Pharmaceutical composed of phenol derivative

Abstract

To provide a compound that is useful as a therapeutic agent for dysphagia, alleviates deglutition reflex, and exhibits a high level of safety and a pharmaceutically acceptable salt thereof, and a pharmaceutical containing the same as an active ingredient.SOLUTION: A pharmaceutical comprises a compound represented by the formula (2) or a pharmaceutically acceptable salt thereof. In the formula (2), R1 represents a hydrogen atom or the like, R2 represents a methoxy group or the like, R3 represents a hydrogen atom or the like, R4 is an optionally substituted C1-6 alkyl group or the like, m represents 0, 1 or 2, n represents 0, 1, 2 or 3, L1 represents -NH-C(=O)-, -C(=O)-NH- or the like, L2 represents a single bond or the like, X represents an optionally substituted phenyl or the like, and Y represents an optionally substituted phenyl or the like, where X and Y are bonded together with carbon atoms on their respective rings.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to phenol derivatives useful as pharmaceuticals and pharmaceutically acceptable salts thereof, as well as pharmaceuticals containing them as active ingredients or drugs for treating dysphagia that can improve the swallowing reflex. [Background technology]

[0002] The act of swallowing consists of five phases: the preparatory phase in which food is recognized, the oral phase in which food is taken into the mouth and chewed, the oral phase in which the tongue moves the food to the pharynx, the pharyngeal phase in which the swallowing reflex is triggered by the food's stimulus and the food is sent down the esophagus, and the esophageal phase in which peristaltic movement moves the food from the esophagus to the stomach. If any of these phases are impaired, smooth swallowing becomes impossible, leading to dysphagia. Abnormalities or declines in the pharyngeal phase swallowing reflex can be caused by various medications, cerebrovascular diseases, neurodegenerative diseases, and aging (Non-patent documents 1, 2).

[0003] Treatment options for dysphagia include swallowing instruction, rehabilitation, and surgical intervention. For delayed swallowing reflexes, selecting highly viscous foods is recommended. Rehabilitation involves using cold pressure stimulation to induce the swallowing reflex, as well as stretching of swallowing organs and swallowing pattern training. However, there is limited evidence of effectiveness from randomized controlled trials, and further research is needed to assess their efficacy. If the above methods are ineffective, swallowing function improvement surgery may be considered, but this must be performed cautiously due to its invasive nature and the possibility of not achieving the desired results. Therefore, there is a need for a treatment method that can clearly demonstrate effectiveness against dysphagia.

[0004] Drugs reported to improve the swallowing reflex include angiotensin converting enzyme (ACE) inhibitors (Non-Patent Document 3), cilostazol (Non-Patent Document 4), nicergoline (Non-Patent Document 5), and Hangekobokuto (Non-Patent Document 6). These drugs increase the amount of substance P released in the periphery, making it easier to induce the swallowing reflex, and as a result, a preventive effect against pneumonia is expected, but their effectiveness is uncertain. Therefore, the creation of drugs to treat dysphagia is desired.

[0005] On the other hand, ingredients used in supplements such as capsaicin, black pepper, and menthol have also been reported to improve the swallowing reflex. These release substance P by acting on transient receptor potential (TRP) channels. Among these, capsaicin has been reported to strongly improve the swallowing reflex as a TRPV1 agonist (Non-Patent Literature 7), and supplements with the expectation of improving swallowing are also sold. However, they are not widely used because they are not pharmaceuticals.

[0006] As TRPV1 agonists, for example, compounds described in Patent Documents 1-5 have been disclosed, but it has been reported that they may have side effects such as irritation and hypothermia upon systemic administration (Non-Patent Documents 8, 9). Therefore, there is a need to create TRPV1 agonists with superior safety. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] International Publication No. 2009 / 136625 [Patent Document 2] International Publication No. 2011 / 058932 [Patent Document 3] International Publication No. 2011 / 058933 [Patent Document 4] International Publication No. 2002 / 100819 [Patent Document 5] International Publication No. 2006 / 115168 [Non-patent literature]

[0008] [Non-Patent Document 1] Nakazawa, H. et al. Chest. 1993,103, 1636-1637. [Non-Patent Document 2] Sekizawa, K. et al. LANCET. 1990,355, 1228-1229. [Non-Patent Document 3] Nakayama, K. et al. Chest. 1998,113(5),1425. [Non-Patent Document 4] Funahashi, H. et al. KyusyuNeuropsychiatry. 2012, 58, 14-21. [Non-Patent Document 5] Nakashima, T. et al. Medicine.2011, 90(4), 279-283. [Non-Patent Document 6] Iwasaki, K. et al. Phytomedicine.1999, 6(2), 103-106. [Non-Patent Document 7] Ebihara, T. et al. LANCET. 1993,341, 432. [Non-Patent Document 8] Fosgerau, K. et al. BMC Cardiovascular Disorders. 2010, 10, 51. [Non-Patent Document 9] Caterina, M. et al. Nature. 1997,389, 816-824. [Overview of the Initiative] [Problems that the invention aims to solve]

[0009] An object of the present disclosure is to provide a compound having an improved swallowing reflex and high safety, a pharmaceutically acceptable salt thereof, and a pharmaceutical containing them as active ingredients, which are useful as therapeutic agents for dysphagia.

Means for Solving the Problems

[0010] As a result of intensive studies, the present inventors have found that the compound represented by the following formula (1) has TRPV1 agonistic activity, exhibits an improving effect on dysphagia, and also has an antedrug-like property, thereby completing the present disclosure. According to the present disclosure, there are provided a phenol derivative represented by the following formula (1) (hereinafter, sometimes referred to as "the compound of the present disclosure"), a pharmaceutically acceptable salt thereof, and a pharmaceutical containing them as active ingredients.

[0011] That is, the present disclosure is as follows.

[0012] (Item 1) Formula (1): [[ID=E19]]

Chemical formula

[0013] Y c Compounds represented by} which are CH or N, and 3) 6-[4-Methoxy-2-(2-{4-[2-(piperidine-1-yl)ethoxy]phenyl}acetamide)phenyl]-5,6,7,8-tetrahydronaphthalene-2-yl 2,2-dimethylpropanoate [excluding] A pharmaceutical product containing a compound represented by [formula] or a pharmaceutically acceptable salt thereof. (Section 7) Formula (2): [ka] [In the formula, R 1 C is a hydrogen atom. 1-6 Alkyl(C) 1-6 Alkyl groups include hydroxyl groups, carboxyl groups, and -NR groups. 11 R 12 A C selected from the group consisting of (which may be substituted with the same or different 1 to 3 substituents), which may be substituted. 1-6 Alkylcarbonyl group or possibly substituted C 6-10 Represents an arylcarbonyl group, R 2 This represents a methoxy group, a hydroxyl group, or a hydrogen atom. R 3 C may be a hydrogen atom, a halogen atom, or a substituted C 1-6 Alkyl alkyl groups, or substituted C 1-4 Alkoxy group, may be substituted C 6-10represents an aryl group or a formyl group, R 4 is an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-7 alicyclic group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 6-10 aryl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted C 3-7 alicyclic oxy group, an optionally substituted C 6-10 aryloxy group or an optionally substituted 4- to 7-membered non-aryl heterocyclic group, wherein, when R 4 is an optionally substituted 4- to 7-membered non-aryl heterocyclic group, a carbon atom on the non-aryl heterocycle is bonded to a carbonyl group, R 11 is a hydrogen atom, an optionally substituted C 1-3 alkyl group, a formyl group, an optionally substituted C 1-3 alkylcarbonyl group, an optionally substituted C 1-4 alkoxycarbonyl group or an optionally substituted C 6-10 arylcarbonyl group, R 12 is a hydrogen atom or an optionally substituted C 1-3 alkyl group, m represents 1 or 2, n represents 0, 1, 2 or 3, L 1 represents -NH-C(=O)-, -C(=O)-NH-, -NH-C(=S)-, -C(=S)-NH-, -NH-C(=O)-CH2-, -C(=O)-NH-CH2-, -NH-C(=O)-CH2-CH2-, -C(=O)-NH-CH2-CH2-, -SO2-NH-, -NH-SO2-, -NH-C(=O)-O- or -O-C(=O)-NH-, L 2 is a single bond or an optionally substituted C 1-6 alkyl group, X represents an optionally substituted phenyl group or an optionally substituted six-membered heteroaryl group. Y is an optionally substituted phenyl group, an optionally substituted 5-membered or 6-membered heteroaryl group, or an optionally substituted C 3-7 Represents an alicyclic group or a substituted 4- to 7-membered nonaryl heterocyclic group, Here, X and Y are bonded at the carbon atoms on their respective rings. however, 1) Formula (W-1): [ka] {In the formula, R 1a However, it is a hydrogen atom or an acetyl group, L 1a However, the compound is represented as -C(=O)-NH- or -SO2-NH-, 2) Formula (W-2): [ka] {In the formula, R 1b However, it is a methyl group or -CD3, R 2b However, the following equations are (W-2A), (W-2B), (W-2C), (W-2D), or (W-2R), [ka] (In the formula, * represents the bonding position with O) R 3b However, the following formulas are (W-2E), (W-2F), (W-2G), (W-2H), (W-2I), (W-2J), (W-2K), (W-2L), (W-2M), (W-2N), (W-2O), (W-2P), or (W-2Q), [ka] (In the formula, * represents the bond position with C=O) Xb However, it is CH or N, Y b However, it is CH or N, Z b However, compounds represented by -CH2- or -CHD-, 3) 4'-{[2-(3,4-dimethoxyphenyl)ethyl]carbamoyl}[1,1'-biphenyl]-4-yl acetate, 4) 2'-(2-{[2-(3,4-dimethoxyphenyl)ethyl]amino}-2-oxoethyl)-4,4',5,5'-tetramethoxy[1,1'-biphenyl]-2-yl acetate, 5) (2'-{[2-(3,4-dimethoxyphenyl)ethyl]carbamoyl}-4,4',5,5'-tetramethoxy[1,1'-biphenyl]-2-yl)methyl benzoate, 6) 6-[4-Methoxy-2-(2-{4-[2-(piperidine-1-yl)ethoxy]phenyl}acetamide)phenyl]-5,6,7,8-tetrahydronaphthalene-2-yl 2,2-dimethylpropanoate, 7) 4'-{[(4-methoxyphenyl)methyl]sulfamoyl}[1,1'-biphenyl]-4-yl acetate, 8) 4'-{[(4-methoxyphenyl)methyl]sulfamoyl}[1,1'-biphenyl]-4-yl benzoate, 9) 4'-{[(4-methoxyphenyl)methyl]sulfamoyl}[1,1'-biphenyl]-4-yl 4-chlorobenzoate, 10) 4'-{[(4-methoxyphenyl)methyl]sulfamoyl}[1,1'-biphenyl]-4-yl 2-chlorobenzoate, 11) 4'-{[(4-methoxyphenyl)methyl]sulfamoyl}[1,1'-biphenyl]-4-yl 3-nitrobenzoate 12) 4'-{[(4-methoxyphenyl)methyl]sulfamoyl}[1,1'-biphenyl]-4-yl 2,4-dichlorobenzoate, and 13)9-(2-{[2-(3,4,5-trimethoxyphenyl)ethyl]carbamoyl}phenyl)-9H-xanthene-3,6-diyl diacetate excluded] A pharmaceutical product containing a compound represented by [formula] or a pharmaceutically acceptable salt thereof. (Section 8) R 3 However, it is a hydrogen atom. A pharmaceutical product as described in any one of items 1 through 7. (Section 9) m is 1 or 2. A compound or a pharmaceutically acceptable salt thereof as described in any one of items 1 to 6. (Section 10) m is 1. A pharmaceutical product as described in any one of items 1 to 8. (Section 11) R 1 However, hydrogen atoms, C 1-6 Alkylcarbonyl group or C 6-10 It is an arylcarbonyl group, A pharmaceutical product as described in any one of items 1 through 10. (Section 12) R 1 However, it is a hydrogen atom. A pharmaceutical product as described in any one of items 1 through 10. (Section 13) R 2 However, it is a methoxy group, A pharmaceutical product as described in any one of items 1 through 12. (Section 14) L 1 However, it is -NH-C(=O)- or -C(=O)-NH-. A pharmaceutical product as described in any one of items 1 through 13. (Section 15) L 2 However, it is a single bond. A pharmaceutical product as described in any one of items 1 through 14. (Section 16) X is given by the following equation (A), [ka] (In the formula, * represents L) 1 (This indicates the connection position with Q or Y, where ** indicates the connection position with Q or Y.) a, CR 8 or N, b, CR 9 or N, c is CR 10 or N, R 8 , R 9 and R 10 However, each is independent of the hydrogen atom, halogen atom, cyano group, and C 1-6 Alkyl sulfonyl group, may be substituted C 1-6 Alkyl alkyl groups or optionally substituted C 1-6 It is an alkoxy group, A pharmaceutical product as described in any one of items 1 through 15. (Section 17) X is given by equation (A), Here, (1) if a is N, then b is CR 9 And c is CR 10 (2) If b is N, then a is CR 8 And c is CR 10 (3) When c is N, a is CR 8 And b is CR 9 That is, A pharmaceutical product as described in any one of items 1 through 16. (Section 18) X is given by equation (A), Here, c is CR 10 (1) If a is N, then b is CR 9 (2) If b is N, then a is CR 8 That is, A pharmaceutical product as described in any one of items 1 through 16. (Section 19) X is given by equation (A), Here, c is CH, (1) when a is N, b is CH, and (2) when b is N, a is CH. A pharmaceutical product as described in any one of items 1 through 16. (Section 20) X is given by equation (A), Here, a, b and c are CH. A pharmaceutical product as described in any one of items 1 through 16. (Section 21) Y is an optionally substituted phenyl group, an optionally substituted six-membered heteroaryl group, or an optionally substituted C 3-7 It is an alicyclic group, A pharmaceutical product listed in any one of items 1 through 20. (Section 22) Y is an optionally substituted phenyl group or an optionally substituted cyclohexyl group. A pharmaceutical product listed in any one of items 1 through 20. (Section 23) Y is given by the following formula (B) or (C): [ka] (In the formula, * represents the bonding position with X or Q, and ** represents L) 2 (Or it represents the bond position with the oxygen atom.) A pharmaceutical product listed in any one of items 1 through 20. (Section 24) R 4 However, C may be substituted. 1-6 Alkyl alkyl groups, or substituted C 3-7 Alicyclic group, may be substituted C 2-6 Alkenyl group, may be substituted C 2-6 C may be substituted with an alkynyl group. 6-10 It is an aryl group, A pharmaceutical product as described in any one of items 1 through 23. (Section 25) R 4 However, C may be substituted. 1-6 Alkyl alkyl groups, or substituted C 3-7 Alicyclic groups or optionally substituted C 6-10 It is an aryl group, A pharmaceutical product as described in any one of items 1 through 23. (Section 26) R 4 However, C 1-6Alkyl alkyl group, C 3-7 Alicyclic group or C 6-10 Aryl group (the C 1-6 Alkyl alkyl group, C 3-7 Alicyclic groups and C 6-10 The aryl group consists of a fluorine atom, a chlorine atom, and a carbon atom. 1-6 Alkyl alkyl group, C 3-7 Alicyclic group, C 6-10 It is a substituent selected from the group consisting of an aryl group, a 5- or 6-membered heteroaryl group, and a 4- to 10-membered non-aryl heterocyclic group, and may be substituted with the same or different 1 to 3 substituents. A pharmaceutical product as described in any one of items 1 through 23. (Section 27) R 4 However, methyl group, ethyl group, isopropyl group, cyclohexyl group, cyclohexylmethyl group, phenyl group or benzyl group (the methyl group, ethyl group, isopropyl group, cyclohexyl group, cyclohexylmethyl group, phenyl group and benzyl group contain fluorine atoms, chlorine atoms and C 1-6 It is a substituent selected from the group consisting of alkyl groups, which may be the same or different (substituting with 1 to 3 substituents), A pharmaceutical product as described in any one of items 1 through 23. (Section 28) R 4 However, methyl group, ethyl group, isopropyl group, cyclohexyl group, phenyl group (the methyl group, ethyl group, isopropyl group, cyclohexyl group and phenyl group are composed of a fluorine atom, a chlorine atom and C 1-6 It is a substituent selected from the group consisting of alkyl groups, which may be the same or different (substituting with 1 to 3 substituents), A pharmaceutical product as described in any one of items 1 through 23. (Section 29) The pharmaceutical product described in item 1, comprising a compound selected from the following compounds or a pharmaceutically acceptable salt thereof: 3-{6-[2-(4-hydroxy-3-methoxyphenyl)acetamide]pyridine-2-yl}phenyl 2-methylpropanoate (Example 1), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamide]phenyl}cyclohexyl cyclohexanecarboxylate (Example 2), 3'-[2-(4-hydroxy-3-methoxyphenyl)acetamide][1,1'-biphenyl]-4-yl benzoate (Example 3), 3'-[2-(4-hydroxy-3-methoxyphenyl)acetamide][1,1'-biphenyl]-4-yl 2-methylpropanoate (Example 4), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamide]phenyl}cyclohexyl cyclohexyl acetate (Example 5), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamide]phenyl}cyclohexyl phenoxyacetate (Example 6), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamide]phenyl}cyclohexyl(3,5-difluorophenyl)acetate (Example 7), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamide]phenyl}cyclohexyl(4-fluorophenyl)acetate (Example 8), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamide]phenyl}cyclohexyl(3-methylphenyl)acetate (Example 9), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamide]phenyl}cyclohexyl(2-chlorophenyl)acetate (Example 10), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamide]phenyl}cyclohexyl(oxa-4-yl)acetate (Example 11), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamide]phenyl}cyclohexyl acetate (Example 12), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamide]phenyl}cyclohexyl(thiophen-2-yl)acetate (Example 13), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamide]phenyl}cyclohexyl(4-chlorophenyl)acetate (Example 14), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamide]phenyl}cyclohexyl(2-fluorophenyl)acetate (Example 15), 3'-[2-(4-hydroxy-3-methoxyphenyl)acetamide][1,1'-biphenyl]-3-yl propanoate (Example 16), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamide]phenyl}cyclohexyl 2-methylpropanoate (Example 17), 3'-[2-(4-hydroxy-3-methoxyphenyl)acetamide][1,1'-biphenyl]-3-yl phenylacetate (Example 18), 2'-Fluoro-5'-[2-(4-hydroxy-3-methoxyphenyl)acetamide][1,1'-biphenyl]-3-yl 2-methylpropanoate (Example 19), 3'-[2-(4-hydroxy-3-methoxyphenyl)acetamide]-4'-methoxy[1,1'-biphenyl]-3-yl 2-methylpropanoate (Example 20), 3'-[2-(4-hydroxy-3-methoxyphenyl)acetamide]-2'-methoxy[1,1'-biphenyl]-3-yl 2-methylpropanoate (Example 21), 4'-Fluoro-3'-[2-(4-hydroxy-3-methoxyphenyl)acetamide][1,1'-biphenyl]-3-yl 2-methylpropanoate (Example 22), 2'-Fluoro-3'-[2-(4-hydroxy-3-methoxyphenyl)acetamide][1,1'-biphenyl]-3-yl 2-methylpropanoate (Example 23), 3'-[2-(4-hydroxy-3-methoxyphenyl)acetamide][1,1'-biphenyl]-3-yl 2-methylpropanoate (Example 24), 3-{2-[2-(4-hydroxy-3-methoxyphenyl)acetamide]pyridine-4-yl}phenyl 2-methylpropanoate (Example 25), 3-{4-[2-(4-hydroxy-3-methoxyphenyl)acetamide]pyridine-2-yl}phenyl 2-methylpropanoate (Example 26), 3'-[2-(4-hydroxy-3-methoxyphenyl)acetamide][1,1'-biphenyl]-3-yl(4-methylphenyl)acetate (Example 27), 3'-[2-(4-hydroxy-3-methoxyphenyl)acetamide][1,1'-biphenyl]-3-yl(2-fluorophenyl)acetate (Example 28), 3'-[2-(4-hydroxy-3-methoxyphenyl)acetamide][1,1'-biphenyl]-3-yl(oxa-4-yl)acetate (Example 29), 3'-[2-(4-hydroxy-3-methoxyphenyl)acetamide][1,1'-biphenyl]-3-ylcyclohexyl acetate (Example 30), 3-{4-[2-(4-hydroxy-3-methoxyphenyl)acetamide]pyridine-2-yl}phenyl cyclohexyl acetate (Example 31), 3-{6-[2-(4-hydroxy-3-methoxyphenyl)acetamide]pyridine-2-yl}phenyl cyclohexyl acetate (Example 32), 3-{4-[2-(4-hydroxy-3-methoxyphenyl)acetamide]pyridine-2-yl}phenyl cyclohexanecarboxylate hydrochloride (Example 33), 3-{6-[2-(4-hydroxy-3-methoxyphenyl)acetamide]pyridine-2-yl}phenyl cyclohexanecarboxylate (Example 34), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamide]phenyl}cyclohexyl phenylacetate (Example 35), Trans-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamide]phenyl}cyclohexyl phenylacetate (Example 36), Trans-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamide]phenyl}cyclohexyl cyclohexanecarboxylate (Example 37), Trans-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamide]phenyl}cyclohexyl acetate (Example 38), 4-(2-{3-[(cis)-4-(acetyloxy)cyclohexyl]anilino}-2-oxoethyl)-2-methoxyphenyl acetate (Example 39), 4-(2-{3-[(trans)-4-(acetyloxy)cyclohexyl]anilino}-2-oxoethyl)-2-methoxyphenyl acetate (Example 40), cis-4-{4-[2-(4-hydroxy-3-methoxyphenyl)acetamide]pyridine-2-yl}cyclohexyl acetate (Example 41), cis-4-(3-{[(4-hydroxy-3-methoxyphenyl)methyl]carbamoyl}phenyl)cyclohexyl acetate (Example 42), 4-[2-({2-[(cis)-4-(acetyloxy)cyclohexyl]pyridine-4-yl}amino)-2-oxoethyl]-2-methoxyphenyl acetate (Example 43), 3'-{[(4-hydroxy-3-methoxyphenyl)methyl]carbamoyl}[1,1'-biphenyl]-3-yl 2-methylpropanoate (Example 44), 3'-{[(4-hydroxy-3-methoxyphenyl)methyl]carbamoyl}[1,1'-biphenyl]-3-ylcyclohexyl acetate (Example 45), 3-(4-{[(4-hydroxy-3-methoxyphenyl)methyl]carbamoyl}pyridine-2-yl)phenyl 2-methylpropanoate (Example 46), 3-(6-{[(4-hydroxy-3-methoxyphenyl)methyl]carbamoyl}pyridine-2-yl)phenyl 2-methylpropanoate (Example 47), Trans-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamide]phenyl}cyclohexyl 2-methylpropanoate (Example 48) and 3-{4-[2-(4-hydroxy-3-methoxyphenyl)acetamide]pyridine-2-yl}phenyl 2-methylpropanoate hydrochloride (Example 49). (Section 30) A compound selected from the following compounds, either one of the compounds described in item 1 or a pharmaceutically acceptable salt thereof: 3-{6-[2-(4-hydroxy-3-methoxyphenyl)acetamide]pyridine-2-yl}phenyl 2-methylpropanoate (Example 1), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamide]phenyl}cyclohexyl cyclohexanecarboxylate (Example 2), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamide]phenyl}cyclohexyl(3-methylphenyl)acetate (Example 9), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamide]phenyl}cyclohexyl(2-chlorophenyl)acetate (Example 10), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamide]phenyl}cyclohexyl acetate (Example 12), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamide]phenyl}cyclohexyl(2-fluorophenyl)acetate (Example 15), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamide]phenyl}cyclohexyl 2-methylpropanoate (Example 17), 2'-Fluoro-5'-[2-(4-hydroxy-3-methoxyphenyl)acetamide][1,1'-biphenyl]-3-yl 2-methylpropanoate (Example 19), 3'-[2-(4-hydroxy-3-methoxyphenyl)acetamide][1,1'-biphenyl]-3-yl 2-methylpropanoate (Example 24), 3-{4-[2-(4-hydroxy-3-methoxyphenyl)acetamide]pyridine-2-yl}phenyl 2-methylpropanoate (Example 26), 3-(4-{[(4-hydroxy-3-methoxyphenyl)methyl]carbamoyl}pyridine-2-yl)phenyl 2-methylpropanoate (Example 46) and 3-{4-[2-(4-hydroxy-3-methoxyphenyl)acetamide]pyridine-2-yl}phenyl 2-methylpropanoate hydrochloride (Example 49). (Section 31) A therapeutic or prophylactic agent for a disorder or disease involving TRPV1, containing a pharmaceutical product as described in any one of items 1 to 30. (Section 32) A therapeutic or prophylactic agent as described in paragraph 31, wherein the disorder or disease involving TRPV1 is dysphagia. (Section 33) A pharmaceutical agent according to any one of claims 1 to 30, for treating or preventing a disorder or disease involving TRPV1. (Section 34) A pharmaceutical product according to any one of claims 1 to 30, for treating or preventing dysphagia. (Section 35) A method for treating or preventing a TRPV1-related disorder or disease, comprising administering to a patient in need of treatment or prevention an effective dose of the medicine described in any one of items 1 to 30. (Section 36) Use of any one of the medicaments described in paragraphs 1 to 30 for the manufacture of a therapeutic or prophylactic agent for a disorder or disease involving TRPV1. (Section 37) A pharmaceutical product as described in any one of paragraphs 1 to 30, for use in the treatment or prevention of a disorder or disease involving TRPV1. (Section 38) A pharmaceutical composition comprising a pharmaceutical product described in any one of items 1 to 30 and one or more other pharmaceutical products. (Section 39) A pharmaceutical product as described in any one of paragraphs 1 to 30, for use in combination with one or more other drugs to treat or prevent a disorder or disease involving TRPV1.

