Pharmaceutical composition containing a GLP-1 receptor agonist having a fused ring

Abstract

The present invention relates to: a compound, or a pharmacologically acceptable salt thereof, that has GLP-1 receptor agonist activity and that is useful as an agent for treating or preventing diseases involving the GLP-1 receptors; and a pharmaceutical composition containing the compound or the pharmacologically acceptable salt.　Provided is a compound represented by formula (I): (in the formula, A1 is C(R5), etc.; A2 is C(R6), etc.; A3 is C(R7), etc.; R5, R6, and R7 each independently are a hydrogen atom, etc.; R1 is a carboxy, etc.; R2 is a substituted or unsubstituted alkyl, etc.; -X- is -O-, etc.; the ring represented by (AAA) is a ring represented by (BBB) (in the formula, R10 each independently are a halogen, etc.; and s is 0, etc.); R13 each independently are a hydrogen atom, etc.; and R3 is a substituted or unsubstituted aromatic carbocyclic group, etc.), or a pharmacologically acceptable salt thereof.

Description

[Technical Field]

[0001] The present invention relates to compounds or pharmaceutically acceptable salts thereof that have GLP-1 receptor agonist activity and are useful as agents for treating or preventing diseases involving the GLP-1 receptor, and to pharmaceutical compositions containing them, particularly agents for preventing and / or treating non-insulin-dependent diabetes mellitus (type 2 diabetes) or obesity. [Background technology]

[0002] Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by intestinal L cells in response to food intake. GLP-1 is known to stimulate glucose-dependent insulin secretion, reduce glucagon secretion, delay gastric emptying, and reduce appetite via the GLP-1 receptor. GLP-1 receptor agonists have been investigated for use in the treatment of diabetes and obesity (Non-Patent Documents 1 and 2). Liraglutide, a representative agonist of human GLP-1, has been shown to potently reduce HbA1c and body weight. Due to these attractive effects, several GLP-1 analogs have been commercialized as antidiabetic and antiobesity drugs. However, due to poor oral absorption, most of these GLP-1 analogs are sold as injectables. Therefore, the development of orally available GLP-1 receptor agonists is anticipated. Specifically, a method for orally absorbing the GLP-1 analogue semaglutide using an absorption enhancer has been put to practical use (Patent Document 1), but improvements in pharmaceutical properties such as bioavailability are still required. Furthermore, attempts have been made to create several small molecule pharmaceuticals as non-peptide GLP-1 receptor agonists (Patent Documents 2 to 33), but the compounds substantially disclosed have structures different from those of the compound of the present invention. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2012 / 080471 [Patent Document 2] International Publication No. 2009 / 111700 [Patent Document 3] International Publication No. 2010 / 114824 [Patent Document 4] International Publication No. 2018 / 056453 [Patent Document 5] International Publication No. 2018 / 109607 [Patent Document 6] International Publication No. 2019 / 239319 [Patent Document 7] International Publication No. 2019 / 239371 [Patent Document 8] International Publication No. 2020 / 103815 [Patent Document 9] International Publication No. 2020 / 207474 [Patent Document 10] International Publication No. 2020 / 263695 [Patent Document 11] International Publication No. 2021 / 018023 [Patent Document 12] International Publication No. 2021 / 081207 [Patent Document 13] International Publication No. 2021 / 096284 [Patent Document 14] International Publication No. 2021 / 096304 [Patent Document 15] International Publication No. 2021 / 112538 [Patent Document 16] International Publication No. 2021 / 155841 [Patent Document 17] International Publication No. 2021 / 160127 [Patent Document 18] International Publication No. 2021 / 187886 [Patent Document 19] Chinese Patent Application Publication No. 113493447 [Patent Document 20] International Publication No. 2021 / 197464 [Patent Document 21] International Publication No. 2021 / 219019 [Patent Document 22] Chinese Patent Application Publication No. 113480534 [Patent Document 23] International Publication No. 2021 / 244645 [Patent Document 24] International Publication No. 2021 / 249492 [Patent Document 25] International Publication No. 2021 / 242817 [Patent Document 26] Chinese Patent Application Publication No. 113773310 [Patent Document 27] Chinese Patent Application Publication No. 113816948 [Patent Document 28] Chinese Patent Application Publication No. 113801136 [Patent Document 29] International Publication No. 2021 / 254470 [Patent Document 30] International Publication No. 2021 / 259309 [Patent Document 31] International Publication No. 2022 / 028572 [Patent Document 32] International Publication No. 2022 / 031994 [Patent Document 33] International Publication No. 2022 / 040600 [Non-patent literature]

[0004] [Non-Patent Document 1] Lancet 374, 1606-1616 (2009) [Non-patent document 2] Clin. Invest. 2, 59-72 (2012) Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide a compound or a pharmaceutically acceptable salt thereof which has GLP-1 receptor agonist activity and is useful as an agent for treating or preventing diseases associated with the GLP-1 receptor, and a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof, particularly an agent for preventing and / or treating non-insulin-dependent diabetes mellitus (type 2 diabetes) or obesity. [Means for solving the problem]

[0006] The present invention relates to the following: (1) Formula (I): [ka] (In the formula, A1 is C(R 5 ) or N, A2 is C(R 6 ) or N, A3 is C(R 7 ) or N, R 5 , R 6 and R 7 each independently represents a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group; R 1 is carboxy or its equivalent, R 2 is a substituted or unsubstituted alkyl; -X- is -C(R 8 )(R 9 )-, -O-, or -N(R 11 )- and R 8 and R 9 are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl; R 11 is a hydrogen atom or a substituted or unsubstituted alkyl; [ka] The ring denoted by [ka] (In the formula, R 10 are each independently halogen, cyano, hydroxy, substituted or unsubstituted alkyl, oxo, substituted or unsubstituted non-aromatic carbocyclic group, or substituted or unsubstituted alkyloxy; s is an integer from 0 to 9; R 13 are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl; R 3 is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof. (2) The compound according to (1) above, wherein s is an integer of 1 to 9, or a pharmaceutically acceptable salt thereof. (3) [ka] The ring shown by [ka] (wherein s' is an integer of 0 to 8, and other symbols have the same meanings as in (1) above), or a pharmaceutically acceptable salt thereof. (4) [ka] The ring shown by [ka] (wherein s' is an integer of 0 to 8, and other symbols are as defined in (1) above), or a pharmaceutically acceptable salt thereof. (5)R 10are each independently halogen, cyano, or substituted or unsubstituted alkyl, or a pharmaceutically acceptable salt thereof. (6)R 3 but, [ka] (In the formula, T1 is a carbon atom or a nitrogen atom, T2 is a carbon atom or a nitrogen atom, R 4 are each independently halogen, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; and m is an integer of 0 to 5.) The compound according to any one of the above (1) to (5), or a pharmaceutically acceptable salt thereof. (7)R 3 but, [ka] (wherein each symbol has the same meaning as in (6) above), or a pharmaceutically acceptable salt thereof. (8)R 4 are each independently a halogen atom, or a pharmaceutically acceptable salt thereof. (9)R 13 are each independently a hydrogen atom, or a substituted or unsubstituted alkyl, or a pharmaceutically acceptable salt thereof. (10)(i) A1 is C(R 5 ) and A2 is C(R 6 ) and A3 is C(R 7 ) or (ii) A1 is N and A2 is C(R 6 ) and A3 is C(R 7 ) or (iii) A1 is C(R 5 ) and A2 is C(R6 ) and A3 is N, or (iv) A1 is N and A2 is C(R 6 ) and A3 is N, or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (9). (11)(i) A1 is C(R 5 ) and A2 is C(R 6 ) and A3 is C(R 7 ) or (ii) A1 is N and A2 is C(R 6 ) and A3 is C(R 7 or a pharmaceutically acceptable salt thereof. (12)R 5 , R 6 and R 7 The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (11), wherein is a hydrogen atom. (13)R 1 The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (12), wherein is carboxy. (14)R 2 is alkyl, alkyl substituted with a substituted or unsubstituted non-aromatic heterocycle, or alkyl substituted with a substituted or unsubstituted aromatic heterocycle, or a pharmaceutically acceptable salt thereof. (15)R 2 is alkyl substituted with a substituted or unsubstituted non-aromatic heterocycle, or alkyl substituted with a substituted or unsubstituted aromatic heterocycle, or a pharmaceutically acceptable salt thereof. (16)-X- is -C(R 8 )(R 9 )- or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (15). (17)R 8 and R 9 The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (16), wherein is a hydrogen atom. (1') Formula (I): [ka] (In the formula, A1 is C(R 5 ) or N, A2 is C(R 6 ) or N, A3 is C(R 7 ) or N, R 5 , R 6 and R 7 each independently represents a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group; R 1 is carboxy or its equivalent or CH2COOH, R 2 is a substituted or unsubstituted alkyl or a substituted or unsubstituted non-aromatic heterocyclic group; -X- is -C(R 8 )(R 9 )-, -O-, or -N(R 11 )- and R 8 and R 9 are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl; R 11 is a hydrogen atom or a substituted or unsubstituted alkyl; [ka] The ring denoted by [ka] [ka] [ka] (In the formula, R10 are each independently halogen, cyano, hydroxy, substituted or unsubstituted alkyl, oxo, substituted or unsubstituted non-aromatic carbocyclic group, or substituted or unsubstituted alkyloxy; s is an integer from 0 to 9; R 13 are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl; R 3 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group.) or a pharmaceutically acceptable salt thereof. (1'-2) Formula (II): [ka] (In the formula, A1 is C(R 5 ) or N, A2 is C(R 6 ) or N, A3 is C(R 7 ) or N, R 5 , R 6 and R 7 each independently represents a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group; R 1 is carboxy or its equivalent or CH2COOH, R 2 is a substituted or unsubstituted alkyl or a substituted or unsubstituted non-aromatic heterocyclic group; R 13 are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl; R 3 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group; E1 is a carbon atom or a nitrogen atom, E2 is a carbon atom or a nitrogen atom, R 10 are each independently halogen, cyano, hydroxy, substituted or unsubstituted alkyl, oxo, substituted or unsubstituted non-aromatic carbocyclic group, or substituted or unsubstituted alkyloxy; and r is an integer of 0 to 9.) or a pharmaceutically acceptable salt thereof. (2') The compound according to (1') above, wherein s is an integer of 1 to 9, or a pharmaceutically acceptable salt thereof. (3') [ka] The ring shown by [ka] [ka] [ka] (wherein s' is an integer of 0 to 8, and other symbols are as defined in (1') above), or a pharmaceutically acceptable salt thereof. (4') [ka] The ring shown by [ka] (wherein s' is an integer of 0 to 8, and other symbols are as defined in (1') above), or a pharmaceutically acceptable salt thereof. (5')R 10are each independently halogen, cyano, or substituted or unsubstituted alkyl, or a pharmaceutically acceptable salt thereof according to any one of (1') to (4') and (1'-2) above. (6')R 3 but, [ka] (In the formula, T1 is a carbon atom or a nitrogen atom, T2 is a carbon atom or a nitrogen atom, R 4 are each independently halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, or substituted or unsubstituted alkylsulfonyl; R 14 is a hydrogen atom or a substituted or unsubstituted alkyl, m is an integer from 0 to 5; and n is an integer of 0 to 2.) The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1') to (5') and (1'-2). (7')R 3 but, [ka] (In the formula, T1 is C(R 12 ) or N, T2 is C(R 12 ) or N, R 12 each independently represents a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted alkylsulfonyl group; R 4has the same meaning as the above (6').) The compound according to the above (6') or a pharmaceutically acceptable salt thereof. (8')R 4 are each independently a halogen, and R 12 are each independently a hydrogen atom or a halogen atom, or a pharmaceutically acceptable salt thereof. (9')R 13 are each independently a hydrogen atom, or a substituted or unsubstituted alkyl, or a pharmaceutically acceptable salt thereof according to any one of the above (1') to (8') and (1'-2). (10')(i)A1 is C(R 5 ) and A2 is C(R 6 ) and A3 is C(R 7 ) or (ii) A1 is N and A2 is C(R 6 ) and A3 is C(R 7 ) or (iii) A1 is C(R 5 ) and A2 is C(R 6 ) and A3 is N, or (iv) A1 is N and A2 is C(R 6 ) and A3 is N, or a pharmaceutically acceptable salt thereof according to any one of the above (1') to (9') and (1'-2). (11')(i) A1 is C(R 5 ) and A2 is C(R 6 ) and A3 is C(R 7 ) or (ii) A1 is N and A2 is C(R 6 ) and A3 is C(R 7 or a pharmaceutically acceptable salt thereof. (12')R 6 is a hydrogen atom and R 5 and R 7 are each independently a hydrogen atom or a halogen atom, or a pharmaceutically acceptable salt thereof. (13')R 1 The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1') to (12') and (1'-2), wherein is carboxy. (14')R 2 is alkyl, alkyl substituted with a substituted or unsubstituted non-aromatic heterocycle, or alkyl substituted with a substituted or unsubstituted aromatic heterocycle, or a pharmaceutically acceptable salt thereof. (15')R 2 is alkyl substituted with a substituted or unsubstituted non-aromatic heterocycle or alkyl substituted with a substituted or unsubstituted aromatic heterocycle, or a pharmaceutically acceptable salt thereof. (16')-X- is -C(R 8 )(R 9 )- or a pharmaceutically acceptable salt thereof according to any one of the above (1') to (15'). (17')R 8 and R 9 The compound according to the above (16') or a pharmaceutically acceptable salt thereof, wherein is a hydrogen atom. (1'') Formula (I): [ka] (In the formula, A1 is C(R 5 ) or N, A2 is C(R 6 ) or N, A3 is C(R 7 ) or N, R 5 , R 6 and R 7 each independently represents a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, or a substituted or unsubstituted non-aromatic carbocyclic group; R 1 is carboxy or its equivalent or CH2COOH, R 2is a substituted or unsubstituted alkyl or a substituted or unsubstituted non-aromatic heterocyclic group; -X- is -C(R 8 )(R 9 )-, -O-, or -N(R 11 )- and R 8 and R 9 are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl; R 11 is a hydrogen atom or a substituted or unsubstituted alkyl; [ka] The ring denoted by [ka] [ka] [ka] (In the formula, R 10 are each independently halogen, cyano, hydroxy, substituted or unsubstituted alkyl, oxo, substituted or unsubstituted non-aromatic carbocyclic group, or substituted or unsubstituted alkyloxy; s is an integer from 0 to 9; R 13 are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl; R 3 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group.) or a pharmaceutically acceptable salt thereof. (2'') Formula (II): [ka] (In the formula, A1 is C(R 5 ) or N, A2 is C(R 6 ) or N, A3 is C(R 7 ) or N, R 5 , R 6 and R 7 each independently represents a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, or a substituted or unsubstituted non-aromatic carbocyclic group; R 1 is carboxy or its equivalent or CH2COOH, R 2 is a substituted or unsubstituted alkyl or a substituted or unsubstituted non-aromatic heterocyclic group; R 13 are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl; R 3 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group; E1 is a carbon atom or a nitrogen atom, E2 is a carbon atom or a nitrogen atom, R 10 are each independently halogen, cyano, hydroxy, substituted or unsubstituted alkyl, oxo, substituted or unsubstituted non-aromatic carbocyclic group, or substituted or unsubstituted alkyloxy; and r is an integer of 0 to 9.) or a pharmaceutically acceptable salt thereof. (3″) The compound according to (1″) above, wherein s is an integer of 1 to 9, or a pharmaceutically acceptable salt thereof. (4'') [ka] The ring shown by [ka] [ka] [ka] (wherein s' is an integer of 0 to 8, and the other symbols are as defined in (1'') above), or a pharmaceutically acceptable salt thereof. (5'') [ka] The ring shown by [ka] (wherein p is an integer of 0 to 6, and other symbols are as defined in (1'') above), or a pharmaceutically acceptable salt thereof. (5''-2) [ka] The ring shown by [ka] (wherein s' is an integer of 0 to 8, and the other symbols are as defined in (1'') above), or a pharmaceutically acceptable salt thereof. (5''-3) [ka] The ring shown by [ka] (wherein s is an integer of 1 to 9, and other symbols are as defined in (1'') above), or a pharmaceutically acceptable salt thereof. (6'')R 10 are each independently halogen, cyano, or substituted or unsubstituted alkyl, or a pharmaceutically acceptable salt thereof according to any one of (1'') to (5'', (5''-2) and (5''-3). (7'')R 3 but, [ka] (In the formula, T1 is a carbon atom or a nitrogen atom, T2 is a carbon atom or a nitrogen atom, R 4 are each independently halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, or substituted or unsubstituted alkylsulfonyl; R 14 is a hydrogen atom or a substituted or unsubstituted alkyl, m is an integer from 0 to 5; and n is an integer of 0 to 2.) The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1'') to (6''), (5''-2) and (5''-3). (8'')R 3 but, [ka] (In the formula, T1 is C(R 12 ) or N, R 12each independently represents a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted alkylsulfonyl group; R 4 and R 14 is the same as defined above in (7'').) or a pharmaceutically acceptable salt thereof. (9'')R 3 but, [ka] (In the formula, T1 is C(R 12 ) or N, R 12 are each independently a hydrogen atom or a halogen atom, R 4 are each independently a halogen atom, a cyano atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, or a substituted or unsubstituted non-aromatic carbocyclic group. (10'')R 4 are each independently a halogen, and R 12 are each independently a hydrogen atom or a halogen atom, or a pharmaceutically acceptable salt thereof. (11'')R 13 are each independently a hydrogen atom or a substituted or unsubstituted alkyl, or a pharmaceutically acceptable salt thereof, according to any one of (1'') to (10''), (5''-2) and (5''-3). (12'')(i)A1 is C(R 5 ) and A2 is C(R 6 ) and A3 is C(R 7 ) or (ii) A1 is N and A2 is C(R 6 ) and A3 is C(R 7) or (iii) A1 is C(R 5 ) and A2 is C(R 6 ) and A3 is N, or (iv) A1 is N and A2 is C(R 6 and A3 is N, or a pharmaceutically acceptable salt thereof, according to any one of the above (1'') to (11''), (5''-2) and (5''-3). (13'')(i) A1 is C(R 5 ) and A2 is C(R 6 ) and A3 is C(R 7 ) or (ii) A1 is N and A2 is C(R 6 ) and A3 is C(R 7 ) or a pharmaceutically acceptable salt thereof. (14'')R 5 is a hydrogen atom or a halogen atom, and R 6 is a hydrogen atom and R 7 The compound according to the above (12'') or (13'') or a pharmaceutically acceptable salt thereof, wherein is a hydrogen atom, halogen, or substituted or unsubstituted alkyloxy. (15'')R 1 The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1'') to (14''), (5''-2) and (5''-3), wherein is carboxy. (16'')R 2 is alkyl, alkyl substituted with a substituted or unsubstituted non-aromatic heterocycle, or alkyl substituted with a substituted or unsubstituted aromatic heterocycle, or a pharmaceutically acceptable salt thereof. (17'')R 2 is alkyl substituted with a substituted or unsubstituted non-aromatic heterocycle or alkyl substituted with a substituted or unsubstituted aromatic heterocycle, or a pharmaceutically acceptable salt thereof. (18'')-X- is -C(R 8 )(R9 )-, or a pharmaceutically acceptable salt thereof, of the compound according to any one of the above (1"), (3") to (17"), (5"-2) and (5"-3). (19'')R 8 and R 9 is a hydrogen atom, or a pharmaceutically acceptable salt thereof. (20'') The compound according to (1'') above, selected from the group consisting of compounds I-035, I-145, I-160, I-218, I-223, I-239, I-242, I-243, I-244, I-245, I-246, I-247, I-249, I-250, I-254, I-255, I-257, I-258, I-259, I-273 and I-274, or a pharmaceutically acceptable salt thereof. (18) A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (17), (1') to (17'), (1'-2), (1'') to (20''), (5''-2) and (5''-3). (19) The pharmaceutical composition according to (18) above, which is a GLP-1 receptor agonist. (20) A method for treating and / or preventing a disease involving the GLP-1 receptor, comprising administering a compound according to any one of (1) to (17), (1') to (17'), (1'-2), (1'') to (20''), (5''-2) and (5''-3) above, or a pharmaceutically acceptable salt thereof. (21) Use of the compound according to any one of the above (1) to (17), (1') to (17'), (1'-2), (1'') to (20''), (5''-2) and (5''-3), or a pharmaceutically acceptable salt thereof, for the manufacture of an agent for treating and / or preventing a disease involving the GLP-1 receptor. (22) The compound according to any one of (1) to (17), (1') to (17'), (1'-2), (1'') to (20''), (5''-2) and (5''-3), or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of a disease involving the GLP-1 receptor. [Effects of the Invention]

[0007] The compounds according to the present invention have GLP-1 receptor agonist activity and are useful as preventive and / or therapeutic agents for diseases involving the GLP-1 receptor, particularly non-insulin-dependent diabetes mellitus (type 2 diabetes) or obesity. DETAILED DESCRIPTION OF THE INVENTION

[0008] The meaning of each term used in this specification is explained below. Unless otherwise specified, each term has the same meaning whether used alone or in combination with other terms. The term "consisting of" means having only the constituent elements. The term "comprising" is meant to be open-ended and not to exclude unlisted elements. The present invention will be described below with reference to embodiments. Throughout this specification, singular expressions should be understood to include the plural concept unless otherwise specified. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, terms used in this specification should be understood to have the meaning commonly used in the above-mentioned field 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 the event of conflict, the present specification (including definitions) will prevail.

[0009] The term "halogen" includes fluorine, chlorine, bromine, and iodine atoms. Particularly, fluorine and chlorine atoms are preferred.

[0010] The term "alkyl" includes straight-chain or branched hydrocarbon groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, and n-decyl. Preferred embodiments of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. More preferred embodiments include methyl, ethyl, n-propyl, isopropyl, and tert-butyl.

[0011] The term "alkenyl" refers to a linear or branched hydrocarbon group having one or more double bonds at any position and having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms. Examples of alkenyl include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, and pentadecenyl. Preferred embodiments of "alkenyl" include vinyl, allyl, propenyl, isopropenyl and butenyl.

[0012] The term "alkynyl" refers to a linear or branched hydrocarbon group having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms, which has one or more triple bonds at any position. It may also have a double bond at any position. Examples of alkynyl include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, and decynyl. Preferred embodiments of "alkynyl" include ethynyl, propynyl, butynyl and pentynyl.

[0013] The term "aromatic carbocyclic group" refers to a monocyclic or bicyclic or more aromatic hydrocarbon group, such as phenyl, naphthyl, anthryl, and phenanthryl. A preferred embodiment of the "aromatic carbocyclic group" is phenyl.

[0014] The term "aromatic carbocyclic ring" refers to a ring derived from the above-mentioned "aromatic carbocyclic group". A preferred embodiment of the "aromatic carbocyclic ring" is a benzene ring.

[0015] The term "non-aromatic carbocyclic group" refers to a monocyclic or bicyclic or multicyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group. The term "non-aromatic carbocyclic group" refers to a monocyclic or bicyclic or multicyclic non-aromatic carbocyclic group that is fused with a ring in the above-mentioned "aromatic carbocyclic group," and the bond may be on either ring. For example, the following ring is shown: [ka] Furthermore, "non-aromatic carbocyclic group" also includes groups that form bridged or spiro rings, such as: [ka] The monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and even more preferably 4 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclohexadienyl. The non-aromatic carbocyclic group having two or more rings preferably has 8 to 20 carbon atoms, more preferably 8 to 16. Examples thereof include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, and fluorenyl.

[0016] The term "non-aromatic carbocyclic ring" refers to a ring derived from the above-mentioned "non-aromatic carbocyclic group".

[0017] The term "aromatic heterocyclic" refers to a monocyclic or bicyclic or more aromatic cyclic group having one or more identical or different heteroatoms selected from O, S and N in the ring. The aromatic heterocyclic group having two or more rings also includes a monocyclic or two or more ring aromatic heterocyclic group fused with a ring in the above-mentioned "aromatic carbocyclic group", and the bond may be on any of the rings. The monocyclic aromatic heterocyclic group is preferably 5- to 8-membered, more preferably 5- or 6-membered. Examples of the 5-membered aromatic heterocyclic group include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, and thiadiazolyl. Examples of the 6-membered aromatic heterocyclic group include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. The bicyclic aromatic heterocyclic group is preferably 8- to 10-membered, more preferably 9- or 10-membered. Examples thereof include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, and thiazolopyridyl. The aromatic heterocyclic group having three or more rings is preferably 13 to 15-membered, and examples thereof include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, and dibenzofuryl.

[0018] The term "aromatic heterocycle" refers to a ring derived from the above-mentioned "aromatic heterocyclic group". The monocyclic aromatic heterocycle is preferably 5- to 8-membered, more preferably 5- or 6-membered. Examples of the 5-membered aromatic heterocycle include a pyrroline ring, an imidazoline ring, a pyrazoline ring, a triazole ring, a tetrazole ring, a furan ring, a thiophene ring, an isoxazole ring, an oxazole ring, an oxadiazole ring, an isothiazole ring, a thiazole ring, and a thiadiazole ring. Examples of the 6-membered aromatic heterocycle include a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, and a triazine ring. The bicyclic aromatic heterocyclic group is preferably an 8- to 10-membered ring, more preferably an 9- or 10-membered ring. Examples thereof include an indole ring, an isoindole ring, an indazole ring, an indolizine ring, a quinoline ring, an isoquinoline ring, a cinnoline ring, a phthalazine ring, a quinazoline ring, a naphthyridine ring, a quinoxaline ring, a purine ring, a pteridine ring, a benzimidazole ring, a benzisoxazole ring, a benzoxazole ring, a benzoxadiazole ring, a benzisothiazole ring, a benzothiadiazole ring, a benzofuran ring, an isobenzofuran ring, a benzothiophene ring, a benzotriazole ring, an imidazopyridine ring, a triazolopyridine ring, an imidazothiazole ring, a pyrazinopyridazine ring, an oxazolopyridine ring, and a thiazolopyridine ring. The aromatic heterocyclic ring having three or more rings is preferably 13 to 15-membered, and examples thereof include a carbazole ring, an acridine ring, a xanthene ring, a phenothiazine ring, a phenoxathiin ring, a phenoxazine ring, and a dibenzofuran ring.

