds to the allosteric site, the structure of the receptor is changed and the binding strength between the endogenous agonist and the receptor is increased. This makes it possible to enhance the signal level dependent on the endogenous agonist stimulation for the receptor. In this specification, a ligand that enhances the signal level of the receptor caused by the endogenous agonist by binding to the allosteric site in this way is called a positive allosteric modulator (PAM). In other words, a positive allosteric modulator means a ligand that enhances the signal of the agonist by binding to an allosteric site different from the orthosteric site where the endogenous agonist binds.

[0083] In recent years, an allosteric site different from the orthosteric site to which endogenous agonists (acetylcholine, muscarine) bind has also been reported for the M3 receptor (see Non-Patent Document 7). It is believed that M3 receptor PAM (hereinafter referred to as "M3 PAM") can enhance the signal level dependent on endogenous agonist stimulation for the M3 receptor. For this reason, M3 PAM can enhance the signal level of the M3 receptor under more physiological conditions, and is expected to be promising for the treatment of diseases involving the M3 receptor.

[0084] As shown in the test examples described later, the compound of the present invention has M3 PAM activity, and has an effect of improving gastrointestinal function and promoting saliva secretion. Here, M3 PAM activity means an effect of enhancing M3 receptor function by binding to a site (allosteric site) in the M3 receptor that is different from the binding site (orthosteric site) of endogenous activators (acetylcholine and muscarine).

[0085] Therefore, the compound of the present invention can be used as an agent for treating or preventing functional gastrointestinal disorders or xerostomia.

[0086] When the compound of the present invention is administered as a medicine, it is administered to mammals, including humans, as it is or as a pharmaceutical composition containing, for example, 0.001% to 99.5%, preferably 0.1% to 90%, of the compound of the present invention in a pharma- ceutical acceptable, non-toxic and inert carrier.

[0087] The disease to which the compound of the present invention can be applied is functional gastrointestinal disorder. Functional gastrointestinal disorder includes functional esophageal disorder, functional gastroduodenal disorder, functional intestinal disorder, functional abdominal pain syndrome, functional gallbladder-sphincter of Oddi disorder, and functional anorectal syndrome. For example, functional esophageal disorder includes functional heartburn, functional gastroduodenal disorder includes functional dyspepsia, and functional intestinal disorder includes irritable bowel syndrome (IBS), functional constipation, and opioid-induced constipation.

[0088] In addition, the disease to which the compound of the present invention can be applied is xerostomia.For example, xerostomia can be caused by a certain disease, aging, salivary gland disorder due to radiation exposure, mental fatigue, or side effects of drug administration.For example, the above-mentioned certain disease can be caused by autoimmune disease, viral disease, diabetes, anemia, hypernatremia, renal disorder, etc.

[0089] The compound of the present invention can be used as it is or mixed with a pharmacologically acceptable carrier or the like to prepare a pharmaceutical composition containing, for example, 0.001% to 99.5%, preferably 0.1% to 90%, and can be used as a therapeutic agent for the various diseases described above in mammals such as humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, and monkeys.

[0090] The dosage as a medicine is preferably adjusted taking into consideration the patient's condition such as age, body weight, type and severity of disease, route of administration, type of the compound of the present invention, whether it is a salt, type of salt, etc., but usually, the amount of the active ingredient of the compound of the present invention for an adult is within the range of 0.01 mg to 5 g / adult, preferably 1 mg to 500 mg / adult per day in the case of oral administration. In some cases, a dosage less than this is sufficient, or conversely, a dosage greater than this may be required. Usually, it is administered once a day or in several divided doses, or in the case of intravenous administration, it can be administered rapidly or continuously within 24 hours.

[0091] One or more hydrogen, carbon and / or other atoms of the compounds of the present invention may be replaced with isotopes of the hydrogen, carbon and / or other atoms, respectively. Examples of such isotopes include, but are not limited to, 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, 123 I and 36 Cl, i.e., hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included. Compounds substituted with such isotopes are also useful as pharmaceuticals, and include all radiolabeled compounds of the compounds of the present invention.

[0092] The present invention will be described in more detail below with reference to Reference Examples, Examples, and Test Examples, but the present invention is not limited thereto.

[0093] The following abbreviations are used in the examples. TFA: Trifluoroacetic acid Pt-C: Platinum-carbon Pd-C: Palladium-carbon Pd2(dba)3·CHCl3: Tris(dibenzylideneacetone)bispalladium·chloroform adduct Pd2(dba)3: Tris(dibenzylideneacetone)bispalladium Pd(dppf)Cl2·CH2Cl2: [1,1'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II)·dichloromethane adduct Pd(OAc)2: Palladium(II) acetate dppf: 1,1'-bis(diphenylphosphino)ferrocene XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl RuPhos: 2-dicyclohexylphosphino-2',6'-diisopropylbiphenyl PPh3: Triphenylphosphine Boc: tert-butoxycarbonyl Bn: Benzyl Ts: 4-Toluenesulfonyl SEM: 2-(trimethylsilyl)ethoxymethyl DAST: (Diethylamino)sulfur trifluoride HATU:O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate DEAD: Diethyl azodicarboxylate DMF: Dimethylformamide DMSO: Dimethyl sulfoxide THF: tetrahydrofuran DIPEA: N,N-diisopropylethylamine TEA: Triethylamine DBU: 1,8-diazabicyclo[5.4.0]-7-undecene CDCl3: deuterated chloroform DMSO-d6: deuterated dimethyl sulfoxide TLC: Thin Layer Chromatography MS: Mass spectrometry LCMS: Liquid Chromatography Mass Spectrometry ESI: Electron Spray Ionization M: Molar concentration (mol / L)

[0094] MS was measured by LCMS. ESI was used as the ionization method. The observed mass spectrometry values ​​are expressed in m / z.

[0095] The measurement conditions for LCMS are as follows. Analytical equipment: ACQUITY UPLC MS / PDA system (Waters) Mass spectrometer: Waters 3100 MS detector Photodiode array detector: ACQUITY PDA detector (UV detection wavelength: 210-400 nm) Column: Acquity BEH C18, 1.7 μm, 2.1×50 mm Flow rate: 0.5 mL / min Column temperature: 40 °C solvent; Solution A: 0.1% formic acid / H2O (v / v; hereafter the same) Solution B: 0.1% formic acid / acetonitrile

[0096] 1 H NMR spectrum was measured using a JNM-ECS400 nuclear magnetic resonance spectrometer (manufactured by JEOL RESONANCE Co., Ltd.). The observed peaks are expressed as chemical shift values ​​δ (ppm) (s = singlet, d = doublet, t = triplet, q = quartet, brs = broad singlet, m = multiplet, dd = double doublet, dt = double triplet).

[0097] For microwave experiments, an Initiator 60 (Biotage) was used, which can achieve temperatures of 40-250°C and pressures up to 20 bar.

[0098] The compound names in this specification were created using naming software conforming to the IUPAC rules, ACD / NAME (registered trademark, Advanced Chemistry Development Inc.), or ChemBioDraw (Version 14.0, Cambridge Soft), or in accordance with the IUPAC nomenclature.

[0099] The r and s (lower case) in compound names indicate the stereochemistry of the pseudo-asymmetric carbon atom according to IUPAC rules.