[0014] In this disclosure, the one or more of the above features are intended to be provided in combinations other than those explicitly stated. Further embodiments and advantages of this disclosure will be apparent to those skilled in the art, by reading and understanding the detailed description below as necessary. [Effects of the Invention]

[0015] Because the compounds disclosed herein exhibit TRPV1 agonism, they are useful as therapeutic agents for drug-induced dysphagia, dysphagia associated with neurodegenerative diseases such as Parkinson's disease, and dysphagia caused by a decrease in the swallowing reflex due to various factors such as cerebrovascular disease and aging. [Brief explanation of the drawing]

[0016] [Figure 1] This figure shows the swallowing improvement effect of haloperidol in a rat dysphagia model in Test Example 2. The vertical axis represents the number of swallows (times), shown as mean ± standard error. The horizontal axis represents the group name (treatment drug). [Modes for carrying out the invention]

[0017] The present disclosure is described in further detail below. Throughout this specification, singular expressions should be understood to include the concept of their plural form unless otherwise specified. Accordingly, singular articles (e.g., "a," "an," "the" in English) should be understood to include the concept of their plural form unless otherwise specified. Furthermore, terms used herein should be understood to have the meaning commonly used in the art unless otherwise specified. Accordingly, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention pertains. In case of any conflict, this specification (including definitions) shall prevail.

[0018] The number of substituents on a group defined as "may be substituted" or "substituted" is not particularly limited as long as substitution is possible. Also, unless otherwise specified, the description of each group applies even if that group is part of or a substituent of another group.

[0019] The substituents in "may be substituted" are selected from the group of substituents α consisting of the following, and may be substituted with the same or different 1 to 5 substituents. There are no particular restrictions on the type of substituent, however, if the atom to which the substituent is bonded is an oxygen atom, nitrogen atom, or sulfur atom, then the substituents are limited to those from the following list to which the bonded atom is a carbon atom. The substituent group α is, 1) Halogen atom, 2) Hydroxyl group, 3) Carboxyl group, 4) Cyano group, 5) C 1-6 alkyl group, 6)C 2-6 Alkenyl group, 7)C 2-6 Alkynyl group, 8)C 1-6 Alkoxy group, 9)C 1-6 Alkylthio group, 10)C 1-6 Alkylcarbonyl group, 11)C1-6 Alkyl sulfonyl group, (However, each substituent from 5) to 11) may be replaced by one to five identical or different substituents selected from substituent group β.) 12)C 3-10 alicyclic group, 13)C 3-10 Alicyclic oxy group, 14)C 6-10 Aryloxy group, 15) Five-membered or six-membered heteroaryloxy group, 16) 4-10 member nonaryl heterocyclic oxy groups, 17)C 3-10 alicyclic thio group, 18)C 6-10 Arylthio group, 19) Five-membered or six-membered heteroarylthio group, 20) 4-10 member nonaryl heterocyclic thio group, 21)C 6-10 Aryl group, 22) Five-membered or six-membered heteroaryl group, 23) 4-10 member non-aryl heterocyclic group, 24)C 3-10 Alicyclic carbonyl group, 25)C 6-10 Arylcarbonyl group, 26) Five-membered or six-membered heteroarylcarbonyl group, 27) 4-10 member non-aryl heterocyclic carbonyl group, 28)C 3-10 Alicyclic sulfonyl group, 29)C 6-10 Aryl sulfonyl group, 30) A 5-membered or 6-membered heteroarylsulfonyl group, 31) 4-10 member non-aryl heterocyclic sulfonyl group, (However, each substituent from 12) to 31) is C 1-6 (The alkyl group may be substituted with 1 to 5 identical or different substituents selected from the substituent group β.) 32)-NR 16 R 17 , 33)-SO2-NR 10b R 11b 、 34)-NR 10c -C(=O)R 11c 、 35)-NR 10d -C(=O)OR 11d 、 36)-NR 12a -C(=O)NR 10e R 11e 、 37)-NR 10f -C(=S)R 11f 、 38)-NR 10g -C(=S)OR 11g 、 39)-NR 12b -C(=S)NR 10h R 11h 、 40)-NR 10i -SO2-R 11i 、 41)-NR 12c -SO2-NR 10j R 11j 、 42)-C(=O)OR 10k 、 43)-C(=O)NR 10l R 11k 、 44)-C(=O)NR 10m OR 11l 、 45)-C(=O)NR 12d -NR 10n R 11m 、 46)-C(=S)OR 10o 、 47)-C(=S)NR 10p R 11n 、 48)-C(=S)NR 10q OR 11o 、 49)-C(=S)NR 12e -NR 10r R 11p 、 50)-C(=NR 13a )R 10s 、 51)-C(=NR 13b )CHO, 52)-C(=NR 13c )NR 10t R 11q , 53)-C(=NR 13d )NR 12f -NR 10u R 11r , 54)-NR 17c -C(=NR 13k )R 17d , 55)-NR 12g -C(=NR 13e )-NR 10v R 11s , 56)-NR 14 -C(=NR 13f )NR 12h -NR 10w R 11t , 57)-OC(=O)R 10x , 58)-OC(=O)OR 10y , 59)-OC(=O)NR 10z1 R 11u , 60)-NR 12i -NR 10z2 R 11v , 61)-NR 10z3 Ure 11w , 62)-C(=N-OR 13a )R 10s , 63)-C(=N-OR 13b )CHO, 64)-C(=N-OR 13c )NR 10t R 11q , 65)-C(=N-OR 13d )NR 12f -NR 10u R 11r , and 66)-C(=O)H It is a group consisting of, The substituent group β is, 1) Halogen atom, 2) Hydroxyl group, 3) Carboxyl group, 4) Cyano group, 5) C 3-10 alicyclic group, 6)C 1-6 Alkoxy group, 7)C 3-10 Alicyclic oxy group, 8)C 1-6 Alkylthio group, 9) Five-membered or six-membered heteroarylthio group, 10)C 6-10 Aryl group, 11) Five-membered or six-membered heteroaryl group, 12) 4-10 member non-aryl heterocyclic group, 13)C 1-6 Alkylcarbonyl group, 14)C 3-10 Alicyclic carbonyl group, 15)C 6-10 Arylcarbonyl group, 16) Five-membered or six-membered heteroarylcarbonyl group, 17) 4-10 member non-aryl heterocyclic carbonyl group, 18)-NR 15a R 16a , 19)-SO2-NR 15b R 16b , 20)-NR 15c -C(=O)R 16c 21)-NR 17a -C(=O)NR 15d R 16d , 22)-C(=O)NR 15e R 16e , 23)-C(=NR 13g )R 15f , 24)-C(=NR 13h )NR 15g R 16f , 25)-NR 16g -C(=NR 13i )R 15h , 26)-NR 17b -C(=NR 13j )-NR 15i R 16h , 27)-C(=N-OR 13g )R 15f , and 28)-C(=N-OR 13h )NR 15g R 16f (However, among the substituent group β, each substituent from 5) to 17) is a halogen atom, hydroxyl group, cyano group, carboxyl group and -NR 18a R 18b The group consists of (which may be substituted with 1 to 5 substituents selected from the group consisting of), R 13a , R 13b , R 13c , R 13d , R 13e , R 13f , R 13g , R 13h , R 13i , R 13j and R 13k Each of these is independently a hydrogen atom, a hydroxyl group, and C 1-6 Alkyl alkyl group or C 1-6 It is an alkoxy group, R 10a , R 10b , R 10c , R 10d , R 10e , R 10f , R 10g , R 10h , R 10i , R 10j , R 10k , R 10l , R 10m , R 10n , R 10o , R 10p , R 10q , R 10r , R 10s , R 10t , R 10u , R 10v , R 10w , R 10x , R 10y , R 10z1 , R 10z2 , R10z3 , R 11a , R 11b , R 11c , R 11d , R 11e , R 11f , R 11g , R 11h , R 11i , R 11j , R 11k , R 11l , R 11m , R 11n , R 11o , R 11p , R 11q , R 11r , 11s , R 11t , R 11u , R 11v , R 11w , R 12a , R 12b , R 12c , R 12d , R 12e , R 12f , R 12g , R 12h , R 12i , R 14 , R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , R 15g , R 15h , R 15i , R 16a , R 16b , R 16c , R 16d , R 16e , R 16f , R 16g , R 16h , R 17a , R 17b , R 17c and R 17d Each of them is independently a hydrogen atom or C 1-6 Alkyl group (the group is a hydroxyl group, a cyano group, C 1-6 Alkoxy groups and -NR 18a R 18b (May be substituted with 1 to 3 substituents selected from the group consisting of) R 18a and R 18bEach of them is independently a hydrogen atom or C 1-6 It is an alkyl group.

[0020] The substituents in "may be substituted" are preferably the following substituents. The substituent group α is preferably, 1) Halogen atom, 2) Hydroxyl group, 3) Carboxyl group, 4) Cyano group, 5) C 1-6 alkyl group, 6)C 1-6 Alkoxy group, 7)C 1-6 Alkylthio group, 8)C 1-6 Alkylcarbonyl group, (However, each substituent in 5) to 8) may be replaced by one to five identical or different substituents selected from substituent group β.) 9)C 3-10 alicyclic group, 10)C 3-10 Alicyclic oxy group, 11)C 6-10 Aryloxy group, 12) Five-membered or six-membered heteroaryloxy group, 13) 4-10 member non-aryl heterocyclic oxy groups, 14)C 3-10 alicyclic thio group, 15)C 6-10 Arylthio group, 16) Five-membered or six-membered heteroarylthio group, 17) 4-10 member nonaryl heterocyclic thio group, 18)C 6-10 Aryl group, 19) Five-membered or six-membered heteroaryl group, 20) 4-10 member non-aryl heterocyclic group, 21)C 3-10 Alicyclic carbonyl group, 22)C 6-10 Arylcarbonyl group, 23) Five-membered or six-membered heteroarylcarbonyl group, 24) 4-10 member non-aryl heterocyclic carbonyl group, (However, each substituent from 9) to 24) is C 1-6 (The alkyl group may be substituted with 1 to 5 identical or different substituents selected from the substituent group β.) 25)-NR 10a R 11a , 26)-SO2-NR 10b R 11b , 27)-NR 10c -C(=O)R 11c , 28)-NR 12a -C(=O)NR 10d R 11d , 29)-NR 10e -SO2-R 11e , 30)-NR 12b -SO2-NR 10f R 11f , 31)-C(=O)NR 10g R 11g , 32)-C(=NR 13a )R 10h , 33)-C(=NR 13b )NR 10i R 11h , 34)-NR 11f -C(=NR 13c )R 10g , 35)-NR 12c -C(=NR 13d )-NR 10j R 11i , 36)-C(=N-OR 13a )R 10h , and 37)-C(=N-OR 13b )NR 10i R 11h It is a group consisting of, The substituent group β is preferably, 1) Halogen atom, 2) Hydroxyl group, 3) Cyano group, 4) C 3-10 alicyclic group, 5) C 1-6 Alkoxy group, 6)C 1-6 Alkylthio group, 7) Five-membered or six-membered heteroarylthio group, 8) A 5-membered or 6-membered heteroaryl group, 9) 4-10 member non-aryl heterocyclic group, 10)C 1-6 Alkylcarbonyl group, 11)C 3-10 Alicyclic carbonyl group, 12)C 6-10 Arylcarbonyl group, 13) Five-membered or six-membered heteroarylcarbonyl group, 14) 4-10 member non-aryl heterocyclic carbonyl group, 15)-NR 15a R 16a , 16)-NR 15b -C(=O)R 16b , 17)-NR 17a -C(=O)NR 15c R 16c , 18)-C(=O)NR 15d R 16d , 19)-C(=NR 13e )R 15e , 20)-C(=NR 13f )NR 15f R 16e , 21)-NR 16f -C(=NR 13g )R 15g , 22)-NR 17b -C(=NR 13h )-NR 15h R 16g , 23)-C(=N-OR 13e )R 15e , and 24)-C(=N-OR 13f)NR 15f R 16e (However, among the substituent group β, each substituent from 4) to 14) is a halogen atom, a hydroxyl group, a cyano group, a carboxyl group, and -NR 18a R 18b The group consists of (which may be substituted with 1 to 5 substituents selected from the group consisting of), R 13a , R 13b , R 13c , R 13d , R 13e , R 13f , R 13g , R 13h Each of these is independently a hydrogen atom, a hydroxyl group, and C 1-6 Alkyl alkyl group or C 1-6 It is an alkoxy group, R 10a , R 10b , R 10c , R 10d , R 10e , R 10f , R 10g , R 10h , R 10i , R 10j , R 11a , R 11b , R 11c , R 11d , R 11e , R 11f , R 11g , R 11h , R 11i , R 12a , R 12b , R 12c , R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , R 15g , R 15h , R 16a , R 16b , R 16c , R 16d , R 16e , R 16f , R 16g , R 17a and R 17b Each of them is independently a hydrogen atom or C 1-6Alkyl group (the group is a hydroxyl group, a cyano group, C 1-6 Alkoxy groups and -NR 18a R 18b A selected from the group consisting of (which may be substituted with 1 to 3 substituents), R 18a , R 18b Each of them is independently a hydrogen atom or C 1-6 It is an alkyl group.

