phenol derivatives

Abstract

A compound represented by formula (2): [in the formula, R1 represents a hydrogen atom, etc., R2 represents a methoxy group, etc., R3 represents a hydrogen atom, etc., R4 represents an optionally substituted C1-6 alkyl group, etc., m represents 0, 1, or 2, n represents 0, 1, 2, or 3, L1 represents -NH-C(=O)-, -C(=O)-NH-, etc., L2 represents a single bond, etc., X represents an optionally substituted phenyl, etc., Y represents an optionally substituted phenyl, etc., where X and Y are bonded by carbon atoms on their respective rings] or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

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

[0002] The swallowing process consists of five stages: the anticipatory stage in which food is recognized; the preparatory stage in which food is taken into the mouth and chewed; the oral stage in which food is sent to the pharynx with the tongue; the pharyngeal stage in which food stimulation triggers a swallowing reflex, sending food into the esophagus; and the esophageal stage in which peristalsis transports food from the esophagus to the stomach. Disruption to any of these stages disrupts smooth swallowing, resulting in dysphagia. Abnormalities or declines in the pharyngeal swallowing reflex can be caused by various drugs, cerebrovascular disease, neurodegenerative diseases, and aging (Non-Patent Documents 1 and 2).

[0003] Treatments for dysphagia include swallowing instruction, rehabilitation, and surgical treatment. To treat a delayed swallowing reflex, it is recommended to choose a highly viscous food form. Rehabilitation involves cold pressure stimulation to induce the swallowing reflex, stretching of the swallowing-related organs, and swallowing pattern training. The effectiveness of these methods has yet to be fully verified through randomized controlled trials, and further investigation into their effectiveness is needed. If the above methods are unsuccessful, surgery to improve swallowing function may be considered, but it must be performed with caution due to its invasive nature and the fact that it may not produce the desired results. Therefore, there is a need for treatments that can clearly demonstrate effectiveness for dysphagia.

[0004] Drugs that have been 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, are expected to have a preventive effect against pneumonia, but their effectiveness is uncertain. Therefore, there is a need for drugs to treat swallowing disorders.

[0005] Meanwhile, ingredients used as 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, as a TRPV1 agonist, has been reported to potently improve the swallowing reflex (Non-Patent Document 7), and supplements with the expected swallowing improvement effect are also available on the market. However, they are not widely used because they are not pharmaceuticals.

[0006] Although compounds described in Patent Documents 1-5 have been disclosed as TRPV1 agonists, they have also been reported to have potential side effects such as irritation and hypothermia when administered systemically (Non-Patent Documents 8 and 9). Therefore, the development of safe TRPV1 agonists is desired. [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. Kyusyu Neuropsychiatry. 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. Summary of the Invention [Problem to be solved by the invention]

[0009] An object of the present disclosure is to provide a compound that is useful as a therapeutic agent for dysphagia, improves swallowing reflex, and has high safety. [Means for solving the problem]

[0010] As a result of intensive research, the present inventors have found that a compound represented by the following formula (1) has TRPV1 agonism, exhibits an effect of improving dysphagia, and also has prodrug-like properties, thereby completing the present disclosure. According to the present disclosure, a phenol derivative represented by the following formula (1) (hereinafter, sometimes referred to as the "compound of the present disclosure") is provided.

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

[0012] (Section 1) Formula (1): [ka] [In the formula, R 1 is a hydrogen atom, optionally substituted C 1-6 alkyl group, optionally substituted C 1-6 Alkylcarbonyl group or optionally substituted C 6-10 represents an arylcarbonyl group, R 2 represents a methoxy group, a hydroxyl group, or a hydrogen atom, R 3 is a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 alkyl group, optionally substituted C 1-4 Alkoxy group, optionally substituted C 6-10 represents an aryl group or a formyl group, R 4 may be substituted C 1-6 alkyl group, optionally substituted C 3-7 Alicyclic groups, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 Alkynyl group, optionally substituted C 6-10 Aryl group, optionally substituted C1-6 Alkoxy group, optionally substituted C 3-7 Alicyclic oxy group, optionally substituted C 6-10 represents an aryloxy group or an optionally substituted 4- to 7-membered non-aryl heterocyclic group, m represents 0, 1 or 2; n represents 0, 1, 2 or 3; L 1 -NH-C(=O)-, -C(=O)-NH-, -OC(=O)-, -C(=O)-O-, -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 -OC(=O)-NH-, Q represents a single bond, -O-, -S-, -SO2-, -NR5- or -CR6R7-; L 2 is a single bond or an optionally substituted C 1-6 represents an alkyl group, X is an optionally substituted C 6-10 represents an aryl group or an optionally substituted 5- to 10-membered heteroaryl group, Y is an optionally substituted C 6-10 an aryl group, an optionally substituted 5- to 10-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, R 5 , R 6 and R 7 are each independently a hydrogen atom, an optionally substituted C 3-6 an alicyclic group or an optionally substituted C 1-6 represents an alkyl group] or a pharmaceutically acceptable salt thereof. (Section 2) L 1is -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 -OC(=O)-NH-, Item 1. The compound according to Item 1 or a pharmaceutically acceptable salt thereof. (Section 3) Q is a single bond; Item 1 or 2, or a pharmaceutically acceptable salt thereof. (Section 4) X is an optionally substituted phenyl group or an optionally substituted 6-membered heteroaryl group; Item 4. The compound according to any one of Items 1 to 3, or a pharmaceutically acceptable salt thereof. (Section 5) Y is an optionally substituted phenyl group, an optionally substituted 5- or 6-membered heteroaryl group, an optionally substituted C 3-7 an alicyclic group or an optionally substituted 4- to 7-membered non-aryl heterocyclic group; Item 5. The compound according to any one of Items 1 to 4, or a pharmaceutically acceptable salt thereof. (Section 6) Formula (2): [ka] [In the formula, R 1 is a hydrogen atom, C 1-6 Alkyl group (C 1-6 The alkyl group is a hydroxyl group, a carboxyl group, and -NR 11 R 12 and optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of: 1-6 Alkylcarbonyl group or optionally substituted C 6-10 represents an arylcarbonyl group, R 2 represents a methoxy group, a hydroxyl group, or a hydrogen atom, R3 is a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 alkyl group, optionally substituted C 1-4 Alkoxy group, optionally substituted C 6-10 represents an aryl group or a formyl group, R 4 may be substituted C 1-6 alkyl group, optionally substituted C 3-7 Alicyclic groups, 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 Alkoxy group, optionally substituted C 3-7 Alicyclic oxy group, optionally substituted C 6-10 represents 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 is a hydrogen atom, 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 is a hydrogen atom or an optionally substituted C 1-3 represents an alkyl group, m represents 0, 1 or 2; n represents 0, 1, 2 or 3; L 1-NH-C(=O)-, -C(=O)-NH-, -NH-C(=S)-, -C(=S)-NH-, -NH-C(=O)-CH2-, -C(=O)-NH-CH2-, -NH- Represents C(=O)-CH2-CH2-, -C(=O)-NH-CH2-CH2-, -SO2-NH-, -NH-SO2-, -NH-C(=O)-O- or -OC(=O)-NH-, 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): [ka] {In the formula, R 1a is a hydrogen atom or an acetyl group, L 1a is —C(═O)—NH— or —SO—NH—; 2) Formula (W-2): [ka] {In the formula, R 1b is a methyl group or -CD3, R 2b is represented by the following formula (W-2A), (W-2B), (W-2C), (W-2D), or (W-2R), [ka] (wherein * represents the bonding position with O) R 3bis 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), [ka] (In the formula, * indicates the bond position with C=O) X b is CH or N, Y b is CH or N, Z b is -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-(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 Item 1. The compound according to item 1, which is represented by the following formula: or a pharmaceutically acceptable salt thereof. (Section 7) R 3 is a hydrogen atom, Item 7. The compound according to any one of Items 1 to 6, or a pharmaceutically acceptable salt thereof. (Section 8) m is 1 or 2; Item 8. The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof. (Section 9) m is 1, Item 9. The compound according to any one of Items 1 to 8, or a pharmaceutically acceptable salt thereof. (Section 10) R 1 is a hydrogen atom, Item 10. The compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof. (Section 11) R 2 is a methoxy group, Item 11. The compound according to any one of Items 1 to 10, or a pharmaceutically acceptable salt thereof. (Section 12) L 1 is -NH-C(=O)- or -C(=O)-NH-; Item 12. The compound according to any one of Items 1 to 11, or a pharmaceutically acceptable salt thereof. (Section 13) L 2 is a single bond, Item 13. The compound according to any one of Items 1 to 12, or a pharmaceutically acceptable salt thereof. (Section 14) X is the following formula (A), [ka] (Wherein * is L 1 represents the bonding position with Q or Y, and ** represents the bonding position with Q or 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 alkyl group or optionally substituted C 1-6 is an alkoxy group, Item 14. The compound according to any one of Items 1 to 13, or a pharmaceutically acceptable salt thereof. (Section 15) X is of formula (A), Here, (1) if a is N, 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) If c is N, then a is CR 8 and b is CR 9 That is, Item 15. The compound according to any one of Items 1 to 14, or a pharmaceutically acceptable salt thereof. (Section 16) X is of formula (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, Item 15. The compound according to any one of Items 1 to 14, or a pharmaceutically acceptable salt thereof. (Section 17) X is of formula (A), wherein c is CH, (1) when a is N, b is CH, and (2) when b is N, a is CH; Item 15. The compound according to any one of Items 1 to 14, or a pharmaceutically acceptable salt thereof. (Section 18) X is of formula (A), wherein a, b and c are CH; Item 15. The compound according to any one of Items 1 to 14, or a pharmaceutically acceptable salt thereof. (Section 19) 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, Item 19. The compound according to any one of Items 1 to 18, or a pharmaceutically acceptable salt thereof. (Section 20) Y is an optionally substituted phenyl group or an optionally substituted cyclohexyl group; Item 20. The compound according to any one of Items 1 to 19, or a pharmaceutically acceptable salt thereof. (Section 21) Y is the following formula (B) or (C): [ka] (In the formula, * represents the bonding position with X or Q, and ** represents L 2 or the bond position with the oxygen atom) 21. The compound according to any one of items 1 to 20, or a pharmaceutically acceptable salt thereof. (Section 22) R 4 may be substituted C 1-6 alkyl group, optionally substituted C 3-7 Alicyclic groups, optionally substituted C 2-6 Alkenyl group, optionally substituted C 2-6 an alkynyl group or an optionally substituted C 6-10 is an aryl group, 22. The compound according to any one of items 1 to 21, or a pharmaceutically acceptable salt thereof. (Section 23) R 4 may be substituted C 1-6 alkyl group, optionally substituted C3-7 an alicyclic group or an optionally substituted C 6-10 is an aryl group, 23. The compound according to any one of items 1 to 22, or a pharmaceutically acceptable salt thereof. (Section 24) 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 groups and C 6-10 The aryl group contains fluorine atoms, chlorine atoms, 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; 24. The compound according to any one of items 1 to 23, or a pharmaceutically acceptable salt thereof. (Section 25) R 4 However, 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 not fluorine atoms, chlorine atoms, and 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 25. The compound according to any one of items 1 to 24, or a pharmaceutically acceptable salt thereof. (Section 26) 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 do not contain fluorine atoms, chlorine atoms and 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 26. The compound according to any one of items 1 to 25, or a pharmaceutically acceptable salt thereof. (Section 27) The compound according to item 1, 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 (Example 1), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl cyclohexanecarboxylate (Example 2), 3'-[2-(4-hydroxy-3-methoxyphenyl)acetamido][1,1'-biphenyl]-4-yl benzoate (Example 3), 3'-[2-(4-hydroxy-3-methoxyphenyl)acetamido][1,1'-biphenyl]-4-yl 2-methylpropanoate (Example 4), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl cyclohexyl acetate (Example 5), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl phenoxyacetate (Example 6), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl(3,5-difluorophenyl)acetate (Example 7), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl(4-fluorophenyl)acetate (Example 8), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl(3-methylphenyl)acetate (Example 9), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl(2-chlorophenyl)acetate (Example 10), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl(ox-4-yl)acetate (Example 11), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl acetate (Example 12), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl(thiophen-2-yl)acetate (Example 13), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl(4-chlorophenyl)acetate (Example 14), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl(2-fluorophenyl)acetate (Example 15), 3'-[2-(4-hydroxy-3-methoxyphenyl)acetamido][1,1'-biphenyl]-3-yl propanoate (Example 16), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl 2-methylpropanoate (Example 17), 3'-[2-(4-hydroxy-3-methoxyphenyl)acetamido][1,1'-biphenyl]-3-yl phenylacetate (Example 18), 2'-fluoro-5'-[2-(4-hydroxy-3-methoxyphenyl)acetamido][1,1'-biphenyl]-3-yl 2-methylpropanoate (Example 19), 3'-[2-(4-hydroxy-3-methoxyphenyl)acetamido]-4'-methoxy[1,1'-biphenyl]-3-yl 2-methylpropanoate (Example 20), 3'-[2-(4-hydroxy-3-methoxyphenyl)acetamido]-2'-methoxy[1,1'-biphenyl]-3-yl 2-methylpropanoate (Example 21), 4'-fluoro-3'-[2-(4-hydroxy-3-methoxyphenyl)acetamido][1,1'-biphenyl]-3-yl 2-methylpropanoate (Example 22), 2'-fluoro-3'-[2-(4-hydroxy-3-methoxyphenyl)acetamido][1,1'-biphenyl]-3-yl 2-methylpropanoate (Example 23), 3'-[2-(4-hydroxy-3-methoxyphenyl)acetamido][1,1'-biphenyl]-3-yl 2-methylpropanoate (Example 24), 3-{2-[2-(4-hydroxy-3-methoxyphenyl)acetamido]pyridin-4-yl}phenyl 2-methylpropanoate (Example 25), 3-{4-[2-(4-hydroxy-3-methoxyphenyl)acetamido]pyridin-2-yl}phenyl 2-methylpropanoate (Example 26), 3'-[2-(4-hydroxy-3-methoxyphenyl)acetamido][1,1'-biphenyl]-3-yl(4-methylphenyl)acetate (Example 27), 3'-[2-(4-hydroxy-3-methoxyphenyl)acetamido][1,1'-biphenyl]-3-yl(2-fluorophenyl)acetate (Example 28), 3'-[2-(4-hydroxy-3-methoxyphenyl)acetamido][1,1'-biphenyl]-3-yl(ox-4-yl)acetate (Example 29), 3'-[2-(4-hydroxy-3-methoxyphenyl)acetamido][1,1'-biphenyl]-3-yl cyclohexyl acetate (Example 30), 3-{4-[2-(4-hydroxy-3-methoxyphenyl)acetamido]pyridin-2-yl}phenyl cyclohexyl acetate (Example 31), 3-{6-[2-(4-hydroxy-3-methoxyphenyl)acetamido]pyridin-2-yl}phenyl cyclohexyl acetate (Example 32), 3-{4-[2-(4-hydroxy-3-methoxyphenyl)acetamido]pyridin-2-yl}phenyl cyclohexanecarboxylate hydrochloride (Example 33), 3-{6-[2-(4-hydroxy-3-methoxyphenyl)acetamido]pyridin-2-yl}phenyl cyclohexanecarboxylate (Example 34), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl phenylacetate (Example 35), trans-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl phenylacetate (Example 36), trans-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl cyclohexanecarboxylate (Example 37), trans-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]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)acetamido]pyridin-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]pyridin-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-yl cyclohexyl acetate (Example 45), 3-(4-{[(4-hydroxy-3-methoxyphenyl)methyl]carbamoyl}pyridin-2-yl)phenyl 2-methylpropanoate (Example 46), 3-(6-{[(4-hydroxy-3-methoxyphenyl)methyl]carbamoyl}pyridin-2-yl)phenyl 2-methylpropanoate (Example 47), trans-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl 2-methylpropanoate (Example 48) and 3-{4-[2-(4-hydroxy-3-methoxyphenyl)acetamido]pyridin-2-yl}phenyl 2-methylpropanoate hydrochloride (Example 49). (Section 28) The compound according to item 1, 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 (Example 1), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl cyclohexanecarboxylate (Example 2), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl(3-methylphenyl)acetate (Example 9), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl(2-chlorophenyl)acetate (Example 10), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl acetate (Example 12), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl(2-fluorophenyl)acetate (Example 15), cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl 2-methylpropanoate (Example 17), 2'-fluoro-5'-[2-(4-hydroxy-3-methoxyphenyl)acetamido][1,1'-biphenyl]-3-yl 2-methylpropanoate (Example 19), 3'-[2-(4-hydroxy-3-methoxyphenyl)acetamido][1,1'-biphenyl]-3-yl 2-methylpropanoate (Example 24), 3-{4-[2-(4-hydroxy-3-methoxyphenyl)acetamido]pyridin-2-yl}phenyl 2-methylpropanoate (Example 26), 3-(4-{[(4-hydroxy-3-methoxyphenyl)methyl]carbamoyl}pyridin-2-yl)phenyl 2-methylpropanoate (Example 46) and 3-{4-[2-(4-hydroxy-3-methoxyphenyl)acetamido]pyridin-2-yl}phenyl 2-methylpropanoate hydrochloride (Example 49). (Section 29) 29. A pharmaceutical comprising the compound according to any one of items 1 to 28 or a pharmaceutically acceptable salt thereof as an active ingredient. (Section 30) 29. A therapeutic or preventive agent for a disorder or disease involving TRPV1, comprising the compound according to any one of items 1 to 28 or a pharmaceutically acceptable salt thereof as an active ingredient. (Section 31) Item 31. The therapeutic or prophylactic agent according to Item 30, wherein the disorder or disease involving TRPV1 is dysphagia. (Section 32) 29. A pharmaceutical composition comprising the compound according to any one of items 1 to 28 or a pharmaceutically acceptable salt thereof. (Section 33) Item 33. The pharmaceutical composition according to Item 32, for treating or preventing a disorder or disease in which TRPV1 is involved. (Section 34) Item 33. The pharmaceutical composition according to Item 32, for treating or preventing dysphagia. (Section 35) A method for treating or preventing a disorder or disease in which TRPV1 is involved, comprising administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of the compound according to any one of items 1 to 28 or a pharmaceutically acceptable salt thereof. (Section 36) Use of the compound according to any one of items 1 to 28 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic or preventive agent for a disorder or disease in which TRPV1 is involved. (Section 37) Item 29. The compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 28 for use in treating or preventing a disorder or disease in which TRPV1 is involved. (Section 38) A pharmaceutical composition comprising a compound according to any one of items 1 to 28 or a pharmaceutically acceptable salt thereof in combination with one or more other drugs. (Section 39) A pharmaceutical composition comprising the compound according to any one of items 1 to 28 or a pharmaceutically acceptable salt thereof for treating or preventing a disorder or disease in which TRPV1 is involved, in combination with one or more other drugs.