[0019] The term "non-aromatic heterocyclic group" refers to a monocyclic or bicyclic or more non-aromatic cyclic group having one or more identical or different heteroatoms selected from O, S, and N in the ring. Bicyclic or more non-aromatic heterocyclic groups include those in which a monocyclic or bicyclic or more non-aromatic heterocyclic group is fused with each ring of the above-mentioned "aromatic carbocyclic group," "non-aromatic carbocyclic group," and / or "aromatic heterocyclic group," as well as those in which a monocyclic or bicyclic or more non-aromatic carbocyclic group is fused with a ring of the above-mentioned "aromatic heterocyclic group," and the bond may be on any ring. Furthermore, the term "non-aromatic heterocyclic group" also encompasses groups that form bridged or spiro rings, such as: [ka] The monocyclic non-aromatic heterocyclic group is preferably 3 to 8-membered, and more preferably 4 to 6-membered. Examples of 3-membered non-aromatic heterocyclic groups include thiiranyl, oxiranyl, and aziridinyl. Examples of 4-membered non-aromatic heterocyclic groups include oxetanyl and azetidinyl. Examples of 5-membered non-aromatic heterocyclic groups include oxathiolanyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, tetrahydrofuryl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxolanyl, dioxolyl, and thiolanyl. Examples of 6-membered non-aromatic heterocyclic groups include dioxanyl, thianyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydropyranyl, dihydrooxazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxazinyl, thiinyl, thiazinyl, etc. Examples of 7-membered non-aromatic heterocyclic groups include hexahydroazepinyl, tetrahydrodiazepinyl, oxepanyl, etc. The non-aromatic heterocyclic group having two or more rings is preferably 8 to 20-membered, more preferably 8 to 10-membered, and examples thereof include indolinyl, isoindolinyl, chromanyl, and isochromanyl.

[0020] The term "non-aromatic heterocycle" refers to a ring derived from the above-mentioned "non-aromatic heterocyclic group".

[0021] The alkyl portion of "alkyloxy," "haloalkyloxy," "alkylcarbonyloxy," "alkylcarbonyl," "alkyloxycarbonyl," "alkylsulfanyl," "alkylsulfinyl," "alkylsulfonyl," "alkyloxyalkyloxy," and "alkyloxyalkyl" has the same meaning as the above "alkyl." The alkenyl moiety of "alkenyloxy", "alkenylcarbonyloxy", "alkenylcarbonyl", "alkenyloxycarbonyl", "alkenylsulfanyl", "alkenylsulfinyl" and "alkenylsulfonyl" has the same meaning as the above "alkenyl". The alkynyl moiety of "alkynyloxy", "alkynylcarbonyloxy", "alkynylcarbonyl", "alkynyloxycarbonyl", "alkynylsulfanyl", "alkynylsulfinyl" and "alkynylsulfonyl" has the same meaning as the above "alkynyl". The "equivalent thereof" in "carboxy or its equivalent" includes: [ka] (wherein R is a substituted or unsubstituted alkyl, a substituted or unsubstituted amine, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, or a substituted or unsubstituted aromatic heterocyclic group).

[0022] In this specification, the phrase "optionally substituted with substituent group A" means "optionally substituted with one or more groups selected from substituent group A." The same applies to substituent groups B, C, α, β, γ, γ', etc.

[0023] Examples of substituents such as "substituted alkyl," "substituted alkenyl," "substituted alkynyl," "substituted alkyloxy," "substituted alkenyloxy," "substituted alkynyloxy," "substituted alkylcarbonyloxy," "substituted alkenylcarbonyloxy," "substituted alkynylcarbonyloxy," "substituted alkylcarbonyl," "substituted alkenylcarbonyl," "substituted alkynylcarbonyl," "substituted alkyloxycarbonyl," "substituted alkenyloxycarbonyl," "substituted alkynyloxycarbonyl," "substituted alkylsulfanyl," "substituted alkenylsulfanyl," "substituted alkynylsulfanyl," "substituted alkylsulfinyl," "substituted alkenylsulfinyl," "substituted alkynylsulfinyl," "substituted alkylsulfonyl," "substituted alkenylsulfonyl," and "substituted alkynylsulfonyl" include the following Substituent Group A. A carbon atom at any position may be bonded to one or more groups selected from the following Substituent Group A. Substituent group A: halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, pentafluorothio, trialkylsilyl, Alkyloxy optionally substituted with substituent group α, alkenyloxy optionally substituted with substituent group α, alkynyloxy optionally substituted with substituent group α, alkylcarbonyloxy optionally substituted with substituent group α, alkenylcarbonyloxy optionally substituted with substituent group α, alkynylcarbonyloxy optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, alkyloxycarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α alkenyloxycarbonyl, alkynyloxycarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α, amino optionally substituted by substituent group β, imino optionally substituted by substituent group β, carbamoyl optionally substituted by substituent group β, sulfamoyl optionally substituted by substituent group β, Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic heterocyclic group optionally substituted with substituent group γ, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic oxy optionally substituted with substituent group γ, non-aromatic carbocyclic oxy optionally substituted with substituent group γ', aromatic heterocyclic oxy optionally substituted with substituent group γ, non-aromatic heterocyclic oxy optionally substituted with substituent group γ', aromatic carbocyclic carbonyloxy optionally substituted with substituent group γ, Non-aromatic carbocyclic carbonyloxy which may be substituted, aromatic heterocyclic carbonyloxy which may be substituted by substituent group γ, non-aromatic heterocyclic carbonyloxy which may be substituted by substituent group γ', aromatic carbocyclic carbonyl which may be substituted by substituent group γ, non-aromatic carbocyclic carbonyl which may be substituted by substituent group γ', aromatic heterocyclic carbonyl which may be substituted by substituent group γ, non-aromatic heterocyclic carbonyl which may be substituted by substituent group γ', aromatic carbocyclic oxycarbonyl which may be substituted by substituent group γ, non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ, aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic alkyloxy optionally substituted with substituent group γ, non-aromatic carbocyclic alkyloxy optionally substituted with substituent group γ', aromatic heterocyclic alkyloxy optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxy optionally substituted with substituent group γ', aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyloxycarbonyl which may be substituted, aromatic heterocyclic alkyloxycarbonyl which may be substituted with substituent group γ, non-aromatic heterocyclic alkyloxycarbonyl which may be substituted with substituent group γ', aromatic carbocyclic sulfanyl which may be substituted with substituent group γ, non-aromatic carbocyclic sulfanyl which may be substituted with substituent group γ', aromatic heterocyclic sulfanyl which may be substituted with substituent group γ, non-aromatic heterocyclic sulfanyl which may be substituted with substituent group γ', aromatic carbocyclic sulfinyl which may be substituted with substituent group γ,Non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ, and non-aromatic heterocyclic sulfonyl optionally substituted with substituent group γ'.

[0024] Substituent group α: halogen, hydroxy, carboxy, alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, sulfanyl, and cyano.

[0025] Substituent group β: halogen, hydroxy, carboxy, cyano, alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, alkynyl optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α, Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic heterocyclic group optionally substituted with substituent group γ, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyl optionally substituted with substituent group γ', aromatic heterocyclic alkyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyl optionally substituted with substituent group γ', aromatic carbocyclic carbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyl optionally substituted with substituent group γ', aromatic heterocyclic carbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfanyl optionally substituted with substituent group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ and non-aromatic heterocyclic sulfonyl optionally substituted with substituent group γ'.

[0026] Substituent group γ: Substituent group α, alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl.

[0027] Substituent group γ': Substituent group γ and oxo.

[0028] Substituents on the ring of an "aromatic carbocyclic group" and "aromatic heterocyclic group", such as "substituted aromatic carbocyclic group", "substituted aromatic carbocyclic groupoxy", "substituted aromatic heterocyclic groupoxy", "substituted aromatic carbocyclic groupcarbonyloxy", "substituted aromatic heterocyclic groupcarbonyloxy", "substituted aromatic carbocyclic groupcarbonyl", "substituted aromatic heterocyclic groupcarbonyl", "substituted aromatic carbocyclic groupcarbonyl", "substituted aromatic heterocyclic groupcarbonyl", "substituted aromatic carbocyclic groupoxycarbonyl", "substituted aromatic heterocyclic groupoxycarbonyl", "substituted aromatic carbocyclic groupsulfanyl", "substituted aromatic heterocyclic groupsulfanyl", "substituted aromatic carbocyclic groupsulfinyl", "substituted aromatic heterocyclic groupsulfinyl", "substituted aromatic carbocyclic groupsulfonyl", and "substituted aromatic heterocyclic groupsulfonyl" include the following substituent group B. An atom at any position on the ring may be bonded to one or more groups selected from the following substituent group B. Substituent group B: halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, pentafluorothio, trialkylsilyl, Alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, alkynyl optionally substituted with substituent group α, alkyloxy optionally substituted with substituent group α, alkenyloxy optionally substituted with substituent group α, alkynyloxy optionally substituted with substituent group α, alkylcarbonyloxy optionally substituted with substituent group α, alkenylcarbonyloxy optionally substituted with substituent group α, alkynylcarbonyloxy optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, substituted with substituent group α alkyloxycarbonyl optionally substituted with substituent group α, alkenyloxycarbonyl optionally substituted with substituent group α, alkynyloxycarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α, amino optionally substituted by substituent group β, imino optionally substituted by substituent group β, carbamoyl optionally substituted by substituent group β, sulfamoyl optionally substituted by substituent group β, An aromatic carbocyclic group optionally substituted with a substituent group γ, a non-aromatic carbocyclic group optionally substituted with a substituent group γ', an aromatic heterocyclic group optionally substituted with a substituent group γ, a non-aromatic heterocyclic group optionally substituted with a substituent group γ', an aromatic carbocyclic oxy optionally substituted with a substituent group γ, a non-aromatic carbocyclic oxy optionally substituted with a substituent group γ', an aromatic heterocyclic oxy optionally substituted with a substituent group γ, a non-aromatic heterocyclic oxy optionally substituted with a substituent group γ', an "aromatic carbocyclic carbonyloxy optionally substituted with a substituent group γ" ", "non-aromatic carbocyclic carbonyloxy optionally substituted by substituent group γ'", "aromatic heterocyclic carbonyloxy optionally substituted by substituent group γ", and "non-aromatic heterocyclic carbonyloxy optionally substituted by substituent group γ'", aromatic carbocyclic carbonyl optionally substituted by substituent group γ, non-aromatic carbocyclic carbonyl optionally substituted by substituent group γ', aromatic heterocyclic carbonyl optionally substituted by substituent group γ, non-aromatic heterocyclic carbonyl optionally substituted by substituent group γ', aromatic carbocyclic carbonyl optionally substituted by substituent group γ heterocyclic oxycarbonyl, non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyl optionally substituted with substituent group γ', aromatic heterocyclic alkyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyl optionally substituted with substituent group γ', aromatic carbocyclic alkyloxy optionally substituted with substituent group γ', non-aromatic carbocyclic alkyloxy optionally substituted with substituent group γ', aromatic heterocyclic alkyloxy optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxy optionally substituted with substituent group γ', aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ',Aromatic carbocyclic alkyloxyalkyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyloxyalkyl optionally substituted with substituent group γ', aromatic heterocyclic alkyloxyalkyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxyalkyl optionally substituted with substituent group γ', aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfanyl optionally substituted with substituent group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ, and non-aromatic heterocyclic sulfonyl optionally substituted with substituent group γ'. ,

[0029] Substituents on the ring of the "non-aromatic carbocyclic group," "substituted non-aromatic heterocyclic group," "substituted non-aromatic carbocycleoxy," "substituted non-aromatic heterocycleoxy," "substituted non-aromatic carbocyclecarbonyloxy," "substituted non-aromatic heterocyclecarbonyloxy," "substituted non-aromatic carbocyclecarbonyl," "substituted non-aromatic heterocyclecarbonyl," "substituted non-aromatic carbocycleoxycarbonyl," "substituted non-aromatic heterocycleoxycarbonyl," "substituted non-aromatic carbocyclesulfanyl," "substituted non-aromatic heterocyclesulfanyl," "substituted non-aromatic carbocyclesulfinyl," "substituted non-aromatic heterocyclesulfinyl," "substituted non-aromatic carbocyclesulfonyl," and "substituted non-aromatic heterocyclesulfonyl" include the following substituent group C. An atom at any position on the ring may be bonded to one or more groups selected from the following substituent group C. Substituent group C: Substituent group B and oxo.

[0030] When a "non-aromatic carbocycle", "non-aromatic heterocycle", "non-aromatic carbocyclic group" or "non-aromatic heterocyclic group" is substituted with "oxo", it means a ring in which two hydrogen atoms on a carbon atom are replaced as follows: [ka]

[0031] Substituents for "substituted amino", "substituted imino", "substituted carbamoyl" and "substituted sulfamoyl" include the following Substituent Group D. Each group may be substituted with one or two groups selected from Substituent Group D. Substituent group D: halogen, hydroxy, carboxy, cyano, alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, alkynyl optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α, amino optionally substituted by substituent group β, imino optionally substituted by substituent group β, carbamoyl optionally substituted by substituent group β, sulfamoyl optionally substituted by substituent group β, Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic heterocyclic group optionally substituted with substituent group γ, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyl optionally substituted with substituent group γ', aromatic heterocyclic alkyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyl optionally substituted with substituent group γ', aromatic carbocyclic carbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyl optionally substituted with substituent group γ', aromatic heterocyclic carbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfanyl optionally substituted with substituent group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ and non-aromatic heterocyclic sulfonyl optionally substituted with substituent group γ'.

[0032] In formula (I), the atom of ring P marked with a is bonded to the group represented by -X-, and the atom of ring Q marked with b is bonded to the group represented by -O-. In formula (III), the atom of ring P marked with a is bonded to the group represented by -CH2-, and the atom of ring Q marked with b is bonded to the group represented by -O-. [ka] In the ring represented by the formula: 10 and includes, for example, the rings shown below: [ka] [ka] The ring shown by [ka] When it is shown as (R 10 ) p indicates that the bond may be formed on ring P, [ka] When it is shown as (R 10 ) s’ indicates that it may be bonded on ring P and / or ring Q.

[0033] In the compound represented by formula (I) or formula (II), A1, A2, A3, R 1 , R 2 , -X-, R 3 , R 13 , E1, E 2、 r, R 10 and [ka] Preferred embodiments of the ring represented by the formula are shown below: As the compound represented by formula (I) or formula (II), all combinations of the specific examples shown below are exemplified. A1 is C(R 5 ) or N (referred to as A-1). A1 is C(R 5 ) can be mentioned (referred to as A-2). A1 includes C(H) (referred to as A-3). A1 includes C(F) (referred to as A-4). A1 includes N (referred to as A-5).

[0034] A2 is C(R 6 ) or N (referred to as B-1). A2 is C(R 6 ) (referred to as B-2). A2 can be C(H) (referred to as B-3). A2 includes N (referred to as B-4).

[0035] A3 is C(R 7 ) or N (referred to as C-1). A3 is C(R 7 ) (referred to as C-2). A3 can be classified as C(F) (let's call it C-3). A3 can be C(Cl) (referred to as C-4). A3 can be C(H) (C-5). A3 includes N (referred to as C-6).

[0036] R 5 , R 6 and R 7 are each independently a hydrogen atom, a halogen atom, a cyano, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyloxy, or a substituted or unsubstituted non-aromatic carbocyclic group (referred to as D-1). R 5 , R 6 and R 7 are each independently a hydrogen atom, a halogen atom, a cyano, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy (referred to as D-2). R5 , R 6 and R 7 are each independently a hydrogen atom, a halogen atom or a cyano (referred to as D-3). R 5 , R 6 and R 7 are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyloxy (referred to as D-4). R 5 , R 6 and R 7 are each independently a hydrogen atom or a halogen (referred to as D-5). R 5 , R 6 and R 7 is a hydrogen atom (referred to as D-6). R 5 is a hydrogen atom or a halogen atom, and R 6 is a hydrogen atom and R 7 Examples of the substituted or unsubstituted alkyloxy include a hydrogen atom, a halogen atom, and substituted or unsubstituted alkyloxy (referred to as D-7). R 6 is a hydrogen atom, and R 5 and R 7 are each independently a hydrogen atom or a halogen (referred to as D-8).

[0037] R 1 is carboxy or its equivalent, or CH2COOH (referred to as E-1). R 1 Examples of the alkyl group include carboxy and its equivalent (referred to as E-2). R 1 is carboxy or one of the groups shown below: [ka] (wherein R is a substituted or unsubstituted alkyl, a substituted or unsubstituted amine, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, or a substituted or unsubstituted aromatic heterocyclic group) (referred to as E-3). R 1 Examples of the alkyl group include carboxy (referred to as E-4).

[0038] R 2 is a substituted or unsubstituted alkyl or a substituted or unsubstituted non-aromatic heterocyclic group (referred to as F-1). R 2 is substituted or unsubstituted alkyl (referred to as F-2). R 2 is substituted or unsubstituted methyl (referred to as F-3). R 2 Examples of the alkyl substituted with a substituted or unsubstituted non-aromatic heterocycle, an alkyl substituted with a substituted or unsubstituted aromatic heterocyclic group, or an unsubstituted alkyl (referred to as F-4). R 2 Examples of the alkyl group include oxetanylalkyl and alkylimidazolylalkyl (referred to as F-5). R 2 Examples of the alkyl group include oxetanylmethyl and ethylimidazolylmethyl (referred to as F-6). R 2 Examples of the methyl group include oxetanylmethyl (referred to as F-7). R 2 Examples of the alkylimidazolylmethyl include alkylimidazolylmethyl (referred to as F-8). R 2 Examples of the methylimidazolyl methyl group include ethylimidazolylmethyl (referred to as F-9).

[0039] -X- is -C(R 8 )(R 9 )-, -O- or -N(R 11 )- is listed (referred to as G-1). -X- is -C(R 8 )(R 9 )- or -O- (referred to as G-2). -X- includes -O- (referred to as G-3). -X- is -C(R 8 )(R 9 )- are listed (referred to as G-4). -X- includes -C(H)(H)- (referred to as G-5). -X- is -N(R 11 )- are listed (referred to as G-6).

[0040] R 8 and R 9 are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl (referred to as H-1). R 8 and R 9 are each independently a hydrogen atom or a halogen (referred to as H-2). R 8 and R 9 is a hydrogen atom (referred to as H-3).

[0041] R 11 is a hydrogen atom or a substituted or unsubstituted alkyl (referred to as I-1). R 11 is a hydrogen atom (referred to as I-2). R 11 is substituted or unsubstituted alkyl (referred to as I-3).

[0042] [ka] Examples of the ring represented by the formula include the ring shown below (referred to as J-1). [ka] [ka] [ka] [ka] Examples of the ring represented by the formula include the ring shown below (referred to as J-2). [ka] [ka] Examples of the ring represented by the formula include the ring shown below (referred to as J-3). [ka] [ka] Examples of the ring represented by the formula include the ring shown below (referred to as J-4). [ka] [ka] [ka] [ka] Examples of the ring represented by the formula include the ring shown below (referred to as J-5). [ka] [ka] Examples of the ring represented by the formula include the ring shown below (referred to as J-6). [ka] [ka] Examples of the ring represented by the formula include the ring shown below (referred to as J-7). [ka] [ka] Examples of the ring represented by the formula include the ring shown below (referred to as J-8). [ka] [ka] Examples of the ring represented by the formula include the ring shown below (referred to as J-9). [ka] [ka] Examples of the ring represented by the formula include the ring shown below (referred to as J-10). [ka] [ka] Examples of the ring represented by the formula include the ring shown below (referred to as J-11). [ka] [ka] Examples of the ring represented by the formula include the ring shown below (referred to as J-12). [ka] [ka] Examples of the ring represented by the formula include the ring shown below (referred to as J-13). [ka] [ka] Examples of the ring represented by the formula include the ring shown below (referred to as J-14). [ka] [ka] Examples of the ring represented by the formula include the ring shown below (referred to as J-15). [ka] [ka] Examples of the ring represented by the formula include the ring shown below (referred to as J-16). [ka] [ka] Examples of the ring represented by the formula include the ring shown below (referred to as J-17). [ka] [ka] Examples of the ring represented by the formula include the ring shown below (referred to as J-18). [ka]

[0043] R 10 are each independently a halogen, cyano, hydroxy, a substituted or unsubstituted alkyl, oxo, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted alkyloxy (referred to as K-1). R 10 are each independently halogen, cyano, substituted or unsubstituted alkyl, oxo, or substituted or unsubstituted alkyloxy (referred to as K-2). R 10 are each independently a halogen or cyano (referred to as K-3). R 10 are each independently a halogen (referred to as K-4). R 10 are each independently cyano (referred to as K-5). R 10 are each independently substituted or unsubstituted alkyl (referred to as K-6). R 10 are each independently substituted or unsubstituted alkyloxy (referred to as K-7). R 10 When is attached to ring P, R 10 Each of the groups independently represents a halogen or a substituted or unsubstituted alkyl (referred to as K-8). R 10 When is attached to ring P, R 10 are each independently halogen or alkyl (referred to as K-9). R 10 When is attached to ring P, R 10are each independently an alkyl (referred to as K-10). R 10 When is attached to ring P, R 10 are each independently a halogen (referred to as K-11). R 10 When attached to ring Q, R 10 Each of the groups independently represents a halogen or a substituted or unsubstituted alkyl (referred to as K-12). R 10 When attached to ring Q, R 10 are each independently a halogen or an alkyl substituted with a halogen (referred to as K-13). R 10 When attached to ring Q, R 10 are each independently an alkyl substituted with halogen or fluorine (referred to as K-14). R 10 When attached to ring Q, R 10 are each independently alkyl substituted with halogen (referred to as K-15). R 10 When attached to ring Q, R 10 each independently represents alkyl substituted with fluorine (referred to as K-16). R 10 When attached to ring Q, R 10 are each independently a halogen (referred to as K-17).

[0044] s is an integer of 0 to 9 (assumed to be L-1). s is an integer of 0 to 3 (defined as L-2). s is an integer of 0 to 2 (defined as L-3). s is an integer of 0 or 1 (defined as L-4). s may be an integer of 1 or 2 (defined as L-5). s can be 0 (let's say L-6). s can be 1 (let's say L-7). s can be 2 (let's call it L-8).

[0045] s' is an integer of 0 to 8 (referred to as M-1). s' is an integer of 0 to 3 (referred to as M-2). s' is an integer of 0 to 2 (referred to as M-3). s' may be an integer of 0 or 1 (referred to as M-4). s' can be 0 (assuming it is M-5). s' can be 1 (assuming it is M-6).

[0046] R 3 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group (referred to as N-1). R 3 is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group (referred to as N-2). R 3 is an aromatic carbocyclic group optionally substituted with substituent group A1 (halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, and cyano) or an aromatic heterocyclic group optionally substituted with substituent group A1 (referred to as N-3). R 3 includes phenyl which may be substituted by substituent group A2 (halogen, alkyl, haloalkyl, haloalkyloxy and cyano), pyridyl which may be substituted by substituent group A2, pyrimidyl which may be substituted by substituent group A2, pyrazyl which may be substituted by substituent group A2, pyrazolyl which may be substituted by substituent group A2, imidazolyl which may be substituted by substituent group A2, isoxazolyl which may be substituted by substituent group A2 or thiazolyl which may be substituted by substituent group A2 (referred to as N-4). R 3 is phenyl optionally substituted with a substituent group A2 (halogen, alkyl, haloalkyl, haloalkyloxy and cyano) (referred to as N-5). R 3 teeth, [ka] Examples include a group represented by the following formula (referred to as N-6). R 3 teeth, [ka] Examples include a group represented by the following formula (referred to as N-7): R 3 teeth, [ka] Examples include a group represented by the following formula (referred to as N-8). R 3 teeth, [ka] Examples include a group represented by the following formula (referred to as N-9): R 3 teeth, [ka] Examples include groups represented by the following formula (referred to as N-10): R 3 teeth, [ka] Examples include a group represented by the following formula (referred to as N-11): R 3 teeth, [ka] Examples include a group represented by the following formula (referred to as N-12): R 3 teeth, [ka] Examples include a group represented by the following formula (referred to as N-13): R 3 teeth, [ka] Examples include a group represented by the following formula (referred to as N-14):

[0047] T1 can be a carbon atom or a nitrogen atom (referred to as O-1). T1 is C(R 12 ) or N (referred to as O-2). T1 may be a carbon atom (assumed to be O-3). T1 is C(R 12 ) (referred to as O-4). T1 may be a nitrogen atom (assumed to be O-5).

[0048] T2 may be a carbon atom or a nitrogen atom (referred to as P-1). T2 is C(R 12 ) or N (referred to as P-2). T2 may be a carbon atom (referred to as P-3). T2 is C(R 12 ) (referred to as P-4). T2 may be a nitrogen atom (referred to as P-5).

[0049] R 4 each independently represents a halogen, cyano, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyloxy, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted alkylsulfonyl (referred to as Q-1). R 4 are each independently a halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or a substituted or unsubstituted non-aromatic carbocyclic group (referred to as Q-2). R 4are each independently a halogen, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy (referred to as Q-3). R 4 are each independently a halogen or a substituted or unsubstituted alkyl (referred to as Q-4). R 4 are each independently a halogen or an alkyl unsubstituted or substituted with a halogen (referred to as Q-5). R 4 are each independently a halogen or a substituted or unsubstituted alkyloxy (referred to as Q-6). R 4 are each independently a halogen or an alkyloxy unsubstituted or substituted with a halogen (referred to as Q-7). R 4 are each independently exemplified by alkyloxy substituted with halogen or fluorine, or unsubstituted alkyloxy (referred to as Q-8). R 4 are each independently a halogen, cyano, unsubstituted alkyl, unsubstituted alkyloxy or an unsubstituted non-aromatic carbocyclic group (referred to as Q-9). R 4 are each independently a halogen (referred to as Q-10).

[0050] R 14 is a hydrogen atom or a substituted or unsubstituted alkyl (referred to as R-1). R 14 is substituted or unsubstituted alkyl (referred to as R-2). R 14 Examples of the alkyl group include alkyl (referred to as R-3).

[0051] R 12 each independently represents a hydrogen atom, a halogen atom, a cyano, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyloxy, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted alkylsulfonyl (referred to as S-1). R 12 are each independently a hydrogen atom or a halogen (referred to as S-2). R 12 is a hydrogen atom (referred to as S-3). R 12 are each independently a halogen (referred to as S-4).

[0052] m is an integer of 0 to 5 (referred to as T-1). m is an integer of 0 to 3 (referred to as T-2). m can be 1 or 2 (referred to as T-3). m can be 1 (referred to as T-4). m can be 2 (T-5).

[0053] n is an integer of 0 to 2 (referred to as U-1). n can be 0 or 1 (referred to as U-2). n can be 0 (U-3). n can be 1 (U-4). n can be 2 (U-5).

[0054] R 13 are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl (referred to as V-1). R 13 are each independently a hydrogen atom or a substituted or unsubstituted alkyl (referred to as V-2). R 13 are each independently substituted or unsubstituted alkyl (referred to as V-3). R 13 One of the groups is a hydrogen atom and the other is a substituted or unsubstituted alkyl (referred to as V-4). R 13 is a hydrogen atom (referred to as V-5).