[0021] The substituents in "may be substituted" are more preferably the following substituents. The substituent group α is more preferably, 1) Halogen atom, 2) Hydroxyl group, 3) Cyano group, 4) C 1-6 alkyl group, 5) C 1-6 Alkoxy group, 6)C 1-6 Alkylthio group, 7)C 1-6 Alkylcarbonyl group, (However, each substituent in 4) to 7) may be replaced by one to five identical or different substituents selected from substituent group β.) 8) A 5-membered or 6-membered heteroaryloxy group, 9) 4-10 member nonaryl heterocyclic oxy groups, 10) Five-membered or six-membered heteroarylthio group, 11) 4-10 member nonaryl heterocyclic thio group, 12)C 6-10 Aryl group, 13) Five-membered or six-membered heteroaryl group, 14) 4-10 member non-aryl heterocyclic group, (However, each substituent from 4) to 14) is C 1-6 (The alkyl group may be substituted with 1 to 5 identical or different substituents selected from the substituent group β.) 15)-NR 10a R 11a , 16)-NR 11b-C(=O)R 10b , 17)-NR 12a -C(=O)NR 10c R 11c , 18)-C(=O)NR 10d R 11d , 19)-C(=NR 13a )R 10e , 20)-C(=NR 13b )NR 10f R 11e , 21)-NR 11f -C(=NR 13c )R 10g , 22)-NR 12b -C(=NR 13d )-NR 10h R 11g , 23)-C(=N-OR 13a )R 10e , and 24)-C(=N-OR 13b )NR 10f R 11e It is a group consisting of, The substituent group β is more preferably, 1) Halogen atom, 2) Hydroxyl group, 3) Cyano group, 4)-NR 15a R 16a , 5)-NR 15b -C(=O)R 16b , 6)-NR 17a -C(=O)NR 15c R 16c , 7)-C(=O)NR 15d R 16d , 8)-C(=NR 13e )R 15e , 9)-C(=NR 13f )NR 15f R 16e , 10)-NR16f -C(=NR 13g )R 15g , 11)-NR 17b -C(=NR 13h )-NR 15h R 16g 12)-C(=N-OR 13e )R 15e , and 13)-C(=N-OR 13f )NR 15f R 16e It is a group consisting of, R 13a , R 13b , R 13c , R 13d , R 13e , R 13f , R 13g and R 13h Each of these is independently a hydrogen atom, a hydroxyl group, and C 1-6 Alkyl alkyl group or C 1-6 It is an alkoxy group, R 10a , R 10b , R 10c , R 10d , R 10e , R 10f , R 10g , R 10h , R 11a , R 11b , R 11c , R 11d , R 11e , R 11f , R 11g , R 12a , R 12b , R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , R 15g , R 15h , R 16a , R 16b , R 16c , R 16d , R 16e , R 16f , R 16g , R 17a and R 17bEach of them is independently a hydrogen atom or C 1-6 Alkyl group (the group is a hydroxyl group, a cyano group, C 1-6 Alkoxy groups and -NR 18a R 18b A selected from the group consisting of (which may be substituted with 1 to 3 substituents), R 18a , R 18b Each of them is independently a hydrogen atom or C 1-6 It is an alkyl group.

[0022] "C 1-6 " means that the number of carbon atoms is between 1 and 6. The same applies to other numbers, for example, "C 1-4 " means that the number of carbon atoms is between 1 and 4.

[0023] "Heteroatoms" refer to oxygen atoms, nitrogen atoms, sulfur atoms, etc.

[0024] A "halogen atom" refers to any atom other than carbon and hydrogen atoms, and includes fluorine, chlorine, bromine, and iodine atoms. Fluorine and chlorine atoms are preferred among these. Sometimes, "halogen atom" is simply referred to as "halogen."

[0025] "C 1-6 "Alkyl" or "C 1-6 "Alkyl group" refers to a linear or branched saturated hydrocarbon group with 1 to 6 carbon atoms. 1-6 Preferably, the alkyl group is "C 1-4 Examples include "alkyl groups", and more preferably "C 1-3 "Alkyl group" is one example. 1-3 Specific examples of alkyl groups include methyl, ethyl, propyl, and 1-methylethyl. 1-4 A specific example of an alkyl group is, for example, the aforementioned "C 1-3 In addition to the examples listed as specific examples of "alkyl groups," other examples include butyl, 1,1-dimethylethyl, 1-methylpropyl, and 2-methylpropyl. 1-6 A specific example of an alkyl group is, for example, the aforementioned "C1-4 In addition to the examples listed as "alkyl groups," other examples include pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, and hexyl.

[0026] "C 2-6 "Alkenil" or "C 2-6 An "alkenyl group" refers to a linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing one or more carbon-carbon double bonds. 2-6 As the "alkenyl group", preferably "C 2-4 It is an "alkenyl group" "C 2-6 Specific examples of "alkenyl groups" include, but are not limited to, vinyl groups, 1-propyrenyl groups, 2-propyrenyl groups, 1-butenyl groups, 2-butenyl groups, 3-butenyl groups, 2-methyl-1-propyrenyl groups, and 2-methyl-2-propyrenyl groups.

[0027] "C 2-6 "Alkinyl" or "C 2-6 An "alkynyl group" refers to a linear or branched unsaturated aliphatic hydrocarbon group having 2 to 6 carbon atoms and possessing one or more carbon-carbon triple bonds. 2-6 "Alkynyl group" is preferably "C 2-4 It is an "alkynyl group" "C 2-6 Specific examples of "alkynyl groups" include, but are not limited to, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 1-methyl-2-propynyl group, 3-butynyl group, 1-pentynyl group, and 1-hexynyl group.

[0028] "C 3-10"Alicyclic group" refers to a monocyclic or bicyclic monovalent non-aromatic hydrocarbon ring group having 3 to 10 carbon atoms, and includes those with some unsaturated bonds, some bridging structures, some spirated structures, and those with one or more carbonyl structures. "Alicyclic group" includes cycloalkyl groups, cycloalkenyl groups, and cycloalkynyl groups. 3-10 Preferably, "C" is used as the "alicyclic group". 3-7 "Alicyclic group", more preferably "C 5-6 "Alicyclic group" is one example. 5-6 Specific examples of "alicyclic groups" include, for example, cyclopentyl and cyclohexyl. 3-7 A specific example of an "alicyclic group" is, for example, the aforementioned "C 5-6 In addition to the examples given as specific examples of "alicyclic groups," other examples include cyclopropyl, cyclobutyl, and cycloheptyl. 3-10 A specific example of an "alicyclic group" is, for example, the aforementioned "C 3-7 In addition to the examples given for "alicyclic groups," other examples include cyclooctyl, cyclononyl, cyclodecyl, and adamantyl.

[0029] "C" has a partially cross-linked structure 3-10 Specific examples of "alicyclic groups" are not limited to those shown below, but include, for example, those with the structures shown below. [ka]

[0030] Also, "C 3-10 The term "alicyclic group" also includes compounds formed by fusion with an aromatic ring. Specific examples include the groups shown below. [ka]

[0031] "C 6-10 An "aryl group" refers to a monocyclic or bicyclic aromatic hydrocarbon group with 6 to 10 carbon atoms. 6-10The "aryl group" may be condensed with the "alicyclic group" or the "non-aryl heterocyclic group" described later at all possible positions. 6-10 Specific examples of "aryl groups" include, for example, the phenyl group, 1-naphthyl group, and 2-naphthyl group. 6-10 A phenyl group is preferred as the "aryl group." Specific examples of the fused ring structure include, for example, the group shown below. [ka] [ka]

[0032] A "5-10 membered heteroaryl group" means a monocyclic or bicyclic aromatic heterocyclic group composed of 5 to 10 atoms, including 1 to 4 atoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms. The "5-10 membered heteroaryl group" may be condensed with the "alicyclic group" or the "non-aryl heterocyclic group" described later at all possible positions. Preferred "5-10 membered heteroaryl groups" include "6 membered heteroaryl groups," "5- or 6 membered heteroaryl groups," "6-10 membered heteroaryl groups," or "9- or 10 membered heteroaryl groups." More preferably, "6 membered heteroaryl groups" or "5- or 6 membered heteroaryl groups" are included. Specific examples of "6 membered heteroaryl groups" include, for example, pyridyl groups, pyrazinyl groups, pyrimidinyl groups, and pyridadinyl groups. Specific examples of "5-membered or 6-membered heteroaryl groups" include, for example, the furyl group, thienyl group, pyrrolyl group, pyrazolyl group, oxazolyl group, thiazolyl group, imidazolyl group, isoxazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, and pyridadinyl group. Specific examples of "6- to 10-membered heteroaryl groups" include the pyridyl group, pyrazinyl group, pyrimidinyl group, pyridadinyl group, quinoxalyl group, triazolopyridyl group, etc. Specific examples of "5- to 10-membered heteroaryl groups" include the aforementioned "6- to 10-membered heteroaryl groups" and "5-membered or 6-membered heteroaryl groups".

[0033] Specific examples of "9-membered or 10-membered heteroaryl groups" include, but are not limited to, those with the structures shown below. [ka] [ka]

[0034] The aforementioned "5-membered or 6-membered heteroaryl group" or "5- to 10-membered heteroaryl group" is C 5-10It may form a fused ring structure with an alicyclic group, or a fused ring structure with a 5-10 membered non-aryl heteroring. Specific examples include the groups shown below. [ka] [ka] [ka]

[0035] A "4-10 member non-aryl heterocyclic group" refers to a monocyclic or bicyclic non-aromatic heterocyclic group composed of 4 to 10 atoms, including 1 to 2 identical or different heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, in addition to carbon atoms, and includes those having some unsaturated bonds, some bridging structures, and / or some spirogenic structures. A "4-7 member non-aryl heterocyclic group" is preferred as a "4-10 member non-aryl heterocyclic group." Specific examples of a "4-7 member non-aryl heterocyclic group" include, for example, azetidinyl group, pyrrolidinyl group, piperidyl group, piperazinyl group, morpholinyl group, oxetanyl group, tetrahydrofuranyl group, and tetrahydropyranyl group. Preferably, azetidinyl group, pyrrolidinyl group, piperidyl group, morpholinyl group, and oxetanyl group are mentioned. The non-aryl heterocyclic group may form a fused ring with an aryl or heteroaryl group. For example, C 6-10Non-aryl heterocycles are also included when they are fused with an aryl group or a 5- or 6-membered heteroaryl group. Furthermore, the non-aryl heterocycle may contain one or more carbonyl groups, thiocarbonyl groups, sulfinyl groups, or sulfonyl groups. For example, cyclic groups such as lactams, thiolactams, lactones, thiolactones, cyclic imides, cyclic carbamates, and cyclic thiocarbamates are also included in the non-aryl heterocycle. Here, the oxygen atoms of carbonyl groups, sulfinyl groups, and sulfonyl groups, and the sulfur atoms of thiocarbonyl groups are not included in the number of members (ring size) and the number of heteroatoms constituting the ring. As for "4- to 10-membered non-aryl heterocycles," "4- to 7-membered non-aryl heterocycles" are preferred. Specific examples of "4- to 7-membered non-aryl heterocycles" include, for example, azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, oxetane, tetrahydrofuran, and tetrahydropyran. Specific examples of "4- to 10-membered non-aryl heterocycles" include, in addition to those listed above as examples of "4- to 7-membered non-aryl heterocycles," those with the structures shown below. [ka]

[0036] Furthermore, specific examples of "4- to 10-membered non-aryl heterocycles" having partial crosslinking and / or spiro structures include, but are not limited to, those with the structures shown below. [ka]

[0037] Furthermore, specific examples of "four-membered non-aryl heterocycles" having some unsaturated bonds include, but are not limited to, those with the structures shown below. [ka]

[0038] Furthermore, specific examples of "5-membered non-aryl heterocycles" that have some unsaturated bonds include, but are not limited to, those with the structures shown below. [ka]

[0039] Furthermore, specific examples of "5-membered non-aryl heterocycles" having a partially cross-linked structure include, but are not limited to, those with the structures shown below. [ka]

[0040] Furthermore, specific examples of "5-membered non-aryl heterocycles" containing carbonyl or thiocarbonyl molecules, etc., are not limited to these, but include, for example, structures like those shown below. [ka]

[0041] Furthermore, while not limited to these examples, specific examples of "six-membered non-aryl heterocycles" that have some unsaturated bonds include those with the structures shown below. [ka]

[0042] Furthermore, specific examples of "six-membered non-aryl heterocycles" having a partially cross-linked structure include, but are not limited to, those with the structures shown below. [ka]

[0043] "C 1-6 "alkoxy" or "C 1-6 An "alkoxy group" is a "C 1-6 This refers to "alkyloxy," and "C 1-6The "alkyl" portion is the aforementioned "C 1-6 It is synonymous with "alkyl". 1-6 Preferably, "C" is used as the "alkoxy" 1-4 "Alkoxy" is one example, and more preferably "C 1-3 "alkoxy" is one example. 1-3 Specific examples of "alkoxy" include, for example, methoxy, ethoxy, propoxy, and 1-methylethoxy. 1-4 A specific example of "alkoxy" is, for example, the aforementioned "C 1-3 In addition to the examples given for "alkyl," other examples include butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, and 2-methylpropoxy. 1-6 A specific example of "alkoxy" is, for example, the aforementioned "C 1-4 In addition to the examples listed for "alkyl," other examples include pentyloxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, and hexyloxy.

[0044] "C 3-7 "Alicyclic oxy" or "C 3-7 "Alicyclic oxy group" refers to (C 3-7 (Alicyclic group)-O- group, and the C 3-7 The alicyclic part is C 3-7 It is synonymous with an alicyclic group. 3-7 "Alicyclic oxy group" is "C 3-7 Contains a "cycloalkoxy group". A "cycloalkoxy group" is the same as "cycloalkyloxy", and the "cycloalkyl" part is synonymous with the aforementioned "cycloalkyl". 3-7 Specific examples of "alicyclic oxy groups" include, for example, cyclopropoxy groups, cyclobutoxy groups, cyclopentoxy groups, and cyclohexoxy groups.

[0045] "C 6-10 C of "aryloxy group" 6-10 The aryl portion is C above. 6-10 It is synonymous with the aryl group. 6-10Preferably, the "aryloxy group" is "C6 or C6". 10 "The aryloxy group of C" is one example. 6-10 Specific examples of "aryloxy groups" are not limited to these, but include, for example, phenoxy group, 1-naphthyloxy group, and 2-naphthyloxy group.

[0046] The 5-membered or 6-membered heteroaryl portion of "5-membered or 6-membered heteroaryloxy group" is synonymous with the above-mentioned "5-membered heteroaryl group" or "6-membered heteroaryl group." Specific examples of "5-membered or 6-membered heteroaryloxy groups" are not limited to these, but include, for example, pyrazoyloxy group, triazoyloxy group, thiazoyloxy group, thiadiazoyloxy group, pyridyloxy group, pyridazoyloxy group, etc.

[0047] The 4-10 member non-aryl heterocyclic portion of "4-10 member non-aryl heterocyclic oxy group" is synonymous with the above-mentioned "4-10 member non-aryl heterocyclic ring". Preferably, the "4-10 member non-aryl heterocyclic oxy group" is a "4-6 member non-aryl heterocyclic oxy group". Specific examples of the "4-10 member non-aryl heterocyclic oxy group" are not limited to these, but include, for example, tetrahydrofuranyloxy group, tetrahydropyranyloxy group, azetidinyloxy group, pyrrolidinyloxy group, piperidinyloxy group, etc.

[0048] "C 1-6 C of alkylthio group 1-6 The alkyl portion is the above C 1-6 It is synonymous with alkyl. 1-6 Preferably, "C" is used as the alkylthio group. 1-4 "alkylthio group", more preferably "C 1-3 It is an alkylthio group. 1-6Specific examples of "alkylthio groups" include, but are not limited to, methylthio group, ethylthio group, propylthio group, butylthio group, isopropylthio group, isobutylthio group, tert-butylthio group, sec-butylthio group, isopentylthio group, neopentylthio group, tert-pentylthio group, 1,2-dimethylpropylthio group, and others.

[0049] "C 3-10 "Alipidic thio" or "C 3-10 "Alicyclic thio group" is (C 3-10 (Alicyclic group) -S- group, and the C 3-10 The alicyclic portion is C above. 3-10 It is synonymous with an alicyclic group. 3-10 Preferably, "C" is used as the "alicyclic thio group". 3-6 It is an alicyclic thio group. 3-6 Specific examples of "alicyclic thio groups" include, but are not limited to, cyclopropylthio groups, cyclobutylthio groups, cyclopentylthio groups, and cyclohexylthio groups.

[0050] "C 6-10 "Alylthio" or "C 6-10 C of the arylthio group 6-10 The aryl portion is C above. 6-10 It is synonymous with the aryl group. 6-10 Preferably, the "arylthio group" is "C6 or C6". 10 One example is the "arylthio group of C". 6-10 Specific examples of "aryloxy groups" are not limited to these, but include, for example, phenylthio groups, 1-naphthylthio groups, and 2-naphthylthio groups.

[0051] The 5-membered or 6-membered heteroaryl portion of "5-membered or 6-membered heteroarylthio" or "5-membered or 6-membered heteroarylthio group" is synonymous with the above-mentioned "5-membered heteroaryl group" or "6-membered heteroaryl group". Specific examples of "5-membered or 6-membered heteroarylthio groups" are not limited to these, but include, for example, pyrazoylthio groups, triazoylthio groups, thiazoylthio groups, thiadiazoylthio groups, pyridylthio groups, pyridazoylthio groups, etc.

[0052] The 4-10 member non-aryl heterocyclic portion of "4-10 member non-aryl heterocyclic thio" or "4-10 member non-aryl heterocyclic thio group" is synonymous with the above-mentioned "4-10 member non-aryl heterocyclic group". Preferably, the "4-10 member non-aryl heterocyclic thio group" is a "4-6 member non-aryl heterocyclic thio group". Specific examples of the "4-10 member non-aryl heterocyclic thio group" are not limited to these, but include, for example, a tetrahydropyranylthio group and a piperidinylthio group.

[0053] "C 1-6 "Alkylcarbonyl" or "C 1-6 The "alkylcarbonyl group" refers to the above "C 1-6 This refers to a carbonyl group substituted with an alkyl group. 1-6 Preferably, "C" is used as the alkylcarbonyl group. 1-4 "Alkyl carbonyl group" or "C 1-3 It is an alkylcarbonyl group. 1-6 Specific examples of "alkylcarbonyl groups" include, but are not limited to, acetyl groups, propionyl groups, and butyryl groups.

[0054] "C 1-6 "alkoxycarbonyl" or "C 1-6 The term "alkoxycarbonyl group" refers to the above "C 1-6 This refers to a carbonyl group substituted with an alkoxy group. 1-6 Preferably, "C" is used as the "alkoxycarbonyl group". 1-4 "alkoxycarbonyl group" or "C 1-3It is an "alkoxycarbonyl group". 1-6 Specific examples of "alkoxycarbonyl groups" include, but are not limited to, methoxycarbonyl groups, ethoxycarbonyl groups, propoxycarbonyl groups, and butoxycarbonyl groups.