[0100] Reference Example 1 1-[1-(ethoxymethyl)cyclopentyl]-N-methylmethanamine hydrochloride [Step 1] Production of 1-(ethoxymethyl)cyclopentane-1-carbonitrile To a solution of 1-(hydroxymethyl)cyclopentane-1-carbonitrile (43.1 g) in DMF (1150 mL), 60% sodium hydride (16.5 g) was added under ice-cooling and stirring, and the mixture was stirred at room temperature for 1 hour. Ethyl iodide (64.4 g) was added thereto under ice-cooling and stirred at room temperature. After confirming the disappearance of the raw materials by TLC, water and ethyl acetate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (48.0 g). [Step 2] Preparation of tert-butyl {[1-(ethoxymethyl)cyclopentyl]methyl}methylcarbamate Lithium aluminum hydride (11.4 g) was suspended in THF (800 mL), and a solution of 1-(ethoxymethyl)cyclopentane-1-carbonitrile (46.0 g) obtained in step 1 in THF (200 mL) was added dropwise under ice-cooling and stirring. After the dropwise addition, the mixture was stirred at room temperature for 2 hours. The reaction mixture was ice-cooled, and water (11.4 mL), 15% aqueous sodium hydroxide solution (11.4 mL), and water (34.2 mL) were added dropwise in that order. After the dropwise addition, the mixture was stirred at room temperature for 2 hours, and the insoluble matter was filtered off with Celite and washed three times with THF (220 mL). To the filtrate, triethylamine (46.0 mL) and di-tert-butyl dicarbonate (72.1 g) were added while stirring at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was dissolved in DMF (600 mL), and 60% sodium hydride (14.4 g) was added under ice-cooling and stirring, followed by stirring at room temperature for 1 hour. The reaction mixture was ice-cooled, and methyl iodide (22.5 mL) was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature for 15 hours. The reaction mixture was ice-cooled, diluted with water, and extracted with ethyl acetate-hexane (1:2). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (71.2 g). [Step 3] Preparation of 1-[1-(ethoxymethyl)cyclopentyl]-N-methylmethanamine hydrochloride A solution of tert-butyl {[1-(ethoxymethyl)cyclopentyl]methyl}methylcarbamate (71.2 g) in ethyl acetate (52.5 mL) obtained in step 2 was stirred at room temperature, hydrogen chloride (4 M in ethyl acetate, 328 mL) was added, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the precipitated solid was collected by filtration, washed with hexane, and then dried to obtain the title compound (50.3 g). Reference Example 2 1-[1-(methoxymethyl)cyclopentyl]-N-methylmethanamine hydrochloride [Step 1] Preparation of tert-butyl {[1-(hydroxymethyl)cyclopentyl]methyl}carbamate Triethylamine (60.2 mL) was added to a solution of [1-(aminomethyl)cyclopentyl]methanol (50.7 g) in THF (304 mL) under ice-cooling and stirring. A solution of di-tert-butyl dicarbonate (94.2 g) in THF (101 mL) was added dropwise thereto. After the dropwise addition, the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and ethyl acetate, and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate-hexane (1:9) (700 mL) and stirred at room temperature for 3 hours. Insoluble matter was collected by filtration, washed with hexane, and then dried to obtain the title compound (49.2 g). The solvent was also distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (15.9 g). [Step 2] Preparation of tert-butyl {[1-(methoxymethyl)cyclopentyl]methyl}methylcarbamate To a solution of tert-butyl {[1-(hydroxymethyl)cyclopentyl]methyl}carbamate (58 g) obtained in step 1 in DMF (505 mL) was added methyl iodide (47 mL) while stirring at room temperature. Subsequently, 60% sodium hydride (30 g) was added in portions while stirring on ice. After stirring for 30 minutes under ice cooling, the temperature was raised to room temperature and stirred overnight. Water (800 mL) was added dropwise to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (68 g). [Step 3] Preparation of 1-[1-(methoxymethyl)cyclopentyl]-N-methylmethanamine hydrochloride The title compound (52 g) was obtained by a method similar to that in Step 3 of Reference Example 1, except that tert-butyl {[1-(methoxymethyl)cyclopentyl]methyl}methylcarbamate obtained in Step 2 was used instead of tert-butyl {[1-(ethoxymethyl)cyclopentyl]methyl}methylcarbamate. Reference Example 3 4-chloro-6-[3-fluoro-5-(trifluoromethyl)phenyl]pyridin-2-amine [3-Fluoro-5-(trifluoromethyl)phenyl]boronic acid (0.6 g), 4,6-dichloropyridin-2-amine (0.45 g), potassium carbonate (1.2 g) were added with 1,4-dioxane (9.6 mL) and water (2.4 mL) and degassed. Pd(dppf)Cl2·CH2Cl2 (118 mg) was added while stirring at room temperature under argon atmosphere, and the mixture was stirred at 80 °C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (0.5 g). Reference Example 4 4-Chloro-6-[3-fluoro-5-(trifluoromethyl)phenyl]-3-nitropyridin-2-amine To 4-chloro-6-[3-fluoro-5-(trifluoromethyl)phenyl]pyridin-2-amine (0.5 g) was added concentrated sulfuric acid (2.5 mL) under ice cooling, and potassium nitrate (165 mg) was added in portions. After stirring for 15 minutes under ice cooling, the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into ice water, and 4 M aqueous sodium hydroxide solution (25 mL) was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (0.35 g). Reference Example 5 6-Chloro-N 4 -(3-Methoxy-2,2-dimethylpropyl)-N 4 -Methyl-3-nitropyridine-2,4-diamine A mixture of 4,6-dichloro-3-nitropyridin-2-amine (6.3 g), 3-methoxy-N,2,2-trimethylpropan-1-amine hydrochloride (6.6 g), DIPEA (16 mL), and 2-propanol (100 mL) was stirred for 1 hour at 60° C. After cooling to room temperature, water (50 mL) was added, and the precipitate was collected by filtration, washed with 2-propanol and water, and then dried to obtain the title compound (8.0 g).

[0101] Reference Example 6 6'-Cyclopropyl-N 4 -{[1-(methoxymethyl)cyclohexyl]methyl}-N 4 -Methyl-5-nitro-5'-(trifluoromethyl)[2,3'-bipyridine]-4,6-diamine 6-Chloro-N 4-{[1-(methoxymethyl)cyclohexyl]methyl}-N 4 A mixture of 2.5 g of 2-methyl-3-nitropyridine-2,4-diamine, 5-(4,4,5,5-tetramethyl-1,3,2,-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridine, 2.7 g, potassium carbonate, 3.0 g, 1,4-dioxane, 29 mL, and water, 11 mL, was degassed and stirred at room temperature under an argon atmosphere, while adding Pd(dppf)Cl2·CH2Cl2 (0.24 g). This was stirred at 95 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (3.5 g). Reference Example 7 2'-Ethoxy-N 4 -{[1-(methoxymethyl)cyclobutyl]methyl}-N 4 -Methyl-6'-(trifluoromethyl)[2,4'-bipyridine]-4,5,6-triamine 2'-Ethoxy-N 4 -{[1-(methoxymethyl)cyclobutyl]methyl}-N 4 To a mixture of 5-methyl-5-nitro-6'-(trifluoromethyl)[2,4'-bipyridine]-4,6-diamine (684 mg), 2-propanol (7.5 mL), and water (2.5 mL), ammonium chloride (234 mg) and reduced iron (powder, 244 mg) were added at room temperature, and the mixture was stirred at 90 ° C overnight. After cooling the reaction solution to room temperature, it was diluted with ethyl acetate and water, and insoluble matter was filtered off using Celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (570 mg). Reference Example 8 6'-Cyclopropyl-N 4 -{[1-(ethoxymethyl)cyclopentyl]methyl}-N 4 -Methyl-5'-(trifluoromethyl)[2,3'-bipyridine]-4,5,6-triamine 6'-Cyclopropyl-N 4 -{[1-(ethoxymethyl)cyclopentyl]methyl}-N 4To a mixture of 5-methyl-5-nitro-5'-(trifluoromethyl)[2,3'-bipyridine]-4,6-diamine (5.8 g), ammonium chloride (1.9 g), 2-propanol (39 mL), and water (20 mL), zinc powder (3.9 g) was added while stirring at room temperature, and the mixture was stirred at 50 ° C for 4 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and insoluble matter was filtered off through Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (5.3 g). Reference Example 9 Ethyl 3-[(3R)-4-(5-formylpyrazin-2-yl)-3-methylpiperazin-1-yl]propanoate [Step 1] Preparation of tert-butyl (3R)-4-(5-formylpyrazin-2-yl)-3-methylpiperazine-1-carboxylate A mixture of 5-chloropyrazine-2-carbaldehyde (350 mg), tert-butyl (3R)-3-methylpiperazine-1-carboxylate (541 mg), DIPEA (1.28 mL), and THF (4.9 mL) was stirred at 70 °C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate, and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (755 mg). [Step 2] Preparation of ethyl 3-[(3R)-4-(5-formylpyrazin-2-yl)-3-methylpiperazin-1-yl]propanoate tert-Butyl (3R)-4-(5-formylpyrazin-2-yl)-3-methylpiperazine-1-carboxylate (816 mg) was dissolved in ethyl acetate (5.3 mL), and hydrogen chloride (4 M ethyl acetate solution, 5.3 mL) was added while stirring at room temperature, and the mixture was stirred at the same temperature for 1 hour. After distilling off the solvent under reduced pressure, the residue was mixed with acetonitrile (5 mL), and DIPEA (2.31 mL) and ethyl 3-bromopropanoate (0.442 mL) were added while stirring at room temperature, and the mixture was stirred at 70 ° C. for 4 hours. After cooling to room temperature, the reaction mixture was purified by silica gel column chromatography to obtain the title compound (676 mg). Reference Example 10 Ethyl 1-(5-formylpyrazin-2-yl)piperidine-4-carboxylate A mixture of 5-chloropyrazine-2-carbaldehyde (0.49 g), ethyl piperidine-4-carboxylate (0.54 g), DMSO (10 mL), and sodium hydrogen carbonate (1.4 g) was stirred at 70 °C for 17 hours. After cooling to room temperature, the mixture was cooled on ice, diluted with water, 2 M hydrochloric acid (6 mL), and ethyl acetate, and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (0.79 g).