[0013] It is contemplated that the present disclosure may provide one or more of the above-described features in combinations other than those explicitly stated. Still further embodiments and advantages of the present disclosure will be recognized by those skilled in the art upon reading and understanding the following detailed description, if necessary. [Effects of the Invention]

[0014] The compounds of the present disclosure exhibit TRPV1 agonism and are therefore useful as therapeutic agents for drug-induced dysphagia, dysphagia caused by neurodegenerative diseases such as Parkinson's disease, and dysphagia caused by a decline in the swallowing reflex due to various causes such as cerebrovascular disease and aging. [Brief explanation of the drawings]

[0015] [Figure 1]1 shows the swallowing improvement effect in a rat haloperidol-induced dysphagia model in Test Example 2. The vertical axis represents the number of swallows (times), shown as the mean ± standard error. The horizontal axis represents the group name (treatment drug). DETAILED DESCRIPTION OF THE INVENTION

[0016] The present disclosure will be described in more detail below. Throughout this specification, unless otherwise specified, singular expressions should be understood to include the plural concept. Thus, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, it should be understood that terms used in this specification are used in the sense commonly used in the art unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by those skilled in the art to which this invention belongs. In case of conflict, the present specification (including definitions) will prevail.

[0017] The number of substituents in a group defined as "optionally substituted" or "substituted" is not particularly limited as long as substitution is possible. In addition, unless otherwise specified, the description of each group also applies when that group is a part or substituent of another group.

[0018] The substituents in "optionally substituted" are selected from the following substituent group α, and may be substituted with 1 to 5 identical or different substituents. Although there are no particular limitations on the type of substituent, when the atom to which the substituent is bonded is an oxygen atom, a nitrogen atom, or a sulfur atom, the substituents listed below are limited to those to which the atom to which the substituent is bonded is a carbon atom. The substituent group α is 1) halogen atoms, 2) hydroxyl group, 3) carboxyl group, 4) a cyano group, 5) C 1-6 alkyl groups, 6) C 2-6alkenyl groups, 7) C 2-6 alkynyl groups, 8) C 1-6 alkoxy groups, 9) C 1-6 alkylthio groups, 10) C 1-6 alkylcarbonyl groups, 11)C 1-6 alkylsulfonyl groups, (However, each of the substituents 5) to 11) may be substituted with 1 to 5 identical or different substituents selected from the substituent group β.) 12)C 3-10 alicyclic group, 13)C 3-10 alicyclic oxy groups, 14)C 6-10 aryloxy groups, 15) 5- or 6-membered heteroaryloxy groups, 16) a 4- to 10-membered non-aryl heterocyclic oxy group, 17)C 3-10 alicyclic thio group, 18)C 6-10 arylthio groups, 19) 5- or 6-membered heteroarylthio groups, 20) 4- to 10-membered non-aryl heterocyclic thio group, 21)C 6-10 aryl groups, 22) 5- or 6-membered heteroaryl groups, 23) 4- to 10-membered non-aryl heterocyclic group, 24)C 3-10 alicyclic carbonyl groups, 25)C 6-10 arylcarbonyl groups, 26) a 5- or 6-membered heteroarylcarbonyl group, 27) 4- to 10-membered non-aryl heterocyclic carbonyl group, 28)C 3-10 alicyclic sulfonyl groups, 29)C 6-10 arylsulfonyl groups, 30) a 5- or 6-membered heteroarylsulfonyl group, 31) 4- to 10-membered non-aryl heterocyclic sulfonyl group, (However, each of the substituents in 12) to 31) is C 1-6 may be substituted with 1 to 5 identical or different substituents selected from alkyl groups and 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 OR 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 is a group consisting of The substituent group β is 1) halogen atoms, 2) hydroxyl group, 3) carboxyl group, 4) a cyano group, 5) C 3-10 alicyclic group, 6) C 1-6 alkoxy groups, 7) C 3-10 alicyclic oxy groups, 8) C 1-6 alkylthio groups, 9) a 5- or 6-membered heteroarylthio group, 10) C 6-10 aryl groups, 11) 5- or 6-membered heteroaryl groups, 12) a 4- to 10-membered non-aryl heterocyclic group, 13)C 1-6 alkylcarbonyl groups, 14)C 3-10 alicyclic carbonyl groups, 15)C 6-10 arylcarbonyl groups, 16) a 5- or 6-membered heteroarylcarbonyl group, 17) 4- to 10-membered 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, in the substituent group β, each of the substituents 5) to 17) is a halogen atom, a hydroxyl group, a cyano group, a carboxyl group, and -NR 18a R 18b and optionally 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 are each independently a hydrogen atom, a hydroxyl group, or C 1-6 Alkyl group or C 1-6 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 , R10p and R 10q and R 10r and R 10s and R 10t and R 10u and R 10v and R 10w and R 10x and R 10y and R 10z1 and R 10z2 and R 10z3 and R 11a and R 11b and R 11c and R 11d and R 11e and R 11f and R 11g and R 11h and R 11i and R 11j and R 11k and R 11l and R 11m and R 11n and R 11o and R 11p and R 11q and R 11r and 11s and R 11t and R 11u and R 11v and R 11w and R 12a and R 12b and R 12c and R 12d and R 12e and R 12f and R 12g and R 12h and R 12i and R 14 and R 15a and R 15b and R 15c and R 15d and R 15e and R 15f and R 15g and R 15h and R 15i and R 16a and R 16b and R 16c and R 16d and R 16e and R 16f and R 16g and R 16h and R 17a and R 17b and R 17c and R 17dare each independently a hydrogen atom or C 1-6 Alkyl groups (these groups include hydroxyl groups, cyano groups, C 1-6 Alkoxy groups and -NR 18a R 18b and optionally substituted with 1 to 3 substituents selected from the group consisting of R 18a and R 18b are each independently a hydrogen atom or C 1-6 It is an alkyl group.

[0019] Preferred examples of the substituent in "optionally substituted" include the following substituents. The substituent group α is preferably 1) halogen atoms, 2) hydroxyl group, 3) carboxyl group, 4) a cyano group, 5) C 1-6 alkyl groups, 6) C 1-6 alkoxy groups, 7) C 1-6 alkylthio groups, 8) C 1-6 alkylcarbonyl groups, (However, each of the substituents 5) to 8) may be substituted with 1 to 5 identical or different substituents selected from the substituent group β.) 9) C 3-10 alicyclic group, 10) C 3-10 alicyclic oxy groups, 11)C 6-10 aryloxy groups, 12) a 5- or 6-membered heteroaryloxy group, 13) a 4- to 10-membered non-aryl heterocyclic oxy group, 14)C 3-10 alicyclic thio group, 15)C 6-10 arylthio groups, 16) 5- or 6-membered heteroarylthio groups, 17) 4- to 10-membered non-aryl heterocyclic thio group, 18)C 6-10 aryl groups, 19) 5- or 6-membered heteroaryl groups, 20) 4- to 10-membered non-aryl heterocyclic group, 21)C 3-10 alicyclic carbonyl groups, 22)C 6-10 arylcarbonyl groups, 23) a 5- or 6-membered heteroarylcarbonyl group, 24) 4- to 10-membered non-aryl heterocyclic carbonyl group, (However, each of the substituents in 9) to 24) is C 1-6 may be substituted with 1 to 5 identical or different substituents selected from alkyl groups and 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-OR13a )R 10h , and 37)-C(=N-OR 13b )NR 10i R 11h is a group consisting of The substituent group β is preferably 1) halogen atoms, 2) hydroxyl group, 3) a cyano group, 4) C 3-10 alicyclic group, 5) C 1-6 alkoxy groups, 6) C 1-6 alkylthio groups, 7) a 5- or 6-membered heteroarylthio group, 8) a 5- or 6-membered heteroaryl group; 9) a 4- to 10-membered non-aryl heterocyclic group, 10) C 1-6 alkylcarbonyl groups, 11)C 3-10 alicyclic carbonyl groups, 12)C 6-10 arylcarbonyl groups, 13) a 5- or 6-membered heteroarylcarbonyl group, 14) a 4- to 10-membered 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 )R15g , 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, in the substituent group β, each of the substituents 4) to 14) is a halogen atom, a hydroxyl group, a cyano group, a carboxyl group, and -NR 18a R 18b and optionally 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 are each independently a hydrogen atom, a hydroxyl group, or C 1-6 Alkyl group or C 1-6 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 , R15h , R 16a , R 16b , R 16c , R 16d , R 16e , R 16f , R 16g , R 17a and R 17b are each independently a hydrogen atom or C 1-6 Alkyl groups (these groups include hydroxyl groups, cyano groups, C 1-6 Alkoxy groups and -NR 18a R 18b and optionally substituted with 1 to 3 substituents selected from the group consisting of R 18a , R 18b are each independently a hydrogen atom or C 1-6 It is an alkyl group.

[0020] More preferred substituents in the term "optionally substituted" include the following substituents. Substituent group α is more preferably 1) halogen atoms, 2) hydroxyl group, 3) a cyano group, 4) C 1-6 alkyl groups, 5) C 1-6 alkoxy groups, 6) C 1-6 alkylthio groups, 7) C 1-6 alkylcarbonyl groups, (However, each of the substituents 4) to 7) may be substituted with 1 to 5 identical or different substituents selected from the substituent group β.) 8) a 5- or 6-membered heteroaryloxy group, 9) a 4- to 10-membered non-aryl heterocyclic oxy group, 10) a 5- or 6-membered heteroarylthio group, 11) a 4- to 10-membered non-aryl heterocyclic thio group, 12)C 6-10 aryl groups, 13) 5- or 6-membered heteroaryl groups, 14) 4- to 10-membered non-aryl heterocyclic group, (However, each of the substituents 4) to 14) is C 1-6 may be substituted with 1 to 5 identical or different substituents selected from alkyl groups and 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 is a group consisting of The substituent group β is more preferably 1) halogen atoms, 2) hydroxyl group, 3) a 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)-NR 16f -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 is a group consisting of R 13a , R 13b , R 13c , R 13d , R 13e , R 13f , R 13g and R 13h are each independently a hydrogen atom, a hydroxyl group, or C 1-6 Alkyl group or C 1-6 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 , R15f , R 15g , R 15h , R 16a , R 16b , R 16c , R 16d , R 16e , R 16f , R 16g , R 17a and R 17b are each independently a hydrogen atom or C 1-6 Alkyl groups (these groups include hydroxyl groups, cyano groups, C 1-6 Alkoxy groups and -NR 18a R 18b and optionally substituted with 1 to 3 substituents selected from the group consisting of R 18a , R 18b are each independently a hydrogen atom or C 1-6 It is an alkyl group.