[0055] E1 may be a carbon atom or a nitrogen atom (referred to as W-1). E1 includes a carbon atom (referred to as W-2). E1 includes a nitrogen atom (referred to as W-3).

[0056] E2 may be a carbon atom or a nitrogen atom (referred to as X-1). E2 is a carbon atom (referred to as X-2). E2 includes a nitrogen atom (referred to as X-3).

[0057] r is an integer of 0 to 9 (referred to as Y-1). r is an integer of 1 to 9 (referred to as Y-2). r is an integer of 1 to 3 (Y-3). r is an integer of 1 to 2 (Y-4). r can be 3 (let's call it Y-5). r can be 2 (let's call it Y-6). r can be 1 (let's call it Y-7).

[0058] p is an integer of 0 to 6 (referred to as Z-1). p is an integer of 0 to 3 (referred to as Z-2). p is an integer of 0 to 2 (referred to as Z-3). p is an integer of 0 or 1 (referred to as Z-4). p can be 0 (let's say Z-5). p can be 1 (referred to as Z-6).

[0059] Formula (III): [ka] In the compound represented by the formula 2 , R 3 , R 7 and [ka] Preferred embodiments of the ring represented by the formula are shown below: As the compound represented by formula (III), all combinations of the specific examples shown below are exemplified. A1 is C(R 5 ) or N (referred to as A'-1). A1 is C(R 5 ) (referred to as A'-2). A1 includes C(H) (referred to as A'-3). A1 includes C(F) (referred to as A'-4). A1 includes N (referred to as A'-5).

[0060] R 5 is a hydrogen atom or a halogen (referred to as B'-1). R 5 is a hydrogen atom (referred to as B'-2). R 5 Examples of the group include halogen (referred to as B'-3).

[0061] R 7 is a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyloxy (assumed to be C'-1). R 7 is a hydrogen atom or a halogen (referred to as C'-2). R 7 is a hydrogen atom (assumed to be C'-3). R 7 Examples of the halogen atom include halogen (assumed to be C'-4).

[0062] R 2 is an alkyl substituted with a substituted or unsubstituted non-aromatic heterocycle or an alkyl substituted with a substituted or unsubstituted aromatic heterocycle (referred to as D'-1). R 2 The alkyl group may be oxetanylalkyl or alkylimidazolylalkyl (referred to as D'-2). R 2 Examples of the alkyl group include oxetanylmethyl and ethylimidazolylmethyl (referred to as D'-3). R 2 Examples of the alkyl group include oxetanylmethyl (referred to as D'-4). R 2 Examples of the alkylimidazolylmethyl include alkylimidazolylmethyl (referred to as D'-5). R 2 Examples of the alkyl group include ethylimidazolylmethyl (referred to as D'-6).

[0063] [ka] Examples of the ring represented by the formula include the rings shown below (referred to as E'-1). [ka] [ka] Examples of the ring represented by the formula include the rings shown below (referred to as E'-2). [ka] [ka] Examples of the ring represented by the formula include the rings shown below (referred to as E'-3). [ka] [ka] Examples of the ring represented by the formula include the rings shown below (referred to as E'-4). [ka]

[0064] R 10are each independently a halogen, cyano, or substituted or unsubstituted alkyl (referred to as F'-1). R 10 are each independently a halogen or a substituted or unsubstituted alkyl (referred to as F'-2). R 10 are each independently a halogen (referred to as F'-3). R 10 are each independently cyano (referred to as F'-4). R 10 are each independently substituted or unsubstituted alkyl (referred to as F'-5). R 10 When is attached to ring P, R 10 are each independently a halogen or a substituted or unsubstituted alkyl (referred to as F'-6). R 10 When is attached to ring P, R 10 are each independently halogen or alkyl (referred to as F'-7). R 10 When is attached to ring P, R 10 are each independently an alkyl group (referred to as F'-8). R 10 When is attached to ring P, R 10 are each independently a halogen (referred to as F'-9). R 10 When attached to ring Q, R 10 can be halogen or substituted or unsubstituted alkyl (referred to as F'-10). R 10 When attached to ring Q, R 10 is halogen or alkyl substituted with halogen (referred to as F'-11). R 10 When attached to ring Q, R 10 Examples of the alkyl group include alkyl substituted with halogen or fluorine (referred to as F'-12). R 10 When attached to ring Q, R 10Examples of the alkyl group include alkyl substituted with halogen (referred to as F'-13). R 10 When attached to ring Q, R 10 Examples of the alkyl group include alkyl substituted with fluorine (referred to as F'-14). R 10 When attached to ring Q, R 10 Examples of the halogen atom include halogen (F'-15).

[0065] p can be an integer of 0 or 1 (referred to as G'-1). p can be 0 (referred to as G'-2). p can be 1 (referred to as G'-3).

[0066] R 3 teeth, [ka] Examples include a group represented by the following formula (referred to as H'-1). R 3 teeth, [ka] (referred to as H'-2). R 3 teeth, [ka] (referred to as H'-3). R 3 teeth, [ka] (referred to as H'-4). R 3 teeth, [ka] (referred to as H'-5).

[0067] T1 is C(R 12 ) or N (referred to as I'-1). T1 is C(R 12 ) (referred to as I'-2). T1 includes N (referred to as I'-3).

[0068] R 4 are each independently a halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or a substituted or unsubstituted non-aromatic carbocyclic group (referred to as J'-1). R 4 are each independently halogen, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy (referred to as J'-2). R 4 are each independently a halogen or a substituted or unsubstituted alkyl (referred to as J'-3). R 4 are each independently a halogen, an alkyl substituted with a halogen, or an unsubstituted alkyl (referred to as J'-4). R 4 are each independently a halogen or a substituted or unsubstituted alkyloxy (referred to as J'-5). R 4 are each independently a halogen, an alkyloxy substituted with a halogen, or an unsubstituted alkyloxy (referred to as J'-6). R 4 are each independently exemplified by alkyloxy substituted with halogen or fluorine, or unsubstituted alkyloxy (referred to as J'-7). R 4 are each independently a halogen, cyano, unsubstituted alkyl, unsubstituted alkyloxy or an unsubstituted non-aromatic carbocyclic group (referred to as J'-8). R 4 are each independently a halogen (referred to as J'-9).

[0069] R 14 is an unsubstituted alkyl (referred to as K'-1). R 14 is methyl, ethyl, n-propyl or isopropyl (referred to as K'-2). R 14 The alkyl group may be methyl or ethyl (referred to as K'-3). R 14 Examples of the alkyl group include methyl (referred to as K'-4).

[0070] R 12 are each independently a hydrogen atom or a halogen (referred to as L'-1). R 12 is a hydrogen atom (referred to as L'-2). R 12 are each independently a halogen (referred to as L'-3).

[0071] The following aspects are particularly preferred. (i) Formula (I): [ka] (In the formula, A1 is C(R 5 ) or N, A2 is C(R 6 ) or N, A3 is C(R 7 ) or N, R 5 , R 6 and R 7 each independently represents a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group; R 1 is carboxy, R 2 is an alkyl substituted with a substituted or unsubstituted non-aromatic heterocycle or an alkyl substituted with a substituted or unsubstituted aromatic heterocycle; -X- is -C(R 8 )(R9 )- and R 8 and R 9 are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl; [ka] The ring denoted by [ka] (In the formula, R 10 are each independently halogen, cyano, hydroxy, substituted or unsubstituted alkyl, oxo, substituted or unsubstituted non-aromatic carbocyclic group, or substituted or unsubstituted alkyloxy; s is an integer from 0 to 9; R 13 are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl; R 3 is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof. (ii) Formula (I): [ka] (In the formula, A1 is C(R 5 ) or N, A2 is C(R 6 ) or N, A3 is C(R 7 ) or N, R 5 , R 6 and R 7 each independently represents a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group; R 1 is carboxy, R2 is an alkyl substituted with a substituted or unsubstituted non-aromatic heterocycle or an alkyl substituted with a substituted or unsubstituted aromatic heterocycle; -X- is -C(R 8 )(R 9 )- and R 8 and R 9 are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl; [ka] The ring denoted by [ka] (In the formula, R 10 are each independently halogen, cyano, hydroxy, substituted or unsubstituted alkyl, oxo, substituted or unsubstituted non-aromatic carbocyclic group, or substituted or unsubstituted alkyloxy; s' is an integer of 0 to 8. R 13 are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl; R 3 is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof. (iii) Formula (I): [ka] (In the formula, (i) A1 is C(R 5 ) and A2 is C(R 6 ) and A3 is C(R 7 ) or (ii) A1 is N and A2 is C(R 6 ) and A3 is C(R 7 ) and R5 , R 6 and R 7 each independently represents a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group; R 1 is carboxy, R 2 is an alkyl substituted with a substituted or unsubstituted non-aromatic heterocycle or an alkyl substituted with a substituted or unsubstituted aromatic heterocycle; -X- is -C(R 8 )(R 9 )- and R 8 and R 9 are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl; [ka] The ring denoted by [ka] (In the formula, R 10 are each independently halogen, cyano, hydroxy, substituted or unsubstituted alkyl, oxo, substituted or unsubstituted non-aromatic carbocyclic group, or substituted or unsubstituted alkyloxy; s is an integer of 1 to 9; R 13 are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl; R 3 is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof. (iv) Formula (I): [ka] (In the formula, (i) A1 is C(R 5) and A2 is C(R 6 ) and A3 is C(R 7 ) or (ii) A1 is N and A2 is C(R 6 ) and A3 is C(R 7 ) and R 5 , R 6 and R 7 each independently represents a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group; R 1 is carboxy, R 2 is an alkyl substituted with a substituted or unsubstituted non-aromatic heterocycle or an alkyl substituted with a substituted or unsubstituted aromatic heterocycle; -X- is -C(R 8 )(R 9 )- and R 8 and R 9 are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl; [ka] The ring denoted by [ka] (In the formula, R 10 are each independently halogen, cyano, hydroxy, substituted or unsubstituted alkyl, oxo, substituted or unsubstituted non-aromatic carbocyclic group, or substituted or unsubstituted alkyloxy; s' is an integer of 0 to 8. R 13 are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl; R 3is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof. (v) Formula (I): [ka] (In the formula, (i) A1 is C(R 5 ) and A2 is C(R 6 ) and A3 is C(R 7 ) or (ii) A1 is N and A2 is C(R 6 ) and A3 is C(R 7 ) and R 5 , R 6 and R 7 each independently represents a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group; R 1 is carboxy, R 2 is an alkyl substituted with a substituted or unsubstituted non-aromatic heterocycle or an alkyl substituted with a substituted or unsubstituted aromatic heterocycle; -X- is -C(R 8 )(R 9 )- and R 8 and R 9 are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl; [ka] The ring denoted by [ka] (In the formula, R 10are each independently halogen, cyano, hydroxy, substituted or unsubstituted alkyl, oxo, substituted or unsubstituted non-aromatic carbocyclic group, or substituted or unsubstituted alkyloxy; s' is an integer of 0 to 8. R 13 are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl; R 3 teeth, [ka] (In the formula, T1 is a carbon atom or a nitrogen atom, T2 is a carbon atom or a nitrogen atom, R 4 are each independently halogen, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; R 14 is a hydrogen atom or a substituted or unsubstituted alkyl, m is an integer from 0 to 5; and n is an integer of 0 to 2. A compound represented by the formula: embedded image or a pharmaceutically acceptable salt thereof. (vi) Formula (I): [ka] (In the formula, (i) A1 is C(R 5 ) and A2 is C(R 6 ) and A3 is C(R 7 ) or (ii) A1 is N and A2 is C(R 6 ) and A3 is C(R 7 ) and R 5 , R 6 and R 7 each independently represents a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group; R 1 is carboxy, R 2 is an alkyl substituted with a substituted or unsubstituted non-aromatic heterocycle or an alkyl substituted with a substituted or unsubstituted aromatic heterocycle; -X- is -C(R 8 )(R 9 )- and R 8 and R 9 are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl; [ka] The ring denoted by [ka] (In the formula, R 10 are each independently halogen, cyano, hydroxy, substituted or unsubstituted alkyl, oxo, substituted or unsubstituted non-aromatic carbocyclic group, or substituted or unsubstituted alkyloxy; s' is an integer of 0 to 8. R 13 are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl; R 3 teeth, [ka] (In the formula, T1 is C(R 12 ) or N, T2 is C(R 12 ) or N, R 12each independently represents a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted alkylsulfonyl group; R 4 are each independently halogen, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy. A compound represented by the formula: A compound represented by the formula: or a pharmaceutically acceptable salt thereof. (vii) Formula (I): [ka] (In the formula, (i) A1 is C(R 5 ) and A2 is C(R 6 ) and A3 is C(R 7 ) or (ii) A1 is N and A2 is C(R 6 ) and A3 is C(R 7 ) and R 5 , R 6 and R 7 each independently represents a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group; R 1 is carboxy, R 2 is oxetanylmethyl or alkylimidazolylmethyl, -X- is -C(R 8 )(R 9 )- and R 8 and R 9 are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl; [ka] The ring denoted by [ka] (In the formula, R 10 are each independently halogen, cyano, hydroxy, substituted or unsubstituted alkyl, oxo, substituted or unsubstituted non-aromatic carbocyclic group, or substituted or unsubstituted alkyloxy; s' is an integer of 0 to 8. R 13 are each independently a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl; R 3 teeth, [ka] (In the formula, T1 is C(R 12 ) or N, T2 is C(R 12 ) or N, R 12 are each independently a hydrogen atom or a halogen atom, R 4 are each independently halogen, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy. A compound represented by the formula: A compound represented by the formula: or a pharmaceutically acceptable salt thereof. (viii) Formula (I): [ka] (In the formula, (i) A1 is C(R 5 ) and A2 is C(R 6 ) and A3 is C(R 7 ) or (ii) A1 is N and A2 is C(R 6 ) and A3 is C(R 7 ) and R 5 , R 6 and R 7each independently represents a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group; R 1 is carboxy, R 2 is oxetanylmethyl or alkylimidazolylmethyl, -X- is -C(R 8 )(R 9 )- and R 8 and R 9 is a hydrogen atom, [ka] The ring denoted by [ka] (In the formula, R 10 are each independently halogen, cyano, hydroxy, substituted or unsubstituted alkyl, oxo, substituted or unsubstituted non-aromatic carbocyclic group, or substituted or unsubstituted alkyloxy; s' is an integer of 0 to 8. R 13 is a hydrogen atom, R 3 teeth, [ka] (In the formula, T1 is C(R 12 ) or N, T2 is C(R 12 ) and R 12 are each independently a hydrogen atom or a halogen atom, R 4 are each independently halogen, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy. A compound represented by the formula: A compound represented by the formula: or a pharmaceutically acceptable salt thereof. (ix) Formula (I): [ka] (In the formula, (i) A1 is C(R 5 ) and A2 is C(R 6 ) and A3 is C(R 7 ) or (ii) A1 is N and A2 is C(R 6 ) and A3 is C(R 7 ) and R 5 , R 6 and R 7 each independently represents a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group; R 1 is carboxy, R 2 is oxetanylmethyl or alkylimidazolylmethyl, -X- is -C(R 8 )(R 9 )- and R 8 and R 9 is a hydrogen atom, [ka] The ring denoted by [ka] (In the formula, R 10 are each independently halogen, cyano, hydroxy, substituted or unsubstituted alkyl, oxo, substituted or unsubstituted non-aromatic carbocyclic group, or substituted or unsubstituted alkyloxy; and p is an integer of 0 to 6. R 13 is a hydrogen atom, R 3 teeth, [ka] (In the formula, T1 is C(R 12 ) or N, R 12 are each independently a hydrogen atom or a halogen atom, R 4 are each independently halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or a substituted or unsubstituted non-aromatic carbocyclic group. A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof. (x) Formula (III): [ka] (In the formula, A1 is C(R 5 ) or N, R 5 is a hydrogen atom or a halogen, R 7 is a hydrogen atom, halogen, or substituted or unsubstituted alkyloxy; R 2 is an alkyl substituted with a substituted or unsubstituted non-aromatic heterocycle or an alkyl substituted with a substituted or unsubstituted aromatic heterocycle; [ka] The ring denoted by [ka] (In the formula, R 10 are each independently halogen, cyano, or substituted or unsubstituted alkyl; p is 0 or 1. R 3 teeth, [ka] (In the formula, T1 is C(R 12 ) or N, R 12 are each independently a hydrogen atom or a halogen atom, R 4 are each independently halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or a substituted or unsubstituted non-aromatic carbocyclic group; R 14 is unsubstituted alkyl. A compound represented by the formula: ) or a pharmaceutically acceptable salt thereof. (xi) Formula (III): [ka] (In the formula, A1 is C(R 5 ) or N, R 5 is a hydrogen atom or a halogen, R 7 is a hydrogen atom, halogen, or substituted or unsubstituted alkyloxy; R 2 is an alkyl substituted with a substituted or unsubstituted non-aromatic heterocycle or an alkyl substituted with a substituted or unsubstituted aromatic heterocycle; [ka] The ring denoted by [ka] (In the formula, R 10 are each independently halogen, cyano, or substituted or unsubstituted alkyl; p is 0 or 1. R 3 teeth, [ka] (In the formula, T1 is C(R 12 ) or N, R 12 are each independently a hydrogen atom or a halogen atom, R 4 are each independently halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or a substituted or unsubstituted non-aromatic carbocyclic group. A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.

[0072] The compounds represented by formula (I), formula (II), or formula (III) are not limited to specific isomers, and include all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers, rotamers, tautomers as described below, etc.), racemates, or mixtures thereof. [ka]

[0073] One or more hydrogen, carbon and / or other atoms of the compounds of formula (I), formula (II) or formula (III) may be replaced with isotopes of hydrogen, carbon and / or other atoms, respectively. Examples of such isotopes include: 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, 123 I and 36The isotopes of the compounds represented by formula (I), formula (II), or formula (III) include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as Cl. The compounds represented by formula (I), formula (II), or formula (III) also include compounds substituted with such isotopes. The isotope-substituted compounds are also useful as pharmaceuticals, and include all radiolabeled compounds of the compounds represented by formula (I), formula (II), or formula (III). The present invention also encompasses a "radiolabeling method" for producing the "radiolabeled compounds," and the "radiolabeled compounds" are useful as research and / or diagnostic tools in metabolism pharmacokinetic studies and binding assays.

[0074] Radiolabeled compounds of Formula (I), (II), or (III) can be prepared by methods well known in the art. For example, tritium-labeled compounds of Formula (I), (II), or (III) can be prepared by introducing tritium into a specific compound of Formula (I), (II), or (III) via catalytic dehalogenation using tritium. This method involves reacting an appropriately halogenated precursor of a compound of Formula (I), (II), or (III) with tritium gas in the presence of a suitable catalyst, such as Pd / C, with or without a base. Other suitable methods for preparing tritium-labeled compounds can be found in "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)." 14 C-labeled compounds are 14 It can be prepared by using a raw material having C carbon.

[0075] Pharmaceutically acceptable salts of the compound represented by formula (I), formula (II), or formula (III) include, for example, salts of the compound represented by formula (I), formula (II), or formula (III) with an alkali metal (e.g., lithium, sodium, potassium, etc.), alkaline earth metal (e.g., calcium, barium, etc.), magnesium, transition metal (e.g., zinc, iron, etc.), ammonia, an organic base (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, methylamine, Examples of suitable salts include salts with amino acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and organic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc.). Particularly preferred are salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, and methanesulfonic acid. These salts can be formed by conventional methods.

[0076] A compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, may form a solvate (e.g., a hydrate), a co-crystal, and / or a crystalline polymorph. The present invention encompasses various solvates, co-crystals, and crystalline polymorphs. A "solvate" may be coordinated with a compound represented by Formula (I), Formula (II), or Formula (III) with any number of solvent molecules (e.g., water molecules). When a compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, is left in the atmosphere, it may absorb moisture, resulting in the formation of adsorbed water or the formation of a hydrate. Furthermore, a compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, may form a crystalline polymorph by recrystallization. A "co-crystal" refers to a compound represented by Formula (I), Formula (II), or Formula (III), or a salt thereof, and a counter molecule present in the same crystal lattice, and may contain any number of counter molecules.

[0077] The compounds of Formula (I), Formula (II), or Formula (III) or pharmaceutically acceptable salts thereof may form prodrugs, and the present invention also encompasses such various prodrugs. Prodrugs are derivatives of the compounds of the present invention having chemically or metabolically decomposable groups, and are compounds that become pharmaceutically active compounds of the present invention in vivo by solvolysis or under physiological conditions. Prodrugs include compounds that are converted to compounds of Formula (I), Formula (II), or Formula (III) by enzymatic oxidation, reduction, hydrolysis, or the like under physiological conditions in vivo, and compounds that are converted to compounds of Formula (I), Formula (II), or Formula (III) by hydrolysis with gastric acid or the like. Methods for selecting and preparing appropriate prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985." Prodrugs may themselves be active.

[0078] When the compound represented by formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof has a hydroxyl group, examples of the prodrug include acyloxy derivatives and sulfonyloxy derivatives produced by reacting the compound having a hydroxyl group with an appropriate acyl halide, an appropriate acid anhydride, an appropriate sulfonyl chloride, an appropriate sulfonyl anhydride or a mixed anhydride, or by reacting the compound using a condensing agent. For example, CH3COO-, C2H5COO-, tert-BuCOO-, C 15 H 31 Examples include COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOCCH2CH2COO-, CH3CH(NH2)COO-, CH2N(CH3)2COO-, CH3SO3-, CH3CH2SO3-, CF3SO3-, CH2FSO3-, CF3CH2SO3-, p-CH3O-PhSO3-, PhSO3-, and p-CH3PhSO3-.

[0079] (Method for producing the compound of the present invention) The compounds represented by formula (I), formula (II), or formula (III) can be produced, for example, by the general synthetic methods shown below. All of the starting materials and reaction reagents used in these syntheses are commercially available, or can be produced using commercially available compounds according to methods well known in the art. Extraction, purification, etc. can be carried out by treatments commonly used in organic chemistry experiments. The compounds of the present invention can be synthesized by referring to methods known in the art. In the following steps, when a compound has a substituent that interferes with the reaction (e.g., hydroxy, mercapto, amino, formyl, carbonyl, carboxyl, etc.), the compound may be protected in advance by a method described in "Protective Groups in Organic Synthesis" by Theodora W. Greene (John Wiley & Sons), etc., and the protecting group may be removed at a desired stage. In addition, for all of the following steps, the order of the steps to be performed can be changed as appropriate, and each intermediate may be isolated and used in the next step. The reaction time, reaction temperature, solvent, reagent, protecting group, etc. are all merely examples and are not particularly limited as long as they do not interfere with the reaction.

[0080] General methods for synthesizing the compounds of the present invention are shown below. All starting materials and reagents used in these syntheses are commercially available or can be prepared using commercially available compounds according to methods well known in the art.

[0081] The compounds of the present invention represented by general formula (I), formula (II) or formula (III) can be produced, for example, by the synthesis route shown below. General synthesis method 1

[0082] [A method] [ka] (In the formula, R 10’ are each independently cyano, substituted or unsubstituted alkyl, or a substituted or unsubstituted non-aromatic carbocyclic group, s'' is an integer of 0 to 7, and X 1 is a leaving group such as a halogen, and X 2 is a leaving group such as halogen, and other symbols have the same meanings as in (1) above. [Process A-1] Compound a2 can be obtained by reacting compound a1 with 2-nitrobenzenesulfonyl chloride in the presence of a base. Examples of the base include sodium hydroxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, calcium carbonate, cesium carbonate, pyridine, triethylamine, etc., and it can be used in an amount of 1 to 5 molar equivalents relative to compound a1. The reaction temperature is -10°C to 80°C, preferably 10°C to 60°C. The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours. Examples of reaction solvents include dichloromethane, tetrahydrofuran, dioxane, acetonitrile, etc., which can be used alone or in combination. [Process A-2] Compound a4 can be obtained by reacting compound a2 with compound a3 in an acid solvent. The reaction temperature is 20°C to 80°C, preferably 30°C to 60°C. The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours. Examples of reaction solvents include acetic acid and concentrated sulfuric acid, which can be used alone or in combination. [Process A-3] Compound a4 can be reacted with a metal catalyst, potassium acetate, and bis(pinacolato)diborane, and then hydrogen peroxide and water can be added to obtain compound a5. Examples of the metal catalyst include [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, and bis(tri-tert-butylphosphine)palladium, and these can be used in an amount of 0.001 to 0.5 molar equivalents relative to compound a4. The reaction temperature is from 0° C. to the reflux temperature of the solvent, and in some cases, the reaction is carried out at a temperature under microwave irradiation. The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours. Examples of reaction solvents include tetrahydrofuran, toluene, DMF, and dioxane, which can be used alone or in combination. [Process A-4] Compound a7 can be obtained by reacting compound a5 with compound a6 in the presence of a base. The reaction temperature is from 0° C. to the reflux temperature of the solvent. The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours. As the base, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, etc. can be used. Examples of reaction solvents include methanol, ethanol, acetonitrile, tetrahydrofuran, dimethylformamide, etc., and these can be used alone or in combination. [Process A-5] Compound a8 can be obtained by reacting compound a7 with a thiol in the presence of a base. The reaction temperature is 0 to 80°C, preferably 30 to 60°C. The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours. As the base, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, etc. can be used. As the thiol, ethanethiol, dodecane-1-thiol, etc. can be used. Examples of reaction solvents include acetonitrile, tetrahydrofuran, DMF, etc., which can be used alone or in combination. [Process A-6] Compound a10 can be obtained by reacting compound a8 with compound a9 in the presence of a base. The reaction temperature is from 0° C. to the reflux temperature of the solvent. The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours. As the base, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, etc. can be used. Examples of reaction solvents include methanol, ethanol, acetonitrile, tetrahydrofuran, DMF, etc., and these can be used alone or in combination.

