Aromatic heterocyclic derivative having GLP-1 receptor agonist activity

Abstract

The present invention pertains to: a compound, or a pharmacologically acceptable salt thereof, having GLP-1 receptor agonist activity and offering utility as an agent for treating or preventing diseases involving GLP-1 receptors; and a pharmaceutical composition containing the compound and the pharmacologically acceptable salt.　A compound or a pharmaceutically acceptable salt thereof, the compound being represented by formula (IA) (where: R1 is an optionally substituted alkyl group; R2 is a group represented by BB; X is N, etc.; L is a group represented by CC (where: R8 is a hydrogen atom, etc.; R9 is a halogen, etc.; each of Z1 and Z2 is independently N, etc.; the atom labelled a bonds to a group represented by DD; and the atom labelled b bonds to a group represented by EE); W is N, etc.; R11 is a hydrogen atom, etc.; each of R12 and R13 is independently a hydrogen atom, etc.; and each of R14 and R15 is independently a hydrogen atom, etc.).

Description

Aromatic heterocyclic derivatives having GLP-1 receptor agonist activity

[0001] The present invention relates to 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 involving the GLP-1 receptor, and to 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.

[0002] Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by intestinal L cells in response to food ingestion. GLP-1 is known to exhibit effects such as glucose-dependent insulin secretion promotion, glucagon secretion reduction, delayed gastric emptying, and appetite reduction 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 human GLP-1 analog, is a representative agonist known to exhibit potent HbA1c-lowering effects and weight loss. Due to these attractive effects, several GLP-1 analogs have been put into practical use as therapeutic agents for diabetes and obesity. However, due to poor oral absorption, most of these GLP-1 analogs are sold as injections. Therefore, the development of orally administrable GLP-1 receptor agonists is anticipated. Specifically, a method for orally absorbing the GLP-1 analogue semaglutide by 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 43), but the compounds disclosed substantially have structures different from those of the compound of the present invention.

[0003] International Publication No. WO 2012 / 080471, International Publication No. WO 2009 / 111700, International Publication No. WO 2010 / 114824, International Publication No. WO 2018 / 056453, International Publication No. WO 2018 / 109607, International Publication No. WO 2019 / 239319, International Publication No. WO 2019 / 239371, International Publication No. WO 2020 / 103815, International Publication No. WO 2020 / 207474, International Publication No. WO 2020 / 263695, International Publication No. WO 2021 / 018023, International Publication No. WO 2021 / 081207, International Publication No. WO 2021 / 096284, International Publication No. WO 2021 / 096304 International Publication No. WO 2021 / 112538 International Publication No. WO 2021 / 155841 International Publication No. WO 2021 / 160127 International Publication No. WO 2021 / 187886 Chinese Patent Application Publication No. 113493447 International Publication No. WO 2021 / 197464 International Publication No. WO 2021 / 219019 Chinese Patent Application Publication No. 113480534 International Publication No. WO 2021 / 244645 International Publication No. WO 2021 / 249492 International Publication No. WO 2021 / 242817 Chinese Patent Application Publication No. 113773310 Chinese Patent Application Publication No. 113816948 No. Specification Chinese Patent Application Publication No. 113801136 Specification International Publication No. 2021 / 254470 International Publication No. 2021 / 259309 International Publication No. 2022 / 028572 International Publication No. 2022 / 031994 International Publication No. 2022 / 040600 International Publication No. 2022 / 078380 International Publication No. 2022 / 078407 International Publication No. 2022 / 078152 International Publication No. 2022 / 109182 International Publication No. 2022 / 116693 International Publication No. 2022 / 111624 Chinese Patent Application Publication No. 114478497 Specification Chinese Patent Patent Application Publication No. 114728940 Chinese Patent Application Publication No. 114728939 Chinese Patent Application Publication No. 114716423 International Publication No. 2022 / 184849 International Publication No. 2022 / 192430 International Publication No. 2022 / 192428 International Publication No. 2022 / 199661 International Publication No. 2022 / 199458 International Publication No. 2022 / 219495 International Publication No. 2022 / 225914 International Publication No. 2022 / 225941 International Publication No. 2022 / 228490 Chinese Patent Application Publication No. 115279750

[0004] Lancet 374, 1606-1616 (2009) Clin. Invest. 2, 59-72 (2012)

[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.

[0006] The present invention relates to the following: (1) A compound of formula (I): (In the formula, R １ is a substituted or unsubstituted alkyl or a substituted or unsubstituted non-aromatic heterocyclic group; R ２ teeth, (In the formula, R ４ is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; R ５ is a hydrogen atom or a substituted or unsubstituted alkyl); X is N or C(R ３ ) and R ３ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, difluoromethyl, trifluoromethyl or C1-C3 alkyl; (In the formula, (A １ , A ２ , A ３ ) combination is (CR ２１ , C.R. ２２ , C.R. ２３ ), (N, CR ２２ , C.R. ２３ ), (CR ２１ , N., C.R. ２３ ) or (CR ２１ , C.R. ２２ , N); R ２１ , R ２２ and R ２３ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, or a cyano; １ , B ２ , B ３ , B ４ ) combination is (CR２４ , C.R. ２５ , C.R. ２６ , C.R. ２７ ), (N, CR ２５ , C.R. ２６ , C.R. ２７ ), (CR ２４ , N., C.R. ２６ , C.R. ２７ ), (N, N, CR ２６ , C.R. ２７ ), (N, CR ２５ , C.R. ２６ ,N), (N,CR ２５ , N., C.R. ２７ ) or (CR ２４ ,N.,N.,CR. ２７ ) and R ２４ , R ２５ , R ２６ and R ２７ are each independently a hydrogen atom, halogen, cyano, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; the atom marked with a is The atom marked with b is bonded to a group represented by R ７ are each independently a fluorine atom or a substituted or unsubstituted alkyl; n is an integer from 0 to 2; Y is N or CH; R １６ , R １７ and R １８ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, or a cyano; R ８ is a hydrogen atom or a substituted or unsubstituted alkyl; R ９ is halogen or substituted or unsubstituted alkyl; Z １ and Z ２ are each independently N or CH; W is a group represented by １５ and R １１ is a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, an aromatic carbocyclic group, a non-aromatic carbocyclic group, an aromatic heterocyclic group, or a non-aromatic heterocyclic group; R １２ and R１３ are each independently a hydrogen atom or a halogen atom; １４ and R １５ are each independently a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group; １１ and R １２ may be taken together to form a substituted or unsubstituted aromatic heterocycle or a substituted or unsubstituted non-aromatic heterocycle; R １１ and R １３ may be taken together to form a substituted or unsubstituted aromatic heterocycle or a substituted or unsubstituted non-aromatic heterocycle), or a pharmaceutically acceptable salt thereof. １ (3) The compound according to the above (1), wherein R 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. １ (4) The compound according to the above (1), wherein R 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. ２ but, (5) The compound according to any one of (1) to (3) above, wherein X is a group represented by the formula: (wherein each symbol has the same meaning as in (1) above), or a pharmaceutically acceptable salt thereof. ３ (6) The compound according to any one of the above (1) to (4), or a pharmaceutically acceptable salt thereof, wherein L is (7) The compound according to any one of (1) to (5) above, which is a group represented by the formula: (wherein each symbol has the same meaning as in (1) above), or a pharmaceutically acceptable salt thereof. １ , A ２ , A ３ ) combination is (CR ２１ , C.R. ２２ , C.R. ２３ ), (N, CR ２２ , C.R. ２３ ), or (CR ２１ , C.R. ２２(8) The compound according to any one of (1) to (6) above, wherein R ２１ is a hydrogen atom or a fluorine atom, and R ２２ and R ２３ is a hydrogen atom, or a pharmaceutically acceptable salt thereof. １ , B ２ , B ３ , B ４ ) combination is (CR ２４ , C.R. ２５ , C.R. ２６ , C.R. ２７ ), (N, CR ２５ , C.R. ２６ , C.R. ２７ (10) The compound according to any one of (1) to (8) above, wherein R １６ is a hydrogen atom or a fluorine atom, and R １７ and R １８ (11) The compound according to any one of the above (1) to (9), wherein R is a hydrogen atom, or a pharmaceutically acceptable salt thereof. ９ (12) The compound according to any one of the above (1) to (10), wherein Z is halogen or haloalkyl, or a pharmaceutically acceptable salt thereof. １ (13) The compound according to any one of (1) to (11) above, wherein R is CH, or a pharmaceutically acceptable salt thereof. １１ is a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, an aromatic carbocyclic group, a non-aromatic carbocyclic group, an aromatic heterocyclic group, or a non-aromatic heterocyclic group; R １２ and R １３ (14) The compound according to any one of (1) to (12) above, wherein R is each independently a hydrogen atom or a halogen atom, or a pharmaceutically acceptable salt thereof. １１ (15) The compound according to any one of the above (1) to (13), wherein R is halogen, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy, or a pharmaceutically acceptable salt thereof. １２ and R １３(16) The compound according to any one of (1) to (14) above, wherein R is a hydrogen atom, or a pharmaceutically acceptable salt thereof. １４ and R １５ are each independently a hydrogen atom or a halogen atom. (17) A compound according to any one of (1) to (16) above, or a pharmaceutically acceptable salt thereof. (18) The pharmaceutical composition according to (17) above, which is a GLP-1 receptor agonist. (19) A method for treating and / or preventing a disease associated with the GLP-1 receptor, comprising administering a compound according to any one of (1) to (16) above, or a pharmaceutically acceptable salt thereof. (20) Use of a compound according to any one of (1) to (16) above, or a pharmaceutically acceptable salt thereof, for the manufacture of an agent for treating and / or preventing a disease associated with the GLP-1 receptor. (21) A compound according to any one of (1) to (16) above, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of a disease associated with the GLP-1 receptor.