[0021] "C 1-6 " means that the number of carbon atoms is 1 to 6. The same applies to other numbers, for example, "C 1-4 " means that the number of carbon atoms is 1 to 4.

[0022] The term "heteroatom" refers to an oxygen atom, a nitrogen atom, a sulfur atom, or the like.

[0023] "Halogen atom" refers to any atom other than carbon and hydrogen atoms, including fluorine, chlorine, bromine, and iodine atoms. Of these, fluorine and chlorine atoms are preferred. "Halogen atom" may also be referred to as "halogen."

[0024] "C 1-6 Alkyl" or "C 1-6 The term "alkyl group" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. 1-6 The alkyl group is preferably "C 1-4 alkyl group," and more preferably "C 1-3 "C alkyl group" 1-3Specific examples of the "alkyl group" include methyl, ethyl, propyl, 1-methylethyl, etc. 1-4 Specific examples of the "alkyl group" include the above-mentioned "C 1-3 In addition to the specific examples of "alkyl group," butyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl, etc. are also included. 1-6 Specific examples of the "alkyl group" include the above-mentioned "C 1-4 In addition to the specific examples of the "alkyl group," examples include pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, hexyl, and the like.

[0025] "C 2-6 alkenyl" or "C 2-6 The term "alkenyl group" means a straight-chain 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 "C alkenyl group." 2-6 Specific examples of the "alkenyl group" include, but are not limited to, a vinyl group, a 1-propylenyl group, a 2-propylenyl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, a 2-methyl-1-propylenyl group, and a 2-methyl-2-propylenyl group.

[0026] "C 2-6 alkynyl" or "C 2-6 The term "alkynyl group" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group having 2 to 6 carbon atoms and one or more carbon-carbon triple bonds. 2-6 As the "alkynyl group", preferably "C 2-4 "Alkynyl group." "C 2-6Specific examples of the "alkynyl group" include, but are not limited to, an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 1-methyl-2-propynyl group, a 3-butynyl group, a 1-pentynyl group, and a 1-hexynyl group.

[0027] "C 3-10 The term "alicyclic group" refers to a monovalent, monocyclic or bicyclic non-aromatic hydrocarbon ring group having 3 to 10 carbon atoms, and includes groups having a partially unsaturated bond, a partially bridged structure, a partially spiro-bonded group, and one or more carbonyl structures. The term "alicyclic group" encompasses cycloalkyl groups, cycloalkenyl groups, and cycloalkynyl groups. 3-10 As the "alicyclic group", preferably "C 3-7 Alicyclic group”, more preferably “C 5-6 Alicyclic groups are examples of "C 5-6 Specific examples of the "alicyclic group" include cyclopentyl and cyclohexyl. 3-7 Specific examples of the "alicyclic group" include the above-mentioned "C 5-6 In addition to the specific examples of "alicyclic group," cyclopropyl, cyclobutyl, cycloheptyl, etc. are also included. 3-10 Specific examples of the "alicyclic group" include the above-mentioned "C 3-7 In addition to the specific examples of the "alicyclic group", cyclooctyl, cyclononyl, cyclodecyl, and adamantyl are also included.

[0028] "C" with a partially cross-linked structure 3-10 Specific examples of the "alicyclic group" include, but are not limited to, those having the structures shown below. [ka]

[0029] Also, "C 3-10 The "alicyclic group" also includes compounds in which an aromatic ring is condensed. Specific examples include the groups shown below. [ka]

[0030] "C 6-10 The term "aryl group" means a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 carbon atoms. 6-10 The "aryl group" may be fused with the "alicyclic group" or the "non-aryl heterocyclic group" described below at any possible position. 6-10 Specific examples of the "aryl group" include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group. 6-10 A preferred example of the "aryl group" is a phenyl group. Specific examples of the fused ring structure include the groups shown below. [ka] [ka]

[0031] The term "5- to 10-membered heteroaryl group" refers to a monocyclic or bicyclic aromatic heterocyclic group consisting of 5 to 10 atoms, including 1 to 4 atoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms. The "5- to 10-membered heteroaryl group" may be fused with the aforementioned "alicyclic group" or the "non-aryl heterocyclic group" described below at any possible position. Preferred examples of the "5- to 10-membered heteroaryl group" include a "6-membered heteroaryl group," a "5- or 6-membered heteroaryl group," a "6- to 10-membered heteroaryl group," and a "9- or 10-membered heteroaryl group." More preferred examples include a "6-membered heteroaryl group" and a "5- or 6-membered heteroaryl group." Specific examples of the "6-membered heteroaryl group" include a pyridyl group, a pyrazinyl group, a pyrimidinyl group, and a pyridazinyl group. Specific examples of "5- or 6-membered heteroaryl groups" include, for example, a furyl group, a thienyl group, a pyrrolyl group, a pyrazolyl group, an oxazolyl group, a thiazolyl group, an imidazolyl group, an isoxazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, and a pyridazinyl group. Specific examples of "6- to 10-membered heteroaryl groups" include a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, a quinoxalyl group, and a triazolopyridyl group. Specific examples of "5- to 10-membered heteroaryl groups" include the above-mentioned specific examples of "6- to 10-membered heteroaryl groups" and "5- or 6-membered heteroaryl groups."

[0032] Specific examples of the "9- or 10-membered heteroaryl group" include, but are not limited to, those with the structures shown below. [ka] [ka]

[0033] The "5- 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- to 10-membered non-aryl heterocycle. Specific examples include groups shown below. [ka] [ka] [ka]

[0034] The term "4- to 10-membered non-aryl heterocyclic group" refers to a monocyclic or bicyclic non-aromatic heterocyclic group consisting of 4 to 10 atoms, including, in addition to carbon atoms, 1 to 2 identical or different heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms. This includes those having a partially unsaturated bond, a partially bridged structure, and / or a partially spiro-substituted heterocyclic group. The "4- to 10-membered non-aryl heterocyclic group" is preferably a "4- to 7-membered non-aryl heterocyclic group." Specific examples of the "4- to 7-membered non-aryl heterocyclic group" include an azetidinyl group, a pyrrolidinyl group, a piperidyl group, a piperazinyl group, a morpholinyl group, an oxetanyl group, a tetrahydrofuranyl group, and a tetrahydropyranyl group. Preferred examples include an azetidinyl group, a pyrrolidinyl group, a piperidyl group, a morpholinyl group, and an oxetanyl group. The non-aryl heterocyclic group may form a fused ring with an aryl or heteroaryl. For example, C 6-10Non-aryl heterocycles also include those 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 the carbonyl groups, sulfinyl groups, and sulfonyl groups and the sulfur atoms of the thiocarbonyl groups are not included in the number of 4 to 10 members (ring size) and the number of heteroatoms constituting the ring. As the "4- to 10-membered non-aryl heterocycle," a "4- to 7-membered non-aryl heterocycle" is preferred. Specific examples of the "4- to 7-membered non-aryl heterocycle" include azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, oxetane, tetrahydrofuran, tetrahydropyran, etc. Specific examples of the "4- to 10-membered non-aryl heterocycle" include those exemplified above as specific examples of the "4- to 7-membered non-aryl heterocycle" as well as those having the structures shown below. [ka]

[0035] Specific examples of the "4- to 10-membered non-aryl heterocycle" having a partial bridge and / or spiro structure include, but are not limited to, those having the structures shown below. [ka]

[0036] Specific examples of the "four-membered non-aryl heterocycle" having a partial unsaturated bond include, but are not limited to, those having the structures shown below. [ka]

[0037] Specific examples of the "five-membered non-aryl heterocycle" having a partial unsaturated bond include, but are not limited to, those having the structures shown below. [ka]

[0038] Specific examples of the "five-membered non-aryl heterocycle" having a partially bridged structure include, but are not limited to, those having the structures shown below. [ka]

[0039] Specific examples of the "5-membered non-aryl heterocycle" containing carbonyl, thiocarbonyl, etc. include, but are not limited to, those having the structures shown below. [ka]

[0040] Specific examples of the "six-membered non-aryl heterocycle" having a partial unsaturated bond include, but are not limited to, those having the structures shown below. [ka]

[0041] Specific examples of the "six-membered non-aryl heterocycle" having a partially bridged structure include, but are not limited to, those having the structures shown below. [ka]

[0042] "C 1-6 Alkoxy" or "C 1-6 "Alkoxy group" means "C 1-6 "C alkyloxy" 1-6The "C alkyl" portion is 1-6 "C" is synonymous with "alkyl." 1-6 The "alkoxy" is preferably "C 1-4 Alkoxy" is preferred, and "C 1-3 "Alkoxy" is one example. 1-3 Specific examples of "alkoxy" include methoxy, ethoxy, propoxy, 1-methylethoxy, etc. 1-4 Specific examples of "alkoxy" include the above-mentioned "C 1-3 Al Koxi In addition to the specific examples of "C", butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, 2-methylpropoxy, etc. are also included. 1-6 Specific examples of "alkoxy" include the above-mentioned "C 1-4 Al Koxi In addition to the specific examples given above, examples include pentyloxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, and hexyloxy.

[0043] "C 3-7 Alicyclic oxy" or "C 3-7 The "alicyclic oxy group" means (C 3-7 means an alicyclic group)-O- group, 3-7 The alicyclic moiety is C 3-7 It is synonymous with alicyclic group. 3-7 Alicyclic oxy group" is "C 3-7 "Cycloalkoxy group" refers to "cycloalkyloxy", and the "cycloalkyl" portion has the same meaning as the above-mentioned "cycloalkyl". 3-7 Specific examples of the "alicyclic oxy group" include a cyclopropoxy group, a cyclobutoxy group, a cyclopentoxy group, and a cyclohexoxy group.

[0044] "C 6-10 Aryloxy group" C 6-10 The aryl moiety is C 6-10It is synonymous with aryl group. 6-10 The "aryloxy group" is preferably a "C6 or C 10 "Aryloxy groups of C 6-10 Specific examples of the "aryloxy group" include, but are not limited to, a phenoxy group, a 1-naphthyloxy group, and a 2-naphthyloxy group.

[0045] The 5- or 6-membered heteroaryl moiety of the "5- or 6-membered heteroaryloxy group" has the same meaning as the above "5-membered heteroaryl group" or "6-membered heteroaryl group." Specific examples of the "5- or 6-membered heteroaryloxy group" include, but are not limited to, a pyrazolyloxy group, a triazolyloxy group, a thiazoyloxy group, a thiadiazoyloxy group, a pyridyloxy group, and a pyridazoyloxy group.

[0046] The 4- to 10-membered non-aryl heterocyclic moiety of the "4- to 10-membered non-aryl heterocyclic oxy group" has the same meaning as the above-mentioned "4- to 10-membered non-aryl heterocyclic ring". The "4- to 10-membered non-aryl heterocyclic oxy group" is preferably a "4- to 6-membered non-aryl heterocyclic oxy group". Specific examples of the "4- to 10-membered non-aryl heterocyclic oxy group" include, but are not limited to, a tetrahydrofuranyloxy group, a tetrahydropyranyloxy group, an azetidinyloxy group, a pyrrolidinyloxy group, and a piperidinyloxy group.

[0047] "C 1-6 Alkylthio group C 1-6 The alkyl portion is the C 1-6 It is synonymous with alkyl. 1-6 As the "alkylthio group," preferably "C 1-4 alkylthio group," and more preferably "C 1-3 "C alkylthio group." 1-6Specific examples of the "alkylthio group" include, but are not limited to, a methylthio group, an ethylthio group, a propylthio group, a butylthio group, an isopropylthio group, an isobutylthio group, a tert-butylthio group, a sec-butylthio group, an isopentylthio group, a neopentylthio group, a tert-pentylthio group, and a 1,2-dimethylpropylthio group.

[0048] "C 3-10 Alicyclic thio" or "C 3-10 The "alicyclic thio group" is (C 3-10 means an alicyclic group)-S- group, 3-10 The alicyclic moiety is C 3-10 It is synonymous with alicyclic group. 3-10 As the "alicyclic thio group", preferably "C 3-6 "C" is an alicyclic thio group. 3-6 Specific examples of the "alicyclic thio group" include, but are not limited to, a cyclopropylthio group, a cyclobutylthio group, a cyclopentylthio group, a cyclohexylthio group, and the like.

[0049] "C 6-10 arylthio" or "C 6-10 Arylthio group" C 6-10 The aryl moiety is C 6-10 It is synonymous with aryl group. 6-10 The "arylthio group" is preferably "C6 or C 10 "Arylthio groups of C" 6-10 Aryl Thio Specific examples of the "group" include, but are not limited to, a phenylthio group, a 1-naphthylthio group, and a 2-naphthylthio group.

[0050] The 5- or 6-membered heteroaryl moiety of the "5- or 6-membered heteroarylthio" or "5- or 6-membered heteroarylthio group" has the same meaning as the above "5-membered heteroaryl group" or "6-membered heteroaryl group." Specific examples of the "5- or 6-membered heteroarylthio group" include, but are not limited to, a pyrazoylthio group, a triazoylthio group, a thiazoylthio group, a thiadiazoylthio group, a pyridylthio group, and a pyridazoylthio group.

[0051] The 4- to 10-membered non-aryl heterocyclic moiety of the "4- to 10-membered non-aryl heterocyclic thio" or "4- to 10-membered non-aryl heterocyclic thio group" has the same meaning as the above-mentioned "4- to 10-membered non-aryl heterocyclic group." The "4- to 10-membered non-aryl heterocyclic thio group" is preferably a "4- to 6-membered non-aryl heterocyclic thio group." Specific examples of the "4- to 10-membered non-aryl heterocyclic thio group" include, but are not limited to, a tetrahydropyranylthio group, a piperidinylthio group, and the like.

[0052] "C 1-6 Alkylcarbonyl" or "C 1-6 The "alkylcarbonyl group" is the same as the above "C 1-6 "C" means a carbonyl group substituted with an "alkyl group." 1-6 As the "alkylcarbonyl group," preferably, "C 1-4 Alkylcarbonyl group" or "C 1-3 "C alkylcarbonyl group." 1-6 Specific examples of the "alkylcarbonyl group" include, but are not limited to, an acetyl group, a propionyl group, and a butyryl group.