[0055] "C 3-10 "Alicyclic carbonyl" or "C 3-10 "Alicyclic carbonyl group" refers to the above "C 3-10 This refers to a carbonyl group substituted with an alicyclic group. 3-10 Preferably, "C" is used as the "alicyclic carbonyl group". 3-6 It is an "alicyclic carbonyl group". 3-10 Specific examples of "alicyclic carbonyl groups" include, but are not limited to, cyclopropyl carbonyl groups and cyclopentyl carbonyl groups.

[0056] "C 6-10 "Arylcarbonyl" or "C 6-10 The term "arylcarbonyl group" refers to the above "C 6-10 This refers to a carbonyl group substituted with an aryl group. 6-10 Preferably, the "arylcarbonyl group" is "C6 or C6". 10 It is the arylcarbonyl group of "C 6-10 Specific examples of "arylcarbonyl groups" are not limited to these, but include, for example, benzoyl groups, 1-naphthylcarbonyl groups, and 2-naphthylcarbonyl groups.

[0057] "Five-membered or six-membered heteroarylcarbonyl" or "five-membered or six-membered heteroarylcarbonyl group" means a carbonyl group substituted with the above-mentioned "five-membered or six-membered heteroaryl group". Specific examples of "five-membered or six-membered heteroarylcarbonyl groups" are not limited to these, but include, for example, pyrazoylcarbonyl group, triazoylcarbonyl group, thiazoylcarbonyl group, thiadiazoylcarbonyl group, pyridylcarbonyl group, pyridazoylcarbonyl group, etc.

[0058] "4-10 member non-aryl heterocyclic carbonyl" or "4-10 member non-aryl heterocyclic carbonyl group" means a carbonyl group substituted with the above-mentioned "4-10 member non-aryl heterocyclic group". Preferably, the "4-10 member non-aryl heterocyclic carbonyl group" is a "4-6 member non-aryl heterocyclic carbonyl group". Specific examples of the "4-10 member non-aryl heterocyclic carbonyl group" are not limited to these, but include, for example, azetidinyl carbonyl group, pyrrolidinyl carbonyl group, piperidinyl carbonyl group, morpholinyl carbonyl group, etc.

[0059] "C 1-6 "Alkylsulfonyl" or "C 1-6 The "alkylsulfonyl group" refers to the above "C 1-6 This refers to a sulfonyl group substituted with an alkyl group. 1-6 Preferably, "C" is used as the alkylsulfonyl group. 1-4 It is an alkylsulfonyl group. 1-6 Specific examples of "alkylsulfonyl groups" are not limited to these, but include, for example, methylsulfonyl groups, propionylsulfonyl groups, and butyrylsulfonyl groups.

[0060] "C 3-10 "Alicyclic sulfonyl" or "C 3-10 "Alicyclic sulfonyl group" refers to the above "C 3-10 This refers to a sulfonyl group substituted with an alicyclic group. 3-10 As an "alicyclic sulfonyl group", preferably "C 3-6 It is an "alicyclic sulfonyl group". 3-10 Specific examples of "alicyclic sulfonyl groups" include, but are not limited to, cyclopropylsulfonyl groups, cyclobutylsulfonyl groups, cyclopentylsulfonyl groups, and cyclohexylsulfonyl groups.

[0061] "C 6-10 "Aryl sulfonyl" or "C 6-10 The term "arylsulfonyl group" refers to the above "C 6-10 This refers to a sulfonyl group substituted with an aryl group. 6-10The "aryl sulfonyl group" is preferably "C6 or C6". 10 It is the aryl sulfonyl group of "C 6-10 Specific examples of "arylsulfonyl groups" include, but are not limited to, phenylsulfonyl groups, 1-naphthylsulfonyl groups, and 2-naphthylsulfonyl groups.

[0062] "Five-membered or six-membered heteroarylsulfonyl" or "five-membered or six-membered heteroarylsulfonyl group" means a sulfonyl group substituted with the above-mentioned "five-membered or six-membered heteroaryl group". Specific examples of "five-membered or six-membered heteroarylsulfonyl groups" are not limited to these, but include, for example, pyrazoylsulfonyl group, triazoylsulfonyl group, thiazoylsulfonyl group, thiadiazoylsulfonyl group, pyridylsulfonyl group, pyridazoylsulfonyl group, etc.

[0063] In the compounds of the present disclosure represented by formula (1) or formula (2), R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , m, n, L 1 , L 2 Preferred Q, X, and Y are as follows, but the technical scope of this disclosure is not limited to the compounds listed below.

[0064] R 1 A preferred embodiment is a hydrogen atom.

[0065] R 2 A preferred embodiment is a methoxy group.

[0066] R 3 A preferred embodiment is a hydrogen atom.

[0067] R 4 A preferred embodiment is C 1-6 Alkyl alkyl group, C 3-7 Alicyclic group or C 6-10 Aryl group (the C 1-6 Alkyl alkyl group, C 3-7 Alicyclic groups and C 6-10 The aryl group consists of a fluorine atom, a chlorine atom, and a carbon atom. 1-6 Alkyl alkyl group, C 3-7 Alicyclic group, C 6-10 Examples include those that are substituted with one to three identical or different substituents selected from the group consisting of aryl groups, 5- or 6-membered heteroaryl groups, and 4- to 10-membered nonaryl heterocyclic groups.

[0068] R 4 A more preferred embodiment includes a methyl group, an ethyl group, an isopropyl group, a cyclohexyl group, a cyclohexylmethyl group, a phenyl group, or a benzyl group (the methyl group, ethyl group, isopropyl group, cyclohexyl group, cyclohexylmethyl group, phenyl group, and benzyl group are composed of a fluorine atom, a chlorine atom, and C 1-6 Examples include alkyl groups (which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of alkyl groups).

[0069] R 4 A more preferred embodiment includes a methyl group, an ethyl group, an isopropyl group, a cyclohexyl group, or a phenyl group (the methyl group, ethyl group, isopropyl group, cyclohexyl group, and phenyl group are composed of a fluorine atom, a chlorine atom, and C 1-6 Examples include alkyl groups (which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of alkyl groups).

[0070] R 5 , R 6 and R 7 A preferred embodiment includes a hydrogen atom, C 3-6 Alicyclic group or C 1-6 Alkyl(C) 3-6 Alicyclic groups and C 1-6 Alkyl groups consist of a halogen atom, a hydroxyl group, and C 1-6Alkoxy group, C 3-10 Alicyclic group, C 6-10 Examples include those that are substituted with the same or different substituents selected from the group consisting of aryl groups and 4-6 membered non-aryl heterocyclic groups.

[0071] R 8 , R 9 and R 10 Preferred embodiments include a hydrogen atom, a halogen atom, a cyano group, and C 1-6 Alkyl sulfonyl group, C 1-6 Alkyl alkyl group or C 1-6 An example is an alkoxy group.

[0072] R 11 A preferred embodiment includes a hydrogen atom, C 1-3 Alkyl group, formyl group, C 1-3 Alkylcarbonyl group, C 1-4 Alkoxycarbonyl group or C 6-10 Arylcarbonyl group (the C 1-3 Alkyl alkyl group, C 1-3 Alkylcarbonyl group, C 1-4 Alkoxycarbonyl group and C 6-10 The arylcarbonyl group consists of a halogen atom, a hydroxyl group, a cyano group, and C 1-6 Alkyl alkyl group, C 1-6 Alkyl sulfonyl group, C 1-6 Alkoxy group, C 3-7 Alicyclic group, C 3-10 Alicyclic oxy group, C 6-10 Aryl group, 4-10 membered non-aryl heterocyclic group, 4-10 membered non-aryl heterocyclic oxy group, C 6-10 Examples include those which may be substituted with one to three identical or different substituents selected from the group consisting of aryloxy groups, 5-membered or 6-membered heteroaryl groups, and 5-membered or 6-membered heteroaryloxy groups.

[0073] R 12 A preferred embodiment includes a hydrogen atom or C 1-3 Alkyl(C) 1-3 Alkyl groups consist of a halogen atom, a hydroxyl group, a cyano group, and C 1-6Alkyl alkyl group, C 1-6 Alkyl sulfonyl group, C 1-6 Alkoxy group, C 3-7 Alicyclic group, C 3-10 Alicyclic oxy group, C 6-10 Aryl group, 4-10 membered non-aryl heterocyclic group, 4-10 membered non-aryl heterocyclic oxy group, C 6-10 Examples include those that are substituted with one to three identical or different substituents selected from the group consisting of aryloxy groups, 5- or 6-membered heteroaryl groups, and 5- or 6-membered heteroaryloxy groups.

[0074] Preferred embodiments of m include 1 or 2.

[0075] A more preferred embodiment of m is 1.

[0076] Preferred embodiments of n include 0, 1, 2, or 3.

[0077] More preferred embodiments of n include 0, 1, or 2.

[0078] A more preferred embodiment of n is 0 or 1.

[0079] L 1 Preferred embodiments include -NH-C(=O)-, -C(=O)-NH-, -NH-C(=S)-, -C(=S)-NH-, -NH-C(=O)-CH2-, -C(=O)-NH-CH2-, -NH-C(=O)-CH2-CH2-, -C(=O)-NH-CH2-CH2-, -NH-C(=O)-O-, or -OC(=O)-NH-.

[0080] L 1 More preferred embodiments include -NH-C(=O)- or -C(=O)-NH-.

[0081] L 2 A preferred embodiment is a single bond.

[0082] A preferred embodiment of Q is a single bond.

[0083] A preferred embodiment of X is C 6-10 An aryl group or a 5-10 membered heteroaryl group (the C 6-10 Aryl groups and 5-10 membered heteroaryl groups include halogen atoms, hydroxyl groups, cyano groups, and C 1-6 Alkyl alkyl group, C 1-6 Alkyl sulfonyl group, C 1-6 Alkoxy group, C 3-7 Alicyclic group, C 3-10 Alicyclic oxy group, C 6-10 Aryl group, 4-10 membered non-aryl heterocyclic group, 4-10 membered non-aryl heterocyclic oxy group, C 6-10 Examples include those which may be substituted with one to three identical or different substituents selected from the group consisting of aryloxy groups, 5-membered or 6-membered heteroaryl groups, and 5-membered or 6-membered heteroaryloxy groups.

[0084] A more preferred embodiment of X is a phenyl group or a 6-membered heteroaryl group (the phenyl group and the 6-membered heteroaryl group are a halogen atom, a hydroxyl group, a cyano group, C 1-6 Alkyl alkyl group, C 1-6 Alkyl sulfonyl group, C 1-6 Alkoxy group, C 3-7 Alicyclic group, C 3-10 Alicyclic oxy group, C 6-10 Aryl group, 4-10 membered non-aryl heterocyclic group, 4-10 membered non-aryl heterocyclic oxy group, C 6-10 Examples include those which may be substituted with one to three identical or different substituents selected from the group consisting of aryloxy groups, 5-membered or 6-membered heteroaryl groups, and 5-membered or 6-membered heteroaryloxy groups.

[0085] Further preferred embodiments of X include the following formulas (A1), (A2), and (A3). [ka] (In the formula, * represents L) 1(This indicates the connection position with Q or Y, where ** indicates the connection position with Q or Y.)

[0086] A preferred embodiment of Y is C 6-10 Aryl group, 5-10 membered heteroaryl group, or C 3-7 Alicyclic group (the C 6-10 Aryl group, 5-10 membered heteroaryl group and C 3-7 Alicyclic groups include halogen atoms, hydroxyl groups, cyano groups, and C 1-6 Alkyl alkyl group, C 1-6 Alkyl sulfonyl group, C 1-6 Alkoxy group, C 3-7 Alicyclic group, C 3-10 Alicyclic oxy group, C 6-10 Aryl group, 4-10 membered non-aryl heterocyclic group, 4-10 membered non-aryl heterocyclic oxy group, C 6-10 Examples include those which may be substituted with one to three identical or different substituents selected from the group consisting of aryloxy groups, 5-membered or 6-membered heteroaryl groups, and 5-membered or 6-membered heteroaryloxy groups.

[0087] A more preferred embodiment of Y is a phenyl group or a cyclohexyl group (the phenyl group and the cyclohexyl group are a halogen atom, a hydroxyl group, a cyano group, C 1-6 Alkyl alkyl group, C 1-6 Alkyl sulfonyl group, C 1-6 Alkoxy group, C 3-7 Alicyclic group, C 3-10 Alicyclic oxy group, C 6-10 Aryl group, 4-10 membered non-aryl heterocyclic group, 4-10 membered non-aryl heterocyclic oxy group, C 6-10 Examples include those which may be substituted with one to three identical or different substituents selected from the group consisting of aryloxy groups, 5-membered or 6-membered heteroaryl groups, and 5-membered or 6-membered heteroaryloxy groups.

[0088] Further preferred embodiments of Y include the following equations (B) and (C). [ka] (where * represents the bonding position with X or Q, and ** represents the bonding position with L 2 or an oxygen atom)

[0089] One embodiment of the compound represented by formula (1) includes the following (A). (A) R 1 is a hydrogen atom, R 2 is a methoxy group, R 3 is a hydrogen atom, R 4 is C 1-6 alkyl group, C 3-7 alicyclic group or C 6-10 aryl group (the C 1-6 alkyl group, C 3-7 alicyclic group and C 6-10 aryl group may be substituted with one to three identical or different substituents selected from the group consisting of a fluorine atom, a chlorine atom, C 1-6 alkyl group, C 3-7 alicyclic group, C 6-10 aryl group, a 5- or 6-membered heteroaryl group, and a 4- to 10-membered non-aryl heterocyclic group), m is 0, 1 or 2, n is 0, 1, 2 or 3, L 1 is -NH-C(=O)-, -C(=O)-NH-, -NH-C(=S)-, -C(=S)-NH-, -NH-C(=O)-CH2-, -C(=O)-NH-CH2-, -NH-C(=O)-CH2-CH2-, -C(=O)-NH-CH2-CH2-, -NH-C(=O)-O- or -O-C(=O)-NH-, L 2 is a single bond or an optionally substituted C<00​​​​​​​​​​Alkyl alkyl group, C 1-6 Alkyl sulfonyl group, C 1-6 Alkoxy group, C 3-7 Alicyclic group, C 3-10 Alicyclic oxy group, C 6-10 Aryl group, 4-10 membered non-aryl heterocyclic group, 4-10 membered non-aryl heterocyclic oxy group, C 6-10 (It may be substituted with one to three identical or different substituents selected from the group consisting of an aryloxy group, a 5-membered or 6-membered heteroaryl group, and a 5-membered or 6-membered heteroaryloxy group.) Y, C 6-10 Aryl group, 5-10 membered heteroaryl group, or C 3-7 Alicyclic group (the C 6-10 Aryl group, 6-membered heteroaryl group and C 3-7 Alicyclic groups include halogen atoms, hydroxyl groups, cyano groups, and C 1-6 Alkyl alkyl group, C 1-6 Alkyl sulfonyl group, C 1-6 Alkoxy group, C 3-7 Alicyclic group, C 3-10 Alicyclic oxy group, C 6-10 Aryl group, 4-10 membered non-aryl heterocyclic group, 4-10 membered non-aryl heterocyclic oxy group, C 6-10 (It may be substituted with one to three identical or different substituents selected from the group consisting of an aryloxy group, a 5-membered or 6-membered heteroaryl group, and a 5-membered or 6-membered heteroaryloxy group.) Here, X and Y are bonded at the carbon atoms on their respective rings. A compound or a pharmaceutically acceptable salt thereof.

[0090] One embodiment of the compound represented by formula (1) is (B) below. (B) R 1 However, it is a hydrogen atom, R 2 However, it is a methoxy group, R 3 However, it is a hydrogen atom, R 4 However, C 1-6 Alkyl alkyl group, C3-7 Alicyclic group or C 6-10 Aryl group (the C 1-6 Alkyl alkyl group, C 3-7 Alicyclic groups and C 6-10 The aryl group consists of a fluorine atom, a chlorine atom, and a carbon atom. 1-6 Alkyl alkyl group, C 3-7 Alicyclic group, C 6-10 (The substituents may be the same or different, selected from the group consisting of aryl groups, 5- or 6-membered heteroaryl groups, and 4- to 10-membered nonaryl heterocyclic groups.) m is 1 or 2, n is 0, 1, 2, or 3, L 1 However, it is -NH-C(=O)- or -C(=O)-NH-, L 2 However, it is a single bond, Q is a single bond, X, C 6-10 An aryl group or a 5-10 membered heteroaryl group (the C 6-10 Aryl groups and 5-10 membered heteroaryl groups include halogen atoms, hydroxyl groups, cyano groups, and C 1-6 Alkyl alkyl group, C 1-6 Alkyl sulfonyl group, C 1-6 Alkoxy group, C 3-7 Alicyclic group, C 3-10 Alicyclic oxy group, C 6-10 Aryl group, 4-10 membered non-aryl heterocyclic group, 4-10 membered non-aryl heterocyclic oxy group, C 6-10 (It may be substituted with one to three identical or different substituents selected from the group consisting of an aryloxy group, a 5-membered or 6-membered heteroaryl group, and a 5-membered or 6-membered heteroaryloxy group.) Y, C 6-10 Aryl group, 5-10 membered heteroaryl group, or C 3-7 Alicyclic group (the C 6-10 Aryl group, 5-10 membered heteroaryl group and C 3-7 Alicyclic groups include halogen atoms, hydroxyl groups, cyano groups, and C 1-6 Alkyl alkyl group, C 1-6 Alkyl sulfonyl group, C 1-6 Alkoxy group, C3-7 an alicyclic group, C 3-10 an alicyclic oxy group, C 6-10 an aryl group, a 4- to 10-member non-aryl heterocyclic group, a 4- to 10-member non-aryl heterocyclic oxy group, C 6-10 an aryloxy group, a 5- or 6-member heteroaryl group, and a 5- or 6-member heteroaryloxy group, which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of), wherein X and Y are bonded to each other by carbon atoms on their respective rings, a compound or a pharmaceutically acceptable salt thereof.

[0091] One embodiment of the compound represented by the formula (1) includes the following (C). (C) R 1 is a hydrogen atom, R 2 is a methoxy group, R 3 is a hydrogen atom, R 4 is C 1-6 an alkyl group, C 3-7 an alicyclic group or C 6-10 an aryl group (the C 1-6 alkyl group, C 3-7 alicyclic group and C 6-10 aryl group may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, C 1-6 an alkyl group, C 3-7 an alicyclic group, C 6-10 aaryl group, a 5- or 6-member heteroaryl group, and a 4- to 10-member non-aryl heterocyclic group), m is 1, n is 0, 1, 2 or 3, L 1 is -NH-C(=O)- or -C(=O)-NH-, L 2 is a single bond, Q is a single bond, X is a phenyl group or a 6-membered heteroaryl group (the phenyl group and the 6-membered heteroaryl group are a halogen atom, a hydroxyl group, a cyano group, C 1-6 Alkyl alkyl group, C 1-6 Alkyl sulfonyl group, C 1-6 Alkoxy group, C 3-7 Alicyclic group, C 3-10 Alicyclic oxy group, C 6-10 Aryl group, 4-10 membered non-aryl heterocyclic group, 4-10 membered non-aryl heterocyclic oxy group, C 6-10 (It may be substituted with one to three identical or different substituents selected from the group consisting of an aryloxy group, a 5-membered or 6-membered heteroaryl group, and a 5-membered or 6-membered heteroaryloxy group.) Y is a phenyl group or a cyclohexyl group (the phenyl group and cyclohexyl group are a halogen atom, a hydroxyl group, a cyano group, C 1-6 Alkyl alkyl group, C 1-6 Alkyl sulfonyl group, C 1-6 Alkoxy group, C 3-7 Alicyclic group, C 3-10 Alicyclic oxy group, C 6-10 Aryl group, 4-10 membered non-aryl heterocyclic group, 4-10 membered non-aryl heterocyclic oxy group, C 6-10 (It may be substituted with one to three identical or different substituents selected from the group consisting of an aryloxy group, a 5-membered or 6-membered heteroaryl group, and a 5-membered or 6-membered heteroaryloxy group.) Here, X and Y are bonded at the carbon atoms on their respective rings. A compound or a pharmaceutically acceptable salt thereof.