[0083] General synthesis method 2 [Method B] [ka] (In the formula, X 1 and X 2 has the same meaning as in [Method A] above, and the other symbols have the same meaning as in (1) above. [Process B-1] Compound b3 can be obtained by reacting compound b1 with compound b2 in the presence of a base. The reaction temperature is from 0° C. to the reflux temperature of the solvent. The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours. As the base, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, etc. can be used. Examples of reaction solvents include methanol, ethanol, acetonitrile, tetrahydrofuran, dimethylformamide, etc., and these can be used alone or in combination. [Process B-2] Compound b4 can be obtained by reacting compound b3 with a fluorinating agent. The reaction temperature is 0 to 80°C, preferably 30 to 60°C. The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours. As the fluorinating agent, N-trifluoride, N-diethylaminosulfur, etc. can be used. Examples of reaction solvents include dichloromethane, tetrahydrofuran, etc., which can be used alone or in combination. [Process B-3] Compound b5 can be obtained by reacting compound b4 with a basic aqueous solution. The reaction temperature is 0°C to 50°C, preferably 0°C to 30°C. The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours. As the base, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. can be used. Examples of reaction solvents include methanol, ethanol, water, acetone, acetonitrile, and tetrahydrofuran, and these can be used alone or in combination. [Process B-4] Compound b7 can be obtained by reacting compound b5 with compound b6 in the presence of a base. The reaction temperature is from 0° C. to the reflux temperature of the solvent. The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours. As the base, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, etc. can be used. Examples of reaction solvents include methanol, ethanol, acetonitrile, tetrahydrofuran, dimethylformamide, etc., and these can be used alone or in combination.

[0084] General synthesis method 3 [C method] [ka] (In the formula, X 1 and X 2 has the same meaning as in [Method A] above, and the other symbols have the same meaning as in (1) above. [Process C-1] Compound c3 can be obtained by reacting compound c1 with compound c2 in the presence of a base. The reaction temperature is from 0° C. to the reflux temperature of the solvent. The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours. As the base, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, etc. can be used. Examples of reaction solvents include methanol, ethanol, acetonitrile, tetrahydrofuran, DMF, etc., and these can be used alone or in combination. [Process C-2] Compound c5 can be obtained by reacting compound c3 with compound c4 in the presence of a base. The reaction temperature is from 0° C. to the reflux temperature of the solvent. The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours. As the base, sodium hydride, potassium tert-butoxide, sodium tert-butoxide, etc. can be used. Examples of reaction solvents include methanol, ethanol, acetonitrile, tetrahydrofuran, DMF, etc., and these can be used alone or in combination.

[0085] General synthesis method 4 [D method] [ka] (In the formula, X 3 is a leaving group such as a halogen, and X 4 is a leaving group such as halogen, and other symbols have the same meanings as in (1) above. [Process D-1] Compound d3 can be obtained by reacting compound d1 with compound d2 in the presence of a base. The reaction temperature is 0°C to 50°C, preferably 0°C to 30°C. The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours. As the base, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, etc. can be used. Examples of reaction solvents include methanol, ethanol, acetonitrile, tetrahydrofuran, dimethylformamide, etc., and these can be used alone or in combination. [Process D-2] Compound d5 can be obtained by reacting compound d3 with compound d4 in the presence of a metal catalyst and zinc fluoride. The metal catalyst may be bis-tert-tributylphosphine palladium, which can be used in an amount of 0.001 to 0.5 molar equivalents relative to compound d3. The reaction temperature is from 20° C. to the reflux temperature of the solvent, and in some cases, the reaction is carried out at a temperature under microwave irradiation. The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours. Examples of reaction solvents include tetrahydrofuran, toluene, DMF, dioxane, water, etc., and these can be used alone or in combination. [Process D-3] Compound d7 can be obtained by reacting compound d5 with compound d6 in the presence of a condensing agent, optionally with a base, and then reacting in an acid solution. Examples of the condensing agent include dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, EDC, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, and HATU, and can be used in an amount of 1 to 5 molar equivalents relative to compound d6. Examples of the base include triethylamine, diisopropylethylamine, and paradimethylaminopyridine. The acid includes acetic acid and the like. The reaction temperature is -20°C to 60°C, preferably 0°C to 30°C, for the condensation reaction, and 10°C to 80°C for the subsequent reaction in the acid solution. The reaction time for the condensation reaction is 0.1 to 24 hours, preferably 1 to 12 hours, and the subsequent reaction in the acid solution is 0.5 to 10 hours.

[0086] General synthesis method 5 [E-method] [ka] (In the formula, R 10’ , s'', X 1 and X 2 has the same meaning as in [Method A] above, and the other symbols have the same meaning as in (1) above. [Process E-1] Compound e3 can be obtained by reacting compound e1 with compound e2 in the presence of a base. Examples of the base include sodium hydroxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, calcium carbonate, cesium carbonate, pyridine, triethylamine, etc., and it can be used in an amount of 1 to 5 molar equivalents relative to compound e1. The reaction temperature is -10°C to 80°C, preferably 10°C to 60°C. The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours. Examples of reaction solvents include dichloromethane, tetrahydrofuran, dioxane, acetonitrile, toluene, etc., and these can be used alone or in combination. [Process E-2] Compound e4 can be obtained by reacting compound e3 with diphosphorus pentoxide and phosphoryl chloride. The reaction temperature is -10°C to 80°C, preferably 10°C to 60°C. The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours. As the reaction solvent, toluene or the like can be used. [Process E-3] Compound e5 can be obtained by reacting compound e4 with formic acid and an amine in the presence of a ruthenium catalyst. Examples of the ruthenium catalyst include [(R,R)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamido]chloro(p-cymene)ruthenium, [(S,S)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamido]chloro(p-cymene)ruthenium, and the like, which can be used in an amount of 0.05 to 1 molar equivalent relative to compound e4. The amine may be triethylamine, which can be used in an amount of 1 to 3 molar equivalents relative to compound e4. The reaction temperature is -10°C to 80°C, preferably 10°C to 60°C. The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours. Acetonitrile or the like can be used as the reaction solvent. As an alternative to step E-3, step E-3' can be carried out. [Process E-3'] Compound e5 can be obtained by reacting compound e4 with a reducing agent. The reducing agent includes sodium borohydride, which can be used in an amount of 1 to 5 molar equivalents relative to compound e4. The reaction temperature is -10°C to 80°C, preferably 0°C to 30°C. The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours. Methanol or the like can be used as the reaction solvent. [Process E-4] Compound e6 can be obtained by reacting compound e5 with trifluoroacetic anhydride. The reaction temperature is -10°C to 80°C, preferably 10°C to 40°C. The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours. Examples of reaction solvents include dichloromethane, tetrahydrofuran, dioxane, acetonitrile, etc., which can be used alone or in combination. [Process E-5] Compound e7 can be obtained by reacting compound e6 with boron tribromide, aluminum chloride, or the like. The reaction temperature is -10°C to 80°C, preferably 0°C to 40°C. The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours. As the reaction solvent, dichloromethane, toluene, or the like can be used. [Process E-6] Compound e9 can be obtained by reacting compound e7 with compound e8 in the presence of a base. The reaction temperature is from 0° C. to the reflux temperature of the solvent. The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours. As the base, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, etc. can be used. Examples of reaction solvents include methanol, ethanol, acetonitrile, tetrahydrofuran, dimethylformamide, etc., and these can be used alone or in combination. [Process E-7] Compound e10 can be obtained by reacting compound e9 with a base. The reaction temperature is 0 to 80°C, preferably 10 to 60°C. The reaction time is 0.5 to 12 hours, preferably 1 to 10 hours. As the base, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. can be used. Examples of reaction solvents include methanol, ethanol, water, acetone, acetonitrile, and tetrahydrofuran, and these can be used alone or in combination. [Process E-8] Compound e12 can be obtained by reacting compound e10 with compound e11 in the presence of a base. The reaction temperature is from 0° C. to the reflux temperature of the solvent. The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours. As the base, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, etc. can be used. Examples of reaction solvents include methanol, ethanol, acetonitrile, tetrahydrofuran, dimethylformamide, etc., and these can be used alone or in combination.

[0087] General synthesis method 6 [F method] [ka] (In the formula, R 50 is alkyl, t is an integer of 0 to 3, and X 3 is a leaving group such as a halogen, and X 1 and X 2 has the same meaning as in [Method A] above, and the other symbols have the same meaning as in (1) above. [Process F-1] Compound f3 can be obtained by allowing compound f2 to act on compound f1 in the presence of a base. The reaction temperature is from 0° C. to the reflux temperature of the solvent. The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours. As the base, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, silver carbonate, etc. can be used. Examples of reaction solvents include methanol, ethanol, acetonitrile, tetrahydrofuran, dimethylformamide, dioxane, etc., and these can be used alone or in combination. [Process F-2] Compound f4 can be obtained by reacting compound f3 with a reducing agent. Examples of the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride, and diisobutylaluminum hydride, and can be used in an amount of 1 to 10 molar equivalents relative to compound f3. The reaction temperature is from 0°C to reflux temperature, preferably from 20°C to reflux temperature. The reaction time is 0.2 to 48 hours, preferably 1 to 24 hours. Examples of reaction solvents include methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, dichloromethane, water, etc., and these can be used alone or in combination. [Process F-3] Compound f6 can be obtained by reacting compounds f4 and f5 in the presence of a metal catalyst and a base, optionally with the addition of tetrabutylammonium bromide or the like. Examples of the metal catalyst include palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, and bis(tri-tert-butylphosphine)palladium, and can be used in an amount of 0.001 to 0.5 molar equivalents relative to compound f4. Examples of the base include dicyclohexylamine, potassium tert-butoxide, sodium carbonate, potassium carbonate, etc., and it can be used in an amount of 1 to 10 molar equivalents relative to compound f4. The reaction temperature is from 20° C. to the reflux temperature of the solvent, and in some cases, the reaction is carried out at a temperature under microwave irradiation. The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours. Examples of reaction solvents include tetrahydrofuran, toluene, DMF, dioxane, water, etc., and these can be used alone or in combination. [Process F-4] Compound f7 can be obtained by reacting compound f6 with hydrogen gas in the presence of a metal catalyst. Examples of the metal catalyst include palladium-carbon, platinum oxide, rhodium-aluminum oxide, and chlorotris(triphenylphosphine)rhodium(I), and can be used in an amount of 0.01 to 100 weight percent based on compound f6. The hydrogen pressure can be 1 to 50 atmospheres. Cyclohexene, 1,4-cyclohexadiene, formic acid, ammonium formate, etc. can also be used as the hydrogen source. The reaction temperature is from 0°C to the reflux temperature of the solvent, preferably from 20°C to 40°C. The reaction time is 0.5 to 72 hours, preferably 1 to 12 hours. Examples of reaction solvents include methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, toluene, ethyl acetate, acetic acid, water, etc., and these can be used alone or in combination. [Process F-5] Compound f8 can be obtained by reacting compound f7 with hydrazine monohydrate or the like. The reaction temperature is 0°C to 100°C, preferably 20°C to 80°C. The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours. As the reaction solvent, ethanol or the like can be used. [Process F-6] Compound f9 can be obtained by reacting compound f8 with trifluoroacetic anhydride. The reaction temperature is -10°C to 80°C, preferably 0°C to 40°C. The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours. Examples of reaction solvents include dichloromethane, tetrahydrofuran, dioxane, acetonitrile, etc., which can be used alone or in combination. [Process F-7] Compound f10 can be obtained by reacting compound f9 with triphenylphosphine and a Mitsunobu reagent. Examples of Mitsunobu reagents include DEAD and DIAD, which can be used in an amount of 1 to 5 molar equivalents relative to compound f9. The reaction temperature is 0°C to 60°C, preferably 10°C to 40°C. The reaction time is 0.1 to 12 hours, preferably 0.2 to 6 hours. Examples of reaction solvents include tetrahydrofuran, dioxane, ethyl acetate, toluene, acetonitrile, etc., and these can be used alone or in combination. [Process F-8] Compound f11 can be obtained by reacting compound f10 with a base. The reaction temperature is 0 to 80°C, preferably 10 to 60°C. The reaction time is 0.5 to 12 hours, preferably 1 to 10 hours. As the base, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. can be used. Examples of reaction solvents include methanol, ethanol, water, acetone, acetonitrile, and tetrahydrofuran, and these can be used alone or in combination. [Process F-9] Compound f13 can be obtained by allowing compound f12 to act on compound f11 in the presence of a base. The reaction temperature is from 0° C. to the reflux temperature of the solvent. The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours. As the base, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, etc. can be used. Examples of reaction solvents include methanol, ethanol, acetonitrile, tetrahydrofuran, dimethylformamide, etc., and these can be used alone or in combination.

[0088] General synthesis method 7 [G method] [ka] (In the formula, X 1 and X 2 has the same meaning as in [Method A] above, and the other symbols have the same meaning as in (1) above. [Process G-1] Compound g3 can be obtained by allowing compound g2 to act on compound g1 in the presence of a base. The reaction temperature is from 0° C. to the reflux temperature of the solvent. The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours. As the base, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, etc. can be used. Examples of reaction solvents include methanol, ethanol, acetonitrile, tetrahydrofuran, dimethylformamide, dioxane, etc., and these can be used alone or in combination. [Process G-2] Compound g4 can be obtained by reacting compound g3 with an acid or a Lewis acid. Examples of the acid include hydrochloric acid-ethyl acetate, hydrochloric acid-methanol, hydrochloric acid-dioxane, sulfuric acid, formic acid, trifluoroacetic acid, etc. Examples of the Lewis acid include trimethylsilyl iodide, BBr3, AlCl3, BF3·(Et2O), etc., and these can be used in an amount of 1 to 10 molar equivalents relative to compound g3. The reaction temperature is 0°C to 60°C, preferably 0°C to 20°C. The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours. Examples of reaction solvents include methanol, ethanol, water, acetone, acetonitrile, DMF, dichloromethane, etc., and these can be used alone or in combination. [Process G-3] Compound g6 can be obtained by allowing compound g4 to undergo a reaction with compound g5 in the presence of a base. The reaction temperature is from 0° C. to the reflux temperature of the solvent. The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours. As the base, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, etc. can be used. Examples of reaction solvents include methanol, ethanol, acetonitrile, tetrahydrofuran, dimethylformamide, etc., and these can be used alone or in combination.

[0089] General synthesis method 8 [H method] [ka] (In the formula, X 4 is a leaving group such as a halogen, and X 1 has the same meaning as in [Method A] above, and the other symbols have the same meaning as in (1) above. [Process H-1] Compound h3 can be obtained by allowing compound h2 to act on compound h1 in the presence of a base. The reaction temperature is from 0° C. to the reflux temperature of the solvent. The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours. As the base, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, silver carbonate, etc. can be used. Examples of reaction solvents include methanol, ethanol, acetonitrile, tetrahydrofuran, dimethylformamide, dioxane, etc., and these can be used alone or in combination. [Process H-2] Compound h5 can be obtained by reacting compound h3 with compound h4 in the presence of a metal catalyst and zinc fluoride. The metal catalyst may be bis-tert-tributylphosphine palladium, which can be used in an amount of 0.001 to 0.5 molar equivalents relative to compound h3. The reaction temperature is from 20° C. to the reflux temperature of the solvent, and in some cases, the reaction is carried out at a temperature under microwave irradiation. The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours. Examples of reaction solvents include tetrahydrofuran, toluene, DMF, dioxane, water, etc., and these can be used alone or in combination. [Process H-3] Compound h5 can be reacted with compound h6 in the presence of a condensing agent, optionally with a base, and then reacted in an acid solution to obtain compound h7. Condensing agents include dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, EDC, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, HATU, etc., and can be used in an amount of 1 to 5 molar equivalents relative to compound h5. Examples of the base include triethylamine, diisopropylethylamine, and paradimethylaminopyridine. The acid includes acetic acid and the like. The reaction temperature is -20°C to 60°C, preferably 0°C to 30°C, for the condensation reaction, and 10°C to 80°C for the subsequent reaction in the acid solution. The reaction time for the condensation reaction is 0.1 to 24 hours, preferably 1 to 12 hours, and the subsequent reaction in the acid solution is 0.5 to 10 hours.

[0090] General synthesis method 9 [I Method] [ka] [ka] (In the formula, R 50 is alkyl, t is an integer of 0 to 3, and X 3 is a leaving group such as a halogen, M is Li, MgCl, MgBr, etc., and X 1 and X 2 has the same meaning as in [Method A] above, and the other symbols have the same meaning as in (1) above. [Process I-1] Compound f3 can be reacted with a basic aqueous solution to obtain compound i1. The reaction temperature is 0°C to 70°C, preferably 0°C to 50°C. The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours. As the base, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. can be used. Examples of reaction solvents include methanol, ethanol, water, acetone, acetonitrile, and tetrahydrofuran, and these can be used alone or in combination. [Process I-2] Compound i3 can be obtained by reacting compound i1 with i2 in the presence of a condensing agent. Examples of the condensing agent include dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, EDC, and HATU, and can be used in an amount of 1 to 5 molar equivalents relative to compound i2. Examples of the base include triethylamine, diisopropylethylamine, and paradimethylaminopyridine. The reaction temperature is -20°C to 80°C, preferably 10°C to 70°C. The reaction time is 0.1 to 24 hours, preferably 1 to 12 hours. Examples of reaction solvents include tetrahydrofuran, dichloromethane, DMF, etc., which can be used alone or in combination. [Process I-3] Compound i4 can be obtained by reacting compound i3 with an organometallic reagent. Examples of the organometallic reagent include Grignard reagents and organolithium reagents, which can be used in an amount of 1 to 10 molar equivalents relative to compound i3. The reaction temperature is -40°C to 60°C, preferably -20°C to 40°C. The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours. Examples of reaction solvents include tetrahydrofuran, diethyl ether, dioxane, etc., which can be used alone or in combination. [Process I-4] Compound i5 can be obtained by reacting compound i4 with formic acid and an amine in the presence of a ruthenium catalyst. Examples of the ruthenium catalyst include [(R,R)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamido]chloro(p-cymene)ruthenium, [(S,S)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamido]chloro(p-cymene)ruthenium, and the like, which can be used in an amount of 0.05 to 1 molar equivalent relative to compound i4. The amine may be triethylamine or the like, which can be used in an amount of 1 to 5 molar equivalents relative to compound i4. The reaction temperature is -10°C to 80°C, preferably 10°C to 60°C. The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours. Acetonitrile or the like can be used as the reaction solvent. [Process I-5] Compound i5 and f5 are reacted in the presence of a metal catalyst and a base, with the addition of tetrabutylammonium bromide or the like as needed, to give compound i6. Examples of the metal catalyst include palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, and bis(tri-tert-butylphosphine)palladium, and can be used in an amount of 0.001 to 0.5 molar equivalents relative to compound i5. Examples of the base include dicyclohexylamine, potassium tert-butoxide, sodium carbonate, and potassium carbonate, and can be used in an amount of 1 to 10 molar equivalents relative to compound i5. The reaction temperature is from 20° C. to the reflux temperature of the solvent, and in some cases, the reaction is carried out at a temperature under microwave irradiation. The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours. Examples of reaction solvents include tetrahydrofuran, toluene, DMF, dioxane, water, etc., and these can be used alone or in combination. [Process I-6] Compound i7 can be obtained by reacting compound i6 with hydrogen gas in the presence of a metal catalyst. Examples of the metal catalyst include palladium-carbon, platinum oxide, rhodium-aluminum oxide, and chlorotris(triphenylphosphine)rhodium(I), and can be used in an amount of 0.01 to 100 weight percent based on compound i6. The hydrogen pressure can be 1 to 50 atmospheres. Cyclohexene, 1,4-cyclohexadiene, formic acid, ammonium formate, etc. can also be used as the hydrogen source. The reaction temperature is from 0°C to the reflux temperature of the solvent, preferably from 20°C to 40°C. The reaction time is 0.5 to 72 hours, preferably 1 to 12 hours. Examples of reaction solvents include methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, toluene, ethyl acetate, acetic acid, water, etc., and these can be used alone or in combination. [Process I-7] Compound i7 can be reacted with hydrazine monohydrate or the like to obtain compound i8. The reaction temperature is 0°C to 100°C, preferably 20°C to 80°C. The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours. As the reaction solvent, ethanol or the like can be used. [Process I-8] Compound i9 can be obtained by reacting compound i8 with trifluoroacetic anhydride. The reaction temperature is -10°C to 80°C, preferably 0°C to 40°C. The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours. Examples of reaction solvents include dichloromethane, tetrahydrofuran, dioxane, acetonitrile, etc., which can be used alone or in combination. [Process I-9] Compound i10 can be obtained by reacting compound i9 with triphenylphosphine and a Mitsunobu reagent. Examples of Mitsunobu reagents include DEAD and DIAD, which can be used in an amount of 1 to 5 molar equivalents relative to compound i9. The reaction temperature is 0°C to 60°C, preferably 10°C to 40°C. The reaction time is 0.1 to 12 hours, preferably 0.2 to 6 hours. Examples of reaction solvents include tetrahydrofuran, dioxane, ethyl acetate, toluene, acetonitrile, etc., and these can be used alone or in combination. [Process I-10] Compound i11 can be obtained by reacting compound i10 with a base. The reaction temperature is 0 to 80°C, preferably 10 to 60°C. The reaction time is 0.5 to 12 hours, preferably 1 to 10 hours. As the base, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. can be used. Examples of reaction solvents include methanol, ethanol, water, acetone, acetonitrile, and tetrahydrofuran, and these can be used alone or in combination. [Process I-11] Compound i12 can be obtained by allowing compound f12 to act on compound i11 in the presence of a base. The reaction temperature is from 0° C. to the reflux temperature of the solvent. The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours. As the base, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, etc. can be used. Examples of reaction solvents include methanol, ethanol, acetonitrile, tetrahydrofuran, dimethylformamide, etc., and these can be used alone or in combination.

[0091] The compounds according to the present invention have GLP-1 receptor agonist activity and are therefore useful as therapeutic and / or preventive agents for diseases associated with the GLP-1 receptor. In the present invention, the term "therapeutic and / or prophylactic agent" also encompasses agents for improving symptoms.

[0092] Diseases involving the GLP-1 receptor include non-insulin-dependent diabetes mellitus (type 2 diabetes), hyperglycemia, impaired glucose tolerance, insulin-dependent diabetes mellitus (type 1 diabetes), diabetic complications, obesity, hypertension, dyslipidemia, arteriosclerosis, myocardial infarction, coronary heart disease, cerebral infarction, non-alcoholic steatohepatitis, Parkinson's disease, and dementia.

[0093] In the present invention, "diabetes" means a disease or condition in which the body is unable to maintain appropriate blood glucose levels, resulting in metabolic abnormalities in the production and utilization of glucose, and includes insulin-dependent diabetes mellitus (type 1 diabetes) and non-insulin-dependent diabetes mellitus (type 2 diabetes).

[0094] "Hyperglycemia" refers to a condition in which plasma glucose levels are higher than normal (e.g., 80-110 mg / dL in humans when fasting) either during fasting or after glucose administration, and is one of the typical symptoms of diabetes.

[0095] "Impaired glucose tolerance" includes insulin-resistant impaired glucose tolerance and insulin secretion disorders.

[0096] "Diabetic complications" refer to complications resulting from diabetes or hyperglycemia, and may be either acute or chronic. Examples of "acute complications" include ketoacidosis and infections (e.g., skin infections, soft tissue infections, biliary tract infections, respiratory infections, and urinary tract infections), while examples of "chronic complications" include microangiopathy (e.g., nephropathy and retinopathy), neuropathy (e.g., sensory neuropathy, motor neuropathy, and autonomic neuropathy), and foot gangrene. Major diabetic complications include diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy. "Coronary heart disease" includes myocardial infarction, angina pectoris, and the like.

[0097] "Dementia" includes, for example, Alzheimer's disease, vascular dementia, and diabetic dementia. The compounds of the present invention not only have GLP-1 receptor agonist activity but also have pharmaceutical utility, and have any or all of the following excellent characteristics: a) It has a weak inhibitory effect on CYP enzymes (e.g., CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.). b) It exhibits good pharmacokinetics, including high bioavailability and moderate clearance. c) High metabolic stability. d) It does not exhibit irreversible inhibitory effects on CYP enzymes (e.g., CYP3A4) within the concentration range of the measurement conditions described herein. e) It is not mutagenic. f) Low cardiovascular risk. g) Low risk of hematologic toxicity. h) High solubility.

[0098] The pharmaceutical composition of the present invention can be administered orally or parenterally, including transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ophthalmic, otic, and vaginal administration.

[0099] For oral administration, the compound may be prepared and administered in any commonly used dosage form, such as a solid preparation for internal use (e.g., tablets, powders, granules, capsules, pills, films, etc.) or a liquid preparation for internal use (e.g., suspensions, emulsions, elixirs, syrups, lemonades, spirits, aromatic perfumes, extracts, decoctions, tinctures, etc.), according to conventional methods. Tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets, or orally disintegrating tablets; powders and granules may be dry syrups; and capsules may be soft capsules, microcapsules, or sustained-release capsules.

[0100] For parenteral administration, the compound can be suitably administered in any of the commonly used dosage forms, such as injections, infusions, and topical preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, infusions, liniments, mouthwashes, enemas, ointments, plasters, jellies, creams, patches, poultices, powders for topical use, suppositories, etc.). Injections may be emulsions such as O / W, W / O, O / W / O, and W / O / W types.

[0101] A pharmaceutical composition can be prepared by mixing an effective amount of the compound of the present invention with various pharmaceutical additives, such as excipients, binders, disintegrants, and lubricants, appropriate for the dosage form. Furthermore, by appropriately adjusting the effective amount of the compound of the present invention, the dosage form, and / or various pharmaceutical additives, the pharmaceutical composition can also be prepared as a pharmaceutical composition for pediatrics, the elderly, critically ill patients, or surgical patients. Pediatric pharmaceutical compositions are preferably administered to patients under 12 or 15 years of age. Pediatric pharmaceutical compositions can also be administered to patients under 27 days old, 28 days to 23 months old, 2 to 11 years old, or 12 to 17 or 18 years old. Elderly pharmaceutical compositions are preferably administered to patients 65 years of age or older.

[0102] The dosage of the pharmaceutical composition of the present invention is desirably determined taking into consideration the patient's age, body weight, type and severity of the disease, route of administration, etc., but when administered orally, it is usually 0.05 to 100 mg / kg / day, preferably 0.1 to 10 mg / kg / day. When administered parenterally, it varies greatly depending on the route of administration, but is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This dosage can be administered once or several times a day.

[0103] The compound of the present invention can be used in combination with a concomitant drug for the purpose of enhancing the effect of the compound or reducing the dose of the compound, etc. In this case, the administration timing 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.

[0104] The dosage of the concomitant drug can be appropriately selected based on the clinically used dosage. The compounding ratio of the compound of the present invention to the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptoms, combination, etc. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.