[0053] "C 1-6 Alkoxycarbonyl" or "C 1-6 The "alkoxycarbonyl group" means the above "C 1-6 "C" means a carbonyl group substituted with an "alkoxy group." 1-6 As the "alkoxycarbonyl group," preferably, "C 1-4 Alkoxycarbonyl group" or "C 1-3"Alkoxycarbonyl group." "C 1-6 Specific examples of the "alkoxycarbonyl group" include, but are not limited to, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, and a butoxycarbonyl group.

[0054] "C 3-10 Alicyclic carbonyl" or "C 3-10 The "alicyclic carbonyl group" is the same as the above "C 3-10 "C" means a carbonyl group substituted with an "alicyclic group." 3-10 As the "alicyclic carbonyl group," preferably, "C 3-6 "C" is an alicyclic carbonyl group. 3-10 Specific examples of the "alicyclic carbonyl group" include, but are not limited to, a cyclopropylcarbonyl group, a cyclopentylcarbonyl group, and the like.

[0055] "C 6-10 arylcarbonyl" or "C 6-10 The "arylcarbonyl group" is the same as the above "C 6-10 "C" means a carbonyl group substituted with an "aryl group." 6-10 The "arylcarbonyl group" is preferably a "C or C 10 "C" is an arylcarbonyl group. 6-10 Specific examples of the "arylcarbonyl group" include, but are not limited to, a benzoyl group, a 1-naphthylcarbonyl group, a 2-naphthylcarbonyl group, and the like.

[0056] The term "5- or 6-membered heteroarylcarbonyl" or "5- or 6-membered heteroarylcarbonyl group" refers to a carbonyl group substituted with the above-mentioned "5- or 6-membered heteroaryl group". Specific examples of the "5- or 6-membered heteroarylcarbonyl group" include, but are not limited to, a pyrazoylcarbonyl group, a triazoylcarbonyl group, a thiazoylcarbonyl group, a thiadiazoylcarbonyl group, a pyridylcarbonyl group, and a pyridazoylcarbonyl group.

[0057] The term "4- to 10-membered non-aryl heterocyclic carbonyl" or "4- to 10-membered non-aryl heterocyclic carbonyl group" refers to a carbonyl group substituted with the above-mentioned "4- to 10-membered non-aryl heterocyclic group". The "4- to 10-membered non-aryl heterocyclic carbonyl group" is preferably a "4- to 6-membered non-aryl heterocyclic carbonyl group". Specific examples of the "4- to 10-membered non-aryl heterocyclic carbonyl group" include, but are not limited to, an azetidinylcarbonyl group, a pyrrolidinylcarbonyl group, a piperidinylcarbonyl group, a morpholinylcarbonyl group, and the like.

[0058] "C 1-6 Alkylsulfonyl" or "C 1-6 The "alkylsulfonyl group" is the same as the above "C 1-6 "C" means a sulfonyl group substituted with an alkyl group. 1-6 As the "alkylsulfonyl group", preferably "C 1-4 "C alkylsulfonyl group." 1-6 Specific examples of the "alkylsulfonyl group" include, but are not limited to, a methylsulfonyl group, a propionylsulfonyl group, a butyrylsulfonyl group, and the like.

[0059] "C 3-10 Alicyclic sulfonyl" or "C 3-10 The "alicyclic sulfonyl group" means the above "C 3-10 "C" means a sulfonyl group substituted with an "alicyclic group." 3-10 As the "alicyclic sulfonyl group", preferably "C 3-6 "C" is an alicyclic sulfonyl group. 3-10 Specific examples of the "alicyclic sulfonyl group" include, but are not limited to, a cyclopropylsulfonyl group, a cyclobutylsulfonyl group, a cyclopentylsulfonyl group, a cyclohexylsulfonyl group, and the like.

[0060] "C 6-10 arylsulfonyl" or "C 6-10 The "arylsulfonyl group" is the same as the above "C 6-10 "C" means a sulfonyl group substituted with an "aryl group." 6-10The "arylsulfonyl group" is preferably "C6 or C 10 "C is an arylsulfonyl group. 6-10 Specific examples of the "arylsulfonyl group" include, but are not limited to, a phenylsulfonyl group, a 1-naphthylsulfonyl group, a 2-naphthylsulfonyl group, and the like.

[0061] The term "5- or 6-membered heteroarylsulfonyl" or "5- or 6-membered heteroarylsulfonyl group" refers to a sulfonyl group substituted with the above-mentioned "5- or 6-membered heteroaryl group". Specific examples of the "5- or 6-membered heteroarylsulfonyl group" include, but are not limited to, a pyrazoylsulfonyl group, a triazoylsulfonyl group, a thiazoylsulfonyl group, a thiadiazoylsulfonyl group, a pyridylsulfonyl group, and a pyridazoylsulfonyl group.

[0062] 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 examples of Q, X, and Y are as follows, but the technical scope of the present disclosure is not limited to the range of compounds listed below.

[0063] R 1 A preferred embodiment of is a hydrogen atom.

[0064] R 2 A preferred embodiment of is a methoxy group.

[0065] R 3 A preferred embodiment of is a hydrogen atom.

[0066] R 4 A preferred embodiment of the formula 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 groups and C 6-10 The aryl group contains fluorine atoms, chlorine atoms, C 1-6 Alkyl group, C 3-7 Alicyclic group, C 6-10 and the like. The aryl group may be substituted with 1 to 3 identical or different substituents 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.

[0067] R 4 More preferred embodiments of the above include 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 The alkyl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl groups.

[0068] R 4 In a more preferred embodiment, the alkyl group is a methyl group, an ethyl group, an isopropyl group, a cyclohexyl group, or a phenyl group (the methyl group, the ethyl group, the isopropyl group, the cyclohexyl group, and the phenyl group are each independently selected from the group consisting of a fluorine atom, a chlorine atom, and a C 1-6 The alkyl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl groups.

[0069] R 5 , R 6 and R 7 Preferred embodiments of the group include a hydrogen atom, C 3-6 Alicyclic group or C 1-6 Alkyl group (C 3-6 Alicyclic groups and C 1-6 The alkyl group is a halogen atom, a hydroxyl group, a C 1-6Alkoxy group, C 3-10 Alicyclic group, C 6-10 and the aryl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of aryl groups and 4- to 6-membered non-aryl heterocyclic groups.

[0070] R 8 , R 9 and R 10 Preferred embodiments of the group include a hydrogen atom, a halogen atom, a cyano group, and C 1-6 Alkylsulfonyl group, C 1-6 Alkyl group or C 1-6 Examples include alkoxy groups.

[0071] R 11 Preferred embodiments of the group include 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 group, C 1-3 Alkylcarbonyl group, C 1-4 Alkoxycarbonyl group and C 6-10 The arylcarbonyl group is a group containing halogen atoms, hydroxyl groups, cyano groups, C 1-6 Alkyl group, C 1-6 Alkylsulfonyl group, C 1-6 Alkoxy group, C 3-7 Alicyclic group, C 3-10 Alicyclic oxy group, C 6-10 Aryl group, 4- to 10-membered non-aryl heterocyclic group, 4- to 10-membered non-aryl heterocyclic oxy group, C 6-10 and the like. The aryloxy group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of an aryloxy group, a 5- or 6-membered heteroaryl group, and a 5- or 6-membered heteroaryloxy group.

[0072] R 12 In a preferred embodiment, 1-3 Alkyl group (C 1-3 The alkyl group is a halogen atom, a hydroxyl group, a cyano group, a C 1-6Alkyl group, C 1-6 Alkylsulfonyl group, C 1-6 Alkoxy group, C 3-7 Alicyclic group, C 3-10 Alicyclic oxy group, C 6-10 Aryl group, 4- to 10-membered non-aryl heterocyclic group, 4- to 10-membered non-aryl heterocyclic oxy group, C 6-10 and the like. The aryloxy group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of an aryloxy group, a 5- or 6-membered heteroaryl, and a 5- or 6-membered heteroaryloxy group.

[0073] Preferred embodiments of m include 1 or 2.

[0074] A more preferred embodiment of m is 1.

[0075] Preferred embodiments of n include 0, 1, 2, and 3.

[0076] More preferred embodiments of n include 0, 1, and 2.

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

[0078] L 1 Preferred embodiments of the above 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-.

[0079] L 1 More preferred embodiments include -NH-C(=O)- or -C(=O)-NH-.

[0080] L 2 A preferred embodiment of is a single bond.

[0081] A preferred embodiment of Q is a single bond.

[0082] A preferred embodiment of X is C 6-10 an aryl group or a 5- to 10-membered heteroaryl group (the C 6-10 The aryl group and the 5- to 10-membered heteroaryl group are substituted with a halogen atom, a hydroxyl group, a cyano group, a C 1-6 Alkyl group, C 1-6 Alkylsulfonyl group, C 1-6 Alkoxy group, C 3-7 Alicyclic group, C 3-10 Alicyclic oxy group, C 6-10 Aryl group, 4- to 10-membered non-aryl heterocyclic group, 4- to 10-membered non-aryl heterocyclic oxy group, C 6-10 and the like. The aryloxy group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of an aryloxy group, a 5- or 6-membered heteroaryl group, and a 5- or 6-membered heteroaryloxy group.

[0083] More preferred embodiments of X include a phenyl group or a 6-membered heteroaryl group (the phenyl group and the 6-membered heteroaryl group are each independently selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a C 1-6 Alkyl group, C 1-6 Alkylsulfonyl group, C 1-6 Alkoxy group, C 3-7 Alicyclic group, C 3-10 Alicyclic oxy group, C 6-10 Aryl group, 4- to 10-membered non-aryl heterocyclic group, 4- to 10-membered non-aryl heterocyclic oxy group, C 6-10 and the like. The aryloxy group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of an aryloxy group, a 5- or 6-membered heteroaryl group, and a 5- or 6-membered heteroaryloxy group.

[0084] More preferred embodiments of X include the following formulae (A1), (A2) and (A3). [ka] (Wherein * is L 1represents the bonding position with Q or Y, and ** represents the bonding position with Q or Y.

[0085] A preferred embodiment of Y is C 6-10 an aryl group, a 5- to 10-membered heteroaryl group, or C 3-7 Alicyclic group (the C 6-10 Aryl groups, 5- to 10-membered heteroaryl groups and C 3-7 Alicyclic groups include halogen atoms, hydroxyl groups, cyano groups, C 1-6 Alkyl group, C 1-6 Alkylsulfonyl group, C 1-6 Alkoxy group, C 3-7 Alicyclic group, C 3-10 Alicyclic oxy group, C 6-10 Aryl group, 4- to 10-membered non-aryl heterocyclic group, 4- to 10-membered non-aryl heterocyclic oxy group, C 6-10 and the like. The aryloxy group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of an aryloxy group, a 5- or 6-membered heteroaryl group, and a 5- or 6-membered heteroaryloxy group.

[0086] A more preferred embodiment of Y is a phenyl group or a cyclohexyl group (the phenyl group and the cyclohexyl group are not substituted with a halogen atom, a hydroxyl group, a cyano group, a C 1-6 Alkyl group, C 1-6 Alkylsulfonyl group, C 1-6 Alkoxy group, C 3-7 Alicyclic group, C 3-10 Alicyclic oxy group, C 6-10 Aryl group, 4- to 10-membered non-aryl heterocyclic group, 4- to 10-membered non-aryl heterocyclic oxy group, C 6-10 and the like. The aryloxy group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of an aryloxy group, a 5- or 6-membered heteroaryl group, and a 5- or 6-membered heteroaryloxy group.

[0087] More preferred embodiments of Y include the following formulae (B) and (C). [ka] (In the formula, * represents the bonding position with X or Q, and ** represents L 2 or the bond position with the oxygen atom)

[0088] One embodiment of the compound represented by formula (1) is the following (A). (A) R 1 is a hydrogen atom, R 2 is a methoxy group, R 3 is a hydrogen atom, 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 groups and C 6-10 The aryl group contains fluorine atoms, chlorine atoms, C 1-6 Alkyl group, C 3-7 Alicyclic group, C 6-10 optionally substituted with 1 to 3 identical or different substituents 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; 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 -OC(=O)-NH-, L 2 is a single bond or an optionally substituted C 1-6 is an alkyl group, Q is a single bond, X is C 6-10 an aryl group or a 5- to 10-membered heteroaryl group (the C 6-10 The aryl group and the 5- to 10-membered heteroaryl group are substituted with a halogen atom, a hydroxyl group, a cyano group, a C 1-6 Alkyl group, C1-6 Alkylsulfonyl group, C 1-6 Alkoxy group, C 3-7 Alicyclic group, C 3-10 Alicyclic oxy group, C 6-10 Aryl group, 4- to 10-membered non-aryl heterocyclic group, 4- to 10-membered non-aryl heterocyclic oxy group, C 6-10 optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of an aryloxy group, a 5- or 6-membered heteroaryl group, and a 5- or 6-membered heteroaryloxy group; Y is C 6-10 an aryl group, a 5- to 10-membered heteroaryl group, or C 3-7 Alicyclic group (the C 6-10 Aryl groups, 6-membered heteroaryl groups and C 3-7 Alicyclic groups include halogen atoms, hydroxyl groups, cyano groups, C 1-6 Alkyl group, C 1-6 Alkylsulfonyl group, C 1-6 Alkoxy group, C 3-7 Alicyclic group, C 3-10 Alicyclic oxy group, C 6-10 Aryl group, 4- to 10-membered non-aryl heterocyclic group, 4- to 10-membered non-aryl heterocyclic oxy group, C 6-10 optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of an aryloxy group, a 5- or 6-membered heteroaryl group, and a 5- or 6-membered heteroaryloxy group; wherein X and Y are attached to carbon atoms on their respective rings. The compound or a pharmaceutically acceptable salt thereof.