[0092] One embodiment of the compound represented by formula (1) is (D) below. (D) R 1 However, it is a hydrogen atom, R 2 However, it is a methoxy group, R 3 However, it is a hydrogen atom, R 4 However, C 1-6 Alkyl alkyl group, C3-7 Alicyclic group or C 6-10 Aryl group (the C 1-6 Alkyl alkyl group, C 3-7 Alicyclic groups and C 6-10 The aryl group consists of a fluorine atom, a chlorine atom, and a carbon atom. 1-6 Alkyl alkyl group, C 3-7 Alicyclic group, C 6-10 (The substituents may be the same or different, selected from the group consisting of aryl groups, 5- or 6-membered heteroaryl groups, and 4- to 10-membered nonaryl heterocyclic groups.) m is 1, n is 0, 1, 2, or 3, L 1 However, it is -NH-C(=O)- or -C(=O)-NH-, L 2 However, it is a single bond, Q is a single bond, X is a phenyl group or a pyridyl group (the phenyl group and pyridyl group are a halogen atom, a hydroxyl group, a cyano group, C 1-6 Alkyl alkyl group, C 1-6 Alkyl sulfonyl group, C 1-6 Alkoxy group, C 3-7 Alicyclic group, C 3-10 Alicyclic oxy group, C 6-10 Aryl group, 4-10 membered non-aryl heterocyclic group, 4-10 membered non-aryl heterocyclic oxy group, C 6-10 (It may be substituted with one to three identical or different substituents selected from the group consisting of an aryloxy group, a 5-membered or 6-membered heteroaryl group, and a 5-membered or 6-membered heteroaryloxy group.) Y is a phenyl group or a cyclohexyl group (the phenyl group and cyclohexyl group are a halogen atom, a hydroxyl group, a cyano group, C 1-6 Alkyl alkyl group, C 1-6 Alkyl sulfonyl group, C 1-6 Alkoxy group, C 3-7 Alicyclic group, C 3-10 Alicyclic oxy group, C 6-10 Aryl group, 4-10 membered non-aryl heterocyclic group, 4-10 membered non-aryl heterocyclic oxy group, C 6-10(It may be substituted with one to three identical or different substituents selected from the group consisting of an aryloxy group, a 5-membered or 6-membered heteroaryl group, and a 5-membered or 6-membered heteroaryloxy group.) Here, X and Y are bonded at the carbon atoms on their respective rings. A compound or a pharmaceutically acceptable salt thereof.

[0093] One embodiment of the compound represented by formula (1) is (E) below. (E) R 1 However, it is a hydrogen atom, R 2 However, it is a methoxy group, R 3 However, it is a hydrogen atom, R 4 However, C 1-6 Alkyl alkyl group, C 3-7 Alicyclic group or C 6-10 Aryl group (the C 1-6 Alkyl alkyl group, C 3-7 Alicyclic groups and C 6-10 The aryl group consists of a fluorine atom, a chlorine atom, and a carbon atom. 1-6 Alkyl alkyl group, C 3-7 Alicyclic group, C 6-10 (The substituents may be the same or different, selected from the group consisting of aryl groups, 5- or 6-membered heteroaryl groups, and 4- to 10-membered nonaryl heterocyclic groups.) m is 1, n is 0, 1, 2, or 3, L 1 However, it is -NH-C(=O)- or -C(=O)-NH-, L 2 However, it is a single bond, Q is a single bond, X is given by the following equation (A), [ka] (In the formula, * represents L) 1 (This represents the bond position with Y, and ** represents the bond position with Y.) a, CR 8 or N, b, CR 9 or N, c is CR 10 or N, R 8 , R 9 and R 10 However, each is independent of the hydrogen atom, halogen atom, cyano group, and C 1-6 Alkyl sulfonyl group, C 1-6 Alkyl alkyl group or C 1-6 It is an alkoxy group, Y is given by the following formula (B) or (C): [ka] (In the formula, * represents the bond position with X, and ** represents the bond position with the oxygen atom.) A compound or a pharmaceutically acceptable salt thereof.

[0094] One embodiment of the compound represented by formula (1) is (F) below. (F) R 1 However, it is a hydrogen atom, R 2 However, it is a methoxy group, R 3 However, it is a hydrogen atom, R 4 However, methyl group, ethyl group, isopropyl group, cyclohexyl group, cyclohexylmethyl group, phenyl group or benzyl group (the methyl group, ethyl group, isopropyl group, cyclohexyl group, cyclohexylmethyl group, phenyl group and benzyl group contain fluorine atoms, chlorine atoms and C 1-6 (The substituents may be the same or different, and may be substituted with 1 to 3 substituents selected from the group consisting of alkyl groups.) m is 1, n is 0, 1, 2, or 3, L 1 However, it is -NH-C(=O)- or -C(=O)-NH-, L 2 However, it is a single bond, Q is a single bond, X is the following formula (A1), (A2), or (A3): [ka] (In the formula, * represents L) 1 (This represents the bond position with Y, and ** represents the bond position with Y.) Y is given by the following formula (B) or (C): [ka] (In the formula, * represents the bond position with X, and ** represents the bond position with the oxygen atom.) A compound or a pharmaceutically acceptable salt thereof.

[0095] One embodiment of the compound represented by formula (1) is (G) below. (G) R 1 However, it is a hydrogen atom, R 2 However, it is a methoxy group, R 3 However, it is a hydrogen atom, R 4 However, methyl group, ethyl group, isopropyl group, cyclohexyl group, phenyl group (the methyl group, ethyl group, isopropyl group, cyclohexyl group and phenyl group are composed of a fluorine atom, a chlorine atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) m is 1, n is 0, 1, 2, or 3, L 1 However, -NH-C(=O)-,-C(=O)-NH-, L 2 However, it is a single bond, Q is a single bond, X is the following formula (A1), (A2), or (A3): [ka] (In the formula, * represents L) 1 (This represents the bond position with Y, and ** represents the bond position with Y.) Y is given by the following formula (B) or (C): [ka] (In the formula, * represents the bond position with X, and ** represents the bond position with the oxygen atom.) A compound or a pharmaceutically acceptable salt thereof.

[0096] Examples of "pharmaceutically acceptable salts" include acid addition salts and base addition salts. For example, acid addition salts include inorganic salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, and phosphate, or organic salts such as citrate, oxalate, phthalate, fumarate, maleate, succinate, malate, acetate, formate, propionate, benzoate, trifluoroacetate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, and camphorsulfonate. Examples of base addition salts include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, barium salt, and aluminum salt, or organic base salts such as trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, dicyclohexylamine, and N,N-dibenzylatelamine. Furthermore, "pharmaceutically acceptable salts" also include amino acid salts with basic or acidic amino acids such as arginine, lysine, ornithine, aspartic acid, or glutamic acid.

[0097] Suitable salts of raw material compounds and intermediates, and salts acceptable as pharmaceutical raw materials, are conventional non-toxic salts, including acid addition salts such as organic acid salts (e.g., acetate, trifluoroacetate, maleate, fumarate, citrate, tartrate, methanesulfonate, benzenesulfonate, formate, or p-toluenesulfonate) and inorganic acid salts (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, or phosphate), salts with amino acids (e.g., arginine, aspartic acid, or glutamic acid), metal salts such as alkali metal salts (e.g., sodium salt or potassium salt) and alkaline earth metal salts (e.g., calcium salt or magnesium salt), ammonium salts, or organic base salts (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, or N,N'-dibenzylethylenediamine salt), which can be appropriately selected by those skilled in the art.

[0098] When it is desired to obtain a salt of the compound of the present invention, if the compound of the present invention is obtained in the form of a salt, it can be purified as is. If it is obtained in the form of a free compound, it can be dissolved or suspended in a suitable organic solvent, and an acid or base can be added to form a salt by a conventional method.

[0099] In the present invention, deuterium converters obtained by converting one or more 1H atoms in any of the compounds represented by formula (1) to 2H(D) are also included in the compounds represented by formula (1).

[0100] The present invention includes compounds represented by formula (1), or pharmaceutically acceptable salts thereof. Furthermore, since the compounds of the present invention may also exist in the form of hydrates and / or solvates with various solvents (such as ethanol hydrates), these hydrates and / or solvates are also included in the compounds of the present invention. Moreover, the present invention includes all tautomers of compound (1) of the present invention, all existing stereoisomers, and all modes of crystalline form, as well as mixtures thereof.

[0101] Some compounds (1) of the present invention may have optical isomers based on an optically active center, atropisomers based on axial or planar chirality resulting from the constraint of intramolecular rotation, other stereoisomers, tautomers, and geometric isomers, but all possible isomers and mixtures thereof, including these, are included in the scope of the present invention.

[0102] In particular, optical isomers and atrop isomers can be obtained as racemates, or as optically active compounds if optically active starting materials or intermediates are used. If necessary, at an appropriate stage of the manufacturing process described below, the corresponding racemates of the starting materials, intermediates, or final products can be physically or chemically separated into their optical isomers by known separation methods such as optically active column methods or fractional crystallization. Specifically, for example, in the diastereomer method, two diastereomers are formed from a racemate by a reaction using an optically active resolving agent. Since these different diastereomers generally have different physical properties, they can be separated by known methods such as fractional crystallization.

[0103] The methods for producing the compounds disclosed herein are described below, but the methods for producing the compounds disclosed herein are not limited to these.

[0104] The compounds disclosed herein, but are not limited to those described below, can be produced by the following manufacturing methods. These manufacturing methods can be appropriately modified based on the knowledge of a person proficient in organic synthesis chemistry. In the manufacturing methods described below, salts of the compounds may be used as raw materials, provided that they do not interfere with the reaction.

[0105] In the manufacturing method described below, even if the use of protecting groups is not explicitly stated, if any functional group other than the reaction site changes under the reaction conditions, or if it is unsuitable for post-reaction processing, the target compound can be obtained by protecting the non-reaction site as necessary and deprotecting it after the reaction is complete or after the series of reactions have been carried out. Protecting groups used in these processes are described in the reference (TW Greene and PGM Wuts, “Protective Group in Organic Synthesis”, 3 rd Conventional protecting groups as described in Ed., John Wiley and Sons, Inc., New York (1999) can be used. Furthermore, the introduction and removal of protecting groups can be carried out by methods commonly used in organic synthesis chemistry (for example, the methods described in the above-mentioned literature) or by methods similar thereto.

[0106] The starting materials and intermediates used in the following manufacturing method are either commercially available or can be obtained by methods described in public literature or by synthesis from known compounds according to known methods. Furthermore, salts of these starting materials and intermediates may be used, provided they do not hinder the reaction.

[0107] The intermediates and target compounds in the manufacturing method described below can also be converted into other compounds included in this disclosure by appropriately changing their functional groups. The conversion of functional groups in this case can be carried out using methods commonly used in organic synthesis chemistry (e.g., RC Larock, “Comprehensive Organic Transformations”, 2 nd This can be done by the method described in Ed., John Wiley and Sons, Inc., New York (1999), or by a similar method.

[0108] In the manufacturing method described below, an inert solvent means a solvent that does not react with the raw materials, reagents, bases, acids, catalysts, ligands, etc. (hereinafter sometimes referred to as "raw materials, etc." used in the reaction) used in the reaction. Furthermore, even if the solvent used in each step reacts with the raw materials, etc. used in the reaction, it can still be used as an inert solvent as long as the desired reaction proceeds and the target compound is obtained.

[0109] The compound of this disclosure represented by formula (1) can be produced, for example, by the following production methods 1 to 5.

[0110] Manufacturing method 1 Of the compounds represented by formula (1), the compound represented by formula [A1] can be produced, for example, by the following method. [ka]

[0111] (In the formula, R 41 and R 42 are the same or different R 4 And L 3 is -NH-C(=O)- or -C(=O)-NH-, and R 2 , R 3 , R 4 (X and Y are equivalent to those in item 1.)

[0112] [Step 1-1: Condensation reaction] Compound a5 is produced by reacting compound a1 with compound a2 in a suitable solvent, in or without various coupling agents and / or bases. Various coupling agents used in conventional methods can be used as coupling agents, but propiophosphonic anhydride or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (including hydrochloride) are preferred. The base is appropriately selected from the bases exemplified below, but diisopropylethylamine or triethylamine are preferred. The solvent is appropriately selected from the solvents exemplified below, but tetrahydrofuran, dimethylformamide, or chloroform are preferred. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, preferably 0°C to 100°C.

[0113] [Step 1-2: Condensation reaction] Compound a5 is produced by reacting compound a3 with compound a4 in a suitable solvent, in or without various coupling agents and / or bases. Various coupling agents used in conventional methods can be used as coupling agents, but propiophosphonic anhydride or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (including hydrochloride) are preferred. The base can be appropriately selected from the bases exemplified below, but diisopropylethylamine or triethylamine are preferred. The solvent can be appropriately selected from the solvents exemplified below, but tetrahydrofuran, dimethylformamide, or chloroform are preferred. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, preferably 0°C to 100°C.

[0114] [Steps 1-3: Coupling reaction] Compound a8 is produced by coupling compound a5 with compound a6 or a7 in the presence of a catalyst and a base. Examples of catalysts include transition metals such as palladium, their salts, complexes thereof, and those supported on polymers. The base can be appropriately selected from the bases exemplified below, but sodium carbonate and potassium carbonate are preferred. The solvent can be appropriately selected from the solvents exemplified below, but a mixed solvent of 1,2-dimethoxyethane and water is preferred. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, preferably 20°C to 150°C. The reaction temperature is usually 0°C to 200°C, preferably 0°C to 100°C.

[0115] [Steps 1-4: Condensation reaction] Compound a12 is produced by reacting compound a8 with compounds a9, a10, or a11 in a suitable solvent, in or without various coupling agents and / or bases. Various coupling agents used in conventional methods can be used as coupling agents, but 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (including hydrochloride) is preferred. As the base, it can be appropriately selected from the bases exemplified below, but diisopropylethylamine or triethylamine is preferred. As the solvent, it can be appropriately selected from the solvents exemplified below, but tetrahydrofuran, dimethylformamide, or chloroform is preferred. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, preferably 0°C to 100°C.

[0116] [Steps 1-5: Debenzylation reaction] Compound A1 is produced by reducing compound a12 in the presence of a catalyst. Examples of reducing agents include hydrogen, salts of formic acid such as ammonium formate, and hydrazine. Examples of catalysts include transition metals such as palladium, nickel, rhodium, cobalt, and platinum, their salts, complexes, and polymers supported on a carrier. The solvent is appropriately selected from the solvents exemplified below, but ethyl acetate, ethanol, or methanol are preferred. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, preferably 0°C to 100°C.

[0117] Compound a1 can be used commercially or prepared by known methods, such as those described in ACS Chem Neurosci. 2018, 9, 587-602.

[0118] Compound a3 can be used commercially or prepared by known methods, such as those described in Nature Commun. 2018, 9, 4123.

[0119] Manufacturing method 2 Of the compounds represented by formula (1), the compound represented by formula [A2] can be produced, for example, by the following method. [ka]

[0120] (In the formula, R 41 and R 42 are the same or different R 4 And L 3 is -NH-C(=O)- or -C(=O)-NH-, and R 2 , R 3 , R 4 (X and Y are equivalent to those in item 1.)

[0121] [Step 2-1: Debenzylation reaction] Compound a13 is produced by reducing compound a8 in the presence of a catalyst. Examples of reducing agents include hydrogen, salts of formic acid such as ammonium formate, and hydrazine. Examples of catalysts include transition metals such as palladium, nickel, rhodium, cobalt, and platinum, their salts, complexes, and polymers supported on a carrier. The solvent is appropriately selected from the solvents exemplified below, but ethyl acetate, ethanol, or methanol are preferred. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, preferably 0°C to 100°C.

[0122] [Step 2-2: Condensation reaction] Compound a14 is produced by reacting compound a13 with compounds a9, a10, or a11 in a suitable solvent, in or without various condensing agents and / or bases. Various condensing agents used in conventional methods can be used as condensing agents, but propiophosphonic anhydride or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (including hydrochloride) are preferred. The base is appropriately selected from the bases exemplified below, but diisopropylethylamine or triethylamine are preferred. The solvent is appropriately selected from the solvents exemplified below, but tetrahydrofuran, dimethylformamide, or chloroform are preferred. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, preferably 0°C to 100°C.

[0123] [Step 2-3: Deacyl reaction] Compound A2 is produced by reacting compound a14 with various bases in a suitable solvent. The base can be appropriately selected from the bases exemplified below, but ammonia is preferred. The solvent can be appropriately selected from the solvents exemplified below, but 2-propanol or tetrahydrofuran are preferred. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, preferably 0°C to 100°C.

[0124] Manufacturing method 3 The compound represented by formula [a13] can be produced, for example, by the following method. [ka]

[0125] (In the formula, Y 1 C has an unsaturated bond. 3-10 It is an alicyclic group, Y 2 C 3-10 It is an alicyclic group, L 3 is -NH-C(=O)- or -C(=O)-NH-, and R 2 , R 3 And X is synonymous with item 1, and a15, a16 and a17 are Y 1 This represents a compound in which the carbonyl group above is acetal-protected.

[0126] [Step 3-1: Coupling reaction] Compound a17 is produced by coupling compound a5 with compound a15 or a16 in the presence of a catalyst and a base. Examples of catalysts include transition metals such as palladium, their salts, complexes thereof, and those supported on polymers. The base is appropriately selected from the bases exemplified below, but sodium carbonate and potassium carbonate are preferred. The solvent is appropriately selected from the solvents exemplified below, but a mixed solvent of 1,2-dimethoxyethane and water is preferred. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, preferably 20°C to 150°C. The reaction temperature is usually 0°C to 200°C, preferably 0°C to 100°C.

[0127] [Step 3-2: Deacetalization reaction] Compound a18 is produced by reacting compound a17 with various acids in a suitable solvent. Examples of acids include hydrochloric acid, trifluoroacetic acid, acetic acid, and sulfuric acid. The solvent can be appropriately selected from the solvents exemplified below, but tetrahydrofuran or acetone are preferred. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, preferably 0°C to 100°C.

[0128] [Step 3-3: Debenzylation reaction] Compound a19 is produced by reducing compound a18 in the presence of a catalyst. Examples of reducing agents include hydrogen, salts of formic acid such as ammonium formate, and hydrazine. Examples of catalysts include transition metals such as palladium, nickel, rhodium, cobalt, and platinum, their salts, complexes, and polymers supported on a carrier. The solvent is appropriately selected from the solvents exemplified below, but ethyl acetate, ethanol, or methanol are preferred. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, preferably 0°C to 100°C.