[0105] The pharmaceutical composition of the present invention can also be used in combination with other anti-obesity drugs (pharmaceutical compositions containing a compound having anti-obesity activity, drugs that can be used for obesity, weight management in obesity, etc.). For example, by using a pharmaceutical composition containing a compound having anti-obesity activity in combination with the compound of the present invention, it can be used for the prevention and / or treatment of obesity, weight management in obesity, etc. Furthermore, by using a pharmaceutical composition containing the compound of the present invention in combination with a pharmaceutical composition containing a compound having anti-obesity activity, it can be used for the prevention and / or treatment of obesity, weight management in obesity, etc. Furthermore, the administration therapy of the pharmaceutical composition of the present invention can be used in combination with diet therapy, drug therapy, exercise, etc. [Example]

[0106] The present invention will be explained in more detail below with reference to Examples, Reference Examples and Test Examples, but the present invention is not limited to these.

[0107] The abbreviations used in this specification have the following meanings. CHCl3: Chloroform CDCl3: deuterated chloroform MeOH: Methanol DMSO-d6: Deuterated dimethyl sulfoxide DMSO: dimethyl sulfoxide DMA: Dimethylacetamide DMF: dimethylformamide THF: tetrahydrofuran NMP: N-methylpyrrolidone Ns: 2-nitrobenzenesulfonyl HOAt: 1-hydroxy-7-azabenzotriazole HOBt: 1-hydroxybenzotriazole EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HATU: 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate DIBAL: Diisobutylaluminum hydride DIAD: Diisopropyl azodicarboxylate DEAD: Diethyl azodicarboxylate BBr3: Boron tribromide AlCl3: Aluminum chloride BF3 (Et2O): Boron trifluoride diethyl ether complex TLC: Thin Layer Chromatography SFC: Supercritical Fluid Chromatography ODS: Octadecylsilyl

[0108] (Method for identifying compounds) The NMR analysis obtained in each example was performed at 400 MHz using DMSO-d or CDCl. Furthermore, when presenting NMR data, not all measured peaks may be listed. In the description, RT refers to retention time in LC / MS (liquid chromatography / mass spectrometry), and was measured under the following conditions. In the specification, the terms [M+H] and [MH] indicate values ​​observed by mass spectrometry.

[0109] (Measurement condition 1) Column: ACQUITY UPLC BEH C18 (1.7 μm id 2.1 x 50 mm) (Waters) Flow rate: 0.8mL / min UV detection wavelength: 254 nm Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient from 5% to 100% solvent [B] in 3.5 minutes, followed by a 0.5 minute hold at 100% solvent [B]. (Measurement condition 2) Column: Shim-pack XR-ODS (2.2 μm, id 3.0 x 50 mm) (Shimadzu) Flow rate: 1.6 mL / min; UV detection wavelength: 254 nm; Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient of 10%-100% solvent [B] was performed over 3 minutes, and then 100% solvent [B] was maintained for 0.5 minutes. (Measurement condition 3) Column: ACQUITY UPLC BEH C18 (1.7 μm id 2.1 x 50 mm) (Waters) Flow rate: 0.8 mL / min; UV detection wavelength: 254 nm; Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient of 5%-100% solvent [B] was performed over 3.5 minutes, and then 100% solvent [B] was maintained for 0.5 minutes. (Measurement condition 4) Column: ACQUITY UPLC BEH C18 (1.7 μm id 2.1 x 50 mm) (Waters) Flow rate: 0.8mL / min UV detection wavelength: 254 nm Mobile phase: [A] is an aqueous solution containing 10 mM ammonium carbonate, [B] is acetonitrile Gradient: A linear gradient from 5% to 100% solvent [B] in 3.5 minutes, followed by a 0.5 minute hold at 100% solvent [B]. (Measurement condition 5) Column: L-column 2 ODS (3 μm id 3 x 50 mm) (Chemicals Evaluation and Research Institute, Japan) Flow rate: 1.5mL / min UV detection wavelength: 220 nm Mobile phase: [A] is an aqueous solution containing 0.05% trifluoroacetic acid, [B] is an acetonitrile solution containing 0.05% trifluoroacetic acid Gradient: A linear gradient of 5%-95% solvent [B] was performed over 3.5 minutes, and then maintained at 95% solvent [B] for 2 minutes.

[0110] Example 1 Synthesis of Compound I-023 [ka] [ka] Step 1: Synthesis of Compound 2 Compound 1 (500 mg, 1.87 mmol) and triethylamine (0.776 mL, 5.60 mmol) were dissolved in dichloromethane (5 mL). 2-Nitrobenzenesulfonyl chloride (434 mg, 1.96 mmol) was added to the reaction mixture and stirred at room temperature for 75 minutes. Water and dichloromethane were added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with 2 mol / L aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and water, and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give compound 2 (623 mg, 74% yield). The residue remaining in the aqueous layer after separation was filtered and dried to give compound 2 (178 mg, 21% yield). 1 H-NMR (CDCl3) δ: 2.87 (2H, t, J = 6.8 Hz), 3.44 (2H, q, J = 6.6 Hz), 5.32-5.37 (1H, m), 7.17 (1H, d, J = 7.3 Hz), 7.38 (1H, s), 7.54 (1H, d, J = 8.3 Hz), 7.69-7.76 (2H, m), 7.83 (1H, d, J = 7.4 Hz), 8.03 (1H, dd, J = 7.4 Hz, 1.5 Hz). [MH]=450.98, measurement condition 1: retention time 2.34 minutes Step 2: Synthesis of Compound 3 Compound 2 (427 mg, 0.942 mmol) was dissolved in acetic acid (4 mL), and paraformaldehyde (141 mg, 4.71 mmol) and concentrated sulfuric acid (2 mL) were added at room temperature. The reaction mixture was ice-cooled, and concentrated sulfuric acid (2 mL) was added. The mixture was stirred at 60°C for 5 hours. The reaction mixture was slowly added dropwise to ice-cooled 2 mol / L aqueous sodium hydroxide solution, followed by extraction with ethyl acetate. The organic layer was washed with 2 mol / L aqueous sodium hydroxide solution and water and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by column chromatography (hexane-ethyl acetate) to give compound 3 as a mixture of compound 4 and compound 2 (431 mg, 80% by weight, 79% yield, compound 3:4:2 = 1:0.05:0.2). [M+H]=465.10, measurement condition 1: retention time 2.53 minutes Step 3: Synthesis of Compound 5 Compound 3 (430 mg, 0.924 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (352 mg, 1.39 mmol) were dissolved in 1,4-dioxane (8 mL). Potassium acetate (454 mg, 4.62 mmol) and (1,1-bis(diphenylphosphino)ferrocene)palladium(II) dichloromethane adduct (75 mg, 0.092 mmol) were added to the reaction mixture and stirred at 100°C for 9 hours under a nitrogen atmosphere. The reaction mixture was cooled on ice, and water (4 mL) and 30% hydrogen peroxide (0.944 mL, 9.24 mmol) were added. The mixture was allowed to stand overnight at room temperature. The reaction mixture was added to water and ethyl acetate and extracted with ethyl acetate. The organic layer was washed with 10% aqueous sodium thiosulfate and water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by column chromatography (hexane-ethyl acetate) to give Compound 5 as a mixture with Compound 6 (312 mg, 68% by weight, yield 57%, Compound 5:Compound 6=1:0.5). [M+H]=403.19, measurement condition 1: retention time 2.10 minutes Step 4 Synthesis of Compound 7 Compound 5 (160 mg, 0.398 mmol), cesium carbonate (259 mg, 0.795 mmol), and 1-(bromomethyl)-4-chloro-2-fluorobenzene (0.065 mL, 0.477 mmol) were dissolved in DMF (1.6 mL) and stirred at room temperature for 90 minutes. The reaction mixture was cooled on ice, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by column chromatography (hexane-ethyl acetate) to give compound 7 (138 mg, 74% by weight, 47% yield) as a mixture with compound 6. 1 H-NMR (CDCl3) δ: 2.89-2.93 (2H, m), 3.64 (2H, t, J = 5.8 Hz), 4.55 (2H, s), 5.15 (2H, s), 6.78 (1H, s), 7.13 (1H, dd, J = 9.7 Hz, 1.5 Hz), 7.19 (1H, d, J = 8.3 Hz), 7.35 (1H, s), 7.49 (1H, t, J = 8.0 Hz), 7.64-7.66 (1H, m), 7.70-7.74 (2H, m), 8.07-8.09 (1H, m). [M+H]=545.07, measurement condition 1: retention time 2.88 minutes Step 5 Synthesis of Compound 8 Compound 7 (135 mg, 0.248 mmol) was dissolved in DMF (1 mL), and cesium carbonate (242 mg, 0.743 mmol) and dodecane-1-thiol (0.177 mL, 0.743 mmol) were added. The mixture was stirred at room temperature for 1.5 hours. Dodecane-1-thiol (0.087 mL) was added to the reaction mixture, and the mixture was allowed to stand overnight. The reaction mixture was added to water and ethyl acetate, and extracted with ethyl acetate. The organic layer was washed with 2 mol / L aqueous sodium carbonate and water and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by aminosilica gel column chromatography (hexane-ethyl acetate, then ethyl acetate-methanol) to give compound 8 as a mixture with compound 9 (35 mg, 78% by weight, 31% yield, compound 8: compound 9 = 1:0.5). 1H-NMR (CDCl3) δ: 2.75 (2H, t, J = 5.8 Hz), 3.13 (2H, t, J = 5.8 Hz), 4.01 (2H, s), 5.14 (2H, s), 6.69 (1H, s), 7.12 (1H, d, J = 9.8 Hz), 7.18 (1H, d, J = 8.3 Hz), 7.32 (1H, s), 7.51 (1H, t, J = 8.3 Hz). [M+H]=360.19, measurement condition 1: retention time 1.91 minutes Step 6 Synthesis of Compound 11 Compound 8 (35 mg, 0.097 mmol) and compound 10 (29 mg, 0.097 mmol) were dissolved in acetonitrile (1.0 mL), potassium carbonate (27 mg, 0.195 mmol) was added, and the mixture was stirred at 60°C for 2 hours. The reaction mixture was added to water and ethyl acetate, and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by aminosilica gel column chromatography (hexane-ethyl acetate) to give compound 11 as a mixture with compound 12 (50 mg, 73 wt%, yield 61%, compound 11: compound 12 = 1:0.5). [M+H]=618.27, measurement condition 1: retention time 2.43 minutes Step 7 Synthesis of Compound I-023 Compound 11 (49 mg, 0.079 mmol) was dissolved in tetrahydrofuran (0.5 mL) and methanol (0.5 mL), and 2 mol / L aqueous sodium hydroxide solution (0.159 mL, 0.317 mmol) was added. The mixture was stirred at 50°C for 90 minutes. Ice-cooled 2 mol / L aqueous hydrochloric acid solution (0.159 mL, 0.317 mmol) and water were added to the reaction mixture. The reaction mixture was filtered and washed with water. The resulting residue was purified by reverse-phase chromatography (water-acetonitrile) on an ODS column to give compound I-023 (11.6 mg, 24% yield). 1H-NMR (CDCl3) δ: 2.36-2.45 (1H, m), 2.65-2.71 (1H, m), 2.87(4H, br-s), 3.70 (2H, s), 4.14-4.22 (2H, m), 4.33-4.38 (1H, m), 4.58-4.75 (3H, m), 5.09 (2H, s), 5.16-5.21 (1H, m), 6.66 (1H, s), 7.10 (1H, d, J = 9.8 Hz), 7.17 (1H, d, J = 8.3 Hz), 7.34 (1H, s), 7.48 (1H, t, J = 8.3 Hz), 7.82 (1H, d, J = 8.5 Hz), 8.06 (1H, d, J = 8.5), 8.21 (1H, s). [M+H]=604, measurement condition 1: retention time 2.18 minutes

[0111] Example 2 Synthesis of Compound I-027 [ka] Step 1: Synthesis of compound 14 Compound 13 (WO2012033195A) (275 mg, 1.01 mmol) was dissolved in DMF (2.5 mL), and cesium carbonate (984 mg, 3.02 mmol) and 1-(bromomethyl)-4-chloro-2-fluorobenzene (0.204 mL, 1.51 mmol) were added to the reaction mixture, followed by stirring at room temperature for 2 hours. The reaction mixture was cooled with ice, water was added, and the solid was collected by filtration. The resulting residue was washed with water and diisopropyl ether and then dried to give compound 14 (176 mg, 42% yield). 1 H-NMR (CDCl3) δ: 2.95 (2H, t, J = 5.4 Hz), 3.83-3.92 (2H, m), 4.77 (0.6H, s), 4.82 (1.4H, s), 5.19 (2H, s), 6.81-6.84 (1H, m), 7.16-7.23 (2H, m), 7.41-7.47 (1H, m), 7.65-7.69 (1H, m), 10.44 (1H, s). [M+H]=416.19, measurement condition 2: retention time 2.55 minutes Step 2: Synthesis of compound 16 Compound 14 (66 mg, 0.159 mmol) was dissolved in dichloromethane (1 mL), and N,N-diethylaminosulfur trifluoride (0.117 mL, 0.794 mmol) was added under ice cooling. The mixture was warmed to room temperature and stirred for 1 hour. N,N-diethylaminosulfur trifluoride (0.117 mL, 0.794 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. N,N-diethylaminosulfur trifluoride (0.117 mL, 0.794 mmol) was added again, and the mixture was allowed to stand overnight at room temperature. The reaction mixture was added to saturated aqueous sodium bicarbonate and ethyl acetate, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue (compound 15) was dissolved in tetrahydrofuran (0.5 mL) and methanol (0.5 mL), and 2 mol / L aqueous sodium hydroxide solution (0.318 mL, 0.636 mmol) was added. The mixture was stirred at 50°C for 50 minutes. The reaction mixture was added to water and ethyl acetate, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by amino column chromatography (hexane-ethyl acetate, then ethyl acetate-methanol) to give compound 16 (19.7 mg, 36% yield over two steps). 1 H-NMR (CDCl3) δ: 2.76 (2H, t, J = 5.6 Hz), 3.13 (2H, t, J = 5.6 Hz), 4.00 (2H, s), 5.10 (2H, s), 6.63 (1H, s), 6.92 (1H, t, J = 55.7Hz), 7.10-7.20 (2H, m), 7.30 (1H, s), 7.42 (1H, t, J = 8.0 Hz). Step 3 Synthesis of compound 18 Compound 16 (19 mg, 0.056 mmol) and compound 17 (16 mg, 0.056 mmol) were dissolved in acetonitrile (0.7 mL), and potassium carbonate (15 mg, 0.111 mmol) was added to the reaction mixture, followed by stirring at 70°C for 2 hours. The reaction mixture was cooled on ice, and the solid was collected by filtration. The resulting residue was purified by aminosilica gel column chromatography (hexane-ethyl acetate) to give compound 18 (23.1 mg, 69% yield). 1 H-NMR (CDCl3) δ: 2.36-2.45 (1H, m), 2.64-2.73 (1H, m), 2.86 (4H, br-s), 3.67 (2H, s), 3.95 (3H, s), 4.11-4.19 (2H, m), 4.33-4.38 (1H, m), 4.57-4.65 (1H, m), 4.68-4.71 (2H, m), 5.05 (2H, s), 5.15-5.23 (1H, m), 6.59 (1H, s), 6.90 (1H, t, J = 55.7Hz), 7.09-7.19 (2H, m), 7.32 (1H, s), 7.38 (1H, t, J = 8.0 Hz), 7.78 (1H, d, J = 8.4 Hz), 7.99 (1H, d, J = 8.4 Hz), 8.14 (1H, s). [M+H]=600.30, measurement condition 1: retention time 2.25 minutes Step 4 Synthesis of Compound I-027 Compound 18 (22 mg, 0.037 mmol) was dissolved in tetrahydrofuran (0.3 mL) and methanol (0.3 mL). 2 mol / L aqueous sodium hydroxide solution (0.073 mL, 0.147 mmol) was added to the reaction mixture, which was then stirred at 50°C for 90 minutes. Ice-cooled 2 mol / L aqueous hydrochloric acid solution (0.073 mL, 0.147 mmol) and water were added to the reaction mixture. The reaction mixture was filtered, and the residue was washed with water. The resulting residue was dried to give compound I-027 (15.9 mg, 74% yield). 1H-NMR (CDCl3) δ: 2.37-2.46 (1H, m), 2.65-2.74 (1H, m), 2.88 (4H, br-s), 3.69 (2H, s), 4.17 (2H, s), 4.34-4.40 (1H, m), 4.58-4.77 (3H, m), 5.05 (2H, s), 5.16-5.23 (1H, m), 6.60 (1H, s), 6.90 (1H, t, J = 55.7Hz), 7.10-7.18 (2H, m), 7.33 (1H, s), 7.38 (1H, t, J = 8.0 Hz), 7.83 (1H, d, J = 8.5 Hz), 8.05 (1H, d, J = 8.5 Hz), 8.21 (1H, s). [M+H]=586, measurement condition 1: retention time 2.03 minutes

[0112] Example 3 Synthesis of Compound I-031 [ka] Step 1: Synthesis of Compound 20 To a solution of compound 19 (350 mg, 1.21 mmol) in DMF (10 mL), cesium carbonate (789 mg, 2.42 mmol) and 4-chloro-2-fluorobenzyl bromide (164 μL, 1.21 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hours. 4-Chloro-2-fluorobenzyl bromide (23 μL, 0.138 mmol) was then added, and the mixture was stirred again at room temperature for 1 hour. Water was added to the reaction mixture, and the resulting solid was collected by filtration to give compound 20 (0.53 g, 100% yield). [M+H]=432, measurement condition 1 retention time 2.33 minutes Step 2: Synthesis of Compound 21 To a solution of compound 20 (100 mg, 0.232 mmol) in DMF (1 mL), copper iodide (48.5 mg, 0.255 mmol) and methyl difluoro(fluorosulfonyl)acetate (146 μL, 1.16 mmol) were added in that order, followed by degassing under reduced pressure and purging with nitrogen. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 5 hours. Water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 21 (27 mg, yield 31%). [M+H]=374, measurement condition 1: retention time 2.30 minutes Step 3: Synthesis of Compound I-031 To a solution of compound 21 (27 mg, 0.072 mmol) in tetrahydrofuran (0.5 mL), sodium hydride (4.1 mg, 0.101 mmol) was added under ice-cooling and stirred for 10 minutes under ice-cooling. Next, compound 22 (30 mg, 0.101 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2.5 hours. Sodium hydride (2.0 mg, 0.050 mmol) was then added, and the mixture was stirred at room temperature for another hour. Methanol (0.5 mL) and a 1 mol / L aqueous sodium hydroxide solution (72 μL) were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and then 2 mol / L hydrochloric acid was added until the pH reached approximately 4. The resulting solid was filtered to obtain a crude product. The crude product was purified by silica gel column chromatography (chloroform-methanol) to obtain compound I-031 (20 mg, 45% yield). 1 H-NMR (DMSO-D6) δ: 2.34-2.43 (1H, m), 2.68-2.76 (1H, m), 3.05 (2H, t, J = 6.5 Hz), 3.78 (2H, t, J = 7.8 Hz), 4.31 (1H, dt, J = 11.2, 4.4 Hz), 4.47 (1H, q, J = 7.1 Hz), 4.63 (1H, dd, J = 15.0, 3.1 Hz), 4.78 (1H, dd, J = 15.0, 6.5 Hz), 5.13-5.17 (2H, m), 5.28 (1H, d, J = 16.4 Hz), 5.36 (2H, s), 7.37 (1H, d, J = 8.3 Hz), 7.51-7.58 (2H, m), 7.67 (1H, s), 7.79 (1H, s), 7.99 (1H, d, J = 8.3 Hz), 8.12 (1H, d, J = 8.3 Hz). [M+H]=619, measurement condition 1: retention time 2.35 minutes

[0113] Example 4 Synthesis of Compound I-006 [ka] Step 1: Synthesis of compound 24 Compound 23 (100 mg, 0.390 mmol) and (4-chloro-2-fluorophenyl)methanol (94.0 mg, 0.585 mmol) were dissolved in tetrahydrofuran (1.5 mL). Potassium tert-butoxide (87 mg, 0.780 mmol) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture. The reaction mixture was filtered, and the residue was washed with water and then dried. The resulting residue was purified by column chromatography (hexane-ethyl acetate) to give compound 24 (121 mg, 81.5% yield). 1 H-NMR (CDCl3) δ: 2.33 (3H, s), 5.57 (2H, s), 7.13-7.16 (2H, m), 7.43-7.46 (1H, m), 7.49-7.53 (2H, m), 7.75 (1H, s), 8.01 (1H, d, J = 1.5 Hz). [M+H]=380.15, measurement condition 3: retention time 3.10 minutes Step 2: Synthesis of compound 25 Compound 24 (113 mg, 0.297 mmol), 1-(tert-butyldimethylsilyloxy)-1-methoxyethene (168 mg, 0.891 mmol), zinc fluoride (92 mg, 0.891 mmol), and bis-tert-tributylphosphine palladium (15.2 mg, 0.030 mmol) were dissolved in DMF (3.4 mL) and stirred in a sealed tube at 130 °C under microwave irradiation for 3 hours. After returning to room temperature, water and ethyl acetate were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by column chromatography (hexane-ethyl acetate) to yield a residue (32.3 mg). The resulting residue was dissolved in a mixed solvent of tetrahydrofuran (0.31 mL) and methanol (0.31 mL), and 1 mol / L aqueous sodium hydroxide solution (0.250 mL, 0.250 mmol) was added and stirred at room temperature for 1 hour. 10% aqueous citric acid solution was added to the reaction solution. The reaction solution was filtered, and the residue was washed with water and then dried to obtain a residue (27.3 mg). The resulting residue was purified by column chromatography (hexane-ethyl acetate) to obtain compound 25 (23.8 mg, two-step yield 23.0%). 1 H-NMR (CDCl3) δ: 2.34 (3H, s), 3.83 (2H, s), 5.58 (2H, s), 5.58 (2H, s), 7.12-7.15 (2H, m), 7.29-7.32 (1H, dd, J = 8.0, 1.5 Hz), 7.52 (1H, t, J = 8.0 Hz), 7.64 (1H, d, J = 8.0 Hz), 7.76 (1H, d, J = 10.3 Hz). [M+H]=360.20, measurement condition 3: retention time 2.48 minutes Step 3 Synthesis of compound 27 Compound 25 (23.5 mg, 0.065 mmol) and compound 26 (15.4 mg, 0.065 mmol) were dissolved in DMF (0.35 mL), and triethylamine (0.091 mL, 0.065 mmol) and 1-(bis(dimethylaminomethylene)-1H-1,2,3-triazolo(4,5-b)pyridinium 3-oxide hexafluorophosphate (24.8 mg, 0.065 mmol) were added and stirred at room temperature for 1 hour. Water was added to the reaction mixture. The reaction mixture was filtered, and the residue was washed with water and then dried to give a residue (30 mg). The resulting residue (30 mg) was dissolved in acetic acid (0.30 mL) and stirred at 60°C for 1 hour. The reaction mixture was concentrated, and the resulting residue was purified by column chromatography (hexane-ethyl acetate) to give compound 27 (21 mg, two-step yield 56.9%). 1 H-NMR (CDCl3) δ: 2.28-2.35 (1H, m), 2.34 (3H, s), 2.56-2.63 (1H, m), 3.94 (3H, s), 4.24-4.40 (3H, m), 4.57-4.70 (3H, m), 5.05-5.08 (1H, m), 5.55 (2H, s), 7.10-7.15 (2H, m), 7.26-7.29 (1H, m), 7.49 (1H, t, J = 8.0 Hz), 7.60 (1H, d, J = 8.3 Hz), 7.68 (1H, s), 7.76 (1H, s), 7.80 (1H, d, J = 8.6 Hz), 7.99 (1H, dd, J = 8.6, 1.3 Hz), 8.08 (1H, s). [M+H]=560.10, measurement condition 3: retention time 2.56 minutes Step 4 Synthesis of Compound I-006 Compound 27 (20.8 mg, 0.037 mmol) was dissolved in a mixed solvent of tetrahydrofuran (0.16 mL) and methanol (0.16 mL), and 1 mol / L aqueous sodium hydroxide solution (0.11 mL, 0.11 mmol) was added and stirred at 60°C for 2 hours. After returning to room temperature, 10% aqueous citric acid solution was added to the reaction solution. The reaction solution was filtered, and the residue was washed with water and then dried to obtain compound I-006 (18.0 mg, yield 88.8%). 1 H-NMR (DMSO-d6) δ: 2.23 (3H, s), 2.23-2.36 (1H, m), 2.50-2.63 (1H, m), 4.31-4.36 (1H, m), 4.41-4.47 (1H, m), 4.51-4.60 (3H, m), 4.64-4.70 (1H, m), 4.87-4.93 (1H, m), 5.52 (2H, s), 7.32 (1H, dd, J = 8.3, 1.5 Hz), 7.39 (1H, dd, J = 8.3, 1.5 Hz), 7.49 (1H, dd, J = 10.0, 1.5 Hz), 7.64 (2H, t, 8.3 Hz), 7.66 (1H, s), 7.75-7.81 (2H, m), 8.05 (1H, s), 8.23 ​​(1H, s) [M+H]=546, measurement condition 3: retention time 2.27 minutes

[0114] Example 5 Synthesis of Compound I-035 [ka] Step 1: Synthesis of compound 29 Compound 28 (WO2019200120A) (1.90 g, 10.72 mmol) was dissolved in dichloromethane (19 mL), trifluoroacetic anhydride (2.27 mL, 16.08 mmol) was added, and the mixture was stirred at room temperature for 3 hours and 15 minutes. Trifluoroacetic anhydride (0.23 mL, 1.61 mmol) was added, and the mixture was stirred at room temperature for 75 minutes. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 29 (2.25 g, 74% yield). [M+H]=274.2, measurement condition 1: retention time 2.28 minutes 1 H-NMR (CDCl3) δ: 1.53 (2.4H, d, J = 6.8 Hz), 1.61 (0.6H, d, J = 6.7 Hz), 2.74-2.82 (1H, m), 2.91-3.00 (1H, m), 3.26 (0.2H, td, J = 12.5, 4.4 Hz), 3.56 (0.8H, td, J = 12.5, 4.3 Hz), 3.79 (2.4H, s), 3.80 (0.6H, s), 4.04 (0.8H, d, J = 12.8 Hz), 4.59 (0.2H, dd, J = 12.8, 5.6 Hz), 5.10 (0.2H, q, J = 6.8 Hz), 5.53 (0.8H, q, J = 6.8 Hz), 6.62 (0.2H, d, J = 2.5 Hz), 6.66 (0.8H, d, J = 2.5 Hz), 6.75-6.80 (1H, m), 7.03-7.07 (1H, m). Step 2: Synthesis of compound 30 Compound 29 (1.95 g, 7.13 mmol) was dissolved in dichloromethane (19 mL), and silver trifluoroacetate (1.74 g, 7.87 mmol) and iodine (1.99 g, 7.84 mmol) were added. The mixture was stirred at room temperature for 1 hour. Insoluble matter was removed by filtration, and aqueous sodium thiosulfate solution was added to the filtrate, followed by extraction with dichloromethane. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 30 (2.00 g, 70% yield). [M+H]=400.2, measurement condition 1: retention time 2.55 minutes 1 H-NMR (CDCl3) δ: 1.53 (2.4H, d, J = 6.8 Hz), 1.61 (0.6H, d, J = 6.8 Hz), 2.71-2.79 (1H, m), 2.89-2.97 (1H, m), 3.23 (0.2H, td, J = 12.7, 4.5 Hz), 3.50-3.57 (0.8H, m), 3.86 (2.4H, s), 3.88 (0.6H, s), 4.01-4.05 (0.8H, m), 4.59 (0.2H, dd, J = 13.3, 5.3 Hz), 5.08 (0.2H, q, J = 6.5 Hz), 5.52 (0.8H, q, J = 6.8 Hz), 6.51 (0.2H, s), 6.55 (0.8H, s), 7.55 (0.8H, s), 7.57 (0.2H, s). Step 3: Synthesis of compound 31 Compound 30 (1.99 g, 4.99 mmol) was dissolved in N,N-dimethylformamide (20 mL), and methyl difluoro(fluorosulfonyl)acetate (3.15 mL, 24.93 mmol) and copper iodide (1.14 g, 5.98 mmol) were added sequentially. The mixture was then degassed under reduced pressure and purged with nitrogen. After stirring at 100 °C for 3 hours under a nitrogen atmosphere, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 31 (1.56 g, 94% yield). [M+H]=342.2, measurement condition 1: retention time 2.51 minutes 1 H-NMR (CDCl3) δ: 1.56 (2.4H, d, J = 6.9 Hz), 1.64 (0.6H, d, J = 6.8 Hz), 2.77-2.86 (1H, m), 2.92-3.02 (1H, m), 3.26 (0.2H, td, J = 12.3, 5.2 Hz), 3.52-3.60 (0.8H, m), 3.89 (2.4H, s), 3.90 (0.6H, s), 4.02-4.13 (0.8H, m), 4.65 (0.2H, dd, J = 13.0, 5.6 Hz), 5.14 (0.2H, q, J = 6.8 Hz), 5.59 (0.8H, q, J = 6.9 Hz), 6.69 (0.2H, s), 6.74 (0.8H, s), 7.33 (0.8H, s), 7.35 (0.2H, s). Step 4 Synthesis of compound 32 Compound 31 (1.55 g, 4.41 mmol) was dissolved in dichloromethane (7.8 mL). A 1 mol / L solution of boron tribromide in dichloromethane (13.2 mL, 13.2 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours and 30 minutes. Methanol (7.8 mL) was added under ice cooling, followed by water and extraction with dichloromethane. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 32 (1.20 g, 78% yield). [MH]=326.2, measurement condition 1: retention time 2.18 minutes Step 5: Synthesis of compound 33 Compound 32 (114 mg, 0.33 mmol), cesium carbonate (212 mg, 0.651 mmol), and 1-(bromomethyl)-4-chloro-2-fluorobenzene (0.051 mL, 0.377 mmol) were added to N,N-dimethylformamide (1.1 mL) and stirred at room temperature for 90 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water. The solvent was removed under reduced pressure, and the resulting residue was purified by column chromatography (hexane-ethyl acetate) to give compound 33 (142 mg, 92% yield). 1 H-NMR (CDCl3) δ: 1.53 (2.4H, d, J = 6.9 Hz), 1.62 (0.6H, d, J = 6.8 Hz), 2.78-2.86 (1H, m), 2.94-3.02 (1H, m), 3.25 (0.2H, td, J = 12.6, 5.2 Hz), 3.51-3.58 (0.8H, m), 4.09 (0.8H, d, J = 15.8 Hz), 4.65 (0.2H, dd, J = 13.7, 5.6 Hz), 5.12-5.21 (2.2H, m), 5.57 (0.8H, q, J = 6.7 Hz), 6.78 (0.2H, s), 6.80 (0.8H, s), 7.14 (1H, dd, J = 9.8, 1.9 Hz), 7.18-7.21 (1H, m), 7.36 (0.8H, s), 7.39 (0.2H, s), 7.47-7.53 (1.0H, m). Step 6 Synthesis of compound 34 Compound 33 (140 mg, 0.298 mmol) was dissolved in tetrahydrofuran (1.4 mL) and methanol (1.4 mL), potassium carbonate (82 mg, 0.596 mmol) was added, and the mixture was stirred at 50 °C for 8 hours and 45 minutes. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with water. The solvent was evaporated under reduced pressure to give compound 34 (104 mg, 94% yield) as a crude product. [M+H]=374.3, measurement condition 1: retention time 2.03 minutes 1 H-NMR (CDCl3) δ: 1.45 (3H, d, J = 6.8 Hz), 2.69 (1H, dt, J = 16.1, 4.6 Hz), 2.77-2.84 (1H, m), 2.96-3.02 (1H, m), 3.26 (1H, dt, J = 12.6, 5.1 Hz), 4.09 (1H, q, J = 6.7 Hz), 5.16 (2H, dd, J = 17.4, 12.7 Hz), 6.80 (1H, s), 7.12 (1H, dd, J = 9.9, 1.9 Hz), 7.18 (1H, dd, J = 8.2, 1.7 Hz), 7.30 (1H, s), 7.52 (1H, t, J = 8.0 Hz). Step 7 Synthesis of compound 36 Compound 34 (51 mg, 0.136 mmol) was dissolved in acetonitrile (0.5 mL), and compound 35 (42 mg, 0.143 mmol) and potassium carbonate (38 mg, 0.273 mmol) were added, followed by stirring at 60°C for 6 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 36 (80 mg, 90% yield). [M+H]=632.5, measurement condition 1: retention time 2.50 minutes 1H-NMR (CDCl3) δ: 1.40 (3H, d, J = 6.8 Hz), 2.35-2.44 (1H, m), 2.61-2.72 (2H, m), 2.76-2.81 (1H, m), 2.85-2.93 (1H, m), 3.07-3.13 (1H, m), 3.90 (1H, q, J = 6.7 Hz), 3.95 (3H, s), 4.11-4.35 (3H, m), 4.55-4.77 (3H, m), 5.10-5.22 (3H, m), 6.72 (1H, s), 7.11 (1H, dd, J = 9.8, 2.0 Hz), 7.18 (1H, dd, J = 8.2, 1.6 Hz), 7.32 (1H, s), 7.51 (1H, t, J = 8.1 Hz), 7.76 (1H, d, J = 8.5 Hz), 7.98 (1H, dd, J = 8.5, 1.5 Hz), 8.13 (1H, d, J = 0.9 Hz). Step 8 Synthesis of Compound I-035 Compound 36 (79 mg, 0.121 mmol) was dissolved in tetrahydrofuran (0.8 mL) and methanol (0.8 mL), and 1 mol / L aqueous sodium hydroxide solution (0.61 mL, 0.61 mmol) was added. The mixture was stirred at 40 °C for 80 min. At room temperature, 2 mol / L aqueous hydrochloric acid was added to adjust the pH to 4. After the pH adjustment, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-methanol). The fractions containing the target product were concentrated to a solid residue, which was then suspended in methyl tert-butyl ether and filtered to give compound I-035 (54 mg, 72% yield). [M+H]=618.0, measurement condition 2: retention time 2.01 minutes 1H-NMR (CDCl3) δ: 1.40 (3H, d, J = 6.7 Hz), 2.36-2.45 (1H, m), 2.63-2.74 (2H, m), 2.78-2.95 (2H, m), 3.09-3.16 (1H, m), 3.92 (1H, q, J = 6.7 Hz), 4.17-4.37 (3H, m), 4.59-4.79 (3H, m), 5.08-5.24 (3H, m), 6.72 (1H, s), 7.10 (1H, dd, J = 9.7, 1.8 Hz), 7.18 (1H, dd, J = 8.2, 1.3 Hz), 7.32 (1H, s), 7.50 (1H, t, J = 8.1 Hz), 7.83 (1H, d, J = 8.5 Hz), 8.05 (1H, d, J = 8.4 Hz), 8.20 (1H, s).

[0115] Example 6 Synthesis of Compound I-110 [ka] Step 1 Synthesis of compound 38 To a suspension of compound 37 (WO2020146682) (2.07 g, 6.89 mmol) in 1,4-dioxane (10 mL), silver carbonate (2.85 g, 10.3 mmol) and 4-chloro-2-fluorobenzyl bromide (1.85 g, 8.26 mmol) were added, and the mixture was stirred at 65 ° C. for 3.5 hours. After removing insoluble matter by filtration, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 38 (3.11 g, yield 100%). [M+H]=442, measurement condition 1: retention time 2.83 minutes 1 H-NMR (CDCl3) δ: 4.01 (3H, s), 5.51 (2H, s), 7.12 (1H, dd, J = 9.6, 1.8 Hz), 7.15 (1H, dd, J = 8.2, 1.8 Hz), 7.46 (1H, t, J = 8.0 Hz), 8.10 (1H, s). Step 2: Synthesis of compound 39 To a solution of compound 38 (1.0 g, 2.26 mmol) in tetrahydrofuran (10 mL), 1 mol / L DIBAL hexane solution (4.97 mL, 4.97 mmol) was added under ice-cooling, followed by stirring for 3 hours. Sodium sulfate decahydrate was added in small portions until bubbling ceased, and the mixture was stirred at room temperature for 30 minutes. After removing insoluble matter by filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 39 (780 mg, 83% yield). [M+H]=414, measurement condition 1: retention time 2.60 minutes 1 H-NMR (CDCl3) δ: 3.59 (1H, td, J = 5.1, 1.4 Hz), 4.73 (2H, dd, J = 5.0, 0.9 Hz), 5.55 (2H, s), 7.13-7.18 (2H, m), 7.43 (1H, t, J = 7.9 Hz), 8.01 (1H, s). Step 3: Synthesis of compound 40 To a solution of compound 39 (300 mg, 0.724 mmol) in N,N-dimethylformamide (4.5 mL), N-vinylphthalimide (125 mg, 0.724 mmol), tetrabutylammonium bromide (233 mg, 0.724 mmol), palladium acetate (16.3 mg, 0.074 mmol), and dicyclohexylmethylamine (230 μL, 1.09 mmol) were added. After degassing under reduced pressure, the mixture was purged with nitrogen and stirred at 110 °C for 1.5 hours. Water was added to the reaction mixture, and the resulting solid was collected by filtration. The solid was then washed with isopropyl acetate to give compound 40 (234 mg, 64% yield). [M+H]=507, measurement condition 1: retention time 2.78 minutes 1H-NMR (CDCl3) δ: 3.87 (1H, t, J = 4.6 Hz), 4.83 (2H, d, J = 4.6 Hz), 5.59 (2H, s), 7.13-7.23 (3H, m), 7.47 (1H, t, J = 8.0 Hz), 7.58 (1H, d, J = 14.8 Hz), 7.80 (2H, dd, J = 5.5, 3.0 Hz), 7.93 (2H, dd, J = 5.3, 3.0 Hz), 8.04 (1H, s). Step 4 Synthesis of compound 41 To a solution of compound 40 (224 mg, 0.442 mmol) in methanol (2.2 mL) and tetrahydrofuran (6.7 mL), 10% palladium-carbon (50% aqueous) (94 mg, 0.044 mmol) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) for 5 hours. After removing insoluble matter by filtration, the solvent was evaporated under reduced pressure to give compound 41 (163 mg, 73% yield). The resulting compound 41 was used directly in the next step without further purification. [M+H]=509, measurement condition 1: retention time 2.76 minutes 1 H-NMR (CDCl3) δ: 2.90 (2H, t, J = 7.7 Hz), 3.80 (1H, t, J = 4.8 Hz), 3.86 (2H, t, J = 7.7 Hz), 4.83 (2H, d, J = 4.8 Hz), 5.54 (2H, s), 7.11-7.17 (2H, m), 7.44 (1H, t, J = 8.0 Hz), 7.73-7.76 (3H, m), 7.82-7.86 (2H, m). Step 5 Synthesis of compound 42 Hydrazine monohydrate (77.8 μL, 1.6 mmol) was added to a solution of compound 41 (163 mg, 0.32 mmol) in ethanol (3.2 mL), followed by stirring at 80°C for 2.5 hours. After insoluble matter was removed by filtration, the solvent was evaporated under reduced pressure, and dichloromethane was added to the resulting residue. After again removing the precipitated insoluble matter by filtration, the solvent was evaporated under reduced pressure to give a crude product (122 mg) containing compound 42. The resulting compound 42 was used directly in the next step without further purification. [M+H]=379, measurement condition 1: retention time 1.84 minutes Step 6 Synthesis of compound 43 Trifluoroacetic anhydride (136 μL, 0.96 mmol) was added to a dichloromethane (1.2 mL) solution of the entire crude product of compound 42 obtained in step 5 (0.32 mmol) under ice-cooling, followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in ethyl acetate and then slowly poured into aqueous sodium bicarbonate solution. After stirring at room temperature for 1 hour, the mixture was extracted twice with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 43 (47 mg, yield 31%). [M+H]=475, measurement condition 1: retention time 2.42 minutes 1 H-NMR (CDCl3) δ: 2.87 (2H, t, J = 7.2 Hz), 3.52 (1H, t, J = 5.0 Hz), 3.57 (2H, q, J = 6.7 Hz), 4.77 (2H, d, J = 5.0 Hz), 5.55 (2H, s), 6.77 (1H, s), 7.13 (1H, dd, J = 9.8, 1.9 Hz), 7.16 (1H, dd, J = 8.2, 1.9 Hz), 7.45 (1H, t, J = 8.0 Hz), 7.71 (1H, s). Step 7 Synthesis of compound 44 To a solution of compound 43 (47 mg, 0.099 mmol) in tetrahydrofuran (2.5 mL), triphenylphosphine (39 mg, 0.15 mmol) and DIAD (29 μL, 0.15 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 44 (40 mg, 89% yield). [M+H]=457, measurement condition 1: retention time 2.88 minutes 1 H-NMR (CDCl3) δ: 2.88-2.93 (2H, m), 3.87 (1.2H, t, J = 5.6 Hz), 3.95 (0.8H, t, J = 5.9 Hz), 4.74 (0.8H, s), 4.78 (1.2H, s), 5.49 (2H, s), 7.11-7.16 (2H, m), 7.45 (1H, t, J = 7.9 Hz), 7.67 (0.6H, s), 7.70 (0.4H, s). Step 8 Synthesis of compound 45 To a solution of compound 44 (40 mg, 0.088 mmol) in methanol (0.5 mL) and tetrahydrofuran (0.5 mL), potassium carbonate (24.2 mg, 0.175 mmol) was added, and the mixture was stirred at 50°C under a nitrogen atmosphere for 4 hours. Brine was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give a crude product containing compound 45 (36 mg). The resulting compound 45 was used directly in the next step without further purification. [M+H]=361, measurement condition 1: retention time 1.72 minutes 1 H-NMR (CDCl3) δ: 2.75 (2H, t, J = 5.8 Hz), 3.13 (2H, t, J = 5.8 Hz), 3.99 (2H, s), 5.47 (2H, s), 7.10 (1H, dd, J = 9.7, 1.9 Hz), 7.13 (1H, d, J = 8.3 Hz), 7.46 (1H, t, J = 8.0 Hz), 7.58 (1H, s). Step 9 Synthesis of compound 47 To a solution of the entire crude product of compound 45 (36 mg) obtained in step 8 in acetonitrile (0.6 mL), compound 46 (27 mg, 0.092 mmol) and potassium carbonate (24.2 mg, 0.175 mmol) were added, and the mixture was stirred at 60°C under a nitrogen atmosphere for 2 hours. Brine was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-ethyl acetate) to give compound 47 (51 mg, yield 94%). [M+H]=619, measurement condition 1: retention time 2.49 minutes 1 H-NMR (CDCl3) δ: 2.36-2.45 (1H, m), 2.66-2.74 (1H, m), 2.82-2.87 (4H, m), 3.73 (2H, s), 3.95 (3H, s), 4.19 (2H, dd, J = 14.7, 13.8 Hz), 4.36 (1H, dt, J = 11.0, 4.6 Hz), 4.59-4.67 (2H, m), 4.72 (1H, dd, J = 15.4, 6.0 Hz), 5.19 (1H, ddd, J = 13.4, 7.2, 3.0 Hz), 5.43 (2H, s), 7.08 (1H, dd, J = 9.7, 2.0 Hz), 7.12 (1H, dd, J = 8.3, 1.7 Hz), 7.43 (1H, t, J = 8.0 Hz), 7.61 (1H, s), 7.79 (1H, d, J = 8.5 Hz), 8.00 (1H, dd, J = 8.4, 1.5 Hz), 8.14 (1H, d, J = 1.0 Hz). Step 10: Synthesis of Compound I-110 To a solution of compound 47 (51 mg, 0.082 mmol) in methanol (0.5 mL) and tetrahydrofuran (0.5 mL), 2 mol / L aqueous sodium hydroxide solution (206 μL, 0.412 mmol) was added, and the mixture was stirred at 45°C under a nitrogen atmosphere for 4.5 hours. Water was added to the reaction mixture, and then dilute sulfuric acid was added until the pH reached approximately 4, followed by extraction with ethyl acetate twice. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give compound I-110 (38 mg, 76% yield). [M+H]=605.5, measurement condition 1: retention time 2.18 minutes 1 H-NMR (DMSO-D6) δ: 2.32-2.41 (1H, m), 2.59-2.67 (1H, m), 2.81-2.85 (4H, m), 3.69 (2H, dd, J = 23.5, 17.0 Hz), 4.03 (1H, d, J = 13.6 Hz), 4.16 (1H, d, J = 13.7 Hz), 4.34 (1H, dt, J = 10.9, 4.5 Hz), 4.45 (1H, dd, J = 13.7, 7.7 Hz), 4.64 (1H, dd, J = 15.2, 2.5 Hz), 4.78 (1H, dd, J = 15.2, 7.2 Hz), 5.04 (1H, dd, J = 14.1, 7.2, 2.5 Hz), 5.42 (2H, s), 7.30 (1H, dd, J = 8.3, 1.9 Hz), 7.46 (1H, dd, J = 10.0, 1.9 Hz), 7.51 (1H, t, J = 8.3 Hz), 7.69 (1H, d, J = 8.5 Hz), 7.82 (1H, dd, J = 8.5, 1.4 Hz), 7.92 (1H, s), 8.27 (1H, s).

[0116] Example 7 Synthesis of Compound I-062 [ka] Step 1: Synthesis of compound 49 Compound 48 (107 mg, 0.43 mmol) and sodium carbonate (91 mg, 0.86 mmol) were dissolved in tetrahydrofuran (2 mL) / water (2 mL), and iodine (114 mg, 0.45 mmol) was added. The mixture was stirred at room temperature for 4.5 hours. The reaction mixture was added to aqueous sodium thiosulfate solution and extracted with ethyl acetate. The organic layer was washed with 10 wt% aqueous citric acid solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by column chromatography (hexane-ethyl acetate) to give compound 49 (58 mg, 36% yield). [M+H]=377.00, Measurement condition 1: Time 1.63 minutes 1 H-NMR (CDCl3) δ: 1.49 (9H, s), 2.92 (2H, t, J = 5.8 Hz), 3.70 (2H, t, J = 5.9 Hz), 4.52 (2H, s), 6.96 (1H, s) Step 2: Synthesis of compound 50 Compound 49 (58 mg, 0.154 mmol), cesium carbonate (100 mg, 0.308 mmol), and 1-(bromomethyl)-4-chloro-2-fluorobenzene (0.021 mL, 0.154 mmol) were dissolved in N,N-dimethylformamide (1.0 mL) and stirred at room temperature for 2.5 hours. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by column chromatography (hexane-ethyl acetate) to give compound 50 (53 mg, 66% yield). [M+H] = 519.00 Measurement condition 1: Time 1.78 min 1H-NMR (CDCl3) δ: 1.50 (9H, s), 2.94 (2H, t, J = 5.3 Hz), 3.70 (2H, t, J = 5.8 Hz), 4.53 (2H, s), 5.14 (2H, s), 6.79 (1H, s), 7.15 (1H, dd, J = 9.8 Hz, 1.9 Hz), 7.22 (1H, d, J = 8.3 Hz), 7.61 (1H, t, J = 7.9 Hz). Step 3: Synthesis of compound 51 Compound 50 (20 mg, 0.039 mmol) was dissolved in N,N-dimethylformamide (0.1 mL) and N-methylpyrrolidone (0.1 mL). Copper iodide (59 mg, 0.308 mmol) and methyl fluorosulfonyldifluoroacetate (0.039 mL, 0.308 mmol) were added at room temperature, and the mixture was stirred at 100 °C for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium bicarbonate and saturated brine, then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give compound 51 (21 mg, 100% yield). [M+H]=461.10, Measurement condition 1: Time 2.84 minutes 1 H-NMR (CDCl3) δ: 1.50 (9H, s), 2.98 (2H, t, J = 5.8 Hz), 3.75 (2H, t, J = 5.8 Hz), 4.63 (2H, s), 5.18 (2H, s), 6.79 (1H, s), 7.15 (2H, m), 7.21 (1H, m), 7.48 (1H, t, J = 8.2 Hz). Step 4 Synthesis of compound 54 Compound 51 (21 mg, 0.046 mmol) was dissolved in dichloromethane (0.2 mL), trifluoroacetic acid (0.029 mL, 2.730 mmol) was added at room temperature, and the mixture was stirred at room temperature for 40 minutes. After standing overnight, the solvent was removed under reduced pressure to give compound 52. The resulting residue was dissolved in acetonitrile (1 mL), potassium carbonate (80 mg, 0.579 mmol) and compound 53 (13 mg, 0.046 mmol) were added, and the mixture was stirred at 50°C for 2 hours. After further stirring at 60°C for 3 hours, the mixture was left standing overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate, followed by chloroform-methanol) to give compound 54 (12 mg, 43% yield). [M+H]=619.15, Measurement condition 1: Time 2.22 minutes 1 H-NMR (CDCl3) δ: 2.41 (1H, m), 2.69 (1H, m), 2.90 - 3.10 (4H, m), 3.73 (2H, s), 3.95 (3H, s), 4.20 (2H, q, J = 8.8 Hz), 4.34 (1H, m), 4.55 - 4.75 (3H, m), 5.11 (2H, s), 5.19 (1H, m), 7.03 (1H, s), 7.12 (1H, dd, J = 10.4 Hz, 2.0 Hz), 7.18 (1H, m), 7.45 (1H, t, J = 2.0 Hz), 7.79 (1H, d, J = 8.4 Hz), 8.00 (1H, dd, J = 8.4 Hz, 1.2 Hz), 8.14 (1H, d, J = 0.8 Hz). Step 5 Synthesis of Compound I-062 Compound 54 (12 mg, 0.019 mmol) was dissolved in tetrahydrofuran (0.2 mL), and 1 mol / L aqueous sodium hydroxide solution (0.1 mL, 0.100 mmol) was added. The mixture was stirred at room temperature for 1 hour and then at 60°C for 1.5 hours. 1 mol / L aqueous sodium hydroxide solution (0.1 mL, 0.100 mmol) was then added, and the mixture was stirred at 60°C for 1 hour. The reaction mixture was added to water, acidified with 10% aqueous citric acid, and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was solidified with n-hexane to give compound I-062 (6.7 mg, 57% yield). [M+H]=605.2, Measurement condition 1: Time 2.02 minutes 1 H-NMR (CDCl3) δ: 2.42 (1H, m), 2.70 (1H, m), 2.95 - 3.10 (4H, m), 3.74 (2H, s), 4.22 (2H, dd, J = 19.6 Hz, 13.2 Hz), 4.36 (1H, m), 4.55 - 4.75 (3H, m), 5.11 (2H, s), 5.15 (1H, m), 7.04 (1H, s), 7.11 (1H, dd, J = 9.6 Hz, 2.0 Hz), 7.18 (1H, m), 7.45 (1H, t, J = 8.0 Hz), 7.83 (1H, d, J = 8.8 Hz), 8.06 (1H, m), 8.21 (1H, m).

[0117] Example 8 Synthesis of Compound I-076 [ka] Step 1: Synthesis of compound 56 Compound 55 (WO2021013735A) (1.02 g, 3.48 mmol) and 4-chloro-2-fluorobenzyl bromide (0.856 g, 3.83 mmol) were dissolved in acetonitrile (20.4 mL), and silver carbonate (1.92 g, 6.96 mmol) was added and stirred at 60 ° C. for 6 hours. After cooling to room temperature, the reaction solution was filtered through Celite, and the Celite was washed with ethyl acetate to obtain a filtrate. The filtrate was concentrated, and the resulting residue was purified by column chromatography (hexane-ethyl acetate) to obtain compound 56 (0.897 g, 59% yield). [M+H]=434.90, measurement condition 1: retention time 3.05 minutes 1 H-NMR (CDCl3) δ: 5.66 (2H, s), 7.14-7.19 (2H, m), 7.50 (1H, t, J =8.0 Hz ), 7.76 (2H, dd, J = 8.8, 2.0 Hz), 7.98 (1H, d, J = 8.8 Hz), 8.11 (1H, d, J = 2.0 Hz). Step 2: Synthesis of compound 57 Compound 56 (100 mg, 0.230 mmol), 1-(tert-butyldimethylsilyloxy)-1-methoxyethene (130 mg, 0.689 mmol), zinc fluoride (71.2 mg, 0.689 mmol), and bis-tert-tributylphosphine palladium (11.3 mg, 0.023 mmol) were dissolved in N,N-dimethylformamide (2.0 mL) and stirred at 130 °C for 3 hours under microwave irradiation. After returning to room temperature, water and ethyl acetate were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by column chromatography (hexane-ethyl acetate) to obtain a residue (40.0 mg). The resulting residue was dissolved in a mixed solvent of tetrahydrofuran (0.39 mL) and methanol (0.39 mL), and 1 mol / L aqueous sodium hydroxide (0.270 mL, 0.270 mmol) was added and stirred at room temperature for 1 hour. 10% aqueous citric acid was added to the reaction solution, and the reaction solution was filtered. The residue was washed with water and then dried to give compound 57 (32.8 mg, 36% yield for two steps). [M+H]=414.85, measurement condition 1: retention time 2.43 minutes 1 H-NMR (CDCl3) δ: 3.92 (2H, s), 5.69 (2H, s), 7.54 (1H, dd, J = 10.0, 2.0 Hz), 7.66 (1H, t, J = 10.0 Hz), 7.71 (1H, dd, J = 8.5, 1.6 Hz), 7.89 (1H, s), 8.11 (1H, d, J = 8.5 Hz). Step 3 Synthesis of compound 59 Compound 57 (32.0 mg, 0.077 mmol) and compound 58 (20.1 mg, 0.085 mmol) were dissolved in N,N-dimethylformamide (0.64 mL) and the solution was added with triethylamine (0.021 mL, 0.154 mmol) and 1-(bis(dimethylaminomethylene)-1H-1,2,3-triazolo(4,5-b)pyridinium 3-oxide hexafluorophosphate (44.0 mg, 0.116 mmol). ol) was added and stirred at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate was added to the reaction solution. The reaction solution was filtered, and the residue was washed with water and then dried to obtain a residue (44.4 mg). The obtained residue (44.0 mg) was dissolved in acetic acid (0.44 ml) and stirred at 60°C for 2 hours. The reaction solution was concentrated, and the obtained residue was purified by column chromatography (hexane-ethyl acetate) to obtain compound 59 (26.0 mg, two-step yield 55%). [M+H]=615.15, measurement condition 1: retention time 2.63 minutes 1 H-NMR (CDCl3) δ: 2.32-2.41 (1H, m), 2.65-2.73 (1H, m), 3.95 (3H, s), 4.27-4.40 (3H, m), 4.65 (1H, dd, J =14.0, 7.6 Hz), 4.68-4.77 (2H, m), 5.12-5.18 (1H, m), 5.63 (2H, s), 7.12-7.18 (2H, m), 7.49 (1H, t, J = 8.0 Hz), 7.62 (1H, dd, J = 8.5, 2.0 Hz), 7.77-7.82 (2H, m), 8.01 (1H, dd, J = 8.4,1.5 Hz), 8.08 (1H, s), 8.08 (1H, d, J = 8.4 Hz). Step 4 Synthesis of Compound I-076 Compound 59 (24.5 mg, 0.040 mmol) was dissolved in a mixture of tetrahydrofuran (0.25 mL) and methanol (0.25 mL), and 1 mol / L aqueous sodium hydroxide (0.12 mL, 0.12 mmol) was added. The mixture was stirred at 60 °C for 1 hour. After returning to room temperature, 10% aqueous citric acid was added to the reaction mixture. The reaction mixture was filtered, and the residue was washed with water and then dried to obtain a residue. The resulting residue was purified by preparative TLC (0.5 mm, CHCl3-MeOH-HO) and then purified by SFC to obtain compound I-076 (14.4 mg, 18% yield). [M+H]=601.1, measurement condition 1: retention time 2.39 minutes 1 H-NMR (DMSO-d6) δ: 2.32-2.40 (1H, m), 2.49-2.69 (1H, m), 4.32-4.37 (1H, m), 4.43-4.48 (1H, m), 4.55-4.74 (4H, m), 4.95-5.02 (1H, m), 5.66 (2H, s), 7.36 (1H, dd, J = 8.2, 1.6 Hz), 7.52-7.57 (2H, m), 7.62-7.73 (1H, m), 7.78 (2H, dd, J = 8.5, 1.2 Hz), 7.90 (1H, s), 8.13 (1H, d, J = 8.6 Hz), 8.19 (1H, s).

[0118] Example 9 Synthesis of Compound I-145 [ka] [ka] Step 1: Synthesis of Compound 61 Compound 60 (51.3 g, 171 mmol), synthesized by the synthetic method described in the patent (WO2020146682), was suspended in dichloromethane (400 mL) and N,O-dimethylhydroxyamine hydrochloride (20 g, 205 mmol), HOBt (4.6 g, 34 mmol), EDC hydrochloride (49 g, 257 mmol), and triethylamine (28 mL, 205 mmol) were added and stirred at room temperature for 1 hour. Water was added to the reaction solution, and the organic layer was separated. The aqueous layer was then extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Isopropyl ether was added to the resulting residue, and the resulting solid was collected by filtration to obtain compound 61 (45.2 g, 77% yield). 1 H-NMR (CDCl3) δ: 3.41 (3H, s), 3.63 (3H, s), 4.04 (3H, s), 8.02 (1H, s). [M+H]=343, measurement condition 1: retention time 2.48 minutes Step 2: Synthesis of compound 62 To a solution of compound 61 (54.7 g, 159 mmol) in tetrahydrofuran (550 mL), a 3 mol / L methylmagnesium bromide diethyl ether solution (159 mL, 478 mmol) was added dropwise over 30 minutes under ice-cooling. After stirring for 3 hours under ice-cooling, the reaction mixture was added to an ice-cooled aqueous ammonium chloride solution. 2 mol / L hydrochloric acid was added until the pH reached approximately 6, followed by extraction twice with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 62 (29.1 g, 61% yield). 1 H-NMR (CDCl3) δ: 2.67 (3H, s), 4.07 (3H, s), 8.10 (1H, s). [M+H]=298, measurement condition 1: retention time 2.93 minutes Step 3 Synthesis of compound 63 To a solution of compound 62 (29.1 g, 98 mmol) in acetonitrile (400 mL), formic acid (16.1 mL, 420 mmol), triethylamine (33.8 mL, 244 mmol), and [(R,R)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamido]chloro(p-cymene)ruthenium(II) (1.24 g, 1.95 mmol) were added and the mixture was stirred at room temperature for 2 hours and 30 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate and washed with aqueous sodium bicarbonate. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 63 (28.5 g, 97% yield). 1 H-NMR (CDCl3) δ: 1.47 (3H, d, J = 6.5 Hz), 3.69 (1H, d, J = 8.7 Hz), 4.08 (3H, s), 5.10 (1H, dt, J = 15.1, 6.5 Hz), 7.98 (1H, s). [M+H]=300, measurement condition 1: retention time 2.10 minutes Step 4 Synthesis of compound 64 To a solution of compound 63 (32 g, 107 mmol) in N,N-dimethylformamide (250 mL), N-vinylphthalimide (18.9 g, 107 mmol), tetrabutylammonium bromide (34.4 g, 107 mmol), palladium acetate (2.4 g, 10.7 mmol), and N,N-dicyclohexyl-N-methylamine (34 mL, 160 mmol) were added. After degassing under reduced pressure, the mixture was purged with nitrogen and stirred at 110 °C for 4 hours. Water was added to the reaction mixture, and the resulting solid was collected by filtration. The solid was then washed with diisopropyl ether to give compound 64 (37 g, 88% yield). 1H-NMR (CDCl3) δ: 1.47 (3H, d, J = 6.5 Hz), 4.10-4.15 (4H, m), 5.12-5.18 (1H, m), 7.21 (1H, d, J = 14.9 Hz), 7.74 (1H, d, J = 14.9 Hz), 7.79-7.82 (2H, m), 7.91-7.95 (2H, m), 8.02 (1H, s). [M+H]=393, measurement condition 1: retention time 2.35 minutes Step 5 Synthesis of compound 65 To a solution of compound 64 (37 g, 94 mmol) in methanol (250 mL) and tetrahydrofuran (500 mL), 10% palladium-carbon (50% aqueous) (20 g, 9.4 mmol) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) for 8 hours and 30 minutes. After removing insoluble matter by filtration, the solvent was evaporated under reduced pressure to give a crude product (53 g) containing compound 65. The resulting compound 65 was used directly in the next step without further purification. 1 H-NMR (CDCl3) δ: 1.50 (3H, d, J = 6.4 Hz), 2.90-3.04 (2H, m), 3.87-3.91 (2H, m), 4.06 (3H, s), 5.13 (1H, d, J = 5.9 Hz), 7.72-7.76 (3H, m), 7.84-7.88 (2H, m). [M+H]=395, measurement condition 1: retention time 2.16 minutes Step 6 Synthesis of Compound 66 Hydrazine monohydrate (22.8 mL, 470 mmol) was added to a solution of the entire crude product of compound 65 (94 mmol) obtained in step 5 in ethanol (500 mL), followed by stirring at 80°C for 1 hour. After removing insoluble matter by filtration, the solvent was evaporated under reduced pressure, and dichloromethane was added to the resulting residue. After removing the precipitated insoluble matter again by filtration, the solvent was evaporated under reduced pressure to give a crude product (24.6 g) containing compound 66. The resulting compound 66 was used directly in the next step without further purification. 1H-NMR (CDCl3) δ: 1.49 (3H, d, J = 6.4 Hz), 2.69-2.92 (3H, m), 3.03-3.09 (1H, m), 4.06 (3H, s), 5.06 (1H, q, J = 6.4 Hz), 7.68 (1H, s). [M+H]=265, measurement condition 1: retention time 1.15 minutes Step 7 Synthesis of compound 67 Trifluoroacetic anhydride (40 mL, 282 mmol) was added dropwise to a dichloromethane (200 mL) solution of the entire crude product of compound 66 (94 mmol) obtained in step 6 under ice-cooling, followed by stirring at room temperature for 1 hour. The solvent was removed under reduced pressure, and the resulting residue was dissolved in toluene. The solvent was again removed under reduced pressure. The resulting residue was dissolved in ethyl acetate and slowly poured into aqueous sodium bicarbonate solution. The mixture was stirred at 30°C for 6 hours, followed by extraction twice with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 67 (22.9 g, yield 68%). 1 H-NMR (CDCl3) δ: 1.51 (3H, d, J = 6.4 Hz), 2.87-2.99 (2H, m), 3.43 (1H, d, J = 8.4 Hz), 3.51-3.66 (2H, m), 4.06 (3H, s), 5.05 (1H, dt, J = 14.6, 6.5 Hz), 6.81 (1H, s), 7.68 (1H, s). [M+H]=361, measurement condition 1: retention time 1.93 minutes Step 8 Synthesis of compound 68 To a solution of compound 67 (21.5 g, 60 mmol) in tetrahydrofuran (500 mL) was added triphenylphosphine (23.5 g, 89 mmol), followed by the dropwise addition of DIAD (17.4 mL, 89 mmol) over 20 min under ice-cooling. After stirring at room temperature for 1 h 30 min, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 68 (16.4 g, 81% yield). 1 H-NMR (CDCl3) δ: 1.60 (2.1H, d, J = 6.9 Hz), 1.67 (0.9H, d, J = 6.8 Hz), 2.71-2.80 (1H, m), 2.91-3.02 (1H, m), 3.18 (0.3H, dt, J = 18.6, 6.4 Hz), 3.44-3.52 (0.7H, m), 4.00-4.01 (3H, m), 4.13-4.19 (0.7H, m), 4.74 (0.3H, dd, J = 13.3, 5.6 Hz), 5.05 (0.3H, q, J = 6.7 Hz), 5.48 (0.7H, q, J = 6.9 Hz), 7.62-7.64 (1H, m). [M+H]=343, measurement condition 1: retention time 2.56 minutes Step 9 Synthesis of compound 69 Sodium iodide (21.6 g, 144 mmol) and trimethylsilyl chloride (18.4 mL, 144 mmol) were added to a solution of compound 68 (16.4 g, 48 mmol) in acetonitrile (200 mL) and the mixture was stirred at 45 °C for 1 hour. Aqueous sodium bicarbonate and aqueous sodium thiosulfate were added to the reaction mixture, which was then extracted twice with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give crude compound 69 (15.8 g). The resulting compound 69 was used directly in the next step without further purification. 1 H-NMR (CDCl3) δ: 1.66 (2.25H, d, J = 6.9 Hz), 1.75 (0.75H, d, J = 6.7 Hz), 2.57-2.65 (1H, m), 2.77-2.89 (1H, m), 3.15-3.22 (0.25H, m), 3.45-3.52 (0.75H, m), 4.16 (0.75H, dd, J = 14.3, 4.6 Hz), 4.73 (0.25H, dd, J = 13.7, 5.8 Hz), 5.01 (0.25H, dd, J = 13.7, 6.8 Hz), 5.50 (0.75H, q, J = 6.7 Hz), 7.63-7.65 (1H, m). [M+H]=329, measurement condition 1: retention time 1.57 minutes Step 10 Synthesis of Compound 70 To a solution of compound 69 (7.1 g, 21.6 mmol) in 1,4-dioxane (70 mL), silver carbonate (8.95 g, 32 mmol) and 4-chloro-2-fluorobenzyl bromide (5.8 g, 26 mmol) were added, and the mixture was stirred at 65° C. for 1 hour. After removing insoluble matter by filtration, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 70 (9.89 g, 97% yield). 1 H-NMR (CDCl3) δ: 1.56 (2.1H, d, J = 4.8 Hz), 1.63 (0.9H, d, J = 6.9 Hz), 2.72-2.80 (1H, m), 2.91-3.02 (1H, m), 3.17 (0.3H, td, J = 12.9, 3.8 Hz), 3.43-3.51 (0.7H, m), 4.16 (0.7H, dd, J = 14.2, 3.8 Hz), 4.73 (0.3H, dd, J = 13.2, 5.6 Hz), 5.04 (0.3H, dd, J = 13.2, 6.8 Hz), 5.45-5.55 (2.7H, m), 7.11-7.16 (2H, m), 7.41-7.46 (1H, m), 7.65-7.67 (1H, m). [M+H]=471, measurement condition 1: retention time 3.11 minutes Step 11 Synthesis of compound 71 To a solution of compound 70 (9.89 g, 21 mmol) in methanol (80 mL) and tetrahydrofuran (80 mL), potassium carbonate (5.8 g, 42 mmol) was added and the mixture was stirred at 50°C for 8 hours. The solvent was evaporated under reduced pressure, and water was added to the residue, which was then extracted twice with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give crude compound 71 (9.31 g). The resulting compound 71 was used directly in the next step without further purification. 1H-NMR (CDCl3) δ: 1.47 (3H, d, J = 6.8 Hz), 2.68 (1H, dt, J = 16.0, 4.0 Hz), 2.80-2.88 (1H, m), 2.97-3.04 (1H, m), 3.27 (1H, dt, J = 12.2, 4.7 Hz), 4.00 (1H, q, J = 6.5 Hz), 5.47 (1H, d, J = 13.4 Hz), 5.52 (1H, d, J = 13.4 Hz), 7.08-7.14 (2H, m), 7.44 (1H, t, J = 8.0 Hz), 7.57 (1H, s). [M+H]=375, measurement condition 1: retention time 2.13 minutes Step 12 Synthesis of compound 73 Compound 72 (4.0 g, 13.6 mmol) and potassium carbonate (4.0 g, 29 mmol) were added to a solution of two-thirds (14 mmol) of the total amount of crude compound 71 obtained in step 11 in acetonitrile (64 mL), and the mixture was stirred at 65 °C for 6 hours. Brine was added to the reaction mixture, which was then extracted twice with ethyl acetate and the solvent was evaporated under reduced pressure. The residue was dissolved in chloroform, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give crude compound 73 (9.67 g). The resulting compound 73 was used directly in the next step without purification. 1H-NMR (CDCl3) δ: 1.47 (3H, d, J = 6.7 Hz), 2.35-2.44 (1H, m), 2.61-2.83 (4H, m), 3.00-3.06 (1H, m), 3.84 (1H, q, J = 6.6 Hz), 3.95 (3H, s), 4.10 (1H, d, J = 13.6 Hz), 4.32 (1H, dt, J = 11.0, 4.6 Hz), 4.39 (1H, d, J = 13.6 Hz), 4.60 (1H, dd, J = 13.8, 8.0 Hz), 4.67 (1H, dd, J = 15.4, 5.7 Hz), 4.73 (1H, dd, J = 15.4, 3.1 Hz), 5.17-5.23 (1H, m), 5.44 (1H, d, J = 13.3 Hz), 5.52 (1H, d, J = 13.3 Hz), 7.07-7.14 (2H, m), 7.44 (1H, t, J = 8.0 Hz), 7.59 (1H, s), 7.77 (1H, d, J = 8.5 Hz), 7.99 (1H, dd, J = 8.5, 1.5 Hz), 8.14 (1H, d, J = 1.0 Hz). [M+H]=633, measurement condition 1: retention time 2.49 minutes Step 13 Synthesis of compound I-145 To a solution of the entire crude product (14 mmol) of compound 73 obtained in step 12 in methanol (55 mL) and tetrahydrofuran (55 mL), 2 mol / L aqueous sodium hydroxide (21.5 mL, 43 mmol) was added, followed by stirring at 45°C for 2 hours. Citric acid solution was added to the reaction mixture, which was then extracted twice with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Ethanol was added to the resulting residue, and the solvent was evaporated under reduced pressure again. Ethanol (20 mL) and water (10 mL) were added to the residue, and the resulting suspension was stirred at 40°C for 15 minutes, followed by stirring at room temperature for 30 minutes. The solid was collected by filtration from the resulting suspension to give compound I-145 (6.55 g, yield 74%). 1H-NMR (DMSO-D6) δ: 1.37 (3H, d, J = 6.8 Hz), 2.30-2.38 (1H, m), 2.57-2.85 (4H, m), 2.96-3.01 (1H, m), 3.86 (1H, dd, J = 13.3, 6.4 Hz), 4.09 (1H, d, J = 13.9 Hz), 4.20 (1H, d, J = 13.9 Hz), 4.29 (1H, dt, J = 10.8, 4.5 Hz), 4.45 (1H, dd, J = 13.7, 7.8 Hz), 4.68 (1H, dd, J = 15.4, 2.8 Hz), 4.77 (1H, dd, J = 15.4, 6.7 Hz), 5.06-5.12 (1H, m), 5.43 (1H, d, J = 12.9 Hz), 5.52 (1H, d, J = 12.9 Hz), 7.31 (1H, dd, J = 8.3, 1.8 Hz), 7.46-7.53 (2H, m), 7.68 (1H, d, J = 8.5 Hz), 7.82 (1H, dd, J = 8.5, 1.3 Hz), 7.89 (1H, s), 8.27 (1H, s).

[0119] The following compounds were synthesized in the same manner using the general synthesis method described above or the synthesis method described in the Examples. Note that I-032, I-044, I-066, and I-133 in the table are diastereomeric mixtures, and I-144 in the table is a racemate.

[0120] [Table 1]

[0121] [Table 2]

[0122] [Table 3]

[0123] Table 4

[0124] Table 5

[0125] Table 6

[0126] Table 7

[0127] Table 8

[0128] Table 9

[0129] Table 10

[0130] Table 11

[0131] Table 12

[0132] Table 13

[0133] Table 14

[0134] Table 15

[0135] Table 16

[0136] Table 17

[0137] Table 18

[0138] Table 19

[0139] Table 20

[0140] Table 21

[0141] Table 22

[0142] Table 23

[0143] Table 24

[0144] Table 25

[0145] Table 26

[0146] Table 27

[0147] Table 28

[0148] Table 29

[0149] Table 30

[0150] Table 31

[0151] Table 32

[0152] Table 33

[0153] Table 34

[0154] Table 35

[0155] Table 36

[0156] Table 37

[0157] Table 38

[0158] Table 39

[0159] Table 40

[0160] Table 41

[0161] Table 42

[0162] Table 43

[0163] Table 44

[0164] Table 45

[0165] Table 46

[0166] Table 47

[0167] Table 48

[0168] Table 49

[0169] Table 50

[0170] Table 51

[0171] Table 52

[0172] Table 53

[0173] Table 54

[0174] Table 55

[0175] Table 56

[0176] Table 57

[0177] Table 58

[0178] Table 59

[0179] Table 60

[0180] Table 61

[0181] Table 62

[0182] Table 63

[0183] Table 64

[0184] Table 65

[0185] Table 66

[0186] Table 67

[0187] Table 68

[0188] Table 69

[0189] Table 70

[0190] Table 71

[0191] Table 72

[0192] Table 73

[0193] Table 74

[0194] Table 75

[0195] Table 76

[0196] Table 77

[0197] Table 78

[0198] Table 79

[0199] Table 80

[0200] Table 81

[0201] Table 82

[0202] Table 83

[0203] Table 84

[0204] Table 85

[0205] Table 86

[0206] Table 87

[0207] [Table 88]

[0208] The following are examples of biological tests for the compounds of the present invention: The compounds of the present invention can be tested essentially as in the test examples below. The compounds of the present invention represented by formula (I), formula (II) or formula (III) have GLP-1 receptor agonist activity. Specifically, in the evaluation method described below, EC 50 Values ​​of 5000 nM or less are preferred, more preferably 1000 nM or less, and even more preferably 100 nM or less.

[0209] Test Example 1 (Measurement of GLP-1 receptor agonist activity) cell culture Human GLP-1 receptor stably expressing cells (hGLP-1R / CHO-K1 cells) were cultured in α-MEM medium (Sigma) containing 10% FBS (Hyclone), 2% GlutaMAX (Gibco), 1% G418 (Nacalai Tesque), and 1% Penicillin-Streptomycin Mixed Solution (Sigma) at 37°C and 5% CO2, and then harvested by treatment with 10-fold diluted 5.0 g / L-trypsin / 5.3 mmol / L-EDTA solution (Nacalai Tesque) and cryopreserved. cAMP assay A DMSO solution containing the compound of the present invention or human GLP-1(7-36) (Phoenix Pharmaceuticals) was dispensed into a 384-well microplate (Greiner) at 62.5 nL / well, and 400 μM Forskolin (Nacalai Tesque) was also dispensed at 7.5 nL / well. Frozen GLP-1R / CHO-K1 cells were then thawed in a 37°C incubator and diluted to 2 × 10 with HBSS buffer (GIBCO) containing 0.1% BSA (Sigma), 20 mM HEPES (GIBCO), 0.1 mM IBMX (Sigma), and 0.2 mM RO20-1724 (Calbiochem). 4 The cells were suspended at 1000 cells / mL and added at 6 μL per well. After incubation at 37°C for 1 hour, intracellular cAMP concentrations were measured using a cAMP Gs dynamic kit (Cisbio) according to the manufacturer's protocol. Specifically, cAMP-d2 and Anti-cAMP-Cryptate were added at 3 μL per well, incubated at room temperature for 1 hour, and time-resolved fluorescence was measured using a PHERAstar (BMG Labtech). The cAMP concentration when human GLP-1 (7-36) was dispensed to a final concentration of 2 nM was set to 100%, and the cAMP concentration when DMSO alone was dispensed was set to 0%. The 50% effective concentration (EC 50 The concentration of the active ingredient (A) and the maximum effect (Emax) are calculated using TIBCO Spotfire (TIBCO Software). The dilution concentration and dilution solvent are changed as necessary. The compounds of the invention were tested essentially as described above. The EC 50 , Emax are shown in the table below.

[0210] [Table 89]

[0211] [Table 90]

[0212] [Table 91]

[0213] [Table 92]

[0214] [Table 93]

[0215] [Table 94]

[0216] [Table 95]

[0217] [Table 96]

[0218] [Table 97] From the above results, the compounds of the present invention exhibited GLP-1 receptor agonist activity, and are therefore expected to be effective as therapeutic or preventive agents for diseases involving the GLP-1 receptor.

[0219] Test Example 2 (Metabolic Stability Test) The compound of the present invention is reacted with commercially available pooled human liver microsomes for a certain period of time, and the remaining rate is calculated by comparing the reacted sample with the unreacted sample to evaluate the degree to which the compound of the present invention is metabolized in the liver.

[0220] Human liver microsomes (0.5 mg protein / mL) were incubated in 0.2 mL of buffer (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) in the presence of 1 mmol / L NADPH at 37°C for 0 or 30 minutes (oxidative reaction). After the reaction, 50 μL of the reaction mixture was added to 100 μL of a 1 / 1 (v / v) methanol / acetonitrile solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the supernatant was quantified by LC / MS / MS, and the remaining amount of the compound of the present invention after the reaction was calculated based on the amount of compound at 0 minutes of reaction (100%). Compounds of the invention can be tested essentially as described above.

[0221] Test Example 2-2: Metabolic stability test The compound of the present invention is reacted with commercially available pooled human liver microsomes for a certain period of time, and the remaining rate is calculated by comparing the reacted sample with the unreacted sample to evaluate the degree to which the compound of the present invention is metabolized in the liver.

[0222] Human liver microsomes (0.5 mg protein / mL) were incubated in 0.2 mL of buffer (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) in the presence of 1 mmol / L NADPH at 37°C for 0 or 30 minutes (oxidation reaction). After the reaction, 70 μL of the reaction mixture was added to 140 μL of a 1 / 1 (v / v) methanol / acetonitrile solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The amount of the compound of the present invention in the supernatant was quantified by LC / MS / MS or solid-phase extraction (SPE) / MS. The amount of the compound of the present invention at 0 minutes of reaction was set at 100%, and the ratio of the amount of compound after the reaction to the remaining amount was expressed as the percentage of the compound remaining. Note that the hydrolysis reaction was performed in the absence of NADPH, and the glucuronidation reaction was performed in the presence of 5 mmol / L UDP-glucuronic acid instead of NADPH. The same procedures were then repeated. The dilution concentration and dilution solvent were adjusted as necessary. Compounds of the invention were tested essentially as described above, with the results shown below. (Results) The residual rate at a compound concentration of 0.5 μmol / L is shown. Compound I-033:87.1% Compound I-035:87.1% Compound I-109:99.6% Compound I-117:96.9% Compound I-123:>99.9% Compound I-145:94.0% Compound I-160:92.4%

[0223] Test Example 3 (Solubility Test) The solubility of the compounds of the present invention is determined under conditions where 1% DMSO is added. A 10 mmol / L compound solution is prepared in DMSO, and 6 μL of the compound solution is added to 594 μL of pH 6.8 simulated intestinal fluid (250 mL of 0.2 mol / L potassium dihydrogen phosphate TS, 118 mL of 0.2 mol / L NaOH TS, and water to 1000 mL). After standing at 25°C for 16 hours, the mixture is filtered under suction. The filtrate is diluted 2-fold with methanol / water = 1 / 1 (V / V), and the concentration in the filtrate is measured using HPLC or LC / MS / MS with the absolute calibration curve method. Compounds of the invention can be tested essentially as described above.

[0224] Test Example 3-2 (Solubility test) The solubility of the compounds of the present invention is determined in the presence of 1% DMSO. A 10 mmol / L compound solution is prepared in DMSO, and 2 μL of the compound solution is added to 594 μL of pH 6.8 simulated intestinal fluid (250 mL of 0.2 mol / L potassium dihydrogen phosphate TS, 118 mL of 0.2 mol / L NaOH TS, and water to 1000 mL). After shaking at room temperature for at least 1 hour (3 hours depending on operability), the mixture is filtered under suction. The filtrate is diluted 100-fold (2 μL of filtrate + 198 μL of MeCN / MeOH / purified water = 1 / 1 / 2 (V / V / V)), and the concentration in the filtrate is measured using HPLC or LC / MS / MS with the absolute calibration curve method. Compounds of the invention can be tested essentially as described above.

[0225] Test Example 3-3 (Solubility test) The solubility of the compound of the present invention is determined under conditions where 1% DMSO is added. A 10 mmol / L compound solution is prepared in DMSO, and 2 μL of the compound solution is added to 198 μL of the second solution of the dissolution test of the Japanese Pharmacopoeia, 17th Edition. After standing and shaking at 25°C for 3 hours, the mixture is filtered by suction. The filtrate is diluted 100-fold with methanol / acetonitrile / water = 1 / 1 (V / V), and the concentration in the filtrate is measured using LC / MS / MS with the absolute calibration curve method. Compounds of the invention can be tested essentially as described above.

[0226] Test Example 3-4 (Solubility test) The solubility of the compound of the present invention is determined under conditions where 1% DMSO is added. A 10 mmol / L compound solution is prepared in DMSO, and 2 μL of the compound solution is added to 198 μL of the second solution of the dissolution test of the Japanese Pharmacopoeia, 17th Edition. After shaking for 3 hours at room temperature, the mixture is filtered under suction. The filtrate is diluted 100-fold with methanol / acetonitrile / water = 1 / 1 (V / V), and the concentration in the filtrate is measured using LC / MS / MS with the absolute calibration curve method. Compounds of the invention can be tested essentially as described above.

[0227] Test Example 4 (CYP Inhibition Test) Using commercially available pooled human liver microsomes, the following typical substrate metabolic reactions of major human CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) are used as indicators: O-deethylation of 7-ethoxyresorufin (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4'-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4), and the extent to which the production of each metabolite is inhibited by the compound of the present invention is evaluated. The reaction conditions were as follows: substrates: 0.5 μmol / L ethoxyresorufin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 30 μmol / L or 50 μmol / L S-mephenytoin (CYP2C19), 5 μmol / L dextromethorphan (CYP2D6), 1 μmol / L terfenadine (CYP3A4); reaction time: 15 minutes; reaction temperature: 37°C; enzyme: pooled human liver microsomes, 0.2 mg protein / mL; concentration of the compound of the present invention: 1, 5, 10, 20 μmol / L (4 points). The reaction solution was prepared in a 96-well plate by adding five substrates, human liver microsomes, and the compound of the present invention in 50 mmol / L Hepes buffer. The coenzyme NADPH was added to initiate the metabolic reaction. After 15 minutes at 37°C, the reaction was stopped by adding a 1:1 (V / V) methanol / acetonitrile solution. After 15 minutes of centrifugation at 3000 rpm, the supernatant was quantified for resorufin (a CYP1A2 metabolite) by fluorescence multilabel counter or LC / MS / MS. Hydroxylated tolbutamide (a CYP2C9 metabolite), 4'-hydroxylated mephenytoin (a CYP2C19 metabolite), dextrorphan (a CYP2D6 metabolite), and terfenadine alcohol (a CYP3A4 metabolite) were quantified by LC / MS / MS. The control (100%) was a reaction system containing only DMSO, the solvent in which the drug was dissolved. The remaining activity (%) was calculated, and the IC was calculated by inverse estimation using a logistic model using the concentration and inhibition rate. 50 Calculate. Compounds of the invention can be tested essentially as described above.

[0228] Test Example 5 (BA test) Materials and methods for oral absorption studies (1) Animals used: Mice or SD rats are used. (2) Rearing conditions: Mice or SD rats are allowed free access to solid food and sterilized tap water. (3) Dosage and grouping: Oral and intravenous administration will be performed at the specified dose. The groups will be set up as follows (dosage may vary depending on the compound): Oral administration: 2-60 μmol / kg or 1-30 mg / kg (n=2-3) Intravenous administration: 1-20 μmol / kg or 0.5-10 mg / kg (n=2-3) (4) Preparation of administration solution: For oral administration, administer as a solution or suspension. For intravenous administration, administer as a solubilized solution. (5) Administration method: Oral administration is by forced administration into the stomach using an oral sonde. Intravenous administration is by administration into the tail vein or femoral vein using a syringe with an injection needle. (6) Evaluation item: Blood samples are collected over time, and the plasma concentration of the compound of the present invention is measured using LC / MS / MS. (7) Statistical analysis: The area under the plasma concentration-time curve (AUC) of the compound of the present invention is calculated by moment analysis for the change in plasma concentration of the compound of the present invention, and the bioavailability (BA) of the compound of the present invention is calculated from the dose ratio and AUC ratio between the oral and intravenous administration groups. Compounds of the invention can be tested essentially as described above.

[0229] Test Example 6: Clearance evaluation test Experimental materials and methods (1) Animals used: SD rats were used. (2) Rearing conditions: SD rats were allowed free access to solid food and sterilized tap water. (3) Dosage and grouping: The animals were administered intravenously at a predetermined dose. The groups were set up as follows: Intravenous administration 1 μmol / kg (n=2) (4) Preparation of administration solution: The solution is solubilized using a solvent of dimethyl sulfoxide / propylene glycol = 1 / 1 and then administered. (5) Administration method: Administer via the tail vein using a syringe with an injection needle attached. (6) Evaluation item: Blood samples are collected over time, and the plasma concentration of the compound of the present invention is measured using LC / MS / MS. (7) Statistical analysis: The total body clearance (CLtot) of the plasma compound of the present invention is calculated by moment analysis. The dilution concentration and dilution solvent are changed as necessary. Compounds of the invention can be tested essentially as described above.

[0230] Test Example 6-2: Clearance evaluation test Experimental materials and methods (1) Animals used: Dogs (Marshallese beagles) were used. (2) Rearing conditions: The dogs were allowed free access to solid food and sterilized tap water. (3) Dosage and grouping: The animals were administered intravenously at a predetermined dose. The groups were set up as follows: Intravenous administration: 0.1-1 mg / kg (n=2) (4) Preparation of administration solution: The drug is solubilized using one of the following solvents: dimethylacetamide / ethanol / carbonate buffer = 2 / 3 / 5, ethanol / carbonate buffer = 1 / 1, or dimethylacetamide / polyethylene glycol 400 / 20% hydroxypropyl-β-cyclodextrin = 1 / 1 / 2, and then administered. (5) Method of administration: Administer intravenously using a syringe with a needle attached. (6) Evaluation item: Blood samples are collected over time, and the plasma concentration of the compound of the present invention is measured using LC / MS / MS. (7) Statistical analysis: The total body clearance (CLtot) of the plasma compound of the present invention is calculated by moment analysis. The dilution concentration and dilution solvent are changed as necessary. Compounds of the invention can be tested essentially as described above.

[0231] Test Example 7 (CYP3A4 (MDZ) MBI test) This test evaluates the mechanism-based inhibition (MBI) ability of the compounds of the present invention in terms of CYP3A4 inhibition by metabolic enhancement. CYP3A4 inhibition is evaluated using pooled human liver microsomes, with the 1-hydroxylation of midazolam (MDZ) as an indicator. The reaction conditions were as follows: substrate, 10 μmol / L MDZ; pre-reaction time, 0 or 30 minutes; reaction time, 2 minutes; reaction temperature, 37°C; pooled human liver microsomes, 0.5 mg / mL during pre-reaction and 0.05 mg / mL (10-fold dilution) during reaction; concentration of the compound of the present invention during pre-reaction, 1, 5, 10, and 20 μmol / L (4 points). A 96-well plate was prepared as a pre-reaction solution by adding pooled human liver microsomes and a solution of the compound of the present invention in K-Pi buffer (pH 7.4) according to the pre-reaction composition. A portion of this mixture was transferred to another 96-well plate so that it was diluted 1 / 10 with substrate and K-Pi buffer, and the coenzyme NADPH was added to initiate the reaction (no pre-reaction). After the specified reaction time, the reaction was stopped by adding a 1 / 1 (V / V) methanol / acetonitrile solution. NADPH was also added to the remaining pre-reaction solution to initiate the pre-reaction (pre-reaction). After the specified reaction time, a portion of this mixture was transferred to another plate so that it was diluted 1 / 10 with substrate and K-Pi buffer, and the reaction was stopped by adding a 1 / 1 (V / V) methanol / acetonitrile solution. Each plate containing the indicator reaction was centrifuged at 3000 rpm for 15 minutes, and 1-hydroxymidazolam in the supernatant was quantified by LC / MS / MS. The control (100%) was a reaction system containing only DMSO, the solvent used to dissolve the compound of the present invention. The residual activity (%) was calculated when each concentration of the compound of the present invention was added, and the IC was calculated by inverse estimation using a logistic model using the concentration and inhibition rate. The shifted IC value was calculated as the IC at 0 min preincubation / IC at 30 min preincubation. A shifted IC of 1.5 or higher was considered positive, and a shifted IC of 1.0 or lower was considered negative. Compounds of the invention can be tested essentially as described above.

[0232] Test Example 7-2 (CYP3A4 (MDZ) MBI test) This test evaluates the mechanism-based inhibition (MBI) ability of the compounds of the present invention in terms of CYP3A4 inhibition by metabolic enhancement. CYP3A4 inhibition is evaluated using pooled human liver microsomes, with the 1-hydroxylation of midazolam (MDZ) as an indicator. The reaction conditions were as follows: substrate, 10 μmol / L MDZ; pre-reaction time, 0 or 30 minutes; reaction time, 2 minutes; reaction temperature, 37°C; pooled human liver microsomes, 0.5 mg / mL during pre-reaction and 0.05 mg / mL (10-fold dilution) during reaction; and concentrations of the compound of the present invention during pre-reaction, 0.83, 5, 10, and 20 μmol / L (4 points). A 96-well plate was prepared as a pre-reaction solution by adding pooled human liver microsomes and a solution of the compound of the present invention in K-Pi buffer (pH 7.4) according to the pre-reaction composition. A portion of this mixture was transferred to another 96-well plate so that it was diluted 1 / 10 with substrate and K-Pi buffer, and the coenzyme NADPH was added to initiate the reaction (no pre-reaction). After the specified reaction time, the reaction was stopped by adding a 1 / 1 (V / V) methanol / acetonitrile solution. NADPH was also added to the remaining pre-reaction solution to initiate the pre-reaction (pre-reaction). After the specified reaction time, a portion of this mixture was transferred to another plate so that it was diluted 1 / 10 with substrate and K-Pi buffer, and the reaction was stopped by adding a 1 / 1 (V / V) methanol / acetonitrile solution. Each plate containing the indicator reaction was centrifuged at 3000 rpm for 15 minutes, and 1-hydroxymidazolam in the supernatant was quantified by LC / MS / MS. The control (100%) was a reaction system containing only DMSO, the solvent used to dissolve the compound of the present invention. The residual activity (%) was calculated when each concentration of the compound of the present invention was added, and the IC was calculated by inverse estimation using a logistic model using the concentration and inhibition rate. The shifted IC value was calculated as the IC at 0 min preincubation / IC at 30 min preincubation. A shifted IC of 1.5 or greater was considered positive, and a shifted IC of less than 1.1 was considered negative. Compounds of the invention can be tested essentially as described above.

[0233] Test Example 8 (Powder solubility test) An appropriate amount of the compound of the present invention is placed in an appropriate container, and 200 μL of JP-1 solution (2.0 g of sodium chloride, 7.0 mL of hydrochloric acid, and water to 1000 mL), JP-2 solution (500 mL of pH 6.8 phosphate buffer solution plus 500 mL of water), or 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (1.08 g of TCA plus JP-2 solution to 100 mL) is added to each container. If the entire amount is dissolved after adding the test solution, additional compound of the present invention is added as appropriate. The container is sealed and shaken at 37°C for 1 hour, then filtered. 100 μL of each filtrate is diluted 2-fold by adding 100 μL of methanol. The dilution ratio may be changed as necessary. Check for the presence of bubbles or precipitates, then seal and shake. The compound of the present invention is quantified using HPLC using the absolute calibration curve method. Compounds of the invention can be tested essentially as described above.

[0234] Test Example 8-2 (Powder solubility test) Place an appropriate amount of the compound of the present invention in an appropriate container and add 200 μL of JP-1 solution (2.0 g of sodium chloride, 7.0 mL of hydrochloric acid, and water to 1000 mL), JP-2 solution (1.70 g of sodium dihydrogen phosphate and 1.775 g of anhydrous disodium hydrogen phosphate in 1000 mL of water to make a buffer solution of pH 6.8-6.9), or 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (1.08 g of TCA and JP-2 solution to 100 mL). If the entire amount is dissolved after adding the test solution, add the compound of the present invention as appropriate. Seal the container, shake at 37°C for 1 hour, and then filter. Dilute 100 μL of each filtrate by adding 100 μL of methanol to make a 2-fold dilution. The dilution ratio may be adjusted as necessary. Check for air bubbles and precipitates, seal the container, and shake. Quantify the compound of the present invention using HPLC using the absolute calibration curve method. Compounds of the invention can be tested essentially as described above.

[0235] Test Example 9 (Fluctuation Ames test) The mutagenicity of the compounds of the present invention is evaluated. 20 μL of frozen Salmonella typhimurium (Salmonella typhimurium TA98 strain, TA100 strain) was inoculated into 10 mL of liquid nutrient medium (2.5% Oxoid nutrient broth No. 2) and pre-cultured with shaking at 37°C for 10 hours. For the TA98 strain, 8.0 to 11.0 mL of the bacterial solution was centrifuged (2000 × g, 10 minutes) to remove the culture medium. Bacteria were suspended in 8.0–11.0 mL of Micro F buffer (K2HPO4: 3.5 g / L, KH2PO4: 1 g / L, (NH4)2SO4: 1 g / L, trisodium citrate dihydrate: 0.25 g / L, MgSO4·7H2O: 0.1 g / L) and added to 120 mL of Exposure medium (Micro F buffer containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL). For the TA100 strain, 3.1 mL of bacterial suspension was added to 120 mL of Exposure medium to prepare the test bacterial solution. DMSO solution of the compound of the present invention (several serial dilutions of 2- to 3-fold from the maximum dose of 50 mg / mL), DMSO as a negative control, and positive controls of 50 μg / mL 4-nitroquinoline-1-oxide DMSO solution for the TA98 strain and 0.25 μg / mL 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide DMSO solution for the TA100 strain under non-metabolic activation conditions, 40 μg / mL 2-aminoanthracene DMSO solution for the TA98 strain and 20 μg / mL 2-aminoanthracene DMSO solution for the TA100 strain under metabolic activation conditions, were mixed with 12 μL of each solution and 588 μL of test bacterial solution (a mixture of 498 μL of test bacterial solution and 90 μL of S9 mix under metabolic activation conditions), and cultured with shaking at 37°C for 90 minutes. 230 μL of the bacterial solution exposed to the compound of the present invention is mixed with 1150 μL of indicator medium (MicroF buffer containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL, and bromocresol purple: 37.5 μg / mL), and 50 μL of the mixture is dispensed into 48 wells of a microplate per dose and incubated statically at 37° C. for 3 days. Wells containing bacteria that have acquired the ability to grow due to a mutation in the amino acid (histidine) synthase gene change color from purple to yellow due to a change in pH, so the number of wells with bacterial growth that have turned yellow out of the 48 wells per dose is counted and evaluated in comparison with the negative control group.Mutagenicity is indicated as negative (-) and positive (+). Compounds of the invention can be tested essentially as described above.

[0236] Test Example 9-2 (Fluctuation Ames test) The mutagenicity of the compounds of the present invention is evaluated. 20 μL of frozen Salmonella typhimurium (Salmonella typhimurium TA98 strain, TA100 strain) was inoculated into 10 mL of liquid nutrient medium (2.5% Oxoid nutrient broth No. 2) and pre-cultured with shaking at 37°C for 10 hours. For the TA98 strain, 8.0 to 11.0 mL of the bacterial solution was centrifuged (2000 × g, 10 minutes) to remove the culture medium. Bacteria were suspended in 8.0–11.0 mL of Micro F buffer (K2HPO4: 3.5 g / L, KH2PO4: 1 g / L, (NH4)2SO4: 1 g / L, trisodium citrate dihydrate: 0.25 g / L, MgSO4·7H2O: 0.1 g / L) and added to 120 mL of Exposure medium (Micro F buffer containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL). For the TA100 strain, 3.0 mL of bacterial suspension was added to 120 mL of Exposure medium to prepare the test bacterial solution. DMSO solution of the compound of the present invention (several serial dilutions of 2- to 3-fold from the maximum dose of 50 mg / mL), DMSO as a negative control, and positive controls of 50 μg / mL 4-nitroquinoline-1-oxide DMSO solution for the TA98 strain and 0.25 μg / mL 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide DMSO solution for the TA100 strain under non-metabolic activation conditions, 40 μg / mL 2-aminoanthracene DMSO solution for the TA98 strain and 20 μg / mL 2-aminoanthracene DMSO solution for the TA100 strain under metabolic activation conditions, were mixed with 12 μL of each solution and 588 μL of test bacterial solution (a mixture of 498 μL of test bacterial solution and 90 μL of S9 mix under metabolic activation conditions), and cultured with shaking at 37°C for 90 minutes. The bacterial solution exposed to the compound of the present invention and indicator medium (MicroF buffer containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL, bromocresol purple: 37.5 μg / mL) are mixed at a ratio of 23:115, and 50 μL of the bacterial solution containing indicator (total 2760 μL) is dispensed into 48 wells of a microplate per well and incubated statically at 37°C for 3 days.Wells containing bacteria that have acquired the ability to grow due to a mutation in the amino acid (histidine) synthase gene change color from purple to yellow due to a change in pH, so the number of wells that have turned yellow out of 48 wells per dose are counted and evaluated by comparing them with the negative control group. Negative mutagenicity is indicated as (-), and positive mutagenicity is indicated as (+). Compounds of the invention can be tested essentially as described above.

[0237] Test Example 10 (hERG test) To evaluate the risk of electrocardiogram QT interval prolongation due to the compounds of the present invention, we used CHO cells expressing the human ether-a-go-go related gene (hERG) channel to evaluate the delayed rectifier K channel, which plays an important role in the ventricular repolarization process. + Current (I Kr The effect of the compound of the present invention on Using a fully automated patch clamp system (QPatch; Sophion Bioscience A / S), the whole-cell patch clamp technique was used to measure the I induced by holding the cell at a membrane potential of -80 mV and applying a leak potential of -50 mV, followed by a depolarizing stimulus of +20 mV for 2 seconds and a repolarizing stimulus of -50 mV for 2 seconds. Kr After the generated current has stabilized, an extracellular solution containing the compound of the present invention dissolved at the desired concentration (NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl2: 2 mmol / L, MgCl2: 1 mmol / L, glucose: 10 mmol / L, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid): 10 mmol / L, pH = 7.4) is applied to the cells at room temperature for 10 minutes. The resulting I Kr The absolute value of the maximum tail current was measured using analysis software (Falster Patch; Sophion Bioscience A / S) based on the current value at the resting membrane potential. Furthermore, the inhibition rate relative to the maximum tail current before application of the compound of the present invention was calculated, and the I of the compound of the present invention was calculated. Kr Evaluate the impact on Compounds of the invention can be tested essentially as described above.

[0238] Test Example 10-2 (hERG test) To evaluate the risk of electrocardiogram QT interval prolongation due to the compounds of the present invention, we used CHO cells expressing the human ether-a-go-go related gene (hERG) channel to evaluate the delayed rectifier K channel, which plays an important role in the ventricular repolarization process. + Current (I Kr The effect of the compound of the present invention on Using a fully automated patch clamp system (QPatch; Sophion Bioscience A / S), the whole-cell patch clamp technique was used to measure the I induced by holding the cell at a membrane potential of -80 mV and applying a leak potential of -50 mV, followed by a depolarizing stimulus of +20 mV for 2 seconds and a repolarizing stimulus of -50 mV for 2 seconds. Kr The extracellular solution containing 0.1% dimethyl sulfoxide (NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl2: 2 mmol / L, MgCl2: 1 mmol / L, glucose: 10 mmol / L, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid): 10 mmol / L, pH = 7.4) was used as a vehicle, and the vehicle and the extracellular solution containing the compound of the present invention dissolved at the desired concentration were applied to the cells at room temperature for 7 minutes or more. The obtained I Kr The absolute value of the maximum tail current was measured using analysis software (QPatch Assay software; Sophion Bioscience A / S) based on the current value at the resting membrane potential. Furthermore, the maximum tail current after application of the compound of the present invention relative to the maximum tail current after application of the vehicle was calculated as an inhibition rate, and the I of the compound of the present invention was calculated. Kr The dilution concentration and dilution solvent will be changed as necessary. Compounds of the invention can be tested essentially as described above.

[0239] Formulation example The compounds of the present invention can be administered as pharmaceutical compositions by any conventional route, particularly enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injection solutions or suspensions, or topically, e.g., in the form of lotions, gels, ointments, or creams, or in the form of intranasal or suppositories. Pharmaceutical compositions containing the compounds of the present invention in free form or in the form of a pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier or diluent can be prepared by conventional mixing, granulation, or coating methods. For example, oral compositions can be tablets, granules, or capsules containing excipients, disintegrants, binders, lubricants, etc., and active ingredients, etc. Injectable compositions can be solutions or suspensions, which may be sterilized and may contain preservatives, stabilizers, buffers, etc.

[0240] The compounds of the present invention can be administered as pharmaceutical compositions by any conventional route, particularly enterally, for example, orally, for example, in the form of tablets or capsules, or parenterally, for example, in the form of injection solutions or suspensions, or topically, for example, in the form of lotions, gels, ointments, or creams, or in the form of nasal or suppositories. Pharmaceutical compositions containing the compounds of the present invention in free form or in the form of a pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier or diluent can be prepared by conventional mixing, granulation, or coating methods. For example, oral compositions can be tablets, granules, or capsules containing excipients, disintegrants, binders, lubricants, etc., and active ingredients, etc. In addition, injectable compositions can be solutions or suspensions, which may be sterilized and may contain preservatives, stabilizers, buffers, etc. [Industrial Applicability]

[0241] The compounds according to the present invention have GLP-1 receptor agonist activity and are considered to be useful as therapeutic and / or preventive agents for diseases or conditions involving the GLP-1 receptor.

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, A １ is C(R ５ ) or N, A ２ is C(R ６ ) or N, A ３ is C(R ７ ) or N, R ５ , R ６ and R ７ are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyloxy, or a substituted or unsubstituted non-aromatic carbocyclic group; R １ is carboxy or any of the groups shown below: 【Chemistry 2】 wherein R is an unsubstituted non-aromatic carbocyclic group. or CH ２ COOH, R ２ is a substituted or unsubstituted alkyl or a substituted or unsubstituted non-aromatic heterocyclic group; -X- is -C(R ８ ) (R ９ ) - and R ８ and R ９ are each independently a hydrogen atom or unsubstituted alkyl; 【Transformation 3】 The ring denoted by 【Chemistry 4】 (In the formula, R １０ are each independently halogen, cyano, substituted or unsubstituted alkyl, oxo, or a substituted or unsubstituted non-aromatic carbocyclic group; and s is an integer of 0 to 9. R １３ are each independently a hydrogen atom or unsubstituted alkyl, R ３ is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group.) or a pharmaceutically acceptable salt thereof.

2. 2. The compound according to claim 1, wherein s is an integer of 1 to 9, or a pharmaceutically acceptable salt thereof. 【Request Item 3】 【Chemistry 5】 The ring shown by 【Transformation 6】 2. The compound according to claim 1, wherein the ring is represented by the formula: (wherein s' is an integer of 0 to 8, and other symbols have the same meanings as in claim 1), or a pharmaceutically acceptable salt thereof. 【Request Item 4】 【Chemistry 7】 The ring shown by 【Transformation 8】 2. The compound according to claim 1, wherein the ring is represented by the formula: wherein s is an integer of 1 to 9, and other symbols have the same meanings as defined in claim 1, or a pharmaceutically acceptable salt thereof. 【Request Item 5】 【Chemistry 9】 The ring shown by 【Chemistry 10】 2. The compound according to claim 1, wherein the ring is represented by the formula: wherein p is an integer of 0 to 6, and the other symbols have the same meanings as in claim 1, or a pharmaceutically acceptable salt thereof.

6. R １０ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein each of

7. R ３ but, 【Chemistry 11】 (In the formula, T １ is a carbon atom or a nitrogen atom, T ２ is a carbon atom or a nitrogen atom, R ４ are each independently halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, or substituted or unsubstituted alkylsulfonyl; R １４ is a hydrogen atom or a substituted or unsubstituted alkyl, m is an integer from 0 to 5; and n is an integer of 0 to 2. The compound according to any one of claims 1 to 6, wherein n is a group represented by the formula:

8. R ３ but, 【Chemistry 12】 (In the formula, T １ is C(R １２ ) or N, R １２ each independently represents a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted alkylsulfonyl group; R ４ and R １４ has the same meaning as in claim 7. The compound according to claim 7, wherein the compound is a group represented by the formula:

9. R ３ but, 【Chemistry 13】 (In the formula, T １ is C(R １２ ) or N, R １２ are each independently a hydrogen atom or a halogen atom, R ４ and each independently represent a halogen atom, a cyano atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, or a substituted or unsubstituted non-aromatic carbocyclic group.

10. R ４ are each independently a halogen, and R １２ The compound according to any one of claims 7 to 9, or a pharmaceutically acceptable salt thereof, wherein each of the is independently a hydrogen atom or a halogen.

11. (i) A １ is C(R ５ ) and A ２ is C(R ６ ) and A ３ is C(R ７ ) or (ii) A １ is N and A ２ is C(R ６ ) and A ３ is C(R ７ ) or (iii) A １ is C(R ５ ) and A ２ is C(R ６ ) and A ３ is N, or (iv) A １ is N and A ２ is C(R ６ ) and A ３ The compound according to any one of claims 1 to 10, wherein is N, or a pharmaceutically acceptable salt thereof.

12. (i) A １ is C(R ５ ) and A ２ is C(R ６ ) and A ３ is C(R ７ ) or (ii) A １ is N and A ２ is C(R ６ ) and A ３ is C(R ７ 12. The compound of claim 11, wherein:

13. R ５ is a hydrogen atom or a halogen atom, and R ６ is a hydrogen atom, and R ７ 13. The compound according to claim 11 or 12, or a pharmaceutically acceptable salt thereof, wherein is a hydrogen atom, halogen, or substituted or unsubstituted alkyloxy.

14. R １ The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein is carboxy.

15. R ２ is alkyl, alkyl substituted with a substituted or unsubstituted non-aromatic heterocycle, or alkyl substituted with a substituted or unsubstituted aromatic heterocycle, or a pharmaceutically acceptable salt thereof.

16. R ２ 16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein is alkyl substituted with a substituted or unsubstituted non-aromatic heterocycle or alkyl substituted with a substituted or unsubstituted aromatic heterocycle.

17. R ８ and R ９ The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein is a hydrogen atom.

18. A pharmaceutical composition comprising the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.

19. 19. The pharmaceutical composition of claim 18, which is a GLP-1 receptor agonist.

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