[0089] One embodiment of the compound represented by formula (1) is the following (B). (B) R 1 is a hydrogen atom, R 2 is a methoxy group, R 3 is a hydrogen atom, R 4 But C 1-6 Alkyl group, C 3-7Alicyclic group or C 6-10 Aryl group (the C 1-6 Alkyl group, C 3-7 Alicyclic groups and C 6-10 The aryl group contains fluorine atoms, chlorine atoms, C 1-6 Alkyl group, C 3-7 Alicyclic group, C 6-10 optionally substituted with 1 to 3 identical or different substituents 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; m is 1 or 2; 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 C 6-10 an aryl group or a 5- to 10-membered heteroaryl group (the C 6-10 The aryl group and the 5- to 10-membered heteroaryl group are substituted with a halogen atom, a hydroxyl group, a cyano group, a C 1-6 Alkyl group, C 1-6 Alkylsulfonyl group, C 1-6 Alkoxy group, C 3-7 Alicyclic group, C 3-10 Alicyclic oxy group, C 6-10 Aryl group, 4- to 10-membered non-aryl heterocyclic group, 4- to 10-membered non-aryl heterocyclic oxy group, C 6-10 optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of an aryloxy group, a 5- or 6-membered heteroaryl group, and a 5- or 6-membered heteroaryloxy group; Y is C 6-10 an aryl group, a 5- to 10-membered heteroaryl group, or C 3-7 Alicyclic group (the C 6-10 Aryl groups, 5- to 10-membered heteroaryl groups and C 3-7 Alicyclic groups include halogen atoms, hydroxyl groups, cyano groups, C 1-6 Alkyl group, C 1-6 Alkylsulfonyl group, C 1-6 Alkoxy group, C 3-7Alicyclic group, C 3-10 Alicyclic oxy group, C 6-10 Aryl group, 4- to 10-membered non-aryl heterocyclic group, 4- to 10-membered non-aryl heterocyclic oxy group, C 6-10 optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of an aryloxy group, a 5- or 6-membered heteroaryl group, and a 5- or 6-membered heteroaryloxy group; wherein X and Y are attached to carbon atoms on their respective rings. The compound or a pharmaceutically acceptable salt thereof.

[0090] One embodiment of the compound represented by formula (1) is the following (C). (C) R 1 is a hydrogen atom, R 2 is a methoxy group, R 3 is a hydrogen atom, 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 groups and C 6-10 The aryl group contains fluorine atoms, chlorine atoms, C 1-6 Alkyl group, C 3-7 Alicyclic group, C 6-10 optionally substituted with 1 to 3 identical or different substituents 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; 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 not limited to halogen atoms, hydroxyl groups, cyano groups, C 1-6 Alkyl group, C 1-6 Alkylsulfonyl group, C 1-6 Alkoxy group, C 3-7 Alicyclic group, C 3-10 Alicyclic oxy group, C 6-10 Aryl group, 4- to 10-membered non-aryl heterocyclic group, 4- to 10-membered non-aryl heterocyclic oxy group, C 6-10 optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of an aryloxy group, a 5- or 6-membered heteroaryl group, and a 5- or 6-membered heteroaryloxy group; Y is a phenyl group or a cyclohexyl group (the phenyl group and the cyclohexyl group are not substituted with a halogen atom, a hydroxyl group, a cyano group, a C 1-6 Alkyl group, C 1-6 Alkylsulfonyl group, C 1-6 Alkoxy group, C 3-7 Alicyclic group, C 3-10 Alicyclic oxy group, C 6-10 Aryl group, 4- to 10-membered non-aryl heterocyclic group, 4- to 10-membered non-aryl heterocyclic oxy group, C 6-10 optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of an aryloxy group, a 5- or 6-membered heteroaryl group, and a 5- or 6-membered heteroaryloxy group; wherein X and Y are attached to carbon atoms on their respective rings. The compound or a pharmaceutically acceptable salt thereof.

[0091] One embodiment of the compound represented by formula (1) is the following (D). (D) R 1 is a hydrogen atom, R 2 is a methoxy group, R 3 is a hydrogen atom, R 4 But C 1-6 Alkyl group, C3-7 Alicyclic group or C 6-10 Aryl group (the C 1-6 Alkyl group, C 3-7 Alicyclic groups and C 6-10 The aryl group contains fluorine atoms, chlorine atoms, C 1-6 Alkyl group, C 3-7 Alicyclic group, C 6-10 optionally substituted with 1 to 3 identical or different substituents 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; 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 pyridyl group (the phenyl group and the pyridyl group are not substituted with a halogen atom, a hydroxyl group, a cyano group, a C 1-6 Alkyl group, C 1-6 Alkylsulfonyl group, C 1-6 Alkoxy group, C 3-7 Alicyclic group, C 3-10 Alicyclic oxy group, C 6-10 Aryl group, 4- to 10-membered non-aryl heterocyclic group, 4- to 10-membered non-aryl heterocyclic oxy group, C 6-10 optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of an aryloxy group, a 5- or 6-membered heteroaryl group, and a 5- or 6-membered heteroaryloxy group; Y is a phenyl group or a cyclohexyl group (the phenyl group and the cyclohexyl group are not substituted with a halogen atom, a hydroxyl group, a cyano group, a C 1-6 Alkyl group, C 1-6 Alkylsulfonyl group, C 1-6 Alkoxy group, C 3-7 Alicyclic group, C 3-10 Alicyclic oxy group, C 6-10 Aryl group, 4- to 10-membered non-aryl heterocyclic group, 4- to 10-membered non-aryl heterocyclic oxy group, C 6-10optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of an aryloxy group, a 5- or 6-membered heteroaryl group, and a 5- or 6-membered heteroaryloxy group; wherein X and Y are attached to carbon atoms on their respective rings. The compound or a pharmaceutically acceptable salt thereof.

[0092] One embodiment of the compound represented by formula (1) is the following (E). (E) R 1 is a hydrogen atom, R 2 is a methoxy group, R 3 is a hydrogen atom, 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 groups and C 6-10 The aryl group contains fluorine atoms, chlorine atoms, C 1-6 Alkyl group, C 3-7 Alicyclic group, C 6-10 optionally substituted with 1 to 3 identical or different substituents 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; 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 the following formula (A), [ka] (Wherein * is L 1 represents the bonding position with Y, and ** represents the bonding position with Y. a is CR8 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, C 1-6 Alkyl group or C 1-6 is an alkoxy group, Y is the following formula (B) or (C): [ka] (In the formula, * represents the bonding position to X, and ** represents the bonding position to the oxygen atom.) The compound or a pharmaceutically acceptable salt thereof.

[0093] One embodiment of the compound represented by formula (1) is the following (F). (F) R 1 is a hydrogen atom, R 2 is a methoxy group, R 3 is a hydrogen atom, R 4 However, 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 not fluorine atoms, chlorine atoms, and C 1-6 alkyl groups, each of which may be the same or different, and which may be substituted with 1 to 3 substituents selected from the group consisting of 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 represented by the following formula (A1), (A2) or (A3): [ka] (Wherein * is L 1 represents the bonding position with Y, and ** represents the bonding position with Y. Y is the following formula (B) or (C): [ka] (In the formula, * represents the bonding position to X, and ** represents the bonding position to the oxygen atom.) The compound or a pharmaceutically acceptable salt thereof.

[0094] One embodiment of the compound represented by formula (1) is the following (G). (G) R 1 is a hydrogen atom, R 2 is a methoxy group, R 3 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 do not contain fluorine atoms, chlorine atoms and C 1-6 and optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl groups; m is 1, n is 0, 1, 2 or 3; L 1 is -NH-C(=O)-, -C(=O)-NH-, L 2 is a single bond, Q is a single bond, X is represented by the following formula (A1), (A2) or (A3): [ka] (Wherein * is L 1 represents the bonding position with Y, and ** represents the bonding position with Y. Y is the following formula (B) or (C): [ka] (In the formula, * represents the bonding position to X, and ** represents the bonding position to the oxygen atom.) The compound or a pharmaceutically acceptable salt thereof.

[0095] "Pharmaceutically acceptable salts" include acid addition salts and base addition salts. For example, acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, and phosphate, and organic acid salts such as citrate, oxalate, phthalate, fumarate, maleate, succinate, malate, acetate, formate, propionate, benzoate, trifluoroacetate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, and camphorsulfonate. Base addition salts include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, barium salt, and aluminum salt, and 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-dibenzylethylamine. 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.

[0096] Suitable salts of the starting 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, p-toluenesulfonate, etc.) and inorganic acid salts (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.); salts with amino acids (e.g., arginine, aspartic acid, glutamic acid, etc.); metal salts such as alkali metal salts (e.g., sodium salt, potassium salt, etc.) and alkaline earth metal salts (e.g., calcium salt, magnesium salt, etc.); ammonium salts; and organic base salts (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), which can be appropriately selected by those skilled in the art.

[0097] 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 may be purified as is, or if it is obtained in the free form, it may be dissolved or suspended in an appropriate organic solvent, and an acid or a base may be added to form a salt by a conventional method.

[0098] In the present invention, deuterium conversion products in which one or more 1H of the compound represented by formula (1) is converted to 2H(D) are also encompassed by the compound represented by formula (1).

[0099] The present invention includes a compound represented by formula (1) or a pharmaceutically acceptable salt thereof. The compound of the present invention may also exist in the form of a hydrate and / or a solvate with various solvents (such as an ethanolate), and these hydrates and / or solvates are also included in the compound of the present invention. Furthermore, the present invention also includes all tautomers, all existing stereoisomers, and all crystalline forms of compound (1) of the present invention, as well as mixtures thereof.

[0100] Compound (1) of the present invention may exist in the form of optical isomers based on optically active centers, atropisomers based on axial or planar chirality resulting from restricted intramolecular rotation, other stereoisomers, tautomers, geometric isomers, and the like. All possible isomers, including these, and mixtures thereof, are included within the scope of the present invention.

[0101] In particular, optical isomers and atropisomers can be obtained as racemates, or as optically active isomers when optically active starting materials or intermediates are used. If necessary, at an appropriate stage in the production process described below, the racemates of the corresponding starting materials, intermediates, or final products can be physically or chemically resolved into their optical antipodes by known separation methods such as a method using an optically active column or fractional crystallization. Specifically, for example, in the diastereomeric method, two diastereomers are formed from a racemate by reaction with an optically active resolving agent. These different diastereomers generally have different physical properties and can be resolved by known methods such as fractional crystallization.

[0102] Methods for producing the compounds of the present disclosure are described below, but the methods for producing the compounds of the present disclosure are not limited to these.

[0103] The compounds of the present disclosure can be produced, for example, by the production methods described below, but are not limited thereto. These production methods can be appropriately improved based on the knowledge of those skilled in organic synthetic chemistry. In the production methods described below, the compounds used as raw materials may be used in the form of salts thereof, as long as they do not interfere with the reaction.

[0104] In the following production methods, even if the use of a protecting group is not specifically specified, if any functional group other than the reactive site changes under the reaction conditions or if it is not suitable for post-reaction treatment, the target compound can be obtained by protecting the site other than the reactive site as necessary and deprotecting it after the reaction or a series of reactions. Protective groups used in these processes are listed in the literature (TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3 rd Ed., John Wiley and Sons, Inc., New York (1999)) can be used. Introduction and removal of the protecting group can be carried out by a method commonly used in organic synthetic chemistry (for example, the method described in the above-mentioned literature) or a method based thereon.

[0105] The starting materials and intermediates in the following production methods are commercially available or can be obtained by synthesis from known compounds according to known methods or methods described in known literature. Furthermore, salts of these starting materials and intermediates may be used as long as they do not interfere with the reaction.

[0106] The intermediates and target compounds in the following production methods can also be converted into other compounds included in the present disclosure by appropriately converting their functional groups. The conversion of functional groups in this case can be carried out by a method commonly used in organic synthetic chemistry (for example, RC Larock, "Comprehensive Organic Transformations", 2 nd Ed., John Wiley and Sons, Inc., New York (1999), or a method similar thereto.

[0107] In the following production methods, an inert solvent means a solvent that does not react with the raw materials, reagents, bases, acids, catalysts, ligands, etc. used in the reaction (hereinafter, sometimes referred to as "raw materials, etc. used in the reaction"). Even if the solvent used in each step reacts with the raw materials, etc. used in the reaction, it can be used as an inert solvent as long as the target reaction proceeds and the target compound is obtained.

[0108] The compound of the present disclosure represented by formula (1) can be produced, for example, by the following production methods 1 to 5.

[0109] Manufacturing method 1 Among the compounds represented by formula (1), the compound represented by formula [A1] can be produced, for example, by the following production method. [ka]

[0110] (In the formula, R 41 and R 42 are the same or different and R 4 and L 3 is -NH-C(=O)- or -C(=O)-NH-, and R 2 , R 3 , R 4 , X and Y have the same meaning as in Item 1.)

[0111] [Step 1-1: Condensation reaction] Compound a5 is produced by reacting compound a1 with compound a2 in an appropriate solvent in the presence or absence of various condensing agents and / or bases. Various condensing agents commonly used in conventional methods can be used as the condensing agent, but propiophosphonic anhydride or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (including hydrochloride) is preferred. The base is appropriately selected from the bases exemplified below, but preferably diisopropylethylamine or triethylamine is preferred. The solvent is appropriately selected from the solvents exemplified below, but preferably 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.

[0112] [Step 1-2: Condensation reaction] Compound a5 is produced by reacting compound a3 with compound a4 in an appropriate solvent in the presence or absence of various condensing agents and / or bases. Various condensing agents commonly used in conventional methods can be used as the condensing agent, but propiophosphonic anhydride or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (including hydrochloride) is preferred. The base is appropriately selected from the bases exemplified below, but preferably diisopropylethylamine or triethylamine is preferred. The solvent is appropriately selected from the solvents exemplified below, but preferably 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.

[0113] [Step 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, salts thereof, complexes thereof, and catalysts supported on carriers such as polymers. The base may be appropriately selected from the bases exemplified below, with preferred examples being sodium carbonate and potassium carbonate. The solvent may be appropriately selected from the solvents exemplified below, with preferred examples being a mixed solvent of 1,2-dimethoxyethane and water. The reaction time is usually 5 minutes to 72 hours, and preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, and preferably 20°C to 150°C. The reaction temperature is usually 0°C to 200°C, and preferably 0°C to 100°C.

[0114] [Step 1-4: Condensation reaction] Compound a12 is produced by reacting compound a8 with compound a9, a10, or a11 in an appropriate solvent in the presence or absence of various condensing agents and / or bases. Various condensing agents commonly used in conventional methods can be used as the condensing agent, but 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (including hydrochloride) is preferred. The base is appropriately selected from the bases exemplified below, but preferably diisopropylethylamine or triethylamine is preferred. The solvent is appropriately selected from the solvents exemplified below, but preferably 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.

[0115] [Step 1-5: Debenzylation Reaction] Compound A1 is produced by reducing compound a12 in the presence of a catalyst. Examples of the reducing agent that can be used include hydrogen, formic acid salts such as ammonium formate, and hydrazine. Examples of the catalyst include transition metals such as palladium, nickel, rhodium, cobalt, and platinum, as well as salts thereof, complexes thereof, and catalysts supported on carriers such as polymers. Examples of the solvent are appropriately selected from the solvents exemplified below, and preferred examples include ethyl acetate, ethanol, and methanol. The reaction time is usually 5 minutes to 72 hours, and preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, and preferably 0°C to 100°C.