[0129] [Step 3-4: Reduction reaction] Compound a13 is produced by reducing compound a19 with a reducing agent in the presence of a catalyst and / or a base. Alternatively, the reaction can be carried out using only a reducing agent. Examples of reducing agents include hydrogen, salts of formic acid such as sodium formate, hydrazine, sodium borohydride, or lithium trisec-butylborohydride. Catalysts include transition metals such as ruthenium, palladium, nickel, rhodium, cobalt, and platinum, as well as their salts, complexes, and polymers supported on a carrier. The base is appropriately selected from the bases exemplified below, but potassium tert-butoxide, potassium hydroxide, and triethylamine are preferred. The solvent is appropriately selected from the solvents exemplified below, but tetrahydrofuran, 2-propanol, ethanol, methanol, or dimethylformamide are preferred. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. The reaction temperature is typically -80°C to 200°C, preferably -80°C to 100°C. More preferably, it is 0°C to 100°C.

[0130] Manufacturing method 4 Of the compounds represented by formula (1), the compound represented by formula [A3] can be produced, for example, by the following method. [ka]

[0131] (In the formula, R 41 and R 42 are the same or different R 4 And L 3 is -NH-C(=O)- or -C(=O)-NH-, and R 1 , R 2 , R 3 , R 4 (X and Y are equivalent to those in item 1.)

[0132] [Step 4-1: Condensation reaction] Compound a22 is produced by reacting compound a20 with compound a2 in a suitable solvent, in or without various coupling agents and / or bases. Various coupling agents used in conventional methods can be used as coupling agents, but propiophosphonic anhydride or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (including hydrochloride) are preferred. The base is appropriately selected from the bases exemplified below, but diisopropylethylamine or triethylamine are preferred. The solvent is appropriately selected from the solvents exemplified below, but tetrahydrofuran, dimethylformamide, or chloroform are preferred. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, preferably 0°C to 100°C.

[0133] [Step 4-2: Condensation reaction] Compound a22 is produced by reacting compound a4 with compound a21 in a suitable solvent, in or without various coupling agents and / or bases. Various coupling agents used in conventional methods can be used as coupling agents, but propiophosphonic anhydride or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (including hydrochloride) are preferred. The base is appropriately selected from the bases exemplified below, but diisopropylethylamine or triethylamine are preferred. The solvent is appropriately selected from the solvents exemplified below, but tetrahydrofuran, dimethylformamide, or chloroform are preferred. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, preferably 0°C to 100°C.

[0134] [Step 4-3: Coupling reaction] Compound a23 is produced by coupling compound a22 with compound a6 or a7 in the presence of a catalyst and a base. Examples of catalysts include transition metals such as palladium, their salts, complexes thereof, and those supported on polymers. The base is appropriately selected from the bases exemplified below, but sodium carbonate and potassium carbonate are preferred. The solvent is appropriately selected from the solvents exemplified below, but a mixed solvent of 1,2-dimethoxyethane and water is preferred. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, preferably 20°C to 150°C. The reaction temperature is usually 0°C to 200°C, preferably 0°C to 100°C.

[0135] [Step 4-4: Condensation reaction] Compound A3 is produced by reacting compound a23 with compounds a9, a10, or a11 in a suitable solvent, in or without various coupling agents and / or bases. Various coupling agents used in conventional methods can be used as coupling agents, but 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (including hydrochloride) is preferred. As the base, it can be appropriately selected from the bases exemplified below, but diisopropylethylamine or triethylamine is preferred. As the solvent, it can be appropriately selected from the solvents exemplified below, but tetrahydrofuran, dimethylformamide, or chloroform is preferred. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, preferably 0°C to 100°C.

[0136] Compound a20 can be used commercially or manufactured by known methods, such as those described in ACS Chem Neurosci. 2018, 9, 587-602.

[0137] Compound a21 can be obtained using commercially available materials or prepared by known methods, such as those described in Nature Commun. 2018, 9, 4123. Manufacturing method 5 The compound represented by formula [a23] can be produced, for example, by the following method. [ka]

[0138] (In the formula, Y 1 C has an unsaturated bond. 3-10 It is an alicyclic group, Y 2 C 3-10 It is an alicyclic group, L 3 is -NH-C(=O)- or -C(=O)-NH-, and R 1 , R 2 , R 3 And X is synonymous with item 1, and a15, a16 and a24 are Y 1 This represents a compound in which the carbonyl group above is acetal-protected.

[0139] [Step 5-1: Coupling reaction] Compound a24 is produced by coupling compound a22 with compound a15 or a16 in the presence of a catalyst and a base. Examples of catalysts include transition metals such as palladium, their salts, complexes thereof, and those supported on polymers. As the base, it can be appropriately selected from the bases exemplified below, but sodium carbonate and potassium carbonate are preferred. As the solvent, it can be appropriately selected from the solvents exemplified below, but a mixed solvent of 1,2-dimethoxyethane and water is preferred. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, preferably 20°C to 150°C.

[0140] [Step 5-2: Deacetalization reaction] Compound a25 is produced by reacting compound a24 with various acids in a suitable solvent. Examples of acids include hydrochloric acid, trifluoroacetic acid, acetic acid, and sulfuric acid. The solvent can be appropriately selected from the solvents exemplified below, but tetrahydrofuran or acetone are preferred. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, preferably 0°C to 100°C.

[0141] [Step 5-3: Hydrogenation reaction] Compound a26 is produced by reducing compound a25 in the presence of a catalyst. Examples of reducing agents include hydrogen, salts of formic acid such as ammonium formate, and hydrazine. Examples of catalysts include transition metals such as palladium, nickel, rhodium, cobalt, and platinum, their salts, complexes, and polymers supported on a carrier. The solvent is appropriately selected from the solvents exemplified below, but ethyl acetate, ethanol, or methanol are preferred. The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, preferably 0°C to 100°C.

[0142] [Step 5-4: Reduction reaction] Compound a23 is produced by reducing compound a26 with a reducing agent in the presence of a catalyst and / or a base. Alternatively, the reaction can be carried out using only a reducing agent. Examples of reducing agents include hydrogen, salts of formic acid such as sodium formate, hydrazine, sodium borohydride, or lithium trisec-butylborohydride. Catalysts include transition metals such as ruthenium, palladium, nickel, rhodium, cobalt, and platinum, as well as their salts, complexes, and polymers supported on a carrier. The base can be appropriately selected from the bases exemplified below, but potassium tert-butoxide, potassium hydroxide, and triethylamine are preferred. The solvent can be appropriately selected from the solvents exemplified below, but tetrahydrofuran, 2-propanol, ethanol, methanol, or dimethylformamide are preferred. The reaction time is typically 5 minutes to 72 hours, preferably 30 minutes to 24 hours. The reaction temperature is typically -80°C to 200°C, preferably -80°C to 100°C. More preferably, it is 0°C to 100°C.

[0143] The bases used in each step of each of the above manufacturing methods should be selected appropriately depending on the reaction and the type of raw material compound, but examples include alkali bicarbonates such as sodium bicarbonate and potassium bicarbonate, alkali carbonates such as sodium carbonate, potassium carbonate and cesium carbonate, metal fluorides such as potassium fluoride and cesium fluoride, metal hydrides such as sodium hydride and potassium hydride, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal alkoxides such as sodium methoxide and sodium tert-butoxide, organometallic bases such as butyllithium, lithium diisopropylamide and lithium (bistrimethylsilyl)amide, and organic bases such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine (DMAP), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) and 1,4-diazabicyclo[2.2.2]octane (DABCO).

[0144] The solvent used in each step of each of the above manufacturing methods should be selected appropriately depending on the reaction and the type of raw material compound. Examples include alcohols such as methanol, ethanol, and 2-propanol; ketones such as acetone and methyl ketone; halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as tetrahydrofuran (THF) and dioxane; aromatic hydrocarbons such as toluene, benzene, and xylene; aliphatic hydrocarbons such as hexane and heptane; esters such as ethyl acetate and propyl acetate; amides such as N,N-dimethylformamide (DMF) and N-methyl-2-pyrrolidone; sulfoxides such as dimethyl sulfoxide (DMSO); and nitriles such as acetonitrile. These solvents can be used alone or in mixtures of two or more. Depending on the type of reaction, organic bases may also be used as solvents.

[0145] The compounds of the present disclosure represented by formula (1) or their intermediates can be separated and purified by methods known to those skilled in the art. Examples include extraction, partitioning, reprecipitation, column chromatography (e.g., silica gel column chromatography, ion-exchange column chromatography, or preparative liquid chromatography), or recrystallization.

[0146] As recrystallization solvents, for example, alcohol-based solvents such as methanol, ethanol, or 2-propanol; ether-based solvents such as diethyl ether; ester-based solvents such as ethyl acetate; aromatic hydrocarbon-based solvents such as benzene or toluene; ketone-based solvents such as acetone; halogen-based solvents such as dichloromethane or chloroform; hydrocarbon-based solvents such as hexane; aprotic solvents such as dimethylformamide or acetonitrile; water; or mixtures thereof can be used. Other purification methods include those described in Volume 1 of "Experimental Chemistry Series" (edited by the Chemical Society of Japan, Maruzen). Furthermore, the molecular structure of the compounds disclosed herein can be easily determined by referring to the structures derived from each starting compound and using spectroscopic techniques such as nuclear magnetic resonance spectroscopy, infrared absorption spectroscopy, and circular dichroism spectroscopy, as well as mass spectrometry.

[0147] Furthermore, the intermediates or final products in the above manufacturing method can be converted to other compounds included in this disclosure by appropriately changing their functional groups, particularly by extending various side chains from amino groups, hydroxyl groups, carbonyl groups, halogen atoms, etc., and by performing the protection and deprotection described below as necessary. The conversion of functional groups and the extension of side chains can be carried out by commonly used methods (see, for example, Comprehensive Organic Transformations, RC Larock, John Wiley & Sons Inc. (1999), etc.).

[0148] Examples of protecting groups for amino groups include alkylcarbonyl groups (e.g., acetyl group, propionyl group), formyl group, phenylcarbonyl group, alkyloxycarbonyl groups (e.g., methoxycarbonyl group, ethoxycarbonyl group, tert-butoxycarbonyl group), phenyloxycarbonyl group, arylalkyloxycarbonyl group (e.g., benzyloxycarbonyl group), trityl group, phthaloyl group, tosyl group, and benzyl group.

[0149] Examples of protecting groups for carboxyl groups include alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), phenyl, benzyl, trityl, and silyl groups (e.g., trimethylsilyl and tert-butyldimethylsilyl).

[0150] Examples of protecting groups for hydroxyl groups include methyl, tert-butyl, allyl, substituted methyl groups (e.g., methoxymethyl, methoxyethoxymethyl), ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trityl, arylalkyl groups (e.g., benzyl), alkylcarbonyl groups (e.g., acetyl, propionyl), formyl, benzoyl, arylalkyloxycarbonyl groups (e.g., benzyloxycarbonyl), and silyl groups (e.g., trimethylsilyl, tert-butyldimethylsilyl).

[0151] Carbonyl group protection can be achieved by converting the carbonyl group to an acyclic ketal (such as dimethyl ketal or diethyl ketal) or a cyclic ketal (such as 1,3-dioxolane or 1,3-dioxane).

[0152] The compounds of the present disclosure represented by formula (1) or pharmaceutically acceptable salts thereof may exhibit chirality or have substituents with chiral carbons, and in such compounds, optical isomers exist. The compounds of the present disclosure include mixtures of these isomers and isolated compounds, which can be prepared by conventional methods.

[0153] Examples of manufacturing methods include using a raw material with a chiral center, or introducing chirality at an intermediate stage. For example, in the case of optical isomers, optical isomers can be obtained by using an optically active raw material or by performing optical resolution at an appropriate stage in the manufacturing process. As for optical resolution methods, for example, if the compound represented by formula (1) or its intermediate has a basic functional group, a diastereomer method can be used to form a salt using an optically active acid (for example, monocarboxylic acids such as mandelic acid, N-benzyloxyalanine, lactic acid, tartaric acid, o-diisopropylidene tartaric acid, malic acid, camphor sulfonic acid, bromocamphor sulfonic acid, etc.) in an inert solvent (e.g., alcohol-based solvents such as methanol, ethanol, 2-propanol, diethyl ether, ester-based solvents such as ethyl acetate, hydrocarbon-based solvents such as toluene, aprotic solvents such as acetonitrile, or a mixed solvent of two or more solvents selected from the above).

[0154] If the compound of the present disclosure represented by formula (1) or its intermediate has an acidic functional group such as a carboxyl group, optical resolution can also be performed by forming a salt using an optically active amine (for example, an organic amine such as 1-phenylethylamine, quinine, quinidine, cinconidine, cinconine, or strychnine).

[0155] The temperature for salt formation is selected from a range of -50°C to the boiling point of the solvent, preferably from 0°C to the boiling point, and more preferably from room temperature to the boiling point of the solvent. To improve optical purity, it is desirable to raise the temperature to near the boiling point of the solvent. When filtering the precipitated salt, cooling can be performed as needed to improve the yield. The amount of optically active acid or amine used is suitable in the range of about 0.5 to about 2.0 equivalents relative to the substrate, preferably around 1 equivalent. If necessary, the crystals can be recrystallized in an inert solvent (for example, alcoholic solvents such as methanol, ethanol, 2-propanol; etheric solvents such as diethyl ether; esteric solvents such as ethyl acetate; hydrocarbon solvents such as toluene; aprotic solvents such as acetonitrile; or a mixed solvent of two or more solvents selected from the above) to obtain a high-purity optically active salt. Alternatively, if necessary, the optically resolved salt can be treated with an acid or base in a conventional manner to obtain a free form.

[0156] Of the raw materials and intermediates used in each of the manufacturing methods described above, those whose manufacturing methods are not specifically mentioned can be commercially available compounds or synthesized from commercially available compounds by methods known to those skilled in the art, or by similar methods.

[0157] "Disorders or diseases involving TRPV1" refer to disorders or diseases caused by increased activity of nerve cells expressing TRPV1, such as dysphagia, pain, skin diseases, respiratory diseases, digestive diseases, urinary tract diseases, diabetes, and obesity. Pain includes neuropathic pain, postherpetic neuralgia, and pain due to osteoarthritis of the knee. Skin diseases include psoriasis, atopic dermatitis, primary hyperhidrosis, and alopecia. Respiratory diseases include cough and asthma. Digestive diseases include acute gastritis, acute gastric mucosal lesions, and fecal incontinence. Urinary tract diseases include cystitis and overactive bladder. Preferably, "disorders or diseases involving TRPV1" are dysphagia.

[0158] This disclosure provides a pharmaceutical composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient for treating or preventing dysphagia. "Dysphagia" refers to a condition in which chewing and swallowing food and drink becomes difficult due to disease, aging, etc. Specifically, this includes swallowing coordination disorders, dysphagia, swallowing disorders, swallowing pain, inability to swallow, cricopharyngeal muscle dysfunction, etc. It also includes dysphagia caused by cerebrovascular diseases such as cerebral infarction and cerebral hemorrhage, neurodegenerative diseases such as Parkinson's disease and ALS, and dementia such as Alzheimer's disease. Furthermore, it also includes situations in which swallowing function is impaired due to therapeutic drugs such as analgesics, antipsychotics, antihistamines, and anticholinergics.

[0159] The effects of the compounds disclosed herein on dysphagia can be evaluated using swallowing function as an indicator in animal models of dysphagia. Similar to dysphagia in humans, dysphagia has been reported to occur in aged animals, cerebral infarction models, and Parkinson's disease models, and can be evaluated in these models. (Dysphagia (2014) 29:61-67, Dysphagia. 2015Jun;30(3):328-42, Dysphagia. 2013 Mar;28(1):95-104).

[0160] In this disclosure, "prevention" refers to the act of administering the active ingredient of this disclosure to healthy individuals who have not developed the disease or who exhibit mild symptoms, for example, with the aim of preventing the onset of the disease. "Treatment" refers to the act of administering the active ingredient of this disclosure to individuals (patients) who have been diagnosed by a physician as having developed the disease.

[0161] The compounds disclosed herein may be administered orally, parenterally, or rectally, and the daily dose will vary depending on the type of compound, the method of administration, and the patient's symptoms and age. For example, in the case of oral administration, typically about 0.01 to 1000 mg per kg of human or mammalian body weight, more preferably about 0.1 to 500 mg, can be administered in one to several divided doses. In the case of parenteral administration, such as intravenous injection, typically, for example, about 0.01 mg to 300 mg per kg of human or mammalian body weight, more preferably about 0.01 mg to 100 mg can be administered.

[0162] The compounds of this disclosure can be administered orally or parenterally, either directly or in a suitable dosage form. Dosage forms include, but are not limited to, tablets, capsules, powders, granules, solutions, suspensions, injections, patches, and poultices. The formulations are manufactured by known methods using pharmaceutically acceptable excipients. Depending on the purpose, excipients may include excipients, disintegrants, binders, fluidizers, lubricants, coatings, solvents, solubilizers, thickeners, dispersants, stabilizers, sweeteners, and flavorings. Specifically, examples include lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, magnesium stearate, stearyl fumarate sodium, polyethylene glycol, propylene glycol, titanium dioxide, and talc.

[0163] The compounds of this disclosure can be used in combination with drugs that may improve swallowing function and can be administered to treat or prevent dysphagia. Examples of drugs that may improve the swallowing reflex include L-Dopa preparations in Parkinson's disease, immunoglobulins in inclusion body myositis, the glucosylceramide synthase inhibitor miglustat in Niemann-Pick disease type C, and ACE inhibitors, cilostazol, nicergoline, and Hangekobokuto. In this disclosure, drugs that can be used in combination with the compounds of the present invention will be abbreviated as "other drugs."

[0164] The administration period of the compound of the present invention and the concomitant drug is not limited, and they may be administered to the target patient simultaneously or with a time difference. Alternatively, the compound of the present invention and the concomitant drug may be used as a combination preparation. The dosage of the concomitant drug can be appropriately selected based on clinically used doses. Furthermore, the mixing ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the target patient, route of administration, target disease, symptoms, and combination. For example, if the target patient is a human, 0.01 to 100 parts by weight of the concomitant drug may be used for 1 part by weight of the compound of the present invention. In addition, for the purpose of suppressing side effects, it can be used in combination with drugs such as antiemetics, hypnotics, and anticonvulsants (concomitant drugs).

[0165] In this specification, "or" is used when "at least one" of the items listed in the text can be adopted. The same applies to "or else". In this specification, when it is specified as "within the range of two values", that range includes the two values ​​themselves.

[0166] References such as scientific literature, patents, and patent applications cited herein are incorporated herein by reference to the same extent as they are specifically described herein.

[0167] The present disclosure has been described above with reference to preferred embodiments for ease of understanding. The present disclosure will now be described based on examples, but the above description and the following examples are provided for illustrative purposes only and not to limit the present disclosure. Accordingly, the scope of the present disclosure is not limited to the embodiments or examples specifically described herein, but is limited only by the claims. [Examples]

[0168] The present disclosure will be further described below with reference examples, examples, and test examples, but this disclosure is not limited thereto. Note that the compound names shown in the following reference examples and examples do not necessarily follow IUPAC nomenclature.

[0169] To simplify the description in the specification, the following abbreviations may be used in the reference examples, examples, and tables within the examples. As abbreviations used for substituents, pin means pinacol. As symbols used in NMR, s means singleline, d means doubleline, dd means doubleline of doubleline, t means tripleline, q means quadrupleline, m means multiline, br means broad, brs means broad singleline, and J means bond constant.

[0170] The measurement conditions for high-performance liquid chromatography-mass spectrometry (LCMS) are as follows, and the observed mass spectrometry value [MS(m / z)] is measured in MH. + The retention time is indicated by Rt (minutes).