[0007] (1') Formula (IA): (In the formula, R １ is a substituted or unsubstituted alkyl or a substituted or unsubstituted non-aromatic heterocyclic group; R ２ teeth, (In the formula, R ４ is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; R ５ is a hydrogen atom or a substituted or unsubstituted alkyl); X is N or C(R ３ ) and R ３ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, difluoromethyl, trifluoromethyl or C1-C3 alkyl; (wherein the atom marked with a is The atom marked with b is bonded to a group represented by R ８ is a hydrogen atom or a substituted or unsubstituted alkyl; R ９is halogen or substituted or unsubstituted alkyl; Z １ and Z ２ are each independently N or CH; W is a group represented by １５ and R １１ is a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, an aromatic carbocyclic group, a non-aromatic carbocyclic group, an aromatic heterocyclic group, or a non-aromatic heterocyclic group; R １２ and R １３ are each independently a hydrogen atom or a halogen atom; １４ and R １５ are each independently a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group; １１ and R １２ may be taken together to form a substituted or unsubstituted aromatic heterocycle or a substituted or unsubstituted non-aromatic heterocycle; R １１ and R １３ may be taken together to form a substituted or unsubstituted aromatic heterocycle or a substituted or unsubstituted non-aromatic heterocycle; R １３ and R １４ may be taken together to form a substituted or unsubstituted aromatic heterocycle or a substituted or unsubstituted non-aromatic heterocycle), or a pharmaceutically acceptable salt thereof. １ (3') The compound according to the above (1') or a pharmaceutically acceptable salt thereof, wherein R is alkyl, alkyl substituted with a substituted or unsubstituted non-aromatic heterocycle, or alkyl substituted with a substituted or unsubstituted aromatic heterocycle. １ (4') The compound according to the above (1') or a pharmaceutically acceptable salt thereof, wherein R is alkyl substituted with a substituted or unsubstituted non-aromatic heterocycle or alkyl substituted with a substituted or unsubstituted aromatic heterocycle. ２ but, (5') The compound according to any one of (1') to (3') above, wherein X is a group represented by the formula: (wherein each symbol has the same meaning as in (1') above), or a pharmaceutically acceptable salt thereof.３ (6') R ９ (7') The compound according to any one of the above (1') to (5') or a pharmaceutically acceptable salt thereof, wherein Z is halogen or haloalkyl. １ (8') The compound according to any one of the above (1') to (6') or a pharmaceutically acceptable salt thereof, wherein R is CH. １１ is a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, an aromatic carbocyclic group, a non-aromatic carbocyclic group, an aromatic heterocyclic group, or a non-aromatic heterocyclic group; R １２ and R １３ (9') The compound according to any one of the above (1') to (7') or a pharmaceutically acceptable salt thereof, wherein R １１ (10') The compound according to any one of the above (1') to (8') or a pharmaceutically acceptable salt thereof, wherein R is halogen, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy. １２ and R １３ (11') The compound according to any one of the above (1') to (9') or a pharmaceutically acceptable salt thereof, wherein R is a hydrogen atom. １４ and R １５ are each independently a hydrogen atom or a halogen atom, or a pharmaceutically acceptable salt thereof. (In the formula, R １ is a substituted or unsubstituted alkyl or a substituted or unsubstituted non-aromatic heterocyclic group; R ２ teeth, (In the formula, R ４ is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; R ５ is a hydrogen atom or a substituted or unsubstituted alkyl); X′ is a group represented by C(R ３’ ) and R ３’is a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, difluoromethyl, trifluoromethyl or C1-C3 alkyl; L' is (In the formula, (A １ , A ２ , A ３ ) combination is (CR ２１ , C.R. ２２ , C.R. ２３ ), (N, CR ２２ , C.R. ２３ ), (CR ２１ , N., C.R. ２３ ) or (CR ２１ , C.R. ２２ , N); R ２１ , R ２２ and R ２３ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, or a cyano; １ , B ２ , B ３ , B ４ ) combination is (CR ２４ , C.R. ２５ , C.R. ２６ , C.R. ２７ ), (N, CR ２５ , C.R. ２６ , C.R. ２７ ), (CR ２４ , N., C.R. ２６ , C.R. ２７ ), (N, N, CR ２６ , C.R. ２７ ), (N, CR ２５ , C.R. ２６ ,N), (N,CR ２５ , N., C.R. ２７ ) or (CR ２４ ,N.,N.,CR. ２７ ) and R ２４ , R ２５ , R ２６ and R ２７ are each independently a hydrogen atom, halogen, cyano, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; the atom marked with a is The atom marked with b is bonded to a group represented by R ７are each independently a fluorine atom or a substituted or unsubstituted alkyl; n is an integer from 0 to 2; Y is N or CH; R １６ , R １７ and R １８ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, or a cyano; W is N or CR １５ and R １１ is a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, an aromatic carbocyclic group, a non-aromatic carbocyclic group, an aromatic heterocyclic group, or a non-aromatic heterocyclic group; R １２ and R １３ are each independently a hydrogen atom or a halogen atom; １４ and R １５ are each independently a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group; １１ and R １２ may be taken together to form a substituted or unsubstituted aromatic heterocycle or a substituted or unsubstituted non-aromatic heterocycle; R １１ and R １３ may be taken together to form a substituted or unsubstituted aromatic heterocycle or a substituted or unsubstituted non-aromatic heterocycle; R １３ and R １４ may be taken together to form a substituted or unsubstituted aromatic heterocycle or a substituted or unsubstituted non-aromatic heterocycle), or a pharmaceutically acceptable salt thereof. １ (14') The compound according to the above (12') or a pharmaceutically acceptable salt thereof, wherein R is alkyl, alkyl substituted with a substituted or unsubstituted non-aromatic heterocycle, or alkyl substituted with a substituted or unsubstituted aromatic heterocycle. １ (15') The compound according to the above (12') or a pharmaceutically acceptable salt thereof, wherein R is alkyl substituted with a substituted or unsubstituted non-aromatic heterocycle or alkyl substituted with a substituted or unsubstituted aromatic heterocycle. ２ but, (16') The compound according to any one of the above (12') to (14'), wherein L' is a group represented by the formula: (wherein each symbol has the same meaning as in the above (12')), or a pharmaceutically acceptable salt thereof. (wherein each symbol has the same meaning as in (12') above) or a pharmaceutically acceptable salt thereof. １ , A ２ , A ３ ) combination is (CR ２１ , C.R. ２２ , C.R. ２３ ), (N, CR ２２ , C.R. ２３ ) or (CR ２１ , C.R. ２２ (18') The compound according to any one of (12') to (16') above, wherein R is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, ２１ is a hydrogen atom or a fluorine atom, and R ２２ and R ２３ is a hydrogen atom, or a pharmaceutically acceptable salt thereof. １ , B ２ , B ３ , B ４ ) combination is (CR ２４ , C.R. ２５ , C.R. ２６ , C.R. ２７ ) or (N, CR ２５ , C.R. ２６ , C.R. ２７ (20') R １６ is a hydrogen atom or a fluorine atom, and R １７ and R １８ (21') The compound according to any one of the above (12') to (19') or a pharmaceutically acceptable salt thereof, wherein R is a hydrogen atom. １１ is a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, an aromatic carbocyclic group, a non-aromatic carbocyclic group, an aromatic heterocyclic group, or a non-aromatic heterocyclic group; R１２ and R １３ (22') The compound according to any one of the above (12') to (20') or a pharmaceutically acceptable salt thereof, wherein R １１ (23') The compound according to any one of the above (12') to (21') or a pharmaceutically acceptable salt thereof, wherein R is halogen, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy. １２ and R １３ (24') The compound according to any one of the above (12') to (22') or a pharmaceutically acceptable salt thereof, wherein R is a hydrogen atom. １４ and R １５ are each independently a hydrogen atom or a halogen atom. (25') A pharmaceutical composition comprising the compound according to any one of (1') to (24') above or a pharmaceutically acceptable salt thereof. (26') The pharmaceutical composition according to (25') above, which is a GLP-1 receptor agonist. (27') A method for treating and / or preventing a disease associated with the GLP-1 receptor, comprising administering the compound according to any one of (1') to (24') above or a pharmaceutically acceptable salt thereof. (28') Use of the compound according to any one of (1') to (24') above or a pharmaceutically acceptable salt thereof for the manufacture of an agent for treating and / or preventing a disease associated with the GLP-1 receptor. (29') A compound according to any one of (1') to (24') above or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of a disease associated with the GLP-1 receptor.

[0008] The compound according to the present invention has a GLP-1 receptor agonist activity and is useful as a preventive and / or therapeutic agent for diseases involving the GLP-1 receptor, particularly non-insulin dependent diabetes mellitus (type 2 diabetes) or obesity.

[0009] 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 "comprises" means not being limited to the constituent elements and does not exclude unrecited elements. The present invention will be explained below with reference to exemplary 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 art unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the event of conflict, the present specification (including definitions) will prevail.

[0010] The term "halogen" includes fluorine, chlorine, bromine, and iodine atoms. Particularly, fluorine and chlorine atoms are preferred.

[0011] The term "alkyl" encompasses 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 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. "C1-C3 alkyl" encompasses straight-chain or branched hydrocarbon groups having 1 to 3 carbon atoms. Examples include methyl, ethyl, n-propyl, and isopropyl.

[0012] "Haloalkyl" means the above alkyl substituted with one or more halogens. When substituted with two or more halogens, the halogens may be the same or different. Examples include fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, etc.

[0013] The term "alkenyl" encompasses straight-chain or branched hydrocarbon groups 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, and having one or more double bonds at any position. Examples 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.

[0014] "Alkynyl" includes a straight-chain 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, and having one or more triple bonds at any position. It may further have a double bond at any position. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc. Preferred embodiments of "alkynyl" include ethynyl, propynyl, butynyl, and pentynyl.

[0015] The term "aromatic carbocyclic group" refers to a cyclic aromatic hydrocarbon group having one or more rings. Examples include phenyl, naphthyl, anthryl, and phenanthryl. A preferred embodiment of the "aromatic carbocyclic group" is phenyl.

[0016] 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.

[0017] The term "non-aromatic carbocyclic group" refers to a monocyclic or bicyclic or more cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group. The term "non-aromatic carbocyclic group" having two or more rings also includes a monocyclic or bicyclic or more cyclic non-aromatic carbocyclic group fused with a ring in the above-mentioned "aromatic carbocyclic group," and the bond may be on either ring. For example, the following rings are shown. Furthermore, "non-aromatic carbocyclic group" also includes groups that form bridged or spiro rings, such as: 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 bicyclic or higher non-aromatic carbocyclic group preferably has 8 to 20 carbon atoms, more preferably 8 to 16 carbon atoms. Examples include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, and fluorenyl.

[0018] The term "non-aromatic carbocyclic ring" refers to a ring derived from the above-mentioned "non-aromatic carbocyclic group".

[0019] "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. Bicyclic or more aromatic heterocyclic groups also include those in which the rings in the above-mentioned "aromatic carbocyclic groups" are fused to a monocyclic or bicyclic or more aromatic heterocyclic group, and the bond may be on any of the rings. Monocyclic aromatic heterocyclic groups are preferably 5- to 8-membered, and more preferably 5- or 6-membered. Examples of 5-membered aromatic heterocyclic groups include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, etc. Examples of 6-membered aromatic heterocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. The bicyclic aromatic heterocyclic group is preferably 8- to 10-membered, and more preferably 9- or 10-membered. Examples 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 tricyclic or more aromatic heterocyclic group is preferably 13- to 15-membered. Examples include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, dibenzofuryl, and the like.

[0020] 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 8- to 10-membered, more preferably 9- or 10-membered. Examples of the aromatic heterocycle 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 heterocycle having three or more rings preferably has 13 to 15 members. Examples include a carbazole ring, an acridine ring, a xanthene ring, a phenothiazine ring, a phenoxathiin ring, a phenoxazine ring, and a dibenzofuran ring.