[0102] Reference Example 11 Ethyl 3-[4-(5-formylpyrazin-2-yl)piperazin-1-yl]propanoate A mixture of ethyl 3-(piperazin-1-yl)propanoate (0.142 mL), 5-chloropyrazine-2-carbaldehyde (100 mg), potassium carbonate (485 mg), and DMSO (3.5 mL) was stirred at 90 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (138 mg). Reference Example 12 Ethyl {[1-(5-formylpyrazin-2-yl)piperidin-4-yl]oxy}acetate A mixture of 5-chloropyrazine-2-carbaldehyde (0.55 g), ethyl [(piperidin-4-yl)oxy]acetate hydrochloride (0.92 g), THF (7.7 mL), and DIPEA (2.7 mL) was stirred at 70° C. for 4 hours. After cooling to room temperature, the reaction mixture was diluted with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (1.0 g). Reference Example 13 2'-Cyclopropyl-N 4 -{[1-(methoxymethyl)cyclohexyl]methyl}-N 4 -Methyl-6'-(trifluoromethyl)[2,4'-bipyridine]-4,5,6-triamine 6-Chloro-N 4 -{[1-(methoxymethyl)cyclohexyl]methyl}-N 4A mixture of 2'-methyl-3-nitropyridine-2,4-diamine (1.0 g), 2-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (1.1 g), potassium carbonate (1.2 g), Pd(dppf)Cl2·CH2Cl2 (95 mg), 1,4-dioxane (12 mL) and water (4.5 mL) was degassed and stirred at 90 °C for 2 hours under argon atmosphere. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2'-cyclopropyl-N 4 -{[1-(methoxymethyl)cyclohexyl]methyl}-N 4 5-Methyl-5-nitro-6'-(trifluoromethyl)[[2,4'-bipyridine]-4,6-diamine was obtained. This was mixed with 2-propanol (9.7 mL), water (2.9 mL), ammonium chloride (0.47 g), and zinc powder (0.95 g) and stirred at room temperature for 1 hour. Insoluble matter was filtered off through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (1.2 g). Reference Example 14 Ethyl [4-(3-fluoro-4-formylphenoxy)piperidin-1-yl]acetate [Step 1] Preparation of tert-butyl 4-(3-fluoro-4-formylphenoxy)piperidine-1-carboxylate PPh3 (782 mg) was added to a mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (400 mg), 2-fluoro-4-hydroxybenzaldehyde (175 mg), and THF (10 mL) while stirring at room temperature. DEAD (1.4 mL) was added under ice cooling, and the mixture was warmed to room temperature and stirred. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and saturated saline, and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (175 mg). [Step 2] Preparation of ethyl [4-(3-fluoro-4-formylphenoxy)piperidin-1-yl]acetate Hydrogen chloride (4 M ethyl acetate solution, 0.68 mL) was added to a methanol (1.4 mL) solution of tert-butyl 4-(3-fluoro-4-formylphenoxy)piperidine-1-carboxylate (175 mg) obtained in step 1 while stirring at room temperature, and the mixture was stirred at the same temperature for 2 hours, at 40 ° C. for 2 hours, and at room temperature overnight. The reaction mixture was concentrated under reduced pressure and then dried to obtain 2-fluoro-4-[(piperidin-4-yl)oxy]benzaldehyde hydrochloride. This was mixed with acetonitrile (2 mL), and while stirring at room temperature, DIPEA (0.47 mL) and ethyl bromoacetate (0.078 mL) were added, and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was purified by silica gel column chromatography to obtain the title compound (130 mg). Reference Example 15 Ethyl [4-(5-{5-[3-fluoro-5-(trifluoromethyl)phenyl]-7-[{[1-(methoxymethyl)cyclobutyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperazin-1-yl]acetate 6-[3-Fluoro-5-(trifluoromethyl)phenyl]-N 4 -{[1-(methoxymethyl)cyclobutyl]methyl}-N 4 A mixture of 1,3-methylpyridine-2,3,4-triamine (50 mg), ethyl [4-(5-formylpyrazin-2-yl)piperazin-1-yl]acetate (35 mg), sodium dithionite (53 mg) and DMF (1 mL) was stirred at 100° C. for 4 hours. Sodium dithionite (21 mg) was added and stirred at 100° C. for 3 hours. After cooling to room temperature, the reaction mixture was diluted with saturated aqueous sodium bicarbonate and water, and the precipitate was collected by filtration, washed with water and dried to obtain the title compound (67 mg).

[0103] Reference Example 16 Ethyl 1-(5-{5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclobutyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylate 2'-Ethoxy-N 4 -{[1-(methoxymethyl)cyclobutyl]methyl}-N 4A mixture of 1,2-methyl-6'-(trifluoromethyl)[2,4'-bipyridine]-4,5,6-triamine (2.30 g), ethyl 1-(5-formylpyrazin-2-yl)piperidine-4-carboxylate (1.45 g), sodium dithionite (2.30 g) and DMF (26 mL) was stirred at 110 ° C for 4.5 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (3.06 g). Reference Example 17 Ethyl {[1-(5-{5-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidin-4-yl]oxy}acetate 2'-Cyclopropyl-N 4 -{[1-(methoxymethyl)cyclopentyl]methyl}-N 4 A mixture of 1-methyl-6'-(trifluoromethyl)[2,4'-bipyridine]-4,5,6-triamine (115 mg), ethyl {[1-(5-formylpyrazin-2-yl)piperidin-4-yl]oxy}acetate (79 mg), sodium dithionite (112 mg) and DMF (2.6 mL) was stirred at 100 °C for 5 hours. After cooling to room temperature, it was diluted with water and saturated aqueous ammonium chloride solution and extracted with ethyl acetate-hexane. The organic layer was washed with water and saturated saline, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (142 mg). Reference Example 18 Ethyl 1-(5-{5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-[(3-methoxy-2,2-dimethylpropyl)(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylate 2'-Ethoxy-N 4 -(3-Methoxy-2,2-dimethylpropyl)-N 4 A mixture of 1,2-methyl-6'-(trifluoromethyl)[2,4'-bipyridine]-4,5,6-triamine (50 mg), ethyl 1-(5-formylpyrazin-2-yl)piperidine-4-carboxylate (32 mg), sodium dithionite (51 mg) and DMF (1 mL) was stirred at 100 °C for 8 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (75 mg). Reference Example 19 Ethyl 1-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(ethoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylate 6'-Cyclopropyl-N 4 -{[1-(ethoxymethyl)cyclopentyl]methyl}-N 4A mixture of 1,2-methyl-5'-(trifluoromethyl)[2,3'-bipyridine]-4,5,6-triamine (50 mg), ethyl 1-(5-formylpyrazin-2-yl)piperidine-4-carboxylate (30 mg), sodium dithionite (23 mg) and DMF (0.72 mL) was stirred for 8 hours at 100° C. After cooling to room temperature, the reaction mixture was purified by silica gel column chromatography to obtain the title compound (76 mg). Reference Example 20 Ethyl 1-(5-{5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylate 2'-Ethoxy-N 4 -{[1-(methoxymethyl)cyclopentyl]methyl}-N 4 A mixture of 1,2-methyl-6'-(trifluoromethyl)[2,4'-bipyridine]-4,5,6-triamine (50 mg), ethyl 1-(5-formylpyrazin-2-yl)piperidine-4-carboxylate (31 mg), sodium dithionite (48 mg) and DMF (1 mL) was stirred at 100 °C for 8 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (75 mg).

[0104] Reference Example 21 Ethyl 3-[4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperazin-1-yl]propanoate 6'-Cyclopropyl-N 4 -{[1-(methoxymethyl)cyclohexyl]methyl}-N 4 A mixture of 1,3-methyl-5'-(trifluoromethyl)[2,3'-bipyridine]-4,5,6-triamine (1.12 g), ethyl 3-[4-(5-formylpyrazin-2-yl)piperazin-1-yl]propanoate (0.742 g), sodium dithionite (1.05 g) and DMF (24 mL) was stirred at 110 ° C for 4 hours. After cooling to room temperature, sodium dithionite (1.05 g) was added and stirred at 100 ° C for 3 hours. After cooling to room temperature, it was diluted with water and saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (1.24 g).