[0171] Measurement conditions Detection equipment: ACQUITY® SQ detector (Waters Corporation) HPLC: ACQUITY UPLC (registered trademark) SYSTEM Column:Waters ACQUITY UPLC(registered trademark) BEH C18(1.7um, 2.1mm × 30mm) Solvent: Solution A: 0.05% formic acid / H2O, Solution B: acetonitrile Gradient Condition: 0.0-1.3 minutes (linear gradient from B 10% to 95%) 1.3-1.5 minutes (B 10%) Flow rate: 0.8 ml / min UV: 220nm and 254nm Column temperature: 40℃

[0172] Reference example 1 2-[4-(benzyloxy)-3-methoxyphenyl]-N-(6-bromopyridine-2-yl)acetamide [ka]

[0173] To a 1,2-dimethoxyethane solution (30 ml) of 4-benzyloxy-3-methoxyphenylacetic acid (4.0 g) and 6-bromopyridine-2-amine (2.8 g), N,N-diisopropylethylamine (5.1 ml) and a 50% propylphosphonic anhydride / ethyl acetate solution (10.5 ml) were added and the mixture was stirred at room temperature for 1.5 hours. After adding water to the reaction mixture, it was extracted with ethyl acetate. The resulting organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and the resulting solid was washed with diethyl ether to obtain Reference Example 1 (4.0 g). LC-MS, m / z; 427.08 (M+H) + ESI, Rt; 1.071 (min)

[0174] Reference example 2 2-[4-(benzyloxy)-3-methoxyphenyl]-N-[6-(3-hydroxyphenyl)pyridine-2-yl]acetamide hydrochloride [ka]

[0175] 2-[4-(benzyloxy)-3-methoxyphenyl]-N-(6-bromopyridine-2-yl)acetamide (8.61 g), 3-hydroxyphenylboronic acid (3.06 g), and potassium carbonate (5.57 g) were mixed in 1,2-dimethoxyethane (200 ml) / water (40 ml). Dichlorobis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) (0.71 g) was added to this mixture and the mixture was heated under reflux for 2 hours. After concentrating the reaction mixture, ethyl acetate was added, and the organic layer was washed with water and saturated brine. Activated carbon was added, and the mixture was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Tetrahydrofuran (100 ml) was added to the resulting crude product. Then, 30 ml of a 4 mol / L hydrogen chloride / cyclopentyl methyl ether solution was added, and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction mixture, the resulting solid was washed with diethyl ether to obtain Reference Example 2 (8.58 g). LC-MS, m / z; 441.25 (M+H) + ESI, Rt; 0.998 (min)

[0176] Example 1 and Reference Example 3 3-{6-[2-(4-hydroxy-3-methoxyphenyl)acetamide]pyridine-2-yl}phenyl 2-methylpropanoate [ka]

[0177] a) Preparation of 3-(6-{2-[4-(benzyloxy)-3-methoxyphenyl]acetamide}pyridine-2-yl)phenyl 2-methylpropanoate (Reference Example 3) 1.0 g of 2-[4-(benzyloxy)-3-methoxyphenyl]-N-[6-(3-hydroxyphenyl)pyridine-2-yl]acetamide hydrochloride and 0.791 ml of triethylamine were dissolved in tetrahydrofuran (23 ml). Isobutyryl chloride (0.263 ml) was added to the solution and stirred at room temperature for 3 hours. Water was added to the reaction mixture, and after extraction with ethyl acetate, the organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine. The mixture was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product of Reference Example 3. LC-MS, m / z; 511.34 (M+H) + ESI, Rt; 1.234 (min)

[0178] b) Preparation of 3-{6-[2-(4-hydroxy-3-methoxyphenyl)acetamide]pyridine-2-yl}phenyl 2-methylpropanoate (Example 1) 3-(6-{2-[4-(benzyloxy)-3-methoxyphenyl]acetamido}pyridine-2-yl)phenyl 2-methylpropanoate (1.159 g) was dissolved in ethyl acetate (30 ml) and palladium-activated carbon (Pd 20%) (1.0 g) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. After purging the reaction mixture with nitrogen, it was filtered by Celite and concentrated under reduced pressure. Hexane was added to the resulting residue to obtain the crude solid product. The obtained solid was recrystallized from 2-propanol to obtain Example 1 (352 mg). LC-MS, m / z; 421.2 (M+H) + ESI, Rt; 0.993 (min) 1 H-NMR(400 MHz, CD3OD) δ: 8.07 (1H, d, J = 8.0 Hz), 7.91 (1H, dd, J = 1.4,7.8 Hz), 7.83-7.79 (2H, m), 7.61 (1H, d, J = 7.2 Hz), 7.48 (1H, t, J = 7.8 Hz),7.14-7.10 (1H, m), 6.97 (1H, d, J = 2.0 Hz), 6.81 (1H, dd, J = 2.0, 8.4 Hz),6.76 (1H, d, J = 7.6 Hz), 3.86 (3H, s), 3.67 (2H, s), 2.86 (1H, p, J =6.9 Hz),1.33 (6H, d, J = 6.8 Hz).

[0179] Reference example 4 N-{[4-(benzyloxy)-3-methoxyphenyl]methyl}-3-bromobenzamide [ka]

[0180] (4-(benzyloxy)-3-methoxyphenyl)methaneamine hydrochloride (5.0 g), 3-bromobenzoic acid (3.95 g), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (6.8 g) were dissolved in dimethylformamide (36 ml), to which N,N-diisopropylethylamine (6.87 ml) was added and the mixture was stirred at room temperature for 24 hours. After adding water to the reaction mixture, it was extracted with ethyl acetate. The resulting organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: hexane:ethyl acetate), and the resulting solid was washed with hexane to obtain Reference Example 4 (8.0 g). LC-MS, m / z; 426.13 (M+H) + ESI, Rt; 1.029 (min)

[0181] Reference example 5 N-{[4-(benzyloxy)-3-methoxyphenyl]methyl}-3'-hydroxy[1,1'-biphenyl]-3-carboxamide [ka]

[0182] N-{[4-(benzyloxy)-3-methoxyphenyl]methyl}-3-bromobenzamide (3.0 g), 3-hydroxyphenylboronic acid (1.65 g), (1,1-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (0.575 g), and cesium carbonate (4.59 g) were added to a solution of 1,2-dimethoxyethane (70 ml) / water (7 ml) and stirred at 100°C for 5 hours. The reaction mixture was filtered through Celite, ethyl acetate was added, and the organic layer was washed with water and saturated brine. The mixture was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent: hexane:ethyl acetate), and the resulting solid was washed with a hexane / ethyl acetate = 10:1 solution to obtain Reference Example 5 (2.62 g). LC-MS, m / z; 440.30 (M+H)+ ESI, Rt; 0.955 (min)

[0183] Reference examples 6~8 2-(4-hydroxy-3-methoxyphenyl)-N-(3-(4-oxocyclohexyl)phenyl)acetamide [ka]

[0184] a) Preparation of 2-[4-(benzyloxy)-3-methoxyphenyl]-N-[3-(1,4-dioxaspiro[4.5]deca-7-en-8-yl)phenyl]acetamide (Reference Example 6) 2-(4-(benzyloxy)-3-methoxyphenyl)-N-(3-bromophenyl)acetamide (500 mg), 1,4-dioxaspiro[4,5]deca-7-ene-8-phenylboronic acid pinacol ester (343 mg), and potassium carbonate (486 mg) were dissolved in 1,2-dimethoxyethane (5 ml) / water (1 ml). Dichlorobis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) (42 mg) was added to this solution and heated under reflux for 3 hours. After concentrating the reaction mixture, chloroform was added, and the organic layer was washed with water, saturated sodium bicarbonate aqueous solution, and saturated brine. The mixture was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product of Reference Example 6 (693 mg) was used directly in the next reaction. LC-MS, m / z; 486.37 (M+H) + ESI, Rt; 1.058 (min)

[0185] b) Preparation of 2-[4-(benzyloxy)-3-methoxyphenyl]-N-(4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-3-yl)acetamide (Reference Example 7) A solution of the crude product of 2-[4-(benzyloxy)-3-methoxyphenyl]-N-[3-(1,4-dioxaspiro[4.5]deca-7-en-8-yl)phenyl]acetamide (693 mg) in tetrahydrofuran (30 ml) was mixed with 5 mol / L hydrochloric acid (30 ml) and stirred at room temperature for 1 hour. After adding water to the reaction mixture, it was extracted with ethyl acetate. The resulting organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product of Reference Example 7 (570 mg) obtained was used directly in the next reaction. LC-MS, m / z; 442.31 (M+H) + ESI, Rt; 0.982 (min)

[0186] c) Preparation of 2-(4-hydroxy-3-methoxyphenyl)-N-(3-(4-oxocyclohexyl)phenyl)acetamide (Reference Example 8) To a solution of 570 mg of the crude product of 2-[4-(benzyloxy)-3-methoxyphenyl]-N-(4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-3-yl)acetamide in 10 ml of ethyl acetate, 250 mg of palladium-activated carbon (Pd 20%) was added and the mixture was stirred at room temperature under a hydrogen atmosphere for 7 hours. After purging the reaction mixture with nitrogen, it was filtered by Celite and concentrated under reduced pressure. Diethyl ether was added to the resulting residue, and the precipitated solid was filtered to obtain Reference Example 8 (202 mg). LC-MS, m / z; 354.14 (M+H) + ESI, Rt; 0.678 (min)

[0187] Reference example 9 N-{3-[(cis)-4-hydroxycyclohexyl]phenyl}-2-(4-hydroxy-3-methoxyphenyl)acetamide [ka]

[0188] To a solution of dichlorobis(triphenylphosphine)(1,2-ethanediamine)ruthenium(II) (492 mg) in 2-propanol (115 ml), potassium tert-butoxide (2.92 g) and tetrahydrofuran (115 ml) were added. Subsequently, Reference Example 8 (2.3 g) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 5.5 hours. After purging the reaction mixture with nitrogen, it was filtered by Celite and concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with 1 mol / L hydrochloric acid and saturated brine, and dried over sodium sulfate. After removing the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate) to obtain Reference Example 9 (1.2 g). LC-MS, m / z; 356.3 (M+H) + ESI, Rt; 0.683 (min)

[0189] Reference example 10 N-{3-[(trans)-4-hydroxycyclohexyl]phenyl}-2-(4-hydroxy-3-methoxyphenyl)acetamide [ka]

[0190] To a solution of 2-(4-hydroxy-3-methoxyphenyl)-N-(3-(4-oxocyclohexyl)phenyl)acetamide (500 mg) in tetrahydrofuran (14 ml), sodium borohydride (107 mg) was added. After stirring at room temperature for 1.5 hours, saturated ammonium chloride aqueous solution was added to the reaction mixture, and it was extracted with ethyl acetate. The resulting organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified with methyl tert-butyl ether to obtain Reference Example 10 (276 mg). LC-MS, m / z; 356.2 (M+H) + ESI, Rt; 0.632 (min)

[0191] Reference example 11 4-[2-(3-{(cis)-4-[(cyclohexanecarbonyl)oxy]cyclohexyl}anilino)-2-oxoethyl]-2-methoxyphenyl cyclohexanecarboxylate [ka]

[0192] To a solution of N-{3-[(cis)-4-hydroxycyclohexyl]phenyl}-2-(4-hydroxy-3-methoxyphenyl)acetamide (1.0 g) and triethylamine (1.6 ml) in tetrahydrofuran (14 ml), cyclohexanecarbonyl chloride (1.1 ml) was added. After stirring at room temperature for 4 days, water was added to the reaction mixture, and it was extracted with chloroform. The resulting organic layer was washed with water and saturated brine. After drying over sodium sulfate, the mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate), and the resulting solid was washed with hexane to obtain Reference Example 11 (1.05 g). LC-MS, m / z; 576.39 (M+H) + ESI, Rt; 1.436 (min)

[0193] Reference example 12 3'-Hydroxy-N-[(4-Hydroxy-3-methoxyphenyl)methyl][1,1'-Biphenyl]-3-Carboxamide [ka]

[0194] To a solution of N-{[4-(benzyloxy)-3-methoxyphenyl]methyl}-3'-hydroxy[1,1'-biphenyl]-3-carboxamide (250 mg) in ethyl acetate (10 ml)-ethanol (10 ml), palladium-activated carbon (Pd 20%) (50 mg) was added and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. After purging the reaction mixture with nitrogen, it was filtered by Celite and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate) to obtain Reference Example 18 (171 mg). LC-MS, m / z; 350.2 (M+H) + ESI, Rt; 0.684 (min)

[0195] Reference examples 13~19 The compounds shown in Table 1 were obtained using the corresponding starting compounds by the same method as in Reference Example 12.

[0196] [Table 1]

[0197] Example 2 cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamide]phenyl}cyclohexyl cyclohexanecarboxylate [ka]

[0198] To a solution of 4-[2-(3-{(cis)-4-[(cyclohexanecarbonyl)oxy]cyclohexyl}anilino)-2-oxoethyl]-2-methoxyphenylcyclohexanecarboxylate (0.91 g) in 2-propanol (330 ml), 28-30% aqueous ammonia (110 ml) was added. After stirring at room temperature for 1 day, 1 mol / L hydrochloric acid was added to the reaction mixture, and it was extracted with ethyl acetate. The resulting organic layer was washed with water and saturated brine. After drying over sodium sulfate, it was filtered and concentrated under reduced pressure. The resulting solid was washed with diethyl ether and recrystallized from acetonitrile to obtain Example 2 (469 mg). 1 H-NMR (400 MHz, CD3OD) δ:7.45 (1H, t, J = 1.8 Hz), 7.39-7.35 (1H, m), 7.22 (1H, t, J = 7.6 Hz), 6.97(1H, d, J = 8.0 Hz), 6.94 (1H, d, J = 1.2 Hz), 6.78 (1H, dd, J = 2.0, 6.0 Hz),6.75 (1H, d, J = 8.0 Hz), 5.04 (1H, s), 3.86 (3H, s), 3.57 (2H, s), 2.63-2.54(1H, m), 2.42-2.33(1H, m), 2.00-1.89 (4H, m), 1.85-1.63 (9H, m), 1.55-1.43 (2H, m), 1.43-1.25 (3H, m). LC-MS, m / z; 466.3 (M+H) + ESI, Rt; 1.134 (min)

[0199] Example 49 3-{4-[2-(4-hydroxy-3-methoxyphenyl)acetamide]pyridine-2-yl}phenyl 2-methylpropanoate hydrochloride [ka]

[0200] To a mixed solution of 3-{4-[2-(4-hydroxy-3-methoxyphenyl)acetamido]pyridine-2-yl}phenyl 2-methylpropanoate (2.5 g) in ethyl acetate (50 ml) / tetrahydrofuran (10 ml), 10 ml of 4 mol / L hydrogen chloride-ethyl acetate solution was added and the mixture was stirred at room temperature. After concentrating the reaction mixture, the resulting solid was washed with diethyl ether to obtain Example 49 (1.97 g). 1H-NMR (400 MHz, CD3OD) δ: 8.51(1H, d, J = 6.4 Hz), 8.22 (1H, d, J = 2.0 Hz), 7.86 (1H, d, J = 6.4 Hz), 7.75(1H, d, J = 8.4 Hz), 7.63-7.58 (2H, m), 7.29 (1H, dd, J = 2.6, 7.8 Hz), 6.94(1H, d, J = 1.6 Hz), 6.81-6.75 (2H, m), 3.86 (3H, s), 3.70 (2H, s), 2.87 (1H, p, J = 7.0 Hz), 1.33 (6H, d, J = 7.2 Hz). LC-MS, m / z; 421.3 (M+H) + ESI, Rt; 0.707 (min)

[0201] Examples 3-48 The compounds shown in Table 2 were obtained using the corresponding starting compounds by the same method as in Examples 1, 2, and 49.

[0202] [Table 2] JPEG2023129387000058.jpg221149 JPEG2023129387000059.jpg217149 JPEG2023129387000060.jpg217149 JPEG2023129387000061.jpg201149 JPEG2023129387000062.jpg212149 JPEG2023129387000063.jpg197149

[0203] Test example The following shows the results of pharmacological tests on representative compounds of the present invention and explains their pharmacological effects; however, the present invention is not limited to these test examples.

[0204] Test Example 1: Evaluation of operability using human TRPV1 transient expression cells (1) Generation of human TRPV1 transient expression cells Human TRPV1 transient expression cells were generated and subjected to culture. Specifically, HEK293 cells (cat#CCL-82.2, ATCC) were used as host cells. Human TRPV1 and apoequorin were transiently expressed by introducing a mammalian cell expression pcDNA3.1 vector (cat#v790-20, Invitrogen) into which the TRPV1 gene (GenBank NP_542435.2) was inserted. Dulbecco's Modified Eagle's Medium (DMEM) medium (cat#11550-043, Thermo Fisher Scientific) containing 10% inactivated fetal bovine serum (cat#10270-106, Thermo Fisher Scientific) was used as the culture medium, and cells were cultured in tissue culture dishes (cat#3020-100, Iwaki). During culture, cells were harvested every 2-3 days by PBS treatment with 10% 2.5g / 1-trypsin / 1mol / L EDTA solution and phenol red (cat#32777-44, Nacalai Tesque), and then subcultured. Three days after subculturing, cells were harvested at approximately 80% confluence by 10% trypsin-PBS treatment, suspended in 10% fetal bovine serum-containing DMEM medium at a concentration of 4000 cells / 35 μl / well, and seeded onto 384-well plates (cat#353962, FALCON). The day after sowing, Viviren (cat#E6492, Promega) was added to a final concentration of 4.5 μM / HBSS (cat#14065-056, Thermo Fisher Scientific) / 90 mM HEPES (cat#17514-15, Nacalai Tesque) / 0.1% BSA (cat#01281-84, Nacalai Tesque) (15 μl / well), and after centrifugation, the mixture was allowed to stand at room temperature in the dark for 2 hours.

[0205] (2) Preparation of test compounds A dimethyl sulfoxide solution was prepared at 1000 times the final concentration of the test compound, and this solution was then adjusted to 10 times the final concentration using Hanks / 20 mmol / L HEPES / 0.1% BSA (cat#01281-84, Nacalai Tesque).

[0206] (3) TRPV1 operability evaluation FDSS7000 (Hamamatsu Photonics) was used to detect the luminescence signal stimulated by TRPV1 agonists. Test compounds were added to plates containing cells and a luminescent substrate. The luminescence signal (center wavelength: 465 nm) after adding the test compound was measured, and Rlu (Max-Min) was calculated. Data for the TRPV1 agonist activity of representative compounds are shown in Tables 3 and 4.

[0207] [Table 3]

[0208] [Table 4]

[0209] As shown in the table above, the compounds of the present invention exhibited TRPV1 agonist activity in TRPV1 agonist evaluation tests. In particular, Examples 1, 2, 9, 10, 15, 17, 19, 24, 26, and 46 showed stronger TRPV1 agonist activity.