[0021] 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 monocyclic or bicyclic or more non-aromatic heterocyclic groups fused with the rings of the above-mentioned "aromatic carbocyclic groups," "non-aromatic carbocyclic groups," and / or "aromatic heterocyclic groups," as well as monocyclic or bicyclic or more non-aromatic carbocyclic groups fused with the rings of the above-mentioned "aromatic heterocyclic groups," and the bond may be on any of the rings. For example, the following rings are shown. Furthermore, the term "non-aromatic heterocyclic group" also encompasses groups that form bridged or spiro rings, such as: 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, and thiazinyl. Examples of 7-membered non-aromatic heterocyclic groups include hexahydroazepinyl, tetrahydrodiazepinyl, and oxepanyl. Non-aromatic heterocyclic groups having two or more rings preferably have 8 to 20 members, and more preferably have 8 to 10 members. Examples include indolinyl, isoindolinyl, chromanyl, and isochromanyl.

[0022] The term "non-aromatic heterocycle" refers to a ring derived from the above-mentioned "non-aromatic heterocyclic group".

[0023] 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 portion of "alkenyloxy," "alkenylcarbonyloxy," "alkenylcarbonyl," "alkenyloxycarbonyl," "alkenylsulfanyl," "alkenylsulfinyl," and "alkenylsulfonyl" has the same meaning as the above "alkenyl." The alkynyl portion of "alkynyloxy," "alkynylcarbonyloxy," "alkynylcarbonyl," "alkynyloxycarbonyl," "alkynylsulfanyl," "alkynylsulfinyl," and "alkynylsulfonyl" has the same meaning as the above "alkynyl."

[0024] In the present 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.

[0025] 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, 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 with substituent group β, imino optionally substituted with substituent group β, carbamoyl optionally substituted with substituent group β, sulfamoyl optionally substituted with 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 optionally substituted with substituent group γ', aromatic heterocyclic carbonyloxy optionally substituted with substituent group γ, non-aromatic heterocyclic carbonyloxy optionally substituted with substituent group γ', aromatic carbocyclic carbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyl optionally substituted by group γ', aromatic heterocyclic carbonyl optionally substituted by substituent group γ, non-aromatic heterocyclic carbonyl optionally substituted by substituent group γ', aromatic carbocyclic oxycarbonyl optionally substituted by substituent group γ, non-aromatic carbocyclic oxycarbonyl optionally substituted by substituent group γ', aromatic heterocyclic oxycarbonyl optionally substituted by substituent group γ, non-aromatic heterocyclic oxycarbonyl optionally substituted by substituent group γ', aromatic carbocyclic alkyloxy optionally substituted by substituent group γ, non-aromatic carbocyclic alkyloxy optionally substituted by substituent group γ', aromatic heterocyclic alkyloxy optionally substituted by substituent group γ, non-aromatic heterocyclic alkyloxy optionally substituted by substituent group γ', aromatic carbocyclic alkyloxycarbonyl optionally substituted by 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 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 α: halogen, hydroxy, carboxy, alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, sulfanyl, and cyano.

[0027] 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'.

[0028] Substituent group γ: Substituent group α, alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl.

[0029] Substituent group γ': Substituent group γ and oxo.

[0030] 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 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, 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 with substituent group β, imino optionally substituted with substituent group β, carbamoyl optionally substituted with substituent group β, sulfamoyl optionally substituted with 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', "aromatic carbocyclic carbonyloxy optionally substituted with a substituent group γ", "non-aromatic carbocyclic carbonyloxy optionally substituted with a substituent group γ'", "aromatic heterocyclic carbonyloxy optionally substituted with a substituent group γ", and "non-aromatic heterocyclic carbonyloxy optionally substituted with a substituent group γ'", an aromatic heterocyclic oxy optionally substituted with a substituent group γ, aromatic carbocyclic carbonyl, 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 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, non-aromatic heterocyclic alkyloxyalkyl optionally substituted with substituent group γ' alkyloxyalkyl, 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'.

[0031]

[0049] 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.

[0032] 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:

[0033] 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 with substituent group β, imino optionally substituted with substituent group β, carbamoyl optionally substituted with substituent group β, sulfamoyl optionally substituted with 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'.

[0034] In formula (I) or formula (IA), the atom with a in the group represented by L is The atom to which b is attached is It bonds to a group represented by the formula:

[0035] In formula (IB), the atom marked with a in the group represented by L′ is The atom to which b is attached is It bonds to a group represented by the formula:

[0036] In the compound of formula (I), R １ , R ２ ,X,L,W,R １１ , R １２ , R １３ and R １４ Preferred embodiments of the formula (I) are shown below: The compounds represented by formula (I) include all combinations of the specific examples shown below.

[0037] R １ R may be a substituted or unsubstituted alkyl group or a substituted or unsubstituted non-aromatic heterocyclic group (referred to as A-1). １ R is substituted or unsubstituted alkyl (referred to as A-2). １ R may be substituted or unsubstituted methyl (referred to as A-3). １ R includes alkyl substituted with a substituted or unsubstituted non-aromatic heterocycle, alkyl substituted with a substituted or unsubstituted aromatic heterocyclic group, or unsubstituted alkyl (referred to as A-4). １ R is oxetanylalkyl or alkylimidazolylalkyl (referred to as A-5). １ R is oxetanylmethyl or ethylimidazolylmethyl (referred to as A-6). １ Examples of R include oxetanylmethyl (referred to as A-7). １ Examples of the alkylimidazolylmethyl include alkylimidazolylmethyl (referred to as A-8).

[0038] R ２ teeth, Examples of the group include a group represented by the formula (referred to as B-1). ２ teeth, Examples of the group include a group represented by the formula (referred to as B-2). ２ teeth, (referred to as B-3) ２ teeth, (referred to as B-4).

[0039] R ４ R is a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl (referred to as C-1). ４ R is a hydrogen atom, a halogen atom, a haloalkyl, or an unsubstituted alkyl (referred to as C-2). ４ The alkyl group may be an alkyl group substituted with a hydrogen atom, a halogen atom, or a fluorine atom, or an unsubstituted alkyl group (referred to as C-3).

[0040] R ５ R is a hydrogen atom or a substituted or unsubstituted alkyl (referred to as D-1). ５ R is a hydrogen atom, haloalkyl, or unsubstituted alkyl (referred to as D-2). ５ is exemplified by a hydrogen atom, alkyl substituted with fluorine, or unsubstituted alkyl (referred to as D-3).

[0041] X is N or C(R ３ ) (referred to as E-1). X is C(R ３ (E-2) X is N (E-3).

[0042] R ３ R is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, difluoromethyl, trifluoromethyl, or C1-C3 alkyl (referred to as F-1). ３ R is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, difluoromethyl, or trifluoromethyl (referred to as F-2). ３ R is a fluorine atom, a chlorine atom, a bromine atom, difluoromethyl, trifluoromethyl, or C1-C3 alkyl (referred to as F-3). ３ R is a fluorine atom, a chlorine atom, a bromine atom, difluoromethyl, trifluoromethyl, or methyl (referred to as F-4). ３ is a chlorine atom, a bromine atom, difluoromethyl, trifluoromethyl or methyl (referred to as F-5).

[0043] L is, (hereinafter referred to as G-1) (hereinafter referred to as G-2). (hereinafter referred to as G-3). (referred to as G-4).

[0044] (A １ , A ２ , A ３ ) combination is (CR ２１ , C.R. ２２ , C.R. ２３ ), (N, CR ２２ , C.R. ２３ ), (CR ２１ , N., C.R. ２３ ) or (CR ２１ , C.R. ２２ , N) (referred to as H-1). １ , A ２ , A ３ ) combination is (CR ２１ , C.R. ２２ , C.R. ２３ ), (N, CR ２２ , C.R. ２３ ) or (CR ２１ , C.R. ２２ , N) (referred to as H-2). １ , A ２ , A ３ ) combination is (CR ２１ , C.R. ２２ , C.R. ２３ ) (H-3) １ , A ２ , A ３ ) combination is (N, CR ２２ , C.R. ２３ ) (H-4) １ , A ２ , A ３ ) combination is (CR ２１ , C.R. ２２ , N) (referred to as H-5).

[0045] R ２１ , R ２２ and R２３ R each independently represents a hydrogen atom, a fluorine atom, a chlorine atom, or a cyano (referred to as I-1). ２１ , R ２２ and R ２３ R each independently represents a hydrogen atom, a fluorine atom, or a chlorine atom (referred to as I-2). ２１ , R ２２ and R ２３ R each independently represents a hydrogen atom or a fluorine atom (referred to as I-3). ２１ is a hydrogen atom or a fluorine atom, and R ２２ and R ２３ is a hydrogen atom (referred to as I-4). ２１ is a fluorine atom, and R ２２ and R ２３ is a hydrogen atom (referred to as I-5). ２１ , R ２２ and R ２３ is a hydrogen atom (referred to as I-6).

[0046] (B １ , B ２ , B ３ , B ４ ) combination is (CR ２４ , C.R. ２５ , C.R. ２６ , C.R. ２７ ), (N, CR ２５ , C.R. ２６ , C.R. ２７ ), (CR ２４ , N., C.R. ２６ , C.R. ２７ ), (N, N, CR ２６ , C.R. ２７ ), (N, CR ２５ , C.R. ２６ ,N), (N,CR ２５ , N., C.R. ２７ ) or (CR ２４ ,N.,N.,CR. ２７ ) (referred to as J-1). (B １ , B ２ , B ３ , B ４ ) combination is (CR ２４ , C.R.２５ , C.R. ２６ , C.R. ２７ ), (N, CR ２５ , C.R. ２６ , C.R. ２７ ) or (N, CR ２５ , C.R. ２６ , N) (referred to as J-2). (B １ , B ２ , B ３ , B ４ ) combination is (CR ２４ , C.R. ２５ , C.R. ２６ , C.R. ２７ ) or (N, CR ２５ , C.R. ２６ , C.R. ２７ ) (referred to as J-3). (B １ , B ２ , B ３ , B ４ ) combination is (CR ２４ , C.R. ２５ , C.R. ２６ , C.R. ２７ ) (referred to as J-4). (B １ , B ２ , B ３ , B ４ ) combination is (N, CR ２５ , C.R. ２６ , C.R. ２７ ) (referred to as J-5).

[0047] R ２４ , R ２５ , R ２６ and R ２７ Each of R independently represents a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group (referred to as K-1). ２４ , R ２５ , R ２６ and R ２７ R each independently represents a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, a substituted or unsubstituted methyl group, or a substituted or unsubstituted methyloxy group (referred to as K-2). ２４ , R ２５ , R ２６and R ２７ R each independently represents a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a methyl group substituted with a halogen atom, an unsubstituted methyl group, a methyloxy group substituted with a halogen atom, or an unsubstituted methyloxy group (referred to as K-3). ２４ , R ２５ , R ２６ and R ２７ R each independently represents a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a methyl group substituted with fluorine, an unsubstituted methyl group, a methyloxy group substituted with fluorine, or an unsubstituted methyloxy group (referred to as K-4). ２４ , R ２５ , R ２６ and R ２７ are each independently a hydrogen atom or a halogen (referred to as K-5).