[0105] Reference Example 22 Ethyl [4-(4-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}-3-fluorophenoxy)piperidin-1-yl]acetate 6'-Cyclopropyl-N 4 -{[1-(methoxymethyl)cyclopentyl]methyl}-N 4 A mixture of 3-methyl-5'-(trifluoromethyl)[2,3'-bipyridine]-4,5,6-triamine (35.6 mg), ethyl [4-(3-fluoro-4-formylphenoxy)piperidin-1-yl]acetate (25.7 mg), sodium dithionite (34.5 mg) and DMF (0.79 mL) was stirred overnight at 110 ° C. After cooling to room temperature, the reaction mixture was purified by silica gel column chromatography to obtain the title compound (40.7 mg). Reference Example 23 Ethyl 3-[(2S)-4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-2-(methoxymethyl)piperazin-1-yl]propanoate 6'-Cyclopropyl-N 4 -{[1-(methoxymethyl)cyclohexyl]methyl}-N 4 A mixture of 1,2-methyl-5'-(trifluoromethyl)[2,3'-bipyridine]-4,5,6-triamine (38 mg), ethyl 3-[(2S)-4-(5-formylpyrazin-2-yl)-2-(methoxymethyl)piperazin-1-yl]propanoate (29 mg), sodium dithionite (36 mg) and DMA (0.82 mL) was stirred at 110 ° C for 11 hours. After cooling to room temperature, it was diluted with water and extracted with dichloromethane. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (48 mg). Reference Example 24 Ethyl 3-[(3R)-4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(ethoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-3-methylpiperazin-1-yl]propanoate 6'-Cyclopropyl-N 4 -{[1-(ethoxymethyl)cyclopentyl]methyl}-N 4A mixture of 1.5 g of methyl-5'-(trifluoromethyl)[2,3'-bipyridine]-4,5,6-triamine, ethyl 3-[(3R)-4-(5-formylpyrazin-2-yl)-3-methylpiperazin-1-yl]propanoate, sodium dithionite, and DMF (15 mL) was stirred at 110 ° C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate, and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (1.9 g). Reference Example 25 Ethyl 3-[(3R)-4-(5-{5-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-3-methylpiperazin-1-yl]propanoate 2'-Cyclopropyl-N 4 -{[1-(methoxymethyl)cyclohexyl]methyl}-N 4 A mixture of 1,2-methyl-6'-(trifluoromethyl)[2,4'-bipyridine]-4,5,6-triamine (50 mg), ethyl 3-[(3R)-4-(5-formylpyrazin-2-yl)-3-methylpiperazin-1-yl]propanoate (36 mg), sodium dithionite (47 mg) and DMF (0.5 mL) was stirred at 110°C for 8 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (76 mg).

[0106] Example 1 [4-(5-{5-[3-fluoro-5-(trifluoromethyl)phenyl]-7-[{[1-(methoxymethyl)cyclobutyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperazin-1-yl]acetic acid To a solution of ethyl [4-(5-{5-[3-fluoro-5-(trifluoromethyl)phenyl]-7-[{[1-(methoxymethyl)cyclobutyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperazin-1-yl]acetate (67 mg) in ethanol (1 mL), 1 M aqueous sodium hydroxide solution (0.134 mL) was added while stirring at room temperature, and the mixture was stirred at the same temperature for 4 hours. The reaction mixture was diluted with water and neutralized with 2 M hydrochloric acid. The precipitate was collected by filtration, washed with water, and then dried to obtain the title compound (60 mg). Example 2 4-Fluoro-1-(5-{5-[3-fluoro-5-(trifluoromethyl)phenyl]-7-[{[1-(methoxymethyl)cyclobutyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid The method of Example 1 was repeated, and the title compound (67 mg) was obtained using ethyl 4-fluoro-1-(5-{5-[3-fluoro-5-(trifluoromethyl)phenyl]-7-[{[1-(methoxymethyl)cyclobutyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperazin-1-yl]acetate instead of ethyl 4-fluoro-1-(5-{5-[3-fluoro-5-(trifluoromethyl)phenyl]-7-[{[1-(methoxymethyl)cyclobutyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylate (77 mg). Example 3 1-(5-{5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclobutyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid A 1 M aqueous solution of sodium hydroxide (0.30 mL) was added to a solution of ethyl 1-(5-{5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclobutyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylate (41 mg) in ethanol (1 mL), and the mixture was stirred at 70° C. for 2 hours. After cooling to room temperature, the mixture was diluted with water and neutralized with 1 M hydrochloric acid. The precipitate was collected by filtration and dried to obtain the title compound (30 mg). Example 4 1-(5-{5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclobutyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid dihydrochloride [Step 1] Preparation of 1-(5-{5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclobutyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid A mixture of ethyl 1-(5-{5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclobutyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylate (285 mg), ethanol (8 mL), and 1 M aqueous sodium hydroxide solution (2.1 mL) was stirred at 50° C. for 1 hour. After cooling to room temperature, the solvent was concentrated under reduced pressure, and the residue was diluted with water and neutralized with 1 M hydrochloric acid. The precipitate was collected by filtration and dried to obtain the title compound (245 mg). [Step 2] Preparation of 1-(5-{5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclobutyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid dihydrochloride 1-(5-{5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclobutyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid (245 mg) obtained in step 1 was diluted with ethyl acetate (8 mL), and hydrogen chloride (4 M ethyl acetate solution, 0.47 mL) was added while stirring at room temperature, and the mixture was stirred at the same temperature for 1 hour. The solvent was distilled off under reduced pressure, the residue was diluted with diethyl ether, and the insoluble matter was collected by filtration, washed with diethyl ether, and then dried to obtain the title compound (244 mg). Example 5 {[1-(5-{5-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidin-4-yl]oxy}acetic acid Lithium hydroxide monohydrate (32.8 mg) was added to a mixture of ethyl {[1-(5-{5-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidin-4-yl]oxy}acetate (141 mg), THF (0.78 mL), methanol (0.78 mL), and water (0.78 mL), and the mixture was stirred at room temperature for 30 minutes and then stirred at 50° C. overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with water. The mixture was neutralized by adding 2 M hydrochloric acid while stirring at room temperature. The precipitate was collected by filtration, washed with water, and then dried to obtain the title compound (133 mg).

[0107] Example 6 1-(4-{5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}-3-fluorophenyl)piperidine-4-carboxylic acid Lithium hydroxide monohydrate (15 mg) was added to a mixture of ethyl 1-(4-{5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}-3-fluorophenyl)piperidine-4-carboxylate (58 mg), THF (0.81 mL), methanol (0.81 mL), and water (0.81 mL), and the mixture was stirred at 50° C. overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with water. 2 M hydrochloric acid was added to the mixture at room temperature while stirring to neutralize the mixture. The precipitate was collected by filtration, washed with water, and then dried to obtain the title compound (53 mg).

[0108] Example 7 1-(5-{5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-[(3-methoxy-2,2-dimethylpropyl)(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid A 1 M aqueous solution of sodium hydroxide (0.56 mL) was added to a solution of ethyl 1-(5-{5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-[(3-methoxy-2,2-dimethylpropyl)(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylate (75 mg) in ethanol (1 mL), and the mixture was stirred at 50° C. for 2 hours. After cooling to room temperature, the mixture was diluted with water and neutralized with 1 M hydrochloric acid. The precipitate was collected by filtration and dried to obtain the title compound (62 mg).

[0109] Example 8 1-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(ethoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid Lithium hydroxide monohydrate (23 mg) was added to a mixture of ethyl 1-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(ethoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylate (76 mg), ethanol (0.54 mL), THF (0.54 mL), and water (0.18 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, diluted with water, and neutralized by adding 6 M hydrochloric acid. The precipitate was collected by filtration to obtain the title compound (40 mg). Example 9 1-(5-{5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid A 1 M aqueous solution of sodium hydroxide (0.54 mL) was added to a solution of ethyl 1-(5-{5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylate (75 mg) in ethanol (1 mL), and the mixture was stirred at 50° C. for 2 hours. After cooling to room temperature, the mixture was diluted with water and neutralized with 1 M hydrochloric acid. The precipitate was collected by filtration and dried to obtain the title compound (63 mg). Example 10 3-[4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperazin-1-yl]propanoic acid To a mixture of ethyl 3-[4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperazin-1-yl]propanoate (1.24 g), THF (8.4 mL), methanol (8.4 mL), and water (8.4 mL), lithium hydroxide monohydrate (0.285 g) was added with stirring at room temperature, and the mixture was stirred at 50 ° C. overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water, and neutralized by adding 2 M hydrochloric acid (3.4 mL) with stirring at room temperature. The precipitate was collected by filtration, washed with water, and then dried to obtain the title compound (1.14 g).

[0110] Example 11 [4-(4-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}-3-fluorophenoxy)piperidin-1-yl]acetic acid To a solution of ethyl [4-(4-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}-3-fluorophenoxy)piperidin-1-yl]acetate (39.5 mg) in ethanol (1.1 mL), 2 M aqueous sodium hydroxide solution (0.134 mL) was added while stirring at room temperature, and the mixture was stirred at the same temperature for 4 hours. The reaction mixture was diluted with water and neutralized with 2 M hydrochloric acid. The precipitate was collected by filtration, washed with water, and then dried to obtain the title compound (35.6 mg). Example 12 3-[(2S)-4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-2-(methoxymethyl)piperazin-1-yl]propanoic acid Ethyl 3-[(2S)-4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-2-(methoxymethyl)piperazin-1-yl]propanoate (96.7 mg), THF (0.74 mL), methanol (0.74 mL), and water (0.74 mL) were stirred at room temperature, and lithium hydroxide monohydrate (21.8 mg) was added and stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and neutralized with 2 M hydrochloric acid. The precipitate was collected by filtration, washed with water, and then dried to obtain the title compound (76.3 mg). Example 13 Sodium 3-[(3R)-4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(ethoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-3-methylpiperazin-1-yl]propanoate [Step 1] Preparation of 3-[(3R)-4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(ethoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-3-methylpiperazin-1-yl]propanoic acid Ethyl 3-[(3R)-4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(ethoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-3-methylpiperazin-1-yl]propanoate (1.82 g), ethanol (9 mL), and a mixture of water (9 mL) was added with 4 M aqueous sodium hydroxide solution (3 mL) while stirring at room temperature, and stirred at 50 ° C. for 1 hour. The reaction mixture was diluted with water and neutralized with 6 M hydrochloric acid. The reaction mixture was stirred at room temperature overnight, and the precipitate was collected by filtration, washed with water, and then dried to obtain the title compound (1.73 g). [Step 2] Preparation of sodium 3-[(3R)-4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(ethoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-3-methylpiperazin-1-yl]propanoate To a mixture of 3-[(3R)-4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(ethoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-3-methylpiperazin-1-yl]propanoic acid (1.20 g) obtained in step 1 and methanol (30 mL), sodium methoxide (0.5 M methanol solution, 3.32 mL) was added while stirring at room temperature, and the mixture was stirred at the same temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was diluted with diethyl ether (20 mL) and stirred at room temperature for 3 hours. Hexane (20 mL) was added thereto, and the mixture was stirred at room temperature for 1 hour. The insoluble matter was collected by filtration, washed with diethyl ether-hexane (1:1), and then dried to obtain the title compound (1.16 g). Example 14 Sodium 3-[(3R)-4-(5-{5-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-3-methylpiperazin-1-yl]propanoate [Step 1] Preparation of 3-[(3R)-4-(5-{5-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-3-methylpiperazin-1-yl]propanoic acid Ethyl 3-[(3R)-4-(5-{5-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-3-methylpiperazin-1-yl]propanoate (76 mg) in ethanol (1 mL) was added with 1 M aqueous sodium hydroxide solution (0.50 mL) at room temperature while stirring, and stirred at the same temperature for 1 hour. The reaction mixture was neutralized by adding 2 M hydrochloric acid, and the reaction mixture was concentrated under reduced pressure, and the residue was diluted with water. The precipitate was collected by filtration, washed with water, and then dried to obtain the title compound (68 mg). [Step 2] Preparation of sodium 3-[(3R)-4-(5-{5-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-3-methylpiperazin-1-yl]propanoate To a mixture of 3-[(3R)-4-(5-{5-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-3-methylpiperazin-1-yl]propanoic acid (68 mg) obtained in step 1 and methanol (1 mL), sodium methoxide (0.5 M methanol solution, 0.19 mL) was added while stirring at room temperature, and the mixture was stirred at the same temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was diluted with diethyl ether-hexane (1:1), and then stirred at room temperature for 1 hour. Insoluble matter was collected by filtration, washed with diethyl ether-hexane (1:1), and then dried to obtain the title compound (63 mg). Example 15 Sodium 3-[(3R)-4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-3-methylpiperazin-1-yl]propanoate [Step 1] Preparation of ethyl 3-[(3R)-4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-3-methylpiperazin-1-yl]propanoate 6'-Cyclopropyl-N 4 -{[1-(methoxymethyl)cyclopentyl]methyl}-N 4 A mixture of 50 mg of methyl-5'-(trifluoromethyl)[2,3'-bipyridine]-4,5,6-triamine, ethyl 3-[(3R)-4-(5-formylpyrazin-2-yl)-3-methylpiperazin-1-yl]propanoate, sodium dithionite, and DMF (0.5 mL) was stirred for 3 hours at 110° C. After cooling to room temperature, the reaction mixture was purified by silica gel column chromatography to obtain the title compound (75 mg). [Step 2] Preparation of 3-[(3R)-4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-3-methylpiperazin-1-yl]propanoic acid To a mixture of ethyl 3-[(3R)-4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-3-methylpiperazin-1-yl]propanoate (75 mg) obtained in step 1, THF (0.5 mL), and water (0.5 mL), 4 M aqueous sodium hydroxide solution (0.127 mL) was added while stirring at room temperature, and the mixture was stirred at 50 ° C. for 1 hour. After cooling the reaction mixture to room temperature, it was diluted with water and neutralized by adding 1 M hydrochloric acid. The precipitate that precipitated was collected by filtration, washed with water, and dried to obtain the title compound (66 mg). [Step 3] Preparation of sodium 3-[(3R)-4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-3-methylpiperazin-1-yl]propanoate Sodium methoxide (0.5 M methanol solution, 0.184 mL) was added to a mixture of 3-[(3R)-4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-3-methylpiperazin-1-yl]propanoic acid (65 mg) obtained in step 2 and methanol (2 mL) while stirring at room temperature, and stirred at the same temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was diluted with diethyl ether-hexane (1:1), and then stirred at room temperature for 1 hour. Insoluble matter was collected by filtration, washed with diethyl ether-hexane (1:1), and then dried to obtain the title compound (65 mg).

[0111] Tables 1 to 10 below show the compounds of Reference Examples and Examples. In the tables, PREx indicates that the compound was produced using the corresponding raw materials by a method similar to the production method of the compound of the corresponding Reference Example number. For example, a Reference Example compound with PREx of 1 means that it was produced by a method similar to Reference Example 1. In the tables, chemical name indicates the name of the compound corresponding to the Reference Example and Example number, and Data indicates instrumental analysis data of the compound, such as mass spectrometry data (m / z value), 1 This includes H NMR data (peak δ (ppm)), elemental analysis data (C, H, N composition (%)), etc.

[0112] [Table 1]

[0113] [Table 2]

[0114] [Table 3]

[0115] [Table 4]

[0116] [Table 5]

[0117] [Table 6]

[0118] [Table 7]

[0119] [Table 8]

[0120] [Table 9]

[0121] [Table 10]

[0122] Examples of pharmacological tests (biological tests) of the compounds used in the present invention are given below.

[0123] The pharmacological activity of each compound in the Examples was examined by the following tests. In the following explanation, each compound in the Examples may be referred to as each "test compound".

[0124] <Test Example 1: Evaluation of M3 PAM activity> CHO-K1 cells stably expressing the M3 receptor by introducing the human muscarinic M3 receptor gene (GenBank accession number: NM_000740.2) (hereinafter, sometimes referred to as "M3R-expressing cells") were subcultured in a growth medium under conditions of 37°C and 5% CO2. The growth medium used was alpha Modified Eagle Minimum Essential Medium (α-MEM, D8042, Sigma) containing a final concentration of 10% inactivated fetal bovine serum (Cat. No. 172012, Sigma), a final concentration of 2 mM GlutaMAX (registered trademark) (Cat. No. 35050, GIBCO), a final concentration of 20 U / mL penicillin and 20 μg / mL streptomycin (penicillin-streptomycin mixed solution, Cat. No. 26253-84, Nacalai Tesque, Inc.), and a final concentration of 0.2 mg / mL G418 (Cat. No. 16513-26, Nacalai Tesque, Inc.).