[0210] Test Example 2: Evaluation of swallowing improvement effect in a rat haloperidol-induced dysphagia model. This study evaluates the effect of a drug on improving dysphagia. Haloperidol causes a decrease in the swallowing reflex by inhibiting dopamine D2 receptors, and is therefore used not only as a model for drug-induced dysphagia caused by antipsychotics and other drugs, but also as a model for dysphagia in the background of neurodegenerative diseases such as Parkinson's disease, and as a model for other dysphagia characterized by a decreased swallowing reflex. Haloperidol was administered to male Crl:CD(SD) rats (8 rats per group, 8 weeks old, body weight 280-310g at the time of arrival). Specifically, it was administered subcutaneously to the back using a disposable polypropylene syringe (Terumo Corporation) fitted with a 23G injection needle (Terumo Corporation). The amount of solution administered was calculated at 5 ml / kg based on the body weight closest to the day of administration, and the number of administrations was 14 times in total, twice a day (12 ± 2 hour intervals) for 7 days to create the model. The number of swallows was measured on the morning of the day following the 7th day of administration. An anesthetic was administered intraperitoneally to animals using a disposable polypropylene syringe (Terumo Corporation) fitted with a 25g injection needle (Terumo Corporation) [Amount of solution administered: calculated at 2.3 ml / kg based on the animal's body weight on the day. Contains ketamine (90 mg / kg) and xylazine (10 mg / kg)]. After induction of anesthesia, the animals' under-chin hair was trimmed with clippers, and they were restrained in a supine position on a heat pad heated to 37°C, ensuring their limbs were immobile. A rat-type tube was inserted once into the animal's mouth, with the tip of the tube held in place in the pharynx. While maintaining this position, 0.1 ml of the test substance solution was injected. After injection, one swallowing action induced by the swallowing reflex was measured as one swallow. Two measurements were taken per animal, and the average of the first and second measurements was calculated. A 0.01% ethanol vehicle was used. The results are shown in Figure 1.

[0211] Test Example 3: Evaluation of taste aversion caused by drinking water This study evaluates the taste aversion of a drug. Crl:CD(SD) rats (8 rats per group, 8 weeks old at arrival) were kept in home cages, and the test substance solution was added to their water bottles. Two water bottles were prepared per cage, each filled with Vehicle (sterilized water containing 0.05% ethanol) and the test substance solution, and kept overnight. The amount of water consumed during this period was measured. The proportion of water consumed by the test substance was calculated from the total water intake from the two water bottles, and taste aversion was evaluated. A higher proportion of water consumed by the test substance indicates lower taste aversion and less irritation from the test substance. The results are shown in Table 5.

[0212] [Table 5]

[0213] Test Example 4: S9 Metabolic Stability Evaluation Test The compound was added to a reaction solution prepared by diluting the liver S9 fraction with phosphate buffer, and incubation was started at 37°C (final compound concentration 10 nM, final volume 300 μL). After incubation for 15 minutes, the reaction was stopped by adding the reaction solution to acetonitrile, and centrifugation was performed. After filtering the supernatant, the amount of compound was measured using LC / MS / MS. From the obtained amount of compound, the residual percentage after 15 minutes from the start of the reaction was calculated relative to the amount of compound before the start of the reaction (0 minutes). The results are shown in Table 6.

[0214] [Table 6]

[0215] Test Example 5: Evaluation of swallowing-enhancing effect in normal rats This study evaluates the swallowing-enhancing effect of a drug. It has been reported that inducing the swallowing reflex in normal rats using water containing NaCl suppresses the number of swallows; therefore, the enhancement of swallowing function was evaluated using a solvent containing NaCl. Crl:CD(SD) male rats (7-8 rats per group, 8-9 weeks old, body weight 280-310g: at arrival) were anesthetized, the hair under the jaw was trimmed with clippers, and the rats were restrained in a supine position on a heat pad heated to 37°C, ensuring their limbs were immobile. A rat feeding tube was inserted into the animal's mouth, with the tip of the tube held in place in the pharynx. In this state, the test substance solution was administered at 12 ml / h for 10 seconds using an infusion pump, and swallowing movements were measured for 30 seconds from the start of administration. The vehicle used was physiological saline containing 1% ethanol and 0.1% Tween 80. The results are shown in Table 7. Compared to the solvent administration group, the number of swallows significantly increased in capsaicin, Example 12, Example 2, and Example 49 (Dunnett's test: * indicates P<0.05, ** indicates P<0.01, and *** indicates P<0.001).

[0216] [Table 7]

[0217] Test Example 6: Evaluation of desensitization of swallowing-enhancing effects in normal rats TRPV1 agonists are known to induce TRPV1 desensitization when administered at high doses or repeatedly. Using a method similar to that in Test Example 5, we investigated the effect of drugs on inducing desensitization of normal rat swallowing function. Crl:CD(SD) male rats (7-8 rats per group, 8-9 weeks old, body weight 280-310g: at arrival) were anesthetized, the hair under the jaw was trimmed with clippers, and the animals were restrained in a supine position on a heat pad heated to 37°C, ensuring that their limbs did not move. A rat feeding tube was inserted into the mouth of each animal, with the tip of the tube held in place in the pharynx. In this state, the test substance was administered at 12 ml / h for 10 seconds using an infusion pump, and swallowing was measured for 30 seconds from the start of administration. The same test was then performed approximately 5 minutes later, and a total of 5 evaluations were conducted. The vehicle used was physiological saline containing 1% ethanol and 0.1% Tween 80. The results are shown in Table 8. With capsaicin, the number of swallows decreased significantly between the fourth and fifth administrations compared to the first administration (Dunnett's test: ** indicates P<0.01). On the other hand, no significant difference was observed in Example 49.

[0218] [Table 8]

[0219] Test Example 7: Evaluation of eye irritation tests in normal rats TRPV1 agonists are irritating, and it has been reported that administering a TRPV1 agonist solution to the eye can induce wiping behavior. The irritating properties of the compound were investigated using normal rats. Crl:CD(SD) male rats (5 rats per group, 8 weeks old, body weight 271-320g) were restrained without anesthesia, and 10 μL was dropped into the right eye using a micropipette. The rats were immediately returned to the observation cage, and wiping behavior was observed for 1 minute. The number of wiping behaviors is shown in Table 9. With capsaicin, wiping behavior significantly increased at concentrations of 30 μM or higher (Dunnett's test: * indicates P<0.05, ** indicates P<0.01). On the other hand, no significant differences were observed in Examples 12, 2, 1, and 49.

[0220] [Table 9]

[0221] As described above, the compound of the present invention is a potent TRPV1 agonist and exhibits an improving effect on the swallowing reflex in haloperidol-induced dysphagia animal models used as models for dysphagia. Because it improves the reduced swallowing reflex by antagonizing dopamine D2 receptors, it is useful as a therapeutic agent for drug-induced dysphagia caused by the administration of antipsychotics and other drugs, as well as for neurodegenerative diseases such as Parkinson's disease, and for dysphagia caused by cerebrovascular diseases and aging, in which the swallowing reflex is reduced. [Industrial applicability]

[0222] Because the compounds disclosed herein exhibit TRPV1 agonism, they are useful as therapeutic agents for drug-induced dysphagia, dysphagia associated with neurodegenerative diseases such as Parkinson's disease, and dysphagia caused by a decrease in the swallowing reflex due to various factors such as cerebrovascular disease and aging.

Claims

1. Formula (2): 【Chemistry 1】 [In the formula, R １ is a hydrogen atom, C １－６ Alkyl group (the C １－６ The alkyl group includes a hydroxyl group, a carboxyl group, and an —NR １１ R １２ and optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of: １－６ an alkylcarbonyl group or an optionally substituted C ６－１０ represents an arylcarbonyl group, R ２ represents a methoxy group, a hydroxyl group, or a hydrogen atom, R ３ represents a hydrogen atom, a halogen atom, or an optionally substituted C １－６ alkyl group, optionally substituted C １－４ an alkoxy group, optionally substituted C ６－１０ represents an aryl group or a formyl group, R ４ is an optionally substituted C １－６ alkyl group, optionally substituted C ３－７ Alicyclic group, optionally substituted C ２－６ Alkenyl group, optionally substituted C ２－６ Alkynyl group, optionally substituted C ６－１０ aryl group, optionally substituted C １－６ an alkoxy group, optionally substituted C ３－７ Alicyclic oxy group, optionally substituted C ６－１０ an aryloxy group or an optionally substituted 4- to 7-membered non-aryl heterocyclic group, Here, R ４ is an optionally substituted 4- to 7-membered non-aryl heterocyclic group, a carbon atom on the non-aryl heterocyclic group is bonded to a carbonyl group, R １１ represents a hydrogen atom, an optionally substituted C １－３ Alkyl group, formyl group, optionally substituted C １－３ alkylcarbonyl group, optionally substituted C １－４ an alkoxycarbonyl group or an optionally substituted C ６－１０ represents an arylcarbonyl group, R １２ represents a hydrogen atom or an optionally substituted C １－３ represents an alkyl group, m represents 1 or 2; n represents 0, 1, 2 or 3; L １ is —NH—C(═O)—, —C(═O)—NH—, —NH—C(═S)—, —C(═S)—NH—, —NH—C(═O)—CH ２ —, —C(═O)—NH—CH ２ —, —NH—C(═O)—CH ２ —CH ２ —, —C(═O)—NH—CH ２ —CH ２ —, —SO ２ —NH—, —NH—SO ２ —, —NH—C(═O)—O— or —O—C(═O)—NH—, and L ２ is a single bond or an optionally substituted C １－６ represents an alkyl group, X represents an optionally substituted phenyl group or an optionally substituted 6-membered heteroaryl group; Y is an optionally substituted phenyl group, an optionally substituted 5- or 6-membered heteroaryl group, an optionally substituted C ３－７ represents an alicyclic group or an optionally substituted 4- to 7-membered non-aryl heterocyclic group, wherein X and Y are attached at carbon atoms on their respective rings; however, 1) Formula (W-1): 【Chemistry 2】 {During the ceremony, R １a is a hydrogen atom or an acetyl group, L １a is —C(═O)—NH— or —SO ２ -NH-}, 2) Formula (W-2): 【Transformation 3】 {During the ceremony, R １ｂ is a methyl group or -CD ３ and R ２ｂ is represented by the following formula (W-2A), (W-2B), (W-2C), (W-2D), or (W-2R), 【Chemistry 4】 (wherein * represents the bonding position with O) R ３ｂ is represented by the following formula (W-2E), (W-2F), (W-2G), (W-2H), (W-2I), (W-2J), (W-2K), (W-2L), (W-2M), (W-2N), (W-2O), (W-2P) or (W-2Q), 【Transformation 5】 (In the formula, * represents the bond position with C═O) X ｂ is CH or N, Y ｂ is CH or N, Z ｂ But -CH ２ - or -CHD-}, 3) 4'-{[2-(3,4-dimethoxyphenyl)ethyl]carbamoyl}[1,1'-biphenyl]-4-yl acetate, 4) 2'-(2-{[2-(3,4-dimethoxyphenyl)ethyl]amino}-2-oxoethyl)-4,4',5,5'-tetramethoxy[1,1'-biphenyl]-2-yl acetate, 5) (2'-{[2-(3,4-dimethoxyphenyl)ethyl]carbamoyl}-4,4',5,5'-tetramethoxy[1,1'-biphenyl]-2-yl)methyl benzoate, 6) 6-[4-methoxy-2-(2-{4-[2-(piperidin-1-yl)ethoxy]phenyl}acetamido)phenyl]-5,6,7,8-tetrahydronaphthalen-2-yl 2,2-dimethylpropanoate, 7) 4'-{[(4-methoxyphenyl)methyl]sulfamoyl}[1,1'-biphenyl]-4-yl acetate, 8) 4'-{[(4-methoxyphenyl)methyl]sulfamoyl}[1,1'-biphenyl]-4-yl benzoate, 9) 4'-{[(4-methoxyphenyl)methyl]sulfamoyl}[1,1'-biphenyl]-4-yl 4-chlorobenzoate, 10) 4'-{[(4-methoxyphenyl)methyl]sulfamoyl}[1,1'-biphenyl]-4-yl 2-chlorobenzoate, 11) 4'-{[(4-methoxyphenyl)methyl]sulfamoyl}[1,1'-biphenyl]-4-yl 3-nitrobenzoate, and 12) 4'-{[(4-methoxyphenyl)methyl]sulfamoyl}[1,1'-biphenyl]-4-yl 2,4-dichlorobenzoate excluded A pharmaceutical composition comprising a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.

2. R ３ is a hydrogen atom, The pharmaceutical composition according to claim 1.

3. m is 1 or 2; A pharmaceutical composition according to claim 1 or 2.

4. m is 1, A pharmaceutical composition according to claim 1 or 2.

5. R １ is a hydrogen atom, A pharmaceutical composition according to claim 1 or 2.

6. R ２ is a methoxy group, A pharmaceutical composition according to claim 1 or 2.

7. L １ is —NH—C(═O)— or —C(═O)—NH—; A pharmaceutical composition according to claim 1 or 2.

8. L ２ is a single bond, A pharmaceutical composition according to claim 1 or 2.

9. X is the following formula (A): 【Transformation 6】 (where * represents L １ represents the bonding position with Y, and ** represents the bonding position with Y. a is CR ８ or N, b is CR ９ or N, c is CR １０ or N, R ８ , R ９ and R １０ are each independently a hydrogen atom, a halogen atom, a cyano group, or C １－６ alkylsulfonyl group, optionally substituted C １－６ an alkyl group or an optionally substituted C １－６ is an alkoxy group, A pharmaceutical composition according to claim 1 or 2.

10. X is formula (A), Here, (1) if a is N, then b is CR ９ and c is CR １０ (2) When b is N, a is CR ８ and c is CR １０ (3) When c is N, a is CR ８ and b is CR ９ That is, A pharmaceutical composition according to claim 1 or 2.

11. X is formula (A), Here, c is CR １０ (1) When a is N, b is CR ９ (2) When b is N, a is CR ８ That is, A pharmaceutical composition according to claim 1 or 2.

12. X is formula (A), wherein c is CH, (1) when a is N, b is CH, and (2) when b is N, a is CH. A pharmaceutical composition according to claim 1 or 2.

13. X is formula (A), wherein a, b and c are CH; A pharmaceutical composition according to claim 1 or 2.

14. Y is an optionally substituted phenyl group, an optionally substituted 6-membered heteroaryl group, or an optionally substituted C ３－７ is an alicyclic group, A pharmaceutical composition according to claim 1 or 2.

15. Y is an optionally substituted phenyl group or an optionally substituted cyclohexyl group; A pharmaceutical composition according to claim 1 or 2.

16. Y is the following formula (B) or (C): 【Transformation 7】 (In the formula, * represents the bonding position with X, and ** represents L ２ or the bond position with the oxygen atom) A pharmaceutical composition according to claim 1 or 2.

17. R ４ is optionally substituted C １－６ alkyl group, optionally substituted C ３－７ Alicyclic group, optionally substituted C ２－６ Alkenyl group, optionally substituted C ２－６ Alkynyl group or optionally substituted C ６－１０ is an aryl group, A pharmaceutical composition according to claim 1 or 2.

18. R ４ is optionally substituted C １－６ alkyl group, optionally substituted C ３－７ an alicyclic group or an optionally substituted C ６－１０ is an aryl group, A pharmaceutical composition according to claim 1 or 2.

19. R ４ But C １－６ Alkyl group, C ３－７ Alicyclic group or C ６－１０ Aryl group (the C １－６ Alkyl group, C ３－７ Alicyclic group and C ６－１０ The aryl group may be a fluorine atom, a chlorine atom, or a C １－６ Alkyl group, C ３－７ Alicyclic group, C ６－１０ aryl groups, 5- or 6-membered heteroaryl groups, and 4- to 10-membered non-aryl heterocyclic groups, each of which may be substituted with 1 to 3 identical or different substituents; A pharmaceutical composition according to claim 1 or 2.

20. R ４ is a methyl group, an ethyl group, an isopropyl group, a cyclohexyl group, a cyclohexylmethyl group, a phenyl group, or a benzyl group (the methyl group, the ethyl group, the isopropyl group, the cyclohexyl group, the cyclohexylmethyl group, the phenyl group, and the benzyl group are each independently selected from the group consisting of a fluorine atom, a chlorine atom, and a C １－６ alkyl groups, each of which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of A pharmaceutical composition according to claim 1 or 2.

21. R ４ However, a methyl group, an ethyl group, an isopropyl group, a cyclohexyl group, a phenyl group (the methyl group, the ethyl group, the isopropyl group, the cyclohexyl group and the phenyl group do not contain a fluorine atom, a chlorine atom and a C １－６ alkyl groups, each of which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of A pharmaceutical composition according to claim 1 or 2.

22. 2. The pharmaceutical composition according to claim 1, comprising a compound selected from the following compounds or a pharmaceutically acceptable salt thereof: 3-{6-[2-(4-hydroxy-3-methoxyphenyl)acetamido]pyridin-2-yl}phenyl 2-methylpropanoate, cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl cyclohexanecarboxylate, cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl(3-methylphenyl)acetate, cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl(2-chlorophenyl)acetate, cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl acetate, cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl(2-fluorophenyl)acetate, cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl 2-methylpropanoate, 2'-fluoro-5'-[2-(4-hydroxy-3-methoxyphenyl)acetamido][1,1'-biphenyl]-3-yl 2-methylpropanoate, 3'-[2-(4-hydroxy-3-methoxyphenyl)acetamido][1,1'-biphenyl]-3-yl 2-methylpropanoate, 3-{4-[2-(4-hydroxy-3-methoxyphenyl)acetamido]pyridin-2-yl}phenyl 2-methylpropanoate 3-(4-{[(4-hydroxy-3-methoxyphenyl)methyl]carbamoyl}pyridin-2-yl)phenyl 2-methylpropanoate, and 3-{4-[2-(4-hydroxy-3-methoxyphenyl)acetamido]pyridin-2-yl}phenyl 2-methylpropanoate hydrochloride.

23. The pharmaceutical composition of claim 1, comprising the following compound or a pharmaceutically acceptable salt thereof: 3-{6-[2-(4-hydroxy-3-methoxyphenyl)acetamido]pyridin-2-yl}phenyl 2-methylpropanoate.

24. The pharmaceutical composition of claim 1, comprising the following compound or a pharmaceutically acceptable salt thereof: cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl cyclohexanecarboxylate.

25. The pharmaceutical composition of claim 1, comprising the following compound or a pharmaceutically acceptable salt thereof: cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl acetate.

26. The pharmaceutical composition of claim 1, comprising the following compound or a pharmaceutically acceptable salt thereof: 3-{4-[2-(4-hydroxy-3-methoxyphenyl)acetamido]pyridin-2-yl}phenyl 2-methylpropanoate.

27. The pharmaceutical composition of claim 1, comprising the following compound or a pharmaceutically acceptable salt thereof: 3-{4-[2-(4-hydroxy-3-methoxyphenyl)acetamido]pyridin-2-yl}phenyl 2-methylpropanoate hydrochloride.

28. A therapeutic or preventive agent for a disorder or disease involving TRPV1, comprising the pharmaceutical agent according to claim 1.

29. The therapeutic or prophylactic agent according to claim 28, wherein the disorder or disease in which TRPV1 is involved is dysphagia.

30. The pharmaceutical composition of claim 1 for treating or preventing a disorder or disease in which TRPV1 is involved.

31. The pharmaceutical composition according to claim 1 for treating or preventing dysphagia.

32. Use of the pharmaceutical agent according to claim 1 for the manufacture of a therapeutic or preventive agent for a disorder or disease in which TRPV1 is involved.

33. The pharmaceutical composition of claim 1 for use in treating or preventing a disorder or disease in which TRPV1 is involved.

34. A pharmaceutical composition comprising the medicament according to claim 1 in combination with one or more other drugs.

35. The pharmaceutical composition of claim 1 for treating or preventing a disorder or disease in which TRPV1 is involved, in combination with one or more other drugs.

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