[0048] R ７ Each of R is independently a fluorine atom or a substituted or unsubstituted alkyl (referred to as L-1). ７ R is independently a fluorine atom, a haloalkyl, a hydroxyalkyl, or an unsubstituted alkyl (referred to as L-2). ７ R each independently represents a fluorine atom, a methyl substituted with a halogen atom, a methyl substituted with a hydroxyl group, or an unsubstituted methyl group (referred to as L-3). ７ are each independently a fluorine atom, methyl substituted with fluorine, methyl substituted with hydroxy, or unsubstituted methyl (referred to as L-4). ７ are each independently methyl (referred to as L-5).

[0049] n may be an integer of 0 to 2 (referred to as M-1), n ​​may be 0 or 1 (referred to as M-2), n may be 0 (referred to as M-3), or n may be 1 (referred to as M-4).

[0050] Examples of Y include N or CH (referred to as N-1). Examples of Y include N (referred to as N-2). Examples of Y include CH (referred to as N-3).

[0051] R１６ , R １７ and R １８ R each independently represents a hydrogen atom, a fluorine atom, a chlorine atom, or a cyano (referred to as O-1). １６ , R １７ and R １８ R each independently represents a hydrogen atom, a fluorine atom, or a chlorine atom (referred to as O-2). １６ , R １７ and R １８ R each independently represents a hydrogen atom or a fluorine atom (referred to as O-3). １６ is a hydrogen atom or a fluorine atom, and R １７ and R １８ is a hydrogen atom (referred to as O-4). １６ is a fluorine atom, and R １７ and R １８ is a hydrogen atom (referred to as O-5). １６ , R １７ and R １８ is a hydrogen atom (referred to as O-6).

[0052] R ８ R is a hydrogen atom or a substituted or unsubstituted alkyl (referred to as P-1). ８ R is a hydrogen atom or a substituted or unsubstituted methyl (referred to as P-2). ８ R is a hydrogen atom, a methyl group substituted with a halogen atom, or an unsubstituted methyl group (referred to as P-3). ８ is a hydrogen atom or unsubstituted methyl (referred to as P-4).

[0053] R ９ R is a halogen atom or a substituted or unsubstituted alkyl group (referred to as Q-1). ９ R can be halogen, haloalkyl, or unsubstituted alkyl (referred to as Q-2). ９ R is halogen or haloalkyl (referred to as Q-3). ９ R is a halogen or a methyl substituted with a halogen (referred to as Q-4). ９R is methyl substituted with halogen or fluorine (referred to as Q-5). ９ R is a halogen (referred to as Q-6). ９ is a chlorine atom or a bromine atom (referred to as Q-7). ９ Examples of the methyl group include methyl substituted with fluorine (referred to as Q-8).

[0054] Z １ and Z ２ are each independently N or CH (referred to as R-1). １ and Z ２ N can be mentioned as an example (referred to as R-2). １ and Z ２ Examples of Z include CH (referred to as R-3). １ is N and Z ２ Examples of Z include CH (referred to as R-4). １ is CH and Z ２ is N (referred to as R-5).

[0055] W is N or CR １５ (S-1) W can be N (S-2). W can be CR １５ (hereinafter referred to as S-3).

[0056] R １１ R is a hydrogen atom, a halogen atom, a cyano, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyloxy, an aromatic carbocyclic group, a non-aromatic carbocyclic group, an aromatic heterocyclic group, or a non-aromatic heterocyclic group (referred to as T-1). １１ R is exemplified by halogen, cyano, substituted or unsubstituted alkyl, and substituted or unsubstituted alkyloxy (referred to as T-2). １１ is a halogen or cyano (referred to as T-3).

[0057] R １２ and R １３ Each of R is independently a hydrogen atom or a halogen (referred to as U-1). １２ is a hydrogen atom or a halogen atom (referred to as U-2). １２is a hydrogen atom (referred to as U-3). １２ R is a halogen (referred to as U-4). １３ is a hydrogen atom or a halogen atom (referred to as U-5). １３ is a hydrogen atom (referred to as U-6). １３ R is a halogen (referred to as U-7). １１ and R １２ may be taken together to form a substituted or unsubstituted aromatic heterocycle or a substituted or unsubstituted non-aromatic heterocycle (referred to as U-8). １１ and R １２ may be taken together to form a substituted or unsubstituted aromatic heterocycle (referred to as U-9). １１ and R １２ may be taken together to form a substituted or unsubstituted non-aromatic heterocycle (referred to as U-10). １１ and R １３ may be taken together to form a substituted or unsubstituted aromatic heterocycle or a substituted or unsubstituted non-aromatic heterocycle (referred to as U-11). １１ and R １３ may be taken together to form a substituted or unsubstituted aromatic heterocycle (referred to as U-12). １１ and R １３ may be taken together to form a substituted or unsubstituted non-aromatic heterocycle (referred to as U-13).

[0058] R １４ and R １５ R 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 (referred to as V-1). １４ and R １５ R each independently represents a hydrogen atom, a halogen atom, or a cyano group (referred to as V-2). １４ and R １５ R each independently represents a hydrogen atom or a halogen (referred to as V-3). １４ is a hydrogen atom or a halogen atom (referred to as V-4). １４is a hydrogen atom (referred to as V-5). １４ R is a halogen (referred to as V-6). １５ R is a hydrogen atom or a halogen atom (referred to as V-7). １５ is a hydrogen atom (referred to as V-8). １５ Examples of the halogen include halogen (referred to as V-9).

[0059] In the compound of formula (IA), R １ , R ２ ,X,L,W,R １１ , R １２ , R １３ and R １４ Preferred embodiments of the formula (IA) are shown below: The compound represented by formula (IA) includes all combinations of the specific examples shown below.

[0060] R １ R may be a substituted or unsubstituted alkyl group or a substituted or unsubstituted non-aromatic heterocyclic group (referred to as A'-1). １ R is substituted or unsubstituted alkyl (referred to as A'-2). １ R may be a substituted or unsubstituted methyl (referred to as A'-3). １ R includes alkyl substituted with a substituted or unsubstituted non-aromatic heterocycle, alkyl substituted with a substituted or unsubstituted aromatic heterocyclic group, or unsubstituted alkyl (referred to as A'-4). １ R is oxetanylalkyl or alkylimidazolylalkyl (referred to as A'-5). １ R is oxetanylmethyl or ethylimidazolylmethyl (referred to as A'-6). １ Examples of R include oxetanylmethyl (referred to as A'-7). １ Examples of the alkylimidazolyl group include alkylimidazolylmethyl (referred to as A'-8).

[0061] R ２ teeth, (hereinafter referred to as B'-1) ２ teeth, (hereinafter referred to as B'-2) ２ teeth, (referred to as B'-3) ２ teeth, (referred to as B'-4). ２ teeth, (referred to as B'-5) ２ teeth, (referred to as B'-6).

[0062] R ４ R is a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl (referred to as C'-1). ４ R is a hydrogen atom, a halogen atom, a haloalkyl, or an unsubstituted alkyl (assumed to be C'-2). ４ The alkyl group may be an alkyl group substituted with a hydrogen atom, a halogen atom, or a fluorine atom, or an unsubstituted alkyl group (assumed to be C'-3).

[0063] R ５ is a hydrogen atom or a substituted or unsubstituted alkyl (referred to as D'-1). ５ R is a hydrogen atom, haloalkyl, or unsubstituted alkyl (referred to as D'-2). ５ is exemplified by a hydrogen atom, alkyl substituted with fluorine, or unsubstituted alkyl (referred to as D'-3).

[0064] X is N or C(R ３ ) (referred to as E'-1). X is C(R ３ (E'-2) X is, for example, N (E'-3).

[0065] R ３ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, difluoromethyl, trifluoromethyl, or C1-C3 alkyl (referred to as F'-1). ３ R is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, difluoromethyl, or trifluoromethyl (referred to as F'-2). ３R is a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, difluoromethyl, trifluoromethyl, or C1-C3 alkyl (referred to as F'-3). ３ R is a fluorine atom, a chlorine atom, a bromine atom, difluoromethyl, trifluoromethyl, or methyl (referred to as F'-4). ３ R is a chlorine atom, a bromine atom, difluoromethyl, trifluoromethyl, or methyl (referred to as F'-5). ３ is a chlorine atom or a bromine atom (referred to as F'-6).

[0066] L is, (referred to as G'-1).

[0067] R ８ is a hydrogen atom or a substituted or unsubstituted alkyl (H'-1). ８ R is a hydrogen atom or a substituted or unsubstituted methyl (referred to as H'-2). ８ R is a hydrogen atom, a methyl group substituted with a halogen atom, or an unsubstituted methyl group (referred to as H'-3). ８ is a hydrogen atom or unsubstituted methyl (H'-4).

[0068] R ９ R is a halogen atom or a substituted or unsubstituted alkyl group (referred to as J'-1). ９ R is a halogen, haloalkyl, or unsubstituted alkyl (referred to as J'-2). ９ is halogen or haloalkyl (referred to as J'-3). ９ R is a halogen atom or a methyl group substituted with a halogen atom (referred to as J'-4). ９ R is methyl substituted with halogen or fluorine (referred to as J'-5). ９ is a halogen (referred to as J'-6). ９ is a chlorine atom or a bromine atom (referred to as J'-7). ９ Examples of the group include methyl substituted with fluorine (referred to as J'-8).

[0069] Z １ and Z ２ Each of Z independently represents N or CH (referred to as K'-1). １ and Z ２ N can be mentioned (referred to as K'-2). Z １ and Z ２ Examples of Z include CH (referred to as K'-3). １ is N and Z ２ Examples of Z include CH (referred to as K'-4). １ is CH and Z ２ N can be mentioned (referred to as K'-5). １ is CH and Z ２ is N or CH (referred to as K'-6). １ is N and Z ２ is N or CH (referred to as K'-7).

[0070] W is N or CR １５ (This will be referred to as L'-1). W can be N (This will be referred to as L'-2). W can be CR １５ (hereinafter referred to as L'-3).

[0071] R １１ R is a hydrogen atom, a halogen atom, a cyano, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyloxy, an aromatic carbocyclic group, a non-aromatic carbocyclic group, an aromatic heterocyclic group, or a non-aromatic heterocyclic group (referred to as M'-1). １１ R is a halogen atom, a cyano atom, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group (referred to as M'-2). １１ is a halogen or cyano (referred to as M'-3).