[0116] Compound a1 may be commercially available or may be produced according to known methods, such as those described in ACS Chem Neurosci. 2018, 9, 587-602.

[0117] Compound a3 may be commercially available or may be produced according to known methods, such as those described in Nature Commun. 2018, 9, 4123, etc.

[0118] Manufacturing method 2 Among the compounds represented by formula (1), the compound represented by formula [A2] can be produced, for example, by the following production method. [ka]

[0119] (In the formula, R 41 and R 42 are the same or different and R 4 and L 3 is -NH-C(=O)- or -C(=O)-NH-, and R 2 , R 3 , R 4 , X and Y have the same meaning as in Item 1.)

[0120] [Step 2-1: Debenzylation Reaction] Compound a13 is produced by reducing compound a8 in the presence of a catalyst. Examples of the reducing agent that can be used include hydrogen, formic acid salts such as ammonium formate, and hydrazine. Examples of the catalyst include transition metals such as palladium, nickel, rhodium, cobalt, and platinum, as well as salts thereof, complexes thereof, and catalysts supported on carriers such as polymers. Examples of the solvent are appropriately selected from the solvents exemplified below, and preferred examples include ethyl acetate, ethanol, and methanol. The reaction time is usually 5 minutes to 72 hours, and preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, and preferably 0°C to 100°C.

[0121] [Step 2-2: Condensation reaction] Compound a14 can be produced by reacting compound a13 with compound a9, a10, or a11 in a suitable solvent in the presence or absence of various condensing agents and / or bases. The condensing agent may be any of various condensing agents commonly used in conventional methods, but preferably includes propiophosphonic anhydride or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (including hydrochloride). The base may be appropriately selected from the bases exemplified below, but preferably includes diisopropylethylamine or triethylamine. The solvent may be appropriately selected from the solvents exemplified below, but preferably includes tetrahydrofuran, dimethylformamide, or chloroform. 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 2-3: Deacylation] Compound A2 is produced by reacting compound a14 with various bases in an appropriate solvent. The base may be appropriately selected from the bases exemplified below, and preferably ammonia. The solvent may be appropriately selected from the solvents exemplified below, and preferably 2-propanol or tetrahydrofuran. The reaction time is usually 5 minutes to 72 hours, and preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, and preferably 0°C to 100°C.

[0123] Manufacturing method 3 The compound represented by formula [a13] can be produced, for example, by the following production method. [ka]

[0124] (In the formula, Y 1 C has an unsaturated bond 3-10 is an alicyclic group, and Y 2 C 3-10 is an alicyclic group, and L 3 is -NH-C(=O)- or -C(=O)-NH-, and R 2 , R 3 and X is the same as item 1, and a15, a16, and a17 are Y 1 The carbonyl group above represents an acetal-protected compound.

[0125] [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, salts thereof, complexes thereof, and catalysts supported on carriers such as polymers. The base may be appropriately selected from the bases exemplified below, with preferred examples being sodium carbonate and potassium carbonate. The solvent may be appropriately selected from the solvents exemplified below, with preferred examples being a mixed solvent of 1,2-dimethoxyethane and water. The reaction time is usually 5 minutes to 72 hours, and preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, and preferably 20°C to 150°C. The reaction temperature is usually 0°C to 200°C, and preferably 0°C to 100°C.

[0126] [Step 3-2: Deacetalization Reaction] Compound a18 can be produced by reacting compound a17 with various acids in an appropriate solvent. Examples of the acid include hydrochloric acid, trifluoroacetic acid, acetic acid, and sulfuric acid. The solvent can be appropriately selected from the solvents exemplified below, and preferably includes tetrahydrofuran or acetone. The reaction time is usually 5 minutes to 72 hours, and preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, and preferably 0°C to 100°C.

[0127] [Step 3-3: Debenzylation Reaction] Compound a19 is produced by reducing compound a18 in the presence of a catalyst. Examples of the reducing agent that can be used include hydrogen, formic acid salts such as ammonium formate, and hydrazine. Examples of the catalyst include transition metals such as palladium, nickel, rhodium, cobalt, and platinum, as well as salts thereof, complexes thereof, and catalysts supported on carriers such as polymers. Examples of the solvent are appropriately selected from the solvents exemplified below, and preferred examples include ethyl acetate, ethanol, and methanol. The reaction time is usually 5 minutes to 72 hours, and preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, and preferably 0°C to 100°C.

[0128] [Step 3-4: Reduction reaction] Compound a13 is produced by reducing compound a19 using 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 the reducing agent that can be used include hydrogen, formic acid salts such as sodium formate, hydrazine, sodium borohydride, and lithium tri-sec-butylborohydride. Examples of the catalyst include transition metals such as ruthenium, palladium, nickel, rhodium, cobalt, and platinum, as well as salts thereof, complexes thereof, and catalysts supported on carriers such as polymers. Examples of the base are appropriately selected from the bases exemplified below, with preferred examples being potassium tert-butoxide, potassium hydroxide, and triethylamine. Examples of the solvent are appropriately selected from the solvents exemplified below, with preferred examples being tetrahydrofuran, 2-propanol, ethanol, methanol, and dimethylformamide. The reaction time is typically 5 minutes to 72 hours, and preferably 30 minutes to 24 hours. The reaction temperature is usually from -80°C to 200°C, preferably from -80°C to 100°C, and more preferably from 0°C to 100°C.

[0129] Manufacturing method 4 Among the compounds represented by formula (1), the compound represented by formula [A3] can be produced, for example, by the following production method. [ka]

[0130] (In the formula, R 41 and R 42 are the same or different and 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 have the same meaning as in Item 1.)

[0131] [Step 4-1: Condensation reaction] Compound a22 can be produced by reacting compound a20 with compound a2 in a suitable solvent in the presence or absence of various condensing agents and / or bases. Various condensing agents commonly used in conventional methods can be used as the condensing agent, but propiophosphonic anhydride or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (including hydrochloride) is preferred. The base can be appropriately selected from the bases exemplified below, but preferably diisopropylethylamine or triethylamine is preferred. The solvent can be appropriately selected from the solvents exemplified below, but preferably 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.

[0132] [Step 4-2: Condensation reaction] Compound a22 is produced by reacting compound a21 with compound a4 in an appropriate solvent in the presence or absence of various condensing agents and / or bases. Various condensing agents commonly used in conventional methods can be used as the condensing agent, but propiophosphonic anhydride or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (including hydrochloride) is preferred. The base is appropriately selected from the bases exemplified below, but preferably diisopropylethylamine or triethylamine is preferred. The solvent is appropriately selected from the solvents exemplified below, but preferably 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.

[0133] [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, salts thereof, complexes thereof, and those supported on carriers such as polymers. The base may be appropriately selected from the bases exemplified below, with preferred examples being sodium carbonate and potassium carbonate. The solvent may be appropriately selected from the solvents exemplified below, with preferred examples being a mixed solvent of 1,2-dimethoxyethane and water. The reaction time is usually 5 minutes to 72 hours, and preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, and preferably 20°C to 150°C. The reaction temperature is usually 0°C to 200°C, and preferably 0°C to 100°C.

[0134] [Step 4-4: Condensation reaction] Compound A3 is produced by reacting compound a23 with compound a9, a10, or a11 in an appropriate solvent in the presence or absence of various condensing agents and / or bases. Various condensing agents commonly used in conventional methods can be used as the condensing agent, but 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (including hydrochloride) is preferred. The base is appropriately selected from the bases exemplified below, but preferably diisopropylethylamine or triethylamine is preferred. The solvent is appropriately selected from the solvents exemplified below, but preferably 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.

[0135] Compound a20 may be commercially available or may be prepared according to known methods, such as those described in ACS Chem Neurosci. 2018, 9, 587-602.

[0136] Compound a21 may be commercially available or may be produced according to known methods, such as those described in Nature Commun. 2018, 9, 4123, etc. Manufacturing method 5 The compound represented by formula [a23] can be produced, for example, by the following production method. [ka]

[0137] (In the formula, Y 1 C has an unsaturated bond 3-10 is an alicyclic group, and Y 2 C 3-10 is an alicyclic group, and L 3 is -NH-C(=O)- or -C(=O)-NH-, and R 1 , R 2 , R 3 and X is the same as item 1, and a15, a16, and a24 are Y 1 The carbonyl group above represents an acetal-protected compound.

[0138] [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, salts thereof, complexes thereof, and those supported on carriers such as polymers. The base may be appropriately selected from the bases exemplified below, with preferred examples being sodium carbonate and potassium carbonate. The solvent may be appropriately selected from the solvents exemplified below, with preferred examples being a mixed solvent of 1,2-dimethoxyethane and water. The reaction time is usually 5 minutes to 72 hours, and preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, and preferably 20°C to 150°C. The reaction temperature is usually 0°C to 200°C, and preferably 0°C to 100°C.

[0139] [Step 5-2: Deacetalization Reaction] Compound a25 can be produced by reacting compound a24 with various acids in an appropriate solvent. Examples of the acid include hydrochloric acid, trifluoroacetic acid, acetic acid, and sulfuric acid. The solvent can be appropriately selected from the solvents exemplified below, and preferably includes tetrahydrofuran or acetone. The reaction time is usually 5 minutes to 72 hours, and preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, and preferably 0°C to 100°C.

[0140] [Step 5-3: Hydrogenation Reaction] Compound a26 is produced by reducing compound a25 in the presence of a catalyst. Examples of the reducing agent that can be used include hydrogen, formic acid salts such as ammonium formate, and hydrazine. Examples of the catalyst include transition metals such as palladium, nickel, rhodium, cobalt, and platinum, as well as salts thereof, complexes thereof, and catalysts supported on carriers such as polymers. Examples of the solvent are appropriately selected from the solvents exemplified below, and preferred examples include ethyl acetate, ethanol, and methanol. The reaction time is usually 5 minutes to 72 hours, and preferably 30 minutes to 24 hours. The reaction temperature is usually 0°C to 200°C, and preferably 0°C to 100°C.

[0141] [Step 5-4: Reduction reaction] Compound a23 is produced by reducing compound a26 using 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 the reducing agent that can be used include hydrogen, formic acid salts such as sodium formate, hydrazine, sodium borohydride, and lithium tri-sec-butylborohydride. Examples of the catalyst include transition metals such as ruthenium, palladium, nickel, rhodium, cobalt, and platinum, as well as salts thereof, complexes thereof, and catalysts supported on carriers such as polymers. Examples of the base are appropriately selected from the bases exemplified below, with preferred examples being potassium tert-butoxide, potassium hydroxide, and triethylamine. Examples of the solvent are appropriately selected from the solvents exemplified below, with preferred examples being tetrahydrofuran, 2-propanol, ethanol, methanol, and dimethylformamide. The reaction time is usually 5 minutes to 72 hours, and preferably 30 minutes to 24 hours. The reaction temperature is usually from -80°C to 200°C, preferably from -80°C to 100°C, and more preferably from 0°C to 100°C.

[0142] The base used in each step of each of the above-mentioned production methods should be selected appropriately depending on the type of reaction and raw material compound, etc., and examples thereof 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).

[0143] The solvent used in each step of the above-mentioned production methods should be selected appropriately depending on the type of reaction and raw material compounds, etc. Examples of suitable solvents 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 combination. Depending on the type of reaction, organic bases can also be used as solvents.

[0144] The compound of the present disclosure represented by formula (1) or an intermediate thereof can be separated and purified by methods known to those skilled in the art, such as extraction, partitioning, reprecipitation, column chromatography (e.g., silica gel column chromatography, ion exchange column chromatography, or preparative liquid chromatography), or recrystallization.

[0145] Examples of recrystallization solvents that can be used include alcoholic solvents such as methanol, ethanol, and 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as benzene and toluene, ketone solvents such as acetone, halogenated solvents such as dichloromethane and chloroform, hydrocarbon solvents such as hexane, aprotic solvents such as dimethylformamide and acetonitrile, water, and mixtures thereof. Other purification methods include those described in Volume 1 of "Experimental Chemistry Lectures" (edited by the Chemical Society of Japan, published by Maruzen). The molecular structures of the compounds of the present disclosure can be easily determined by spectroscopic techniques such as nuclear magnetic resonance, infrared absorption, and circular dichroism spectroscopy, and mass spectrometry, with reference to the structures derived from the respective starting compounds.

[0146] Furthermore, the intermediates or final products in the above production methods can be converted into other compounds included in the present disclosure by appropriately converting their functional groups, particularly by extending various side chains from amino groups, hydroxyl groups, carbonyl groups, halogen atoms, etc., and, if necessary, by carrying out the protection and deprotection described below. Functional group conversion and side chain extension can be carried out by commonly used general methods (see, for example, Comprehensive Organic Transformations, R.C. Larock, John Wiley & Sons Inc. (1999)).

[0147] Examples of the protecting group for an amino group include an alkylcarbonyl group (e.g., an acetyl group, a propionyl group), a formyl group, a phenylcarbonyl group, an alkyloxycarbonyl group (e.g., a methoxycarbonyl group, an ethoxycarbonyl group, a tert-butoxycarbonyl group), a phenyloxycarbonyl group, an arylalkyloxycarbonyl group (e.g., a benzyloxycarbonyl group), a trityl group, a phthaloyl group, a tosyl group, and a benzyl group.

[0148] Examples of the protecting group for a carboxyl group include an alkyl group (e.g., a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and a tert-butyl group), a phenyl group, a benzyl group, a trityl group, and a silyl group (e.g., a trimethylsilyl group and a tert-butyldimethylsilyl group).

[0149] Examples of the protecting group for a hydroxy group include a methyl group, a tert-butyl group, an allyl group, a substituted methyl group (e.g., a methoxymethyl group, a methoxyethoxymethyl group), an ethoxyethyl group, a tetrahydropyranyl group, a tetrahydrofuranyl group, a trityl group, an arylalkyl group (e.g., a benzyl group), an alkylcarbonyl group (e.g., an acetyl group, a propionyl group), a formyl group, a benzoyl group, an arylalkyloxycarbonyl group (e.g., a benzyloxycarbonyl group), and a silyl group (e.g., a trimethylsilyl group, a tert-butyldimethylsilyl group).

[0150] Protection of the carbonyl group can be carried out by converting the carbonyl group into an acyclic ketal (dimethyl ketal, diethyl ketal, etc.) or a cyclic ketal (1,3-dioxolane, 1,3-dioxane, etc.).

[0151] The compound of the present disclosure represented by formula (1) or a pharmaceutically acceptable salt thereof may have asymmetry or a substituent having an asymmetric carbon, and such a compound may have optical isomers. The compound of the present disclosure includes a mixture or isolated form of these isomers, and can be produced according to a conventional method.