[0125] Intracellular Ca 2+ On the day before the concentration measurement, M3R-expressing cells were suspended in growth medium and seeded into a black, clear-bottom 96-well plate (Cat. No. 215006, Porvair Sciences) at 40,000 cells / well. The M3R-expressing cells seeded into the 96-well plate were cultured overnight at 37°C in 5% CO2.

[0126] Using a calcium measurement assay kit (Screen Quest Fluo-8 Medium Removal Calcium Assay Kit, Cat. No. 36309, AAT Bioquest), the Ca in M3R-expressing cells was measured according to the attached instruction manual. 2+The concentration was measured. On the day of measurement, the growth medium was removed, 100 μL / well of loading buffer was added to the 96-well plate, and the plate was cultured for 30 minutes under 37 ° C. and 5% CO2 conditions, and then left to stand at room temperature for 30 minutes. This allowed the visible light-excited calcium indicator (Fluo-8 (registered trademark), manufactured by AAT Bioquest) to be loaded onto the M3R-expressing cells. As the loading buffer, a buffer containing a calcium indicator was used. As the buffer, a pH 7.4 Hanks' balanced salt solution (HBSS buffer) containing a final concentration of 20 mM HEPES (Cat. No. 340-01371, manufactured by Dojindo Laboratories) and a final concentration of 2.5 mM probenecid (165-15472, manufactured by Wako Pure Chemical Industries, Ltd.) was used. The Hanks' balanced salt solution was prepared by diluting 10×HBSS (Cat. No. 14065-056, manufactured by GIBCO) 10 times with ultrapure water.

[0127] The 96-well plate was then transferred to a fluorescence screening system (FLIPR TETRA (registered trademark), Molecular Devices) to measure the intracellular Ca2+ levels induced by the test compounds. 2+ The concentration-dependent fluorescence intensity was measured with an excitation wavelength of 470-495 nm and a fluorescence wavelength of 515-575 nm.

[0128] A medium containing a test compound or only the medium was added to a 96-well plate, and the fluorescence intensity was measured for 2 minutes. HBSS buffer was used as the medium. The test compound was dissolved in dimethyl sulfoxide and then added to the HBSS buffer. The final concentration of dimethyl sulfoxide was set to 2.5%. The final concentration of the test compound was varied in the range of 0 to 30 μM. Then, the EC 20 (20% Effective Concentration) of acetylcholine was added, and the fluorescence intensity was measured for 1 minute. 20 was in the range of approximately 10 to 30 nM.

[0129] The fluorescence intensity Lb when only HBSS buffer was added instead of the test compound and acetylcholine was added at a final concentration of 100 μM was defined as 100%, and the EC 20 The fluorescence intensity La was set to 0% when only HBSS buffer was added instead of the test compound in the presence of 1000 μg of acetylcholine. The fluorescence intensity when the test compound was added was set to Lc, and the enhancement rate Gr (unit: %) of the fluorescence intensity by the test compound was calculated by the following formula (1). The M3 PAM activity of the test compound was evaluated based on the enhancement rate Gr.

[0130] Gr=100×(Lc-La) / (Lb-La)...(1)

[0131] Based on the enhancement rate Gr at each concentration of the test compound, the EC 50 The results of this test are shown in Table 11. EC of the enhancement rate Gr 50 The lower the value, the higher the M3 PAM activity.

[0132] [Table 11]

[0133] As shown in Table 11, all of the test compounds (compounds of Examples 1 to 15) were found to exhibit high M3 PAM activity.

[0134] In addition, the addition of the test compound alone in the absence of acetylcholine did not increase the fluorescence intensity, indicating that the test compound does not exhibit M3 receptor agonist activity.

[0135] As described above, the test compound was confirmed to have M3 PAM activity in vitro.

[0136] <Test Example 2: Evaluation of test compounds in Magnus test> Female SD rats (Japan SLC) aged 9 to 15 weeks were killed by exsanguination through carotid artery transection under isoflurane anesthesia. The ileum was then excised from the rat and cut into 2 cm lengths while removing the mesentery and connective tissue to prepare intestinal specimens. The specimens were suspended in a Magnus tank, immersed in 20 mL of Krebs solution (118 mM NaCl, 4.7 mM KCl, 2.5 mM CaCl2, 1.2 mM MgSO4, 1.2 mM KH2PO4, 11 mM D-glucose, 20 mM NaHCO3) at 37°C and aerated with a mixed gas of 95% O2 and 5% CO2. A load of 1 g was then applied to the specimens, and the tension was stabilized.

[0137] One end of the specimen was connected to an isotonic transducer (IT-10, Medical Agent Co., Ltd.), and data on tension (contraction force) was input to a personal computer via Power Lab (registered trademark) (A&D instruments). Carbachol (Carbamylcholine Chloride, Cat. No. 036-09841, Fujifilm Wako Pure Chemical Industries, Ltd.) was added to the Krebs solution in the Magnus bath to a final concentration of 1000 nM, and the contraction of the specimen was confirmed. The contraction force Tb of the specimen at this time was set to 100%. The Magnus bath was then washed three times with Krebs solution to wash out the carbachol, and finally the Magnus bath was filled with 20 mL of Krebs solution.

[0138] Next, dimethyl sulfoxide (DMSO, Cat. No. 13445-74, manufactured by Nacalai Tesque, Inc.) was added to the Krebs solution in the Magnus tank, and then carbachol was added to the Krebs solution in the Magnus tank to a final concentration of 50 nM, and the contraction of the specimen was confirmed. The contraction force Ta of the specimen at this time was set to 0%. Then, the Magnus tank was washed three times with Krebs solution to wash out carbachol and DMSO, and finally the Magnus tank was filled with 20 mL of Krebs solution. Next, the test compound dissolved in DMSO was added to the Krebs solution in the Magnus tank to a final concentration of 10 μM, and then carbachol was added to the Krebs solution in the Magnus tank to a final concentration of 50 nM, and the contraction of the specimen was confirmed.

[0139] As described above, the contractile force Tb of the specimen when carbachol was added at a final concentration of 1000 nM was set to 100%, and the contractile force Ta of the specimen when carbachol was added at a final concentration of 50 nM under the condition that DMSO was added first instead of the test compound was set to 0%. The contractile force of the specimen when carbachol was added at a final concentration of 50 nM under the condition that the test compound was added at a final concentration of 10 μM first was set to Tc, and the enhancement rate P (unit: %) of the contractile force by the test compound was calculated by the following formula (2). The increase in the contractile force by the test compound was evaluated based on the enhancement rate P. The number of cases in each addition group was 3 to 7.

[0140] P=100×(Tc-Ta) / (Tb-Ta)...(2)

[0141] [Table 12]

[0142] The results of the Magnus test are shown in Table 12. In Table 12, the enhancement rate P is shown as the mean value ± standard error. All of the test compounds increased the enhancement rate P. This demonstrated that the test compounds are effective in enhancing gastrointestinal function.

[0143] Furthermore, the test compound alone does not show agonistic activity against the M3 receptor, but has ileal contraction activity in the presence of carbachol. This means that the test compound with M3 PAM activity can enhance the signal level of the M3 receptor under more physiological conditions, and is expected to be promising in the treatment of diseases involving the M3 receptor (especially gastrointestinal diseases). In addition, the test compound may be able to avoid the cholinergic-derived side effects (cholinergic crisis) reported for existing drugs (e.g. distigmine bromide), and may become a safer therapeutic drug.

[0144] <Test Example 3: Evaluation of test compounds in a mouse constipation model> Loperamide, a μ-opioid receptor agonist, inhibits intestinal contraction and causes a delay in intestinal transit. For this reason, mice administered loperamide are known as an experimental model of constipation (hereinafter, sometimes referred to as "constipation model mice") (Acta gastroenterologica latinoamericana, 1991, Vol. 21, No. 1, p. 3-9.). Therefore, we investigated the efficacy of test compounds that show M3 PAM activity in constipation model mice.

[0145] Seven-week-old male ICR mice (Japan SLC) were kept in a wire cage measuring 20 cm wide x 23 cm deep x 15 cm high for more than one week from the time of arrival, and allowed to acclimate. After that, loperamide (Loperamide Hydrochloride, Cat. No. 129-05721, Fujifilm Wako Pure Chemical Industries, Ltd.) was orally administered at 5 mg / kg. 20 minutes after loperamide administration, 10 mg / kg of the test compound or vehicle (0.5% methylcellulose solution) was orally administered, and the number of feces was counted 6 hours later. At this time, loperamide was dissolved in water (Otsuka Distilled Water, Otsuka Pharmaceutical Factory, Inc.), the test compound was suspended in a 0.5% methylcellulose solution, and the administration volume was 10 mL / kg. In the loperamide non-administered group (Normal group), only water was orally administered at 10 mL / kg. The number of animals in each administration group was 5 to 6.

[0146] The results of the constipation model mice are shown in Figs. 1 to 8. Figs. 1 and 5 show the results when the compounds of Examples 1 to 4, Figs. 2 and 6 show the results when the compounds of Examples 6 and 7, Figs. 3 and 7 show the results when the compounds of Examples 8 to 11, and Figs. 4 and 8 show the results when the compounds of Examples 12 to 15 were administered. The vertical axis of Figs. 1 to 4 shows the number of feces per animal (unit: pieces), and the vertical axis of Figs. 5 to 8 shows the total weight of the feces after drying per animal (unit: mg). "N" and "Vh" in the figures indicate the Normal group and the Vehicle group, respectively. Also, the numbers "1 to 4, 6 to 15" in the figures indicate the compounds of Examples 1 to 4 and 6 to 15, respectively. Hereinafter, the total weight of the feces after drying may be referred to as "dry weight". The number of feces and dry weight were reduced in the group administered only loperamide and the vehicle (Vehicle group) compared to the group not administered loperamide (Normal group). This confirmed the establishment of the constipation model.

[0147] In the test compound group, the number of feces and dry weight increased compared to the vehicle group, and constipation was improved. In addition, both the number of feces and dry weight increased in the test compound group compared to the vehicle group. Therefore, it was confirmed that administration of the test compound not only increased the number of small feces excreted and the frequency of defecation, but also increased the amount of feces excreted.

[0148] From the above results, it was found that the test compound is effective against irritable bowel syndrome, functional constipation, and opioid-induced constipation. It was confirmed by visual observation that no diarrhea was observed in any of the normal group, vehicle group, and test compound administration group.

[0149] <Test Example 4: Saliva secretion measurement experiment in anesthetized mice> Eight-week-old male ICR mice (Japan SLC Co., Ltd.) were anesthetized with urethane (1650 mg / kg, intraperitoneal administration). Approximately one hour later, 10 mg / kg of the test compound or vehicle (10% DMSO-containing saline (Otsuka saline injection, manufactured by Otsuka Pharmaceutical Factory Co., Ltd.)) was intravenously administered, and immediately after that, 1 to 2 pieces (0.1 to 0.2 mg) of absorbent cotton balls (Roller Cotton (cotton ball) SS, manufactured by Nichiei Co., Ltd.) were inserted into the mouth. The difference between the weight of the absorbent cotton ball 30 minutes after insertion and the weight of the absorbent cotton ball before insertion was taken as the amount of saliva secretion. At this time, the test compound was dissolved in DMSO and then diluted 10-fold with physiological saline. The administration volume of the test compound and the vehicle was 5 mL / kg. The experiment was carried out in three separate sessions. The number of animals in each administration group was 3 to 4.

[0150] [Table 13]

[0151] The results of the test for measuring the amount of saliva secretion are shown in Table 13. In Table 13, the amount of saliva secretion (unit: mg) is shown as the mean value ± standard error. In experiment #1, the compounds of Examples 1 to 5, in experiment #2, Examples 6 to 10, and in experiment #3, Examples 11 to 15 were evaluated. In all test compound administration groups, the amount of saliva secretion was increased compared to the vehicle group (administered only the vehicle). In addition, no aspiration of saliva into the trachea was observed in the vehicle group and the test compound administration group. In this test, pilocarpine (a muscarinic receptor agonist similar to carbachol) also showed a saliva secretion promoting effect.

[0152] As shown in the above Test Examples 1 to 4, the compound of the present invention exhibits M3 PAM activity and also exhibits efficacy in in vivo models, and is useful as a therapeutic or preventive agent for functional gastrointestinal disorders or xerostomia. [Industrial Applicability]

[0153] The present invention can be used as a therapeutic and preventive agent for functional gastrointestinal disorders and xerostomia.

Claims

1. The following formula [1]: 【Chemistry 1】 [In the formula, R １ is a hydrogen atom or an alkyl group, or two R １ may be taken together with adjacent carbon atoms to form a 3- to 7-membered cycloalkyl or oxygen-containing non-aromatic heterocycle; R ２ is a hydrogen atom, an alkyl group, a cycloalkyl group, an alkyl group substituted with a cycloalkyl group, or an alkoxyalkyl group; R ３ is a hydrogen atom, alkyl, or alkoxyalkyl; R ４ is pyridyl optionally substituted with one or two groups selected from the group consisting of alkyl, trihaloalkyl, alkoxy, cyano, and cycloalkyl, or phenyl optionally substituted with one to three groups selected from the group consisting of trihaloalkyl, halogen, alkoxy, and cycloalkyl; A is A-1, A-2, A-3, A-4, or A-5 below: 【Chemistry 2】 (The left bond of each group is bonded to the 2-position of the azabenzimidazole of formula [1], the right bond is bonded to W of formula [1], and R １１ is a group selected from a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, and a nitro group; W is a bond or the following W-1, W-2, or W-3: 【Chemistry 3】 (R ２１ is a hydrogen atom or an alkyl group; B is B-1, B-2, B-3, or B-4 below: 【Chemistry 4】 (The left bond of each group is bonded to W in formula [1], the right bond is bonded to Y in formula [1], and U １ is a nitrogen atom, or CR ４１ And U ２ is a nitrogen atom, or CR ４２ and R ４１ and R ４２ are each independently a hydrogen atom, an alkyl group, a halogen atom, or a hydroxyl group; m and n are each 1, 2, or 3; R ３１ and R ３２ are each independently a hydrogen atom, an alkyl, a halogen, or an alkoxyalkyl, or R ３１ and R ３２ may together with adjacent carbon atoms form an alkylene bridge (R ３１ and R ３２ U １ , and U ２ Substitute in any position other than the above.) Y is a hydrogen atom or the following Y-1 to Y-4, or Y-11 to Y-16: 【Chemistry 5】 (R ５１ is alkyl, p is 1, 2, or 3, q ​​is 0, 1, or 2, r is 1, 2, or 3, and T is O, S, SO ２ , or NR ６１ where R ６１ is a hydrogen atom or an alkyl group, s is 0, 1, 2, or 3, and t is 0 or 1. (a) When W is a bond ・B is B-1 or B-2, and U ２ is a nitrogen atom, Y is Y-1, Y-2, Y-3, or Y-4; ・B is B-1, B-2, and U ２ is CR ４２ When (R ４２ has the same meaning as above), U １ is a nitrogen atom, Y is Y-11, Y-12, Y-13, Y-14, Y-15, or Y-16; When B is B-3 or B-4, Y is a hydrogen atom; (b) When W is W-1 B is B-1, U １ is a nitrogen atom, U ２ is a nitrogen atom, Y is Y-1, Y-2, Y-3, or Y-4; B is B-1, U １ is a nitrogen atom, ・U ２ is CR ４２ When (R ４２ has the same meaning as above), Y is Y-11, Y-12, Y-13, Y-14, Y-15, or Y-16; (c) When W is W-2 - B is B-1 or B-2, U １ is a nitrogen atom, U ２ is a nitrogen atom, Y is Y-1, Y-2, Y-3, or Y-4; - B is B-1 or B-2, U １ is a nitrogen atom, U ２ is CR ４２ When (R ４２ has the same meaning as above), Y is Y-11, Y-12, Y-13, Y-14, Y-15, or Y-16; When B is B-3 or B-4, Y is a hydrogen atom; (d) When W is W-3, B is B-1, U １ is CR ４１ (R ４１ has the same meaning as above), U ２ When is a nitrogen atom, Y is Y-1, Y-2, Y-3, or Y-4. or a medicament for treating or preventing a functional gastrointestinal disorder, comprising, as an active ingredient, an azabenzimidazole compound represented by the following formula:

2. The therapeutic or prophylactic agent according to claim 1 , wherein W is a bond.

3. The following cases are (1), (2), or (3): (1) B is B-1 or B-2, U ２ is a nitrogen atom, Y is Y-1, Y-2, or Y-3; (2) B is B-1 or B-2, U ２ is CR ４２ and Y is Y-11, Y-12, or Y-15; (3) The therapeutic or prophylactic agent according to claim 1 or 2, wherein B is B-4 and Y is a hydrogen atom.

4. R ４ The therapeutic or prophylactic agent according to claim 3, wherein is one group selected from the group consisting of alkyl, trihaloalkyl, alkoxy, cyano, and cycloalkyl, and is pyridyl substituted with trihaloalkyl.

5. The therapeutic or prophylactic agent according to claim 4, wherein A is A-4.

6. The therapeutic or prophylactic agent according to any one of claims 1 to 5, wherein the azabenzimidazole compound is any one of the following compounds (1) to (15): (1) [4-(5-{5-[3-fluoro-5-(trifluoromethyl)phenyl]-7-[{[1-(methoxymethyl)cyclobutyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperazin-1-yl]acetic acid, (2) 4-fluoro-1-(5-{5-[3-fluoro-5-(trifluoromethyl)phenyl]-7-[{[1-(methoxymethyl)cyclobutyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid, (3) 1-(5-{5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclobutyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid, (4) 1-(5-{5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclobutyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid, (5) {[1-(5-{5-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidin-4-yl]oxy}acetic acid, (6) 1-(4-{5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}-3-fluorophenyl)piperidine-4-carboxylic acid, (7) 1-(5-{5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-[(3-methoxy-2,2-dimethylpropyl)(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid, (8) 1-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(ethoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid, (9) 1-(5-{5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid, (10) 3-[4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperazin-1-yl]propanoic acid, (11) [4-(4-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}-3-fluorophenoxy)piperidin-1-yl]acetic acid, (12) 3-[(2S)-4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-2-(methoxymethyl)piperazin-1-yl]propanoic acid, (13) 3-[(3R)-4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(ethoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-3-methylpiperazin-1-yl]propanoic acid, (14) 3-[(3R)-4-(5-{5-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-3-methylpiperazin-1-yl]propanoic acid, (15) 3-[(3R)-4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-3-methylpiperazin-1-yl]propanoic acid.

7. The therapeutic or preventive agent according to any one of claims 1 to 6, wherein the functional gastrointestinal disorder is irritable bowel syndrome (IBS).

8. The therapeutic or preventive agent according to any one of claims 1 to 6, wherein the functional gastrointestinal disorder is functional constipation.

9. The following formula [1] 【Chemistry 6】 [In the formula, R １ is a hydrogen atom or an alkyl group, or two R １ may be taken together with adjacent carbon atoms to form a 3- to 7-membered cycloalkyl or oxygen-containing non-aromatic heterocycle; R ２ is a hydrogen atom, an alkyl group, a cycloalkyl group, an alkyl group substituted with a cycloalkyl group, or an alkoxyalkyl group; R ３ is a hydrogen atom, alkyl, or alkoxyalkyl; R ４ is pyridyl optionally substituted with one or two groups selected from the group consisting of alkyl, trihaloalkyl, alkoxy, cyano, and cycloalkyl, or phenyl optionally substituted with one to three groups selected from the group consisting of trihaloalkyl, halogen, alkoxy, and cycloalkyl; A is A-1, A-2, A-3, A-4, or A-5 below: 【Chemistry 7】 (The left bond of each group is bonded to the 2-position of the azabenzimidazole of formula [1], the right bond is bonded to W of formula [1], and R １１ is a group selected from a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, and a nitro group; W is a bond or the following W-1, W-2, or W-3: 【Chemistry 8】 (R ２１ is a hydrogen atom or an alkyl group; B is B-1, B-2, B-3, or B-4 below: 【Chemistry 9】 (The left bond of each group is bonded to W in formula [1], the right bond is bonded to Y in formula [1], and U １ is a nitrogen atom, or CR ４１ And U ２ is a nitrogen atom, or CR ４２ and R ４１ and R ４２ are each independently a hydrogen atom, an alkyl group, a halogen atom, or a hydroxyl group; m and n are each 1, 2, or 3; R ３１ and R ３２ are each independently a hydrogen atom, an alkyl, a halogen, or an alkoxyalkyl, or R ３１ and R ３２ may together with adjacent carbon atoms form an alkylene bridge (R ３１ and R ３２ U １ , and U ２ Substitute in any position other than the above.) Y is a hydrogen atom or the following Y-1 to Y-4, or Y-11 to Y-16: 【Chemistry 10】 (R ５１ is alkyl, p is 1, 2, or 3, q ​​is 0, 1, or 2, r is 1, 2, or 3, and T is O, S, SO ２ , or NR ６１ where R ６１ is a hydrogen atom or an alkyl group, s is 0, 1, 2, or 3, and t is 0 or 1. (a) When W is a bond ・B is B-1 or B-2, and U ２ is a nitrogen atom, Y is Y-1, Y-2, Y-3, or Y-4; ・B is B-1, B-2, and U ２ is CR ４２ When (R ４２ has the same meaning as above), U １ is a nitrogen atom, Y is Y-11, Y-12, Y-13, Y-14, Y-15, or Y-16; When B is B-3 or B-4, Y is a hydrogen atom; (b) When W is W-1 B is B-1, U １ is a nitrogen atom, U ２ is a nitrogen atom, Y is Y-1, Y-2, Y-3, or Y-4; B is B-1, U １ is a nitrogen atom, ・U ２ is CR ４２ When (R ４２ has the same meaning as above), Y is Y-11, Y-12, Y-13, Y-14, Y-15, or Y-16; (c) When W is W-2 - B is B-1 or B-2, U １ is a nitrogen atom, U ２ is a nitrogen atom, Y is Y-1, Y-2, Y-3, or Y-4; - B is B-1 or B-2, U １ is a nitrogen atom, U ２ is CR ４２ When (R ４２ has the same meaning as above), Y is Y-11, Y-12, Y-13, Y-14, Y-15, or Y-16; When B is B-3 or B-4, Y is a hydrogen atom; (d) When W is W-3, B is B-1, U １ is CR ４１ (R ４１ has the same meaning as above), U ２ When is a nitrogen atom, Y is Y-1, Y-2, Y-3, or Y-4. or a medicament for treating or preventing xerostomia, comprising as an active ingredient an azabenzimidazole compound represented by the following formula:

10. The therapeutic or prophylactic agent according to claim 9 , wherein W is a bond.

11. The following cases are (1), (2), or (3): (1) B is B-1 or B-2, U ２ is a nitrogen atom, Y is Y-1, Y-2, or Y-3; (2) B is B-1 or B-2, U ２ is CR ４２ and Y is Y-11, Y-12, or Y-15; (3) The therapeutic or prophylactic agent according to claim 9 or 10, wherein B is B-4 and Y is a hydrogen atom.

12. R ４ The therapeutic or prophylactic agent according to claim 11, wherein is one group selected from the group consisting of alkyl, trihaloalkyl, alkoxy, cyano, and cycloalkyl, and is pyridyl substituted with trihaloalkyl.

13. The therapeutic or prophylactic agent according to claim 12, wherein A is A-4.

14. The therapeutic or prophylactic agent according to any one of claims 9 to 13, wherein the azabenzimidazole compound is any one of the following compounds (1) to (15): (1) [4-(5-{5-[3-fluoro-5-(trifluoromethyl)phenyl]-7-[{[1-(methoxymethyl)cyclobutyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperazin-1-yl]acetic acid, (2) 4-fluoro-1-(5-{5-[3-fluoro-5-(trifluoromethyl)phenyl]-7-[{[1-(methoxymethyl)cyclobutyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid, (3) 1-(5-{5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclobutyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid, (4) 1-(5-{5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclobutyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid, (5) {[1-(5-{5-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidin-4-yl]oxy}acetic acid, (6) 1-(4-{5-[6-ethoxy-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}-3-fluorophenyl)piperidine-4-carboxylic acid, (7) 1-(5-{5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-[(3-methoxy-2,2-dimethylpropyl)(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid, (8) 1-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(ethoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid, (9) 1-(5-{5-[2-ethoxy-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperidine-4-carboxylic acid, (10) 3-[4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)piperazin-1-yl]propanoic acid, (11) [4-(4-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}-3-fluorophenoxy)piperidin-1-yl]acetic acid, (12) 3-[(2S)-4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-2-(methoxymethyl)piperazin-1-yl]propanoic acid, (13) 3-[(3R)-4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(ethoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-3-methylpiperazin-1-yl]propanoic acid, (14) 3-[(3R)-4-(5-{5-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-7-[{[1-(methoxymethyl)cyclohexyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-3-methylpiperazin-1-yl]propanoic acid, (15) 3-[(3R)-4-(5-{5-[6-cyclopropyl-5-(trifluoromethyl)pyridin-3-yl]-7-[{[1-(methoxymethyl)cyclopentyl]methyl}(methyl)amino]-1H-imidazo[4,5-b]pyridin-2-yl}pyrazin-2-yl)-3-methylpiperazin-1-yl]propanoic acid.

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