[0072] R １２ and R １３ are each independently a hydrogen atom or a halogen (referred to as N'-1). １２ is a hydrogen atom or a halogen atom (referred to as N'-2). １２ is a hydrogen atom (referred to as N'-3). １２is a halogen (referred to as N'-4). １３ is a hydrogen atom or a halogen atom (referred to as N'-5). １３ is a hydrogen atom (referred to as N'-6). １３ is a halogen (referred to as N'-7). １１ and R １２ may be taken together to form a substituted or unsubstituted aromatic heterocycle or a substituted or unsubstituted non-aromatic heterocycle (referred to as N'-8). １１ and R １２ may be taken together to form a substituted or unsubstituted aromatic heterocycle (referred to as N'-9). １１ and R １２ may be taken together to form a substituted or unsubstituted non-aromatic heterocycle (referred to as N'-10). １１ and R １３ may be taken together to form a substituted or unsubstituted aromatic heterocycle or a substituted or unsubstituted non-aromatic heterocycle (referred to as N'-11). １１ and R １３ may be taken together to form a substituted or unsubstituted aromatic heterocycle (referred to as N'-12). １１ and R １３ may be taken together to form a substituted or unsubstituted non-aromatic heterocycle (referred to as N'-13).

[0073] R １４ and R １５ are each independently a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group (referred to as O'-1). １４ and R １５ are each independently a hydrogen atom, a halogen atom, or a cyano group (referred to as O'-2). １４ and R １５ are each independently a hydrogen atom or a halogen (referred to as O'-3). １４ is a hydrogen atom or a halogen atom (referred to as O'-4). １４is a hydrogen atom (referred to as O'-5). １４ is a halogen (referred to as O'-6). １５ is a hydrogen atom or a halogen atom (referred to as O'-7). １５ is a hydrogen atom (referred to as O'-8). １５ Examples of the group include halogen (O'-9).

[0074] In the compound of formula (IB), R １ , R ２ , X', L', W, R １１ , R １２ , R １３ and R １４ Preferred embodiments of the formula (IB) are shown below: The compounds of formula (IB) include all combinations of the specific examples shown below.

[0075] R １ R may be a substituted or unsubstituted alkyl group or a substituted or unsubstituted non-aromatic heterocyclic group (referred to as A''-1). １ R is substituted or unsubstituted alkyl (referred to as A″-2). １ R may be a substituted or unsubstituted methyl (referred to as A″-3). １ R includes alkyl substituted with a substituted or unsubstituted non-aromatic heterocycle, alkyl substituted with a substituted or unsubstituted aromatic heterocyclic group, or unsubstituted alkyl (referred to as A″-4). １ R is oxetanylalkyl or alkylimidazolylalkyl (referred to as A″-5). １ R is oxetanylmethyl or ethylimidazolylmethyl (referred to as A″-6). １ Examples of R include oxetanylmethyl (referred to as A″-7). １ Examples of the alkylimidazolylmethyl include alkylimidazolylmethyl (referred to as A''-8).

[0076] R ２ teeth, (hereinafter referred to as B″-1). ２ teeth, (hereinafter referred to as B″-2). ２ teeth, (referred to as B″-3). ２ teeth, (referred to as B″-4). ２ teeth, (referred to as B″-5). ２ teeth, (referred to as B″-6).

[0077] R ４ R is a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl (referred to as C″-1). ４ R is a hydrogen atom, a halogen atom, a haloalkyl, or an unsubstituted alkyl (referred to as C″-2). ４ The alkyl group may be an alkyl group substituted with a hydrogen atom, a halogen atom, or a fluorine atom, or an unsubstituted alkyl group (referred to as C''-3).

[0078] R ５ is a hydrogen atom or a substituted or unsubstituted alkyl (referred to as D″-1). ５ is a hydrogen atom, haloalkyl, or unsubstituted alkyl (referred to as D″-2). ５ is exemplified by a hydrogen atom, alkyl substituted with fluorine, or unsubstituted alkyl (referred to as D''-3).

[0079] X' is C(R ３’ ) (referred to as E''-1).

[0080] R ３’ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, difluoromethyl, trifluoromethyl, or C1-C3 alkyl (referred to as F″-1). ３’ R is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, difluoromethyl, or trifluoromethyl (referred to as F″-2). ３’is a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, difluoromethyl, trifluoromethyl, or C1-C3 alkyl (referred to as F″-3). ３’ R is a fluorine atom, a chlorine atom, a bromine atom, difluoromethyl, trifluoromethyl or methyl (referred to as F″-4). ３’ R is a chlorine atom, a bromine atom, difluoromethyl, trifluoromethyl, or methyl (referred to as F″-5). ３’ is a chlorine atom or a bromine atom (referred to as F''-6).

[0081] L' is (hereinafter referred to as G″-1). L′ is a group represented by (hereinafter referred to as G″-2). L′ is a group represented by (referred to as G″-3). L′ is a group represented by (referred to as G″-4).

[0082] (A １ , A ２ , A ３ ) combination is (CR ２１ , C.R. ２２ , C.R. ２３ ), (N, CR ２２ , C.R. ２３ ), (CR ２１ , N., C.R. ２３ ) or (CR ２１ , C.R. ２２ , N) (referred to as H″-1). (A １ , A ２ , A ３ ) combination is (CR ２１ , C.R. ２２ , C.R. ２３ ), (N, CR ２２ , C.R. ２３ ) or (CR ２１ , C.R. ２２ , N) (referred to as H″-2). (A １ , A ２ , A ３ ) combination is (CR ２１ , C.R. ２２, C.R. ２３ ) (referred to as H''-3). (A １ , A ２ , A ３ ) combination is (N, CR ２２ , C.R. ２３ ) (referred to as H″-4). (A １ , A ２ , A ３ ) combination is (CR ２１ , C.R. ２２ , N) (referred to as H″-5).

[0083] R ２１ , R ２２ and R ２３ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, or a cyano (referred to as J''-1). ２１ , R ２２ and R ２３ are each independently a hydrogen atom, a fluorine atom or a chlorine atom (referred to as J''-2). ２１ , R ２２ and R ２３ are each independently a hydrogen atom or a fluorine atom (referred to as J''-3). ２１ is a hydrogen atom or a fluorine atom, and R ２２ and R ２３ is a hydrogen atom (referred to as J″-4). ２１ is a fluorine atom, and R ２２ and R ２３ is a hydrogen atom (referred to as J″-5). ２１ , R ２２ and R ２３ is a hydrogen atom (referred to as J''-6).

[0084] (B １ , B ２ , B ３ , B ４ ) combination is (CR ２４ , C.R. ２５ , C.R. ２６ , C.R. ２７ ), (N, CR ２５ , C.R. ２６ , C.R.２７ ), (CR ２４ , N., C.R. ２６ , C.R. ２７ ), (N, N, CR ２６ , C.R. ２７ ), (N, CR ２５ , C.R. ２６ ,N), (N,CR ２５ , N., C.R. ２７ ) or (CR ２４ ,N.,N.,CR. ２７ ) (referred to as K''-1). (B １ , B ２ , B ３ , B ４ ) combination is (CR ２４ , C.R. ２５ , C.R. ２６ , C.R. ２７ ), (N, CR ２５ , C.R. ２６ , C.R. ２７ ) or (N, CR ２５ , C.R. ２６ , N) (referred to as K''-2). (B １ , B ２ , B ３ , B ４ ) combination is (CR ２４ , C.R. ２５ , C.R. ２６ , C.R. ２７ ) or (N, CR ２５ , C.R. ２６ , C.R. ２７ ) (referred to as K''-3). (B １ , B ２ , B ３ , B ４ ) combination is (CR ２４ , C.R. ２５ , C.R. ２６ , C.R. ２７ ) (referred to as K''-4). (B １ , B ２ , B ３ , B ４ ) combination is (N, CR ２５ , C.R. ２６ , C.R. ２７ ) (referred to as K''-5).

[0085] R ２４ , R ２５ , R ２６ and R ２７ are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group (referred to as L″-1). ２４ , R ２５ , R ２６ and R ２７ are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, a substituted or unsubstituted methyl group, or a substituted or unsubstituted methyloxy group (referred to as L″-2). ２４ , R ２５ , R ２６ and R ２７ are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a methyl group substituted with a halogen atom, an unsubstituted methyl group, a methyloxy group substituted with a halogen atom, or an unsubstituted methyloxy group (referred to as L″-3). ２４ , R ２５ , R ２６ and R ２７ are each independently a hydrogen atom, halogen, cyano, hydroxy, methyl substituted with fluorine, unsubstituted methyl, methyloxy substituted with fluorine, or unsubstituted methyloxy (referred to as L″-4). ２４ , R ２５ , R ２６ and R ２７ are each independently a hydrogen atom or a halogen (referred to as L''-5).

[0086] R ７ Each of R independently represents a fluorine atom or a substituted or unsubstituted alkyl (referred to as M″-1). ７ Each of R independently represents a fluorine atom, a haloalkyl, a hydroxyalkyl, or an unsubstituted alkyl (referred to as M″-2). ７ are each independently a fluorine atom, a methyl substituted with a halogen atom, a methyl substituted with a hydroxyl group, or an unsubstituted methyl group (referred to as M″-3). ７are each independently a fluorine atom, a methyl substituted with a fluorine atom, a methyl substituted with a hydroxyl group, or an unsubstituted methyl group (referred to as M″-4). ７ are each independently methyl (referred to as M″-5).

[0087] n may be an integer of 0 to 2 (referred to as N''-1). n may be 0 or 1 (referred to as N''-2). n may be 0 (referred to as N''-3). n may be 1 (referred to as N''-4).

[0088] Examples of Y include N or CH (referred to as O''-1). Examples of Y include N (referred to as O''-2). Examples of Y include CH (referred to as O''-3).

[0089] R １６ , R １７ and R １８ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, or a cyano (referred to as P″-1). １６ , R １７ and R １８ R each independently represents a hydrogen atom, a fluorine atom, or a chlorine atom (referred to as P″-2). １６ , R １７ and R １８ are each independently a hydrogen atom or a fluorine atom (referred to as P″-3). １６ is a hydrogen atom or a fluorine atom, and R １７ and R １８ is a hydrogen atom (referred to as P″-4). １６ is a fluorine atom, and R １７ and R １８ is a hydrogen atom (referred to as P″-5). １６ , R １７ and R １８ is a hydrogen atom (referred to as P''-6).

[0090] W is N or CR １５ (referred to as Q''-1). W can be N (referred to as Q''-2). W can be CR １５(referred to as Q''-3).

[0091] R １１ R can be a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, an aromatic carbocyclic group, a non-aromatic carbocyclic group, an aromatic heterocyclic group, or a non-aromatic heterocyclic group (referred to as R″-1). １１ R includes halogen, cyano, substituted or unsubstituted alkyl, and substituted or unsubstituted alkyloxy (referred to as R″-2). １１ is halogen or cyano (referred to as R''-3).

[0092] R １２ and R １３ are each independently a hydrogen atom or a halogen (referred to as S''-1). １２ is a hydrogen atom or a halogen atom (referred to as S″-2). １２ is a hydrogen atom (referred to as S″-3). １２ is a halogen (referred to as S″-4). １３ is a hydrogen atom or a halogen atom (referred to as S″-5). １３ is a hydrogen atom (referred to as S″-6). １３ is a halogen (referred to as S″-7). １１ and R １２ may be taken together to form a substituted or unsubstituted aromatic heterocycle or a substituted or unsubstituted non-aromatic heterocycle (referred to as S''-8). １１ and R １２ may be taken together to form a substituted or unsubstituted aromatic heterocycle (referred to as S''-9). １１ and R １２ may be taken together to form a substituted or unsubstituted non-aromatic heterocycle (referred to as S''-10). １１ and R １３ may be taken together to form a substituted or unsubstituted aromatic heterocycle or a substituted or unsubstituted non-aromatic heterocycle (referred to as S''-11). １１ and R１３ may be taken together to form a substituted or unsubstituted aromatic heterocycle (referred to as S''-12). １１ and R １３ may be taken together to form a substituted or unsubstituted non-aromatic heterocycle (referred to as S''-13). １３ and R １４ may be taken together to form a substituted or unsubstituted non-aromatic heterocycle (referred to as S''-14).

[0093] R １４ and R １５ are each independently a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group (referred to as T″-1). １４ and R １５ are each independently a hydrogen atom, a halogen atom, or a cyano group (referred to as T″-2). １４ and R １５ are each independently a hydrogen atom or a halogen (referred to as T″-3). １４ is a hydrogen atom or a halogen atom (referred to as T″-4). １４ is a hydrogen atom (referred to as T″-5). １４ is a halogen (referred to as T″-6). １５ is a hydrogen atom or a halogen atom (referred to as T″-7). １５ is a hydrogen atom (referred to as T″-8). １５ Examples of the halogen atom include halogen (referred to as T''-9).

[0094] The following embodiments are particularly preferred: (i) Formula (I): (In the formula, R １ is a substituted or unsubstituted alkyl or a substituted or unsubstituted non-aromatic heterocyclic group; R ２ teeth, (In the formula, R ４ is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; R ５is a hydrogen atom or a substituted or unsubstituted alkyl); X is N or C(R ３ ) and R ３ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, difluoromethyl, trifluoromethyl or C1-C3 alkyl; (In the formula, (A １ , A ２ , A ３ ) combination is (CR ２１ , C.R. ２２ , C.R. ２３ ), (N, CR ２２ , C.R. ２３ ), (CR ２１ , N., C.R. ２３ ) or (CR ２１ , C.R. ２２ , N); R ２１ , R ２２ and R ２３ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, or a cyano; １ , B ２ , B ３ , B ４ ) combination is (CR ２４ , C.R. ２５ , C.R. ２６ , C.R. ２７ ), (N, CR ２５ , C.R. ２６ , C.R. ２７ ), (CR ２４ , N., C.R. ２６ , C.R. ２７ ), (N, N, CR ２６ , C.R. ２７ ), (N, CR ２５ , C.R. ２６ ,N), (N,CR ２５ , N., C.R. ２７ ) or (CR ２４ ,N.,N.,CR. ２７ ) and R ２４ , R ２５ , R ２６ and R ２７are each independently a hydrogen atom, halogen, cyano, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; the atom marked with a is The atom marked with b is bonded to a group represented by R ７ are each independently a fluorine atom or a substituted or unsubstituted alkyl; n is an integer from 0 to 2; Y is N or CH; R １６ , R １７ and R １８ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, or a cyano; R ８ is a hydrogen atom or a substituted or unsubstituted alkyl; R ９ is halogen or substituted or unsubstituted alkyl; Z １ and Z ２ are each independently N or CH; W is a group represented by １５ and R １１ is a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, an aromatic carbocyclic group, a non-aromatic carbocyclic group, an aromatic heterocyclic group, or a non-aromatic heterocyclic group; R １２ and R １３ are each independently a hydrogen atom or a halogen atom; １４ and R １５ and each independently represent a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group, or a pharmaceutically acceptable salt thereof. (In the formula, R １ is a substituted or unsubstituted alkyl or a substituted or unsubstituted non-aromatic heterocyclic group; R ２ teeth, (In the formula, R ４ is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; R ５ is a hydrogen atom or a substituted or unsubstituted alkyl); X is N or C(R３ ) and R ３ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, difluoromethyl, trifluoromethyl or C1-C3 alkyl; (In the formula, (A １ , A ２ , A ３ ) combination is (CR ２１ , C.R. ２２ , C.R. ２３ ), (N, CR ２２ , C.R. ２３ ), (CR ２１ , N., C.R. ２３ ) or (CR ２１ , C.R. ２２ , N); R ２１ , R ２２ and R ２３ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, or a cyano; １ , B ２ , B ３ , B ４ ) combination is (CR ２４ , C.R. ２５ , C.R. ２６ , C.R. ２７ ), (N, CR ２５ , C.R. ２６ , C.R. ２７ ), (CR ２４ , N., C.R. ２６ , C.R. ２７ ), (N, N, CR ２６ , C.R. ２７ ), (N, CR ２５ , C.R. ２６ ,N), (N,CR ２５ , N., C.R. ２７ ) or (CR ２４ ,N.,N.,CR. ２７ ) and R ２４ , R ２５ , R ２６ and R ２７ are each independently a hydrogen atom, halogen, cyano, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; the atom marked with a is The atom marked with b is bonded to a group represented by R ７ are each independently a fluorine atom or a substituted or unsubstituted alkyl; n is an integer from 0 to 2; Y is N or CH; R １６ , R １７ and R １８ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, or a cyano; R ８ is a hydrogen atom or a substituted or unsubstituted alkyl; R ９ is halogen or substituted or unsubstituted alkyl; Z １ and Z ２ are each independently N or CH; W is a group represented by １５ and R １１ is a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, an aromatic carbocyclic group, a non-aromatic carbocyclic group, an aromatic heterocyclic group, or a non-aromatic heterocyclic group; R １２ and R １３ are each independently a hydrogen atom or a halogen atom; １４ and R １５ and each independently represent a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group, or a pharmaceutically acceptable salt thereof. (In the formula, R １ is a substituted or unsubstituted alkyl or a substituted or unsubstituted non-aromatic heterocyclic group; R ２ teeth, (In the formula, R ５ is a hydrogen atom or a substituted or unsubstituted alkyl); X is N or C(R ３ ) and R ３ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, difluoromethyl, trifluoromethyl or C1-C3 alkyl; (In the formula, (A １ , A ２ , A ３) combination is (CR ２１ , C.R. ２２ , C.R. ２３ ), (N, CR ２２ , C.R. ２３ ), (CR ２１ , N., C.R. ２３ ) or (CR ２１ , C.R. ２２ , N); R ２１ , R ２２ and R ２３ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, or a cyano; １ , B ２ , B ３ , B ４ ) combination is (CR ２４ , C.R. ２５ , C.R. ２６ , C.R. ２７ ), (N, CR ２５ , C.R. ２６ , C.R. ２７ ), (CR ２４ , N., C.R. ２６ , C.R. ２７ ), (N, N, CR ２６ , C.R. ２７ ), (N, CR ２５ , C.R. ２６ ,N), (N,CR ２５ , N., C.R. ２７ ) or (CR ２４ ,N.,N.,CR. ２７ ) and R ２４ , R ２５ , R ２６ and R ２７ are each independently a hydrogen atom, halogen, cyano, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; the atom marked with a is The atom marked with b is bonded to a group represented by R ７ are each independently a fluorine atom or a substituted or unsubstituted alkyl; n is an integer from 0 to 2; Y is N or CH; R １６ , R １７ and R １８are each independently a hydrogen atom, a fluorine atom, a chlorine atom, or a cyano; R ８ is a hydrogen atom or a substituted or unsubstituted alkyl; R ９ is halogen or substituted or unsubstituted alkyl; Z １ and Z ２ are each independently N or CH; W is a group represented by １５ and R １１ is a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, an aromatic carbocyclic group, a non-aromatic carbocyclic group, an aromatic heterocyclic group, or a non-aromatic heterocyclic group; R １２ and R １３ are each independently a hydrogen atom or a halogen atom; １４ and R １５ and each independently represent a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group, or a pharmaceutically acceptable salt thereof. (In the formula, R １ is alkyl, alkyl substituted with a substituted or unsubstituted non-aromatic heterocycle, or alkyl substituted with a substituted or unsubstituted aromatic heterocycle; R ２ teeth, (In the formula, R ５ is a hydrogen atom or a substituted or unsubstituted alkyl); X is N or C(R ３ ) and R ３ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, difluoromethyl, trifluoromethyl or C1-C3 alkyl; (In the formula, (A １ , A ２ , A ３ ) combination is (CR ２１ , C.R. ２２ , C.R. ２３ ), (N, CR ２２ , C.R. ２３ ), (CR ２１ , N., C.R. ２３) or (CR ２１ , C.R. ２２ , N); R ２１ , R ２２ and R ２３ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, or a cyano; １ , B ２ , B ３ , B ４ ) combination is (CR ２４ , C.R. ２５ , C.R. ２６ , C.R. ２７ ), (N, CR ２５ , C.R. ２６ , C.R. ２７ ), (CR ２４ , N., C.R. ２６ , C.R. ２７ ), (N, N, CR ２６ , C.R. ２７ ), (N, CR ２５ , C.R. ２６ ,N), (N,CR ２５ , N., C.R. ２７ ) or (CR ２４ ,N.,N.,CR. ２７ ) and R ２４ , R ２５ , R ２６ and R ２７ are each independently a hydrogen atom, halogen, cyano, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; the atom marked with a is The atom marked with b is bonded to a group represented by R ７ are each independently a fluorine atom or a substituted or unsubstituted alkyl; n is an integer from 0 to 2; Y is N or CH; R １６ , R １７ and R １８ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, or a cyano; R ８ is a hydrogen atom or a substituted or unsubstituted alkyl; R ９ is halogen or substituted or unsubstituted alkyl; Z １ and Z２ are each independently N or CH; W is a group represented by １５ and R １１ is a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, an aromatic carbocyclic group, a non-aromatic carbocyclic group, an aromatic heterocyclic group, or a non-aromatic heterocyclic group; R １２ and R １３ are each independently a hydrogen atom or a halogen atom; １４ and R １５ and each independently represent a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group, or a pharmaceutically acceptable salt thereof. (In the formula, R １ is alkyl, alkyl substituted with a substituted or unsubstituted non-aromatic heterocycle, or alkyl substituted with a substituted or unsubstituted aromatic heterocycle; R ２ teeth, (In the formula, R ５ is a hydrogen atom or a substituted or unsubstituted alkyl); X is N or C(R ３ ) and R ３ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, difluoromethyl, trifluoromethyl or C1-C3 alkyl; (In the formula, (A １ , A ２ , A ３ ) combination is (CR ２１ , C.R. ２２ , C.R. ２３ ), (N, CR ２２ , C.R. ２３ ) or (CR ２１ , C.R. ２２ , N); R ２１ , R ２２ and R ２３ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, or a cyano; １ , B ２ , B ３ , B４ ) combination is (CR ２４ , C.R. ２５ , C.R. ２６ , C.R. ２７ ) or (N, CR ２５ , C.R. ２６ , C.R. ２７ ) and R ２４ , R ２５ , R ２６ and R ２７ are each independently a hydrogen atom, halogen, cyano, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; the atom marked with a is The atom marked with b is bonded to a group represented by R ７ are each independently a fluorine atom or a substituted or unsubstituted alkyl; n is an integer from 0 to 2; Y is N or CH; R １６ , R １７ and R １８ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, or a cyano; R ８ is a hydrogen atom or a substituted or unsubstituted alkyl; R ９ is halogen or substituted or unsubstituted alkyl; Z １ and Z ２ are each independently N or CH; W is a group represented by １５ and R １１ is a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, an aromatic carbocyclic group, a non-aromatic carbocyclic group, an aromatic heterocyclic group, or a non-aromatic heterocyclic group; R １２ and R １３ are each independently a hydrogen atom or a halogen atom; １４ and R １５ and each independently represent a hydrogen atom, a halogen atom, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group, or a pharmaceutically acceptable salt thereof. (In the formula, R １ is alkyl, alkyl substituted with a substituted or unsubstituted non-aromatic heterocycle, or alkyl substituted with a substituted or unsubstituted aromatic heterocycle; R ２ teeth, (In the formula, R ５ is a hydrogen atom or a substituted or unsubstituted alkyl); X is N or C(R ３ ) and R ３ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, difluoromethyl, trifluoromethyl or C1-C3 alkyl; (In the formula, (A １ , A ２ , A ３ ) combination is (CR ２１ , C.R. ２２ , C.R. ２３ ), (N, CR ２２ , C.R. ２３ ) or (CR ２１ , C.R. ２２ , N); R ２１ is a hydrogen atom or a fluorine atom, and R ２２ and R ２３ is a hydrogen atom; １ , B ２ , B ３ , B ４ ) combination is (CR ２４ , C.R. ２５ , C.R. ２６ , C.R. ２７ ) or (N, CR ２５ , C.R. ２６ , C.R. ２７ ) and R ２４ , R ２５ , R ２６ and R ２７ are each independently a hydrogen atom, halogen, cyano, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; the atom marked with a is The atom marked with b is bonded to a group represented by R ７are each independently a fluorine atom or a substituted or unsubstituted alkyl; n is an integer from 0 to 2; Y is N or CH; R １６ is a hydrogen atom or a fluorine atom, and R １７ and R １８ is a hydrogen atom; R ８ is a hydrogen atom or a substituted or unsubstituted alkyl; R ９ is halogen or substituted or unsubstituted alkyl; Z １ and Z ２ are each independently N or CH; W is a group represented by １５ and R １１ is a hydrogen atom, halogen or cyano; R １２ and R １３ is a hydrogen atom; R １４ and R １５ and each independently represent a hydrogen atom or a halogen atom, or a pharmaceutically acceptable salt thereof. (In the formula, R １ is alkyl substituted with a non-aromatic heterocycle; R ２ teeth, X is a group represented by C(R ３ ) and R ３ is a chlorine atom, a bromine atom or an iodine atom; L is (wherein the atom marked with a is The atom marked with b is bonded to a group represented by R ８ is a hydrogen atom or alkyl; R ９ is halogen or haloalkyl; Z １ and Z ２ are each independently N or CH; W is a group represented by １５ and R １１ is a hydrogen atom, halogen or cyano; R １２ and R １３ is a hydrogen atom; R１４ and R １５ and each independently represent a hydrogen atom or a halogen atom, or a pharmaceutically acceptable salt thereof.

[0095] The compounds represented by formula (I), formula (IA) or formula (IB) 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. R ２ in The group represented by the formula: is preferably in trans form.

[0096] One or more hydrogen, carbon and / or other atoms of the compounds of formula (I), formula (IA) or formula (IB) 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 ３６ The isotopes of the compounds represented by formula (I), formula (IA), or formula (IB) include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as Cl. The compounds represented by formula (I), formula (IA), or formula (IB) also include compounds substituted with such isotopes. The isotope-substituted compounds are also useful as pharmaceuticals, and include all radiolabeled compounds of formula (I), formula (IA), or formula (IB). The present invention also includes a "radiolabeling method" for producing the "radiolabeled compound," and the "radiolabeled compound" is useful as a research and / or diagnostic tool in metabolism pharmacokinetic studies and binding assays.

[0097] Radiolabeled compounds of Formula (I), (IA), or (IB) can be prepared by methods well known in the art. For example, tritium-labeled compounds of Formula (I), (IA), or (IB) can be prepared by introducing tritium into a specific compound of Formula (I), (IA), or (IB) via catalytic dehalogenation using tritium. This method involves reacting an appropriately halogen-substituted precursor of Formula (I), (IA), or (IB) with tritium gas in the presence of a suitable catalyst, such as Pd / C, with or without a base. For other suitable methods for preparing tritium-labeled compounds, see "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.

[0098] Pharmaceutically acceptable salts of the compound represented by formula (I), formula (IA) or formula (IB) include, for example, salts of the compound represented by formula (I), formula (IA) or formula (IB) 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, organic base (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, methanamine, Examples of suitable salts include salts with inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and amino acids, and salts with 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.

[0099] A compound represented by Formula (I), Formula (IA), or Formula (IB), or a pharmaceutically acceptable salt thereof, may form a solvate (e.g., a hydrate), a co-crystal, and / or a crystalline polymorph, and the present invention encompasses such various solvates, co-crystals, and crystalline polymorphs. A "solvate" may be coordinated with a compound represented by Formula (I), Formula (IA), or Formula (IB) with any number of solvent molecules (e.g., water molecules). When a compound represented by Formula (I), Formula (IA), or Formula (IB), or a pharmaceutically acceptable salt thereof, is left in the atmosphere, it may absorb moisture, resulting in the adsorbed water adsorbed thereon or forming a hydrate. Furthermore, a compound represented by Formula (I), Formula (IA), or Formula (IB), or a pharmaceutically acceptable salt thereof, may form a crystalline polymorph by recrystallization. A "co-crystal" means that a compound represented by Formula (I), Formula (IA), or Formula (IB) or a salt thereof and a counter molecule are present in the same crystal lattice, and may contain any number of counter molecules.

[0100] The compounds of Formula (I), Formula (IA), or Formula (IB) 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 (IA), or Formula (IB) by enzymatic oxidation, reduction, hydrolysis, or the like under physiological conditions in vivo, and compounds that are converted to compounds of Formula (I), Formula (IA), or Formula (IB) 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.

[0101] When the compound represented by formula (I), formula (IA) or formula (IB) 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 and a mixed anhydride, or by reacting the compound using a condensing agent. For example, CH ３ COO-, C ２ H ５ COO-, tert-BuCOO-, C １５ H ３１ COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOCCH ２ CH ２ COO-, CH ３ CH(NH ２ ) COO-, CH ２ N (CH ３ ) ２ COO-, CH ３ SO ３ -, CH ３ CH ２ SO３ -, CF ３ SO ３ -, CH ２ FSO ３ -, CF ３ CH ２ SO ３ -, p-CH ３ O-PhSO ３ -, PhSO ３ -, p-CH ３ PhSO ３ - are some examples.

[0102] (Method for Producing Compounds of the Present Invention) The compounds represented by formula (I), formula (IA), or formula (IB) can be produced, for example, by the general synthetic method 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, and the like can be carried out by treatments performed in ordinary organic chemistry experiments. The compounds of the present invention can be synthesized with reference to methods well known in the art. In the following steps, if the compound has a substituent that interferes with the reaction (e.g., hydroxy, mercapto, amino, formyl, carbonyl, carboxyl, etc.), it may be protected in advance by a method described in "Protective Groups in Organic Synthesis," 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.

[0103] 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.

[0104] The compounds of the present invention represented by general formula (I), formula (IA) or formula (IB) can be produced, for example, by the synthesis route shown below.

[0105] General synthesis method 1 [Method A] (In the formula, X １ is a leaving group such as a chlorine atom, a bromine atom, or an iodine atom, and X ２ is a leaving group such as a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and R ４０ and R ４１ are each independently a hydrogen atom or alkyl, and R ４０ and R ４１may form a substituted or unsubstituted non-aromatic heterocycle together with the oxygen atom to which they are bonded, PG is a suitable protecting group for an amino group (e.g., Boc, Cbz, etc.), and other symbols are as defined above in (1), etc.) [Step 1] Compound a3 can be obtained by reacting compound a1 with compound a2 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 hours to 12 hours, preferably 1 hour to 6 hours. Potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, etc. can be used as the base. Reaction solvents include methanol, ethanol, acetonitrile, tetrahydrofuran, dimethylformamide, etc., and these can be used alone or in combination. [Step 2] Compound a5 can be obtained by reacting compound a3 with compound a4 in the presence of a metal catalyst and a base. Examples of metal catalysts 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 a3. Examples of bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, and potassium hydrogen phosphate, and can be used in an amount of 1 to 10 molar equivalents relative to compound a3. Compound a4 can be used in an amount of 1 to 10 molar equivalents relative to compound a3. The reaction temperature is 20°C to the reflux temperature of the solvent, and may be performed under microwave irradiation, as the case may be. The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours. Examples of the reaction solvent include tetrahydrofuran, toluene, DMF, dioxane, water, etc., which can be used alone or in combination. [Step 3] Compound a6 can be obtained by reacting compound a5 in a hydrogen atmosphere in the presence of a metal catalyst.Examples of metal catalysts include palladium-carbon, palladium hydroxide, and platinum catalysts, and can be used in an amount of 0.001 to 0.5 molar equivalents relative to compound a5. The reaction is carried out at a temperature between 20°C and the reflux temperature of the solvent. The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours. Examples of reaction solvents include methanol, ethanol, 2-propanol, ethyl acetate, and tetrahydrofuran, and these can be used alone or in combination. [Step 4] Compound a7 can be obtained by deprotecting compound a6 using an appropriate method. (In the formula, X ３ is a leaving group such as a bromine atom or an iodine atom, and R ４５is alkyl, R is alkyl, PG' is a suitable protecting group for a hydroxyl group (e.g., TBS, etc.), and other symbols are as defined in (1) above.) [Step 5] Compound a10 can be obtained by reacting compound a9 with compound a8 in the presence of a base. The reaction temperature is 0°C to 100°C, preferably 10°C to 70°C. The reaction time is 0.5 hours to 24 hours, preferably 1 hour to 12 hours. Potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, etc. can be used as the base. Examples of reaction solvents include methanol, ethanol, acetonitrile, tetrahydrofuran, dimethylformamide, etc., and these can be used alone or in combination. [Step 6] Compound a11 can be obtained by reacting compound a10 with a reducing agent. Examples of reducing agents include lithium aluminum hydride, etc., and these can be used in an amount of 1 to 5 molar equivalents relative to compound a10. The reaction temperature is −40°C to 50°C, preferably −10°C to 30°C. The reaction time is 0.5 hours to 24 hours, preferably 1 to 12 hours. Tetrahydrofuran or the like can be used as a reaction solvent. [Step 7] Compound a12 can be obtained by introducing an appropriate protecting group, such as a TBS group, into the hydroxyl group of compound a11. [Step 8] Compound a13 can be obtained by treating compound a12 with a base and then reacting with dimethylformamide. Examples of the base include n-butyllithium. The reaction temperature is −78°C to 30°C, preferably −78°C to −40°C. The reaction time is 0.1 hours to 24 hours, preferably 0.5 hours to 12 hours. Tetrahydrofuran or the like can be used as a reaction solvent. [Step 9] Compound a14 can be obtained by sequentially treating compound a13 with compound a7 and a reducing agent in the presence of an acid. Examples of the acid that can be used include acetic acid and tosylic acid. The reducing agent includes sodium triacetoxyborohydride, sodium cyanoborohydride, 2-picoline borane, etc., and can be used in an amount of 1 to 5 molar equivalents relative to compound a13.The reaction temperature is −10° C. to 80° C., preferably 10° C. to 40° C. The reaction time is 0.5 hours to 48 hours, preferably 1 to 24 hours. Examples of reaction solvents include dichloromethane, tetrahydrofuran, dioxane, acetonitrile, etc., and these can be used alone or in combination. [Step 10] Compound a15 can be obtained by deprotecting compound a14. [Step 11] Compound a16 can be obtained by reacting compound a15 with an oxidizing agent. Examples of oxidizing agents include manganese dioxide. The reaction temperature is −10° C. to 80° C., preferably 10° C. to 40° C. The reaction time is 1 hour to 96 hours, preferably 12 to 72 hours. Examples of reaction solvents include dichloromethane, tetrahydrofuran, dioxane, acetonitrile, etc., and these can be used alone or in combination. [Step 12] Compound a18 can be obtained by reacting compound a16 with compound a17. Compound a17 can be used in an amount of 1 to 10 molar equivalents relative to compound a16. The reaction temperature is −10° C. to 80° C., preferably 10° C. to 40° C. The reaction time is 0.5 to 72 hours, preferably 1 to 48 hours. Examples of reaction solvents include dichloromethane, tetrahydrofuran, dioxane, acetonitrile, etc., which can be used alone or in combination. [Step 13] Compound a19 can be obtained by reacting compound a18 with a basic aqueous solution. 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. Examples of bases that can be used include sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, and potassium hydroxide. Examples of reaction solvents include methanol, ethanol, water, acetone, acetonitrile, and tetrahydrofuran, which can be used alone or in combination.

[0106] General synthesis method 2 [Method B] (wherein each symbol has the same meaning as in the above [Method A]) [Step 1] Compound b1 can be obtained by reacting compound a18 in the presence of a metal catalyst under a hydrogen atmosphere. Examples of metal catalysts include palladium-carbon, palladium hydroxide, platinum oxide, etc., and can be used in an amount of 0.001 to 0.5 molar equivalents relative to compound a18. The reaction is carried out at a temperature of 20°C to the reflux temperature of the solvent. The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours. Examples of reaction solvents include methanol, ethanol, 2-propanol, ethyl acetate, tetrahydrofuran, etc., and these can be used alone or in combination. [Step 2] Compound b2 can be obtained by reacting compound b1 with a basic aqueous solution. 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. Usable bases include sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. Reaction solvents include methanol, ethanol, water, acetone, acetonitrile, tetrahydrofuran, etc., and these can be used alone or in combination.

[0107] General synthesis method 3 [Method C] (wherein each symbol has the same meaning as in the above [Method A].) [Step 1] Compound c1 can be obtained by reacting compound a18 with trimethylsulfoxonium iodide in the presence of a base. Examples of bases include potassium tert-butoxide and sodium hydride, and 1 to 5 molar equivalents can be used relative to compound a18. The reaction temperature is −10° C. to 80° C., preferably 0° C. to 60° C. The reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours. Examples of reaction solvents include dimethyl sulfoxide, dichloromethane, tetrahydrofuran, dioxane, etc., and these can be used alone or in combination. [Step 2] Compound c2 can be obtained by reacting compound c1 with a basic aqueous solution. 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. Usable bases include sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. Reaction solvents include methanol, ethanol, water, acetone, acetonitrile, tetrahydrofuran, etc., and these can be used alone or in combination.

[0108] General synthesis method 4 [Method D] (In the formula, each symbol has the same meaning as in the above [Method A].) [Step 1] Compound a15 can be reacted with 2-hydroxy-2-azaadamantane in the presence of DMAP, copper(I) chloride, and 2,2'-bipyridine in air to obtain d1. The reaction temperature is -20°C to 50°C, preferably 0°C to 30°C. The reaction time is 1 hour to 96 hours, preferably 3 hours to 72 hours. Acetonitrile or the like can be used as the reaction solvent. [Step 2] Compound d2 can be obtained by reacting compound d1 with hydrazine in the presence of a condensing agent. Condensing agents include dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, EDC, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, HATU, and the like, and can be used in an amount of 1 to 5 molar equivalents relative to compound e1. Bases 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 hours to 24 hours, preferably 1 hour to 12 hours. [Step 3] Compound d3 can be obtained by reacting compound d2 with carbonyldiimidazole. The reaction temperature is −20°C to 50°C, preferably 0°C to 30°C. The reaction time is 0.1 hours to 48 hours, preferably 1 hour to 24 hours. Examples of reaction solvents include dichloromethane, acetonitrile, tetrahydrofuran, etc., which can be used alone or in combination.

[0109] General synthesis method 5 [Method E] (In the formula, X ５is a leaving group such as a bromine atom or an iodine atom, and other symbols are as defined in Method A above.) [Step 1] Compound e1 can be obtained by reacting compound d1 with ammonium chloride in the presence of a base and a condensing agent. Condensing agents include dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, EDC, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, HATU, and the like, and can be used in an amount of 1 to 5 molar equivalents relative to compound d1. Examples of bases include triethylamine, diisopropylethylamine, and paradimethylaminopyridine. The reaction temperature for the condensation reaction is −20°C to 60°C, preferably 0°C to 50°C. The reaction time for the condensation reaction is 0.1 to 24 hours, preferably 1 to 12 hours. [Step 2] Compound e2 can be obtained by reacting compound e1 with trifluoroacetic anhydride in the presence of a base. Examples of bases include triethylamine, diisopropylethylamine, and paradimethylaminopyridine. The reaction temperature for the condensation reaction is −20°C to 60°C, preferably 0°C to 50°C. The reaction time for the condensation reaction is 0.1 to 24 hours, preferably 1 to 12 hours. Examples of reaction solvents include dichloromethane, acetonitrile, and tetrahydrofuran, which can be used alone or in combination. [Step 3] Compound e3 can be obtained by reacting compound e2 with hydrazine. The reaction temperature for the condensation reaction is −10°C to 100°C, preferably 0°C to 80°C. The reaction time for the condensation reaction is 0.1 to 24 hours, preferably 1 to 12 hours. Examples of reaction solvents include methanol, ethanol, 2-propanol, water, acetone, acetonitrile, and tetrahydrofuran, which can be used alone or in combination. [Step 4] Compound e4 can be obtained by treating compound e3 with carbonyldiimidazole, optionally with a base. The reaction temperature is −10° C. to 100° C., preferably 0° C. to 80° C. The reaction time is 0.1 hours to 48 hours, preferably 1 hour to 24 hours.Examples of the base include DBU, triethylamine, diisopropylethylamine, and pyridine. Examples of the reaction solvent include dichloromethane, acetonitrile, tetrahydrofuran, dioxane, and dimethylformamide, and these can be used alone or in combination. [Step 5] Compound e6 and / or e7 can be obtained by reacting compound e5 with compound e4 in the presence of a base. The reaction temperature is −10° C. to 100° C., preferably 0° C. to 80° C. The reaction time is 0.1 hours to 48 hours, preferably 1 hour to 24 hours. Examples of the base that can be used include potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, triethylamine, diisopropylethylamine, and pyridine. Examples of the reaction solvent include methanol, ethanol, acetonitrile, tetrahydrofuran, and dimethylformamide, and these can be used alone or in combination.

[0110] General synthesis method 6 [F method] (wherein each symbol has the same meaning as in the above [Method A]) [Step 1] Compound f1 can be obtained by reacting compound e2 with hydroxylamine. The reaction temperature for the condensation reaction is -10°C to 100°C, preferably 0°C to 80°C. The reaction time for the condensation reaction is 0.1 to 24 hours, preferably 1 to 12 hours. Reaction solvents include methanol, ethanol, 2-propanol, water, acetone, acetonitrile, tetrahydrofuran, etc., and these can be used alone or in combination. [Step 2] Compound f2 can be obtained by reacting compound f1 with carbonyldiimidazole, and, if necessary, a base. Examples of bases include DBU, triethylamine, diisopropylethylamine, pyridine, etc. The reaction temperature is -10°C to 100°C, preferably 0°C to 80°C. The reaction time is 0.1 to 48 hours, preferably 1 to 24 hours. Examples of reaction solvents include dichloromethane, acetonitrile, tetrahydrofuran, dioxane, dimethylformamide, etc., and these can be used alone or in combination.

[0111] General Synthesis Method 7 [Method G] (Where R ４６is alkyl, and the other symbols are as defined in Method A above.) [Step 1] Compound g2 can be obtained by reacting compound g1 with compound a9 in the presence of a base. The reaction temperature is 0°C to 100°C, preferably 10°C to 70°C. The reaction time is 0.5 hours to 24 hours, preferably 1 hour to 12 hours. Potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, etc. can be used as the base. Reaction solvents include methanol, ethanol, acetonitrile, tetrahydrofuran, dimethylformamide, etc., and these can be used alone or in combination. [Step 2] Compound g3 can be obtained by halogenating compound g2. Examples of halogenating agents include N-iodosuccinimide and N-bromosuccinimide. The reaction temperature is 0°C to 100°C, preferably 10°C to 70°C. The reaction time is 0.5 hours to 24 hours, preferably 1 hour to 12 hours. Examples of reaction solvents include dichloromethane, acetonitrile, tetrahydrofuran, dimethylformamide, etc., and these can be used alone or in combination. [Step 3] Compound g5 can be obtained by reacting compound g4 with compound g3 in the presence of a base and copper(I) iodide. Potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, etc. can be used as the base. The reaction temperature is 10°C to 150°C, preferably 30°C to 120°C. The reaction time is 0.5 hours to 24 hours, preferably 1 hour to 12 hours. Examples of reaction solvents include dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, etc., and these can be used alone or in combination. [Step 4] Compound g6 can be obtained by reacting compound g5 with a base and then reacting with dimethylformamide. The base includes n-butyllithium, etc. The