[0152] Examples of production methods include a method using a raw material having an asymmetric center or a method introducing asymmetry 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 production process. Examples of optical resolution methods include, when the compound represented by formula (1) or an intermediate thereof has a basic functional group, a diastereomeric method in which a salt is formed using an optically active acid (e.g., monocarboxylic acid such as mandelic acid, N-benzyloxyalanine, lactic acid, dicarboxylic acid such as tartaric acid, o-diisopropylidenetartaric acid, malic acid, sulfonic acid such as camphorsulfonic acid, bromocamphorsulfonic acid) in an inert solvent (e.g., alcoholic solvents such as methanol, ethanol, 2-propanol, etc.; ether solvents such as diethyl ether, ester solvents such as ethyl acetate, hydrocarbon solvents such as toluene, aprotic solvents such as acetonitrile, or a mixed solvent of two or more of the above solvents).

[0153] When the compound of the present disclosure represented by formula (1) or an intermediate thereof 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 (e.g., an organic amine such as 1-phenylethylamine, quinine, quinidine, cinchonidine, cinchonine, or strychnine).

[0154] The temperature for salt formation is selected from the 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 first raise the temperature to near the boiling point of the solvent. When filtering the precipitated salt, cooling can be performed as needed to improve yield. The amount of optically active acid or amine used is preferably in the range of about 0.5 to about 2.0 equivalents relative to the substrate, preferably about 1 equivalent. If necessary, the crystals can be recrystallized in an inert solvent (e.g., alcoholic solvents such as methanol, ethanol, and 2-propanol; ether solvents such as diethyl ether; ester solvents such as ethyl acetate; hydrocarbon solvents such as toluene; aprotic solvents such as acetonitrile; or a mixed solvent of two or more of the above solvents) to obtain a highly pure optically active salt. Furthermore, if necessary, the optically resolved salt can be treated with an acid or base by a conventional method to obtain a free form.

[0155] Of the raw materials and intermediates in each of the production methods explained above, those for which the production method is not particularly described are commercially available compounds or can be synthesized from commercially available compounds by methods known to those skilled in the art or methods similar thereto.

[0156] "Disorders or diseases involving TRPV1" refer to disorders or diseases caused by increased activity of neurons expressing TRPV1, and examples thereof include dysphagia, pain, skin diseases, respiratory diseases, digestive diseases, urinary diseases, diabetes, and obesity. Examples of pain include neuropathic pain, postherpetic neuralgia, and pain caused by osteoarthritis of the knee. Examples of skin diseases include psoriasis, atopic dermatitis, primary hyperhidrosis, and alopecia. Examples of respiratory diseases include cough and asthma. Examples of digestive diseases include acute gastritis, acute gastric mucosal lesions, and fecal incontinence. Examples of urinary diseases include cystitis and overactive bladder. A preferred "disorder or disease involving TRPV1" is dysphagia.

[0157] The present disclosure provides a pharmaceutical composition for treating or preventing dysphagia, comprising as an active ingredient a compound of the present invention or a pharmaceutically acceptable salt thereof. "Dysphagia" refers to a condition in which chewing or swallowing food or drink becomes difficult due to disease, aging, or the like. Specific examples include swallowing coordination disorder, dysphagia, dysphagia, dysphagia, inability to swallow, and cricopharyngeal muscle dysfunction. 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. It also includes conditions in which swallowing function is impaired by therapeutic drugs such as analgesics, antipsychotics, antihistamines, and anticholinergics.

[0158] The effect of the compounds of the present disclosure on dysphagia can be evaluated using the swallowing function of dysphagia model animals as an indicator. Similar to dysphagia in humans, dysphagia has been reported to occur in aged animals, cerebral infarction model animals, Parkinson's disease model animals, and the like, and these models can be used to evaluate the effect of the compounds of the present disclosure on dysphagia. (Dysphagia (2014) 29:61-67, Dysphagia. 2015 Jun;30(3):328-42, Dysphagia. 2013 Mar;28(1):95-104)

[0159] In the present disclosure, "prevention" refers to administering an active ingredient of the present disclosure to a healthy person who has not developed a disease or who has mild symptoms, for example, with the aim of preventing the onset of a disease. "Treatment" refers to administering an active ingredient of the present disclosure to a person (patient) who has been diagnosed by a doctor as having developed a disease.

[0160] The compound of the present disclosure may be administered orally, parenterally, or rectally, and the daily dosage varies depending on the type of compound, the administration method, the patient's symptoms, age, etc. For example, in the case of oral administration, the dosage is typically about 0.01 to 1000 mg, more preferably about 0.1 to 500 mg, per kg body weight of a human or mammal, administered once or in divided doses. In the case of parenteral administration such as intravenous injection, the dosage is typically about 0.01 mg to 300 mg, more preferably about 0.01 mg to 100 mg, per kg body weight of a human or mammal.

[0161] The compounds of the present disclosure can be administered orally or parenterally, either directly or after formulation using an appropriate dosage form. Examples of dosage forms include, but are not limited to, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, and poultices. The formulations are prepared by known methods using pharmaceutically acceptable additives. Depending on the purpose, additives that can be used include excipients, disintegrants, binders, flow agents, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers, sweeteners, and flavors. Specific examples of additives 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, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, and talc.

[0162] The compounds of the present 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 swallowing include L-Dopa preparations for Parkinson's disease, immunoglobulins for inclusion body myositis, and the glucosylceramide synthase inhibitor miglustat for Niemann-Pick disease type C. Drugs that may improve the swallowing reflex include ACE inhibitors, cilostazol, nicergoline, and Hange-Koboku-To. In this disclosure, drugs that can be used in combination with the compounds of the present invention are referred to as "other drugs."

[0163] The administration period of the compound of the present invention and the concomitant drug is not limited, and they may be administered to a subject simultaneously or at staggered times. The compound of the present invention and the concomitant drug may also be used as a combination drug. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention to the concomitant drug can be appropriately selected depending on the subject, administration route, target disease, symptoms, combination, etc. For example, when the subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per part by weight of the compound of the present invention. Furthermore, for the purpose of suppressing side effects, the compound of the present invention may be used in combination with drugs (concomitant drugs) such as antiemetics, hypnotics, and anticonvulsants.

[0164] In this specification, "or" is used when "at least one or more" of the items listed in the sentence can be employed. The same applies to "or." When specified in this specification as "within a range of two values," the range includes the two values ​​themselves.

[0165] All references cited herein, including scientific literature, patents, patent applications, and the like, are incorporated by reference in their entirety to the same extent as if each were specifically set forth.

[0166] The present disclosure has been described above by showing preferred embodiments for ease of understanding. Hereinafter, the present disclosure will be described based on examples. However, the above description and the following examples are provided for illustrative purposes only and are not intended to limit the present disclosure. Therefore, the scope of the present disclosure is not limited to the embodiments or examples specifically described herein, but is limited only by the scope of the claims. [Example]

[0167] The present disclosure will be explained in more detail below with reference to examples, examples, and test examples, but the present disclosure is not limited thereto. Note that the compound names shown in the following reference examples and examples do not necessarily conform to the IUPAC nomenclature.

[0168] To simplify the description in the specification, the following abbreviations may be used in the Reference Examples, Examples, and Tables in the Examples. As an abbreviation used as a substituent, pin means pinacol. As symbols used in NMR, s means a singlet, d means a doublet, dd means a doublet of doublets, t means a triplet, q means a quartet, m means a multiplet, br means a broad, brs means a broad singlet, and J means a coupling constant.

[0169] The measurement conditions for the high-performance liquid chromatograph mass spectrometer (LCMS) were as follows. The observed mass spectrometry values ​​[MS (m / z)] were calculated as MH. + and retention time is shown as Rt (min).

[0170] Measurement conditions Detector: ACQUITY (registered trademark) SQ detector (Waters) HPLC: ACQUITY UPLC® 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℃

[0171] Reference example 1 2-[4-(benzyloxy)-3-methoxyphenyl]-N-(6-bromopyridin-2-yl)acetamide [ka]

[0172] To a solution of 4-benzyloxy-3-methoxyphenylacetic acid (4.0 g) and 6-bromopyridin-2-amine (2.8 g) in 1,2-dimethoxyethane (30 ml), N,N-diisopropylethylamine (5.1 ml) and a 50% propylphosphonic anhydride ethyl acetate solution (10.5 ml) were added and stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, followed by extraction 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 solid was washed with diethyl ether to give Reference Example 1 (4.0 g). LC-MS, m / z: 427.08 (M+H) + ESI, Rt; 1.071 (min)

[0173] Reference example 2 2-[4-(benzyloxy)-3-methoxyphenyl]-N-[6-(3-hydroxyphenyl)pyridin-2-yl]acetamide hydrochloride [ka]

[0174] To a solution of 2-[4-(benzyloxy)-3-methoxyphenyl]-N-(6-bromopyridin-2-yl)acetamide (8.61 g), 3-hydroxyphenylboronic acid (3.06 g), and potassium carbonate (5.57 g) in 1,2-dimethoxyethane (200 ml) / water (40 ml) was added dichlorobis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) (0.71 g) and heated to 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. A 4 mol / L solution of hydrogen chloride in cyclopentyl methyl ether (30 ml) was then added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the resulting solid was washed with diethyl ether to give Reference Example 2 (8.58 g). LC-MS, m / z: 441.25 (M+H) + ESI, Rt; 0.998 (min)

[0175] Example 1 and Reference Example 3 3-{6-[2-(4-hydroxy-3-methoxyphenyl)acetamido]pyridin-2-yl}phenyl 2-methylpropanoate [ka]

[0176] a) Preparation of 3-(6-{2-[4-(benzyloxy)-3-methoxyphenyl]acetamido}pyridin-2-yl)phenyl 2-methylpropanoate (Reference Example 3) Isobutyryl chloride (0.263 ml) was added to a solution of 2-[4-(benzyloxy)-3-methoxyphenyl]-N-[6-(3-hydroxyphenyl)pyridin-2-yl]acetamide hydrochloride (1.0 g) and triethylamine (0.791 ml) in tetrahydrofuran (23 ml), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate 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)

[0177] b) Preparation of 3-{6-[2-(4-hydroxy-3-methoxyphenyl)acetamido]pyridin-2-yl}phenyl 2-methylpropanoate (Example 1) Palladium-activated carbon (Pd 20%) (1.0 g) was added to a solution (30 ml) of 3-(6-{2-[4-(benzyloxy)-3-methoxyphenyl]acetamido}pyridin-2-yl)phenyl 2-methylpropanoate (1.159 g) in ethyl acetate, and the mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. The reaction mixture was purged with nitrogen, filtered through Celite, and concentrated under reduced pressure. Hexane was added to the residue to obtain a crude solid product. The resulting 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).

[0178] Reference example 4 N-{[4-(benzyloxy)-3-methoxyphenyl]methyl}-3-bromobenzamide [ka]

[0179] N,N-Diisopropylethylamine (6.87 ml) was added to a dimethylformamide (36 ml) solution of (4-(benzyloxy)-3-methoxyphenyl)methanamine 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), and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, followed by extraction 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 crude product was purified by silica gel column chromatography (eluent: hexane:ethyl acetate), and the resulting solid was washed with hexane to give Reference Example 4 (8.0 g). LC-MS, m / z; 426.13 (M+H) + ESI, Rt; 1.029 (min)

[0180] Reference example 5 N-{[4-(benzyloxy)-3-methoxyphenyl]methyl}-3'-hydroxy[1,1'-biphenyl]-3-carboxamide [ka]

[0181] 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) and 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). The resulting solid was washed with a hexane / ethyl acetate = 10:1 solution to give Reference Example 5 (2.62 g). LC-MS, m / z; 440.30 (M+H)+ ESI, Rt; 0.955 (min)

[0182] Reference examples 6~8 2-(4-hydroxy-3-methoxyphenyl)-N-(3-(4-oxocyclohexyl)phenyl)acetamide [ka]

[0183] a) Preparation of 2-[4-(benzyloxy)-3-methoxyphenyl]-N-[3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenyl]acetamide (Reference Example 6) To a solution of 2-(4-(benzyloxy)-3-methoxyphenyl)-N-(3-bromophenyl)acetamide (500 mg), 1,4-dioxaspiro[4,5]dec-7-ene-8-phenylboronic acid pinacol ester (343 mg), and potassium carbonate (486 mg) in 1,2-dimethoxyethane (5 ml) / water (1 ml) was added dichlorobis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) (42 mg), and the mixture was heated to reflux for 3 hours. After concentrating the reaction solution, chloroform was added, and the organic layer was washed with water, a saturated aqueous solution of sodium bicarbonate, and saturated brine. The mixture was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product (693 mg) of Reference Example 6 obtained was used directly in the next reaction. LC-MS, m / z; 486.37 (M+H) + ESI, Rt; 1.058 (min)

[0184] 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) To a solution of the crude product of 2-[4-(benzyloxy)-3-methoxyphenyl]-N-[3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenyl]acetamide (693 mg) in tetrahydrofuran (30 ml), 5 mol / L hydrochloric acid (30 ml) was added and stirred at room temperature for 1 hour. Water was added to the reaction solution, followed by extraction 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 crude product of Reference Example 7 (570 mg) was used directly in the next reaction. LC-MS, m / z: 442.31 (M+H) + ESI, Rt; 0.982 (min)

[0185] c) Preparation of 2-(4-hydroxy-3-methoxyphenyl)-N-(3-(4-oxocyclohexyl)phenyl)acetamide (Reference Example 8) To a solution of crude 2-[4-(benzyloxy)-3-methoxyphenyl]-N-(4'-oxo-2',3',4',5'-tetrahydro[1,1'-biphenyl]-3-yl)acetamide (570 mg) in ethyl acetate (10 ml), palladium-activated carbon (Pd 20%) (250 mg) was added and the mixture was stirred at room temperature under a hydrogen atmosphere for 7 hours. The reaction mixture was purged with nitrogen, filtered through Celite, and concentrated under reduced pressure. To the residue obtained, diethyl ether was added, and the precipitated solid was collected by filtration to give Reference Example 8 (202 mg). LC-MS, m / z; 354.14 (M+H) + ESI, Rt; 0.678 (min)

[0186] Reference example 9 N-{3-[(cis)-4-hydroxycyclohexyl]phenyl}-2-(4-hydroxy-3-methoxyphenyl)acetamide [ka]

[0187] To a solution of dichlorobis(triphenylphosphine)(1,2-ethanediamine)ruthenium(II) (492 mg) in 2-propanol (115 ml) were added potassium tert-butoxide (2.92 g) and tetrahydrofuran (115 ml). 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. The reaction mixture was purged with nitrogen, filtered through 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. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate) to give Reference Example 9 (1.2 g). LC-MS, m / z; 356.3 (M+H) + ESI, Rt; 0.683 (min)

[0188] Reference example 10 N-{3-[(trans)-4-hydroxycyclohexyl]phenyl}-2-(4-hydroxy-3-methoxyphenyl)acetamide [ka]

[0189] Sodium borohydride (107 mg) was added to a solution of 2-(4-hydroxy-3-methoxyphenyl)-N-(3-(4-oxocyclohexyl)phenyl)acetamide (500 mg) in tetrahydrofuran (14 ml). After stirring at room temperature for 1.5 hours, saturated aqueous ammonium chloride solution was added to the reaction mixture, which was then 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 give Reference Example 10 (276 mg). LC-MS, m / z; 356.2 (M+H) + ESI, Rt; 0.632 (min)

[0190] Reference example 11 4-[2-(3-{(cis)-4-[(cyclohexanecarbonyl)oxy]cyclohexyl}anilino)-2-oxoethyl]-2-methoxyphenyl cyclohexanecarboxylate [ka]

[0191] 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) was added cyclohexanecarbonyl chloride (1.1 ml). After stirring at room temperature for 4 days, water was added to the reaction mixture, which was then 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 give Reference Example 11 (1.05 g). LC-MS, m / z; 576.39 (M+H) + ESI, Rt; 1.436 (min)

[0192] Reference example 12 3'-Hydroxy-N-[(4-hydroxy-3-methoxyphenyl)methyl][1,1'-biphenyl]-3-carboxamide [ka]

[0193] Palladium-activated carbon (Pd 20%) (50 mg) was added 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), and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The reaction mixture was purged with nitrogen, filtered through Celite, and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluent: hexane:ethyl acetate) to give Reference Example 18 (171 mg). LC-MS, m / z; 350.2 (M+H) + ESI, Rt; 0.684 (min)

[0194] Reference examples 13~19 The compounds shown in Table 1 were obtained in the same manner as in Reference Example 12 using the corresponding starting compounds.

[0195] [Table 1]

[0196] Example 2 cis-4-{3-[2-(4-hydroxy-3-methoxyphenyl)acetamido]phenyl}cyclohexyl cyclohexanecarboxylate [ka]

[0197] To a solution of 4-[2-(3-{(cis)-4-[(cyclohexanecarbonyl)oxy]cyclohexyl}anilino)-2-oxoethyl]-2-methoxyphenyl cyclohexanecarboxylate (0.91 g) in 2-propanol (330 ml) was added 28-30% aqueous ammonia (110 ml). After stirring at room temperature for 1 day, 1 mol / L hydrochloric acid was added to the reaction solution, which was extracted with ethyl acetate. The resulting organic layer was washed with water and saturated brine. It was then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was washed with diethyl ether and recrystallized from acetonitrile to give 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)

[0198] Example 49 3-{4-[2-(4-hydroxy-3-methoxyphenyl)acetamido]pyridin-2-yl}phenyl 2-methylpropanoate hydrochloride [ka]

[0199] To a solution of 3-{4-[2-(4-hydroxy-3-methoxyphenyl)acetamido]pyridin-2-yl}phenyl 2-methylpropanoate (2.5 g) in a mixture of ethyl acetate (50 ml) and tetrahydrofuran (10 ml), a 4 mol / L hydrogen chloride-ethyl acetate solution (10 ml) was added and stirred at room temperature. The reaction mixture was concentrated, and the resulting solid was washed with diethyl ether to give 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)

[0200] Examples 3 to 48 The compounds shown in Table 2 were obtained by the same methods as in Examples 1, 2 and 49 using the corresponding starting compounds.

[0201] [Table 2] JPEG0007797394000053.jpg222149JPEG0007797394000054.jpg217149JPEG0007797394000055.jpg217149 JPEG0007797394000056.jpg201149JPEG0007797394000057.jpg213149JPEG0007797394000058.jpg197149

[0202] Test Example The pharmacological test results of representative compounds of the present invention are shown below, and the pharmacological actions of the compounds are explained, but the present invention is not limited to these test examples.

[0203] Test Example 1: Evaluation of agonism using human TRPV1 transiently expressing cells (1) Generation of human TRPV1 transiently expressing cells Human TRPV1-transfected cells were prepared and cultured. Specifically, HEK293 cells (cat# CCL-82.2, ATCC) were used as host cells. Human TRPV1 and apoaequorin were transiently expressed by introducing the TRPV1 gene (GenBank NP_542435.2) into the mammalian cell expression vector pcDNA3.1 (cat# v790-20, Invitrogen). The cells were cultured in tissue culture dishes (cat#3020-100, Iwaki) in Dulbecco's Modified Eagle's Medium (DMEM) medium (cat#11550-043, Thermo Fisher Scientific) containing 10% heat-inactivated fetal bovine serum (cat#10270-106, Thermo Fisher Scientific). Every 2–3 days, the cells were harvested and subcultured using PBS containing 10% 2.5 g / L trypsin, 1 mol / L EDTA, and phenol red (cat#32777-44, Nacalai Tesque). Three days after subculture, when the cells were approximately 80% confluent, they were harvested by treatment with 10% trypsin-PBS, suspended in DMEM medium containing 10% fetal bovine serum at 4000 cells / 35 μl / well, and seeded into a 384-well plate (cat#353962, FALCON). The day after seeding, Viviren (cat# E6492, Promega) was added (15 μl / well) to a final concentration of 4.5 μM in HBSS (cat# 14065-056, Thermo Fisher Scientific) / 90 mM HEPES (cat# 17514-15, Nacalai Tesque) / 0.1% BSA (cat# 01281-84, Nacalai Tesque). After centrifugation, the plates were left to stand at room temperature for 2 hours in the dark.

[0204] (2) Preparation of test compounds A dimethyl sulfoxide solution of the test compound was prepared at a concentration 1000 times the final concentration, and this solution was adjusted to 10 times the final concentration with Hanks / 20 mmol / L HEPES / 0.1% BSA (cat#01281-84, Nacalai Tesque).

[0205] (3) TRPV1 agonism assessment FDSS7000 (Hamamatsu Photonics) was used to detect the luminescence signal induced by TRPV1 agonist stimulation. Test compounds were added to the plate containing cells and luminescent substrate. The luminescence signal (center wavelength: 465 nm) after addition of the test compound was measured and Rlu (Max-Min) was calculated. Data on the TRPV1 agonist activity of representative compounds are shown in Tables 3 and 4.

[0206] [Table 3]

[0207] [Table 4]

[0208] As shown in the table above, the compounds of the present invention had TRPV1 agonistic activity in the TRPV1 agonism evaluation test. In particular, Examples 1, 2, 9, 10, 15, 17, 19, 24, 26 and 46 showed stronger TRPV1 agonistic activity.

[0209] Test Example 2: Evaluation of swallowing improvement effect in a rat haloperidol-induced dysphagia model This study evaluated the efficacy of drugs in improving dysphagia. Haloperidol inhibits dopamine D2 receptors, causing a decrease in the swallowing reflex. Therefore, it is used not only as a model of antipsychotic-induced dysphagia, but also as a model of dysphagia associated with neurodegenerative diseases such as Parkinson's disease, and other swallowing disorders with a decreased swallowing reflex. Crl:CD(SD) male rats (groups of 8 rats, 8 weeks old, weighing 280-310 g at time of delivery) were administered haloperidol subcutaneously on the dorsum using a disposable polypropylene syringe (Terumo Corporation) equipped with a 23G needle (Terumo Corporation). The volume of the administered solution was calculated at 5 ml / kg based on the body weight closest to the day of administration. The administration frequency was 14 times, twice daily (12 ± 2 h intervals) for 7 days. Swallowing frequency was measured in the morning following the 7th day of administration. The animals were administered an anesthetic intraperitoneally using a disposable polypropylene syringe (Terumo Corporation) fitted with a 25g needle (Terumo Corporation). The volume of the solution administered was calculated at 2.3ml / kg based on the body weight on the day of anesthesia. It contained ketamine (90mg / kg) and xylazine (10mg / kg). After anesthesia induction, the animal's submandibular hair was shaved with clippers, and the animal was placed in a supine position on a heat pad maintained at 37°C, preventing movement of the limbs. A rat probe was inserted into the animal's mouth once, and the tip of the probe was placed in the pharynx. While maintaining this position, 0.1ml of the test substance solution was injected. After injection, one swallowing movement induced by the swallowing reflex was counted as one swallow. Two measurements were taken per animal, and the average of the first and second measurements was calculated. 0.01% ethanol was used as the vehicle. The results are shown in Figure 1.

[0210] Test Example 3: Evaluation of taste aversion by drinking water This test was conducted to evaluate the taste aversion of drugs. Crl:CD(SD) rats (groups of 8 rats, 8 weeks old at time of arrival) were housed in their 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. The rats were housed overnight, and the amount of water consumed during this period was measured. The percentage of rats that drank the test substance was calculated from the total amount of water consumed from the two water bottles, and this was used to evaluate taste aversion. The greater the percentage of rats that drank the test substance, the less taste aversion there was, and the less irritation the test substance caused. The results are shown in Table 5.

[0211] [Table 5]

[0212] Test Example 4: S9 metabolic stability evaluation test The compound was added to a reaction solution prepared by diluting liver S9 fraction with phosphate buffer, and incubation was initiated at 37°C (final compound concentration: 10 nM, final volume: 300 μL). After 15 minutes of incubation, the reaction was stopped by adding acetonitrile to the reaction solution, followed by centrifugation. The supernatant was filtered and the amount of compound measured using LC / MS / MS. The remaining percentage of the compound 15 minutes after the start of the reaction relative to the amount of compound before the start of the reaction (0 minutes) was calculated from the obtained compound amount. The results are shown in Table 6.

[0213] [Table 6]

[0214] Test Example 5: Evaluation of swallowing enhancement effect in normal rats This study evaluated the effects of drugs on swallowing function. It has been reported that inducing the swallowing reflex in normal rats with water containing NaCl suppresses the number of swallows. Therefore, we evaluated the effect of a vehicle containing NaCl on swallowing function. Male Crl:CD(SD) rats (7-8 rats per group, 8-9 weeks old, weighing 280-310 g at time of arrival) were anesthetized. After anesthesia, the animals' submandibular hair was shaved with clippers and they were placed in a supine position on a heat pad maintained at 37°C, preventing movement of their limbs. A rat probe was inserted into the animal's mouth, and the tip of the probe was fixed in the pharynx. The test substance solution was then administered at 12 ml / h for 10 seconds using an infusion pump, and swallowing behavior was measured for 30 seconds after the start of administration. Physiological saline containing 1% ethanol and 0.1% Tween 80 was used as the vehicle. The results are shown in Table 7. Compared to the vehicle-administered group, the number of swallows was significantly increased in the capsaicin, Example 12, Example 2, and Example 49 groups (Dunnett's test: * indicates P<0.05, ** indicates P<0.01, *** indicates P<0.001).

[0215] [Table 7]

[0216] Test Example 6: Evaluation of desensitization of swallowing enhancement in normal rats TRPV1 agonists are known to induce TRPV1 desensitization at high doses or with repeated administration. Using a method similar to that described in Test Example 5, the desensitization effect of drugs on swallowing function in normal rats was examined. Male Crl:CD(SD) rats (7-8 rats per group, 8-9 weeks old, weighing 280-310 g at time of arrival) were anesthetized, and the animals' submandibular hair was shaved with clippers. They were then placed in a supine position on a heat pad maintained at 37°C, preventing movement of the limbs. A rat probe was inserted into the animal's mouth, and the tip of the probe was placed in the pharynx. The test substance solution was then administered at 12 ml / h for 10 seconds using an infusion pump, and swallowing behavior was measured for 30 seconds after the start of administration. The same test was then repeated approximately 5 minutes later, for a total of five repeated evaluations. Physiological saline containing 1% ethanol and 0.1% Tween 80 was used as the vehicle. The results are shown in Table 8. In the case of capsaicin, the number of swallowings was significantly reduced in 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.

[0217] [Table 8]

[0218] Test Example 7: Evaluation of eye irritation test in normal rats TRPV1 agonists are irritating, and administration of a TRPV1 agonist solution to the eye has been reported to induce wiping behavior. The irritation potential of these compounds was examined using normal rats. Crl:CD(SD) male rats (groups of 5, 8 weeks old, weighing 271-320 g) were held under unanesthetized conditions, and 10 μL of the solution was instilled into the right eye using a micropipette. The rats were immediately returned to observation cages, and wiping behavior was observed for 1 minute. The number of wiping events is shown in Table 9. Capsaicin significantly increased wiping behavior at concentrations of 30 μM or higher (Dunnett's test: * indicates P<0.05, ** indicates P<0.01). However, no significant differences were observed in Examples 12, 2, 1, and 49.

[0219] [Table 9]

[0220] As described above, the compounds of the present invention are potent TRPV1 agonists and show an effect of improving the swallowing reflex in an animal model of haloperidol-induced dysphagia, which is used as a model of swallowing disorders. Because they improve impaired swallowing reflexes by antagonizing dopamine D2 receptors, they are useful as therapeutic agents for drug-induced dysphagia caused by the administration of antipsychotics, neurodegenerative diseases such as Parkinson's disease, and dysphagia caused by cerebrovascular disease and aging, which are associated with impaired swallowing reflexes. [Industrial Applicability]

[0221] The compounds of the present disclosure exhibit TRPV1 agonism and are therefore useful as therapeutic agents for drug-induced dysphagia, dysphagia caused by neurodegenerative diseases such as Parkinson's disease, and dysphagia caused by a decline in the swallowing reflex due to various causes such as cerebrovascular disease and aging.

Claims

1. Formula (2): 【Chemistry 1】 [In the formula, R １ represents a hydrogen atom, R ２ represents a methoxy group, R ３ represents a hydrogen atom, 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 alkyl groups, m represents 1; n represents 0, 1, 2 or 3; L １ represents —NH—C(═O)— or —C(═O)—NH—; L ２ represents a single bond, X is the following formula (A): 【Chemistry 2】 (where * represents L １ represents the bonding position with Y, and ** represents the bonding position with Y. wherein c is CH, (1) when a is N, b is CH, and (2) when b is N, a is CH or a, b, and c are CH; Y is represented by the following formula (B) or (C): 【Transformation 3】 (In the formula, * represents the bonding position to X, and ** represents the bonding position to the oxygen atom.) wherein X and Y are attached to carbon atoms on the respective rings. or a pharmaceutically acceptable salt thereof.

2. 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 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. 2. The compound of claim 1, 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, 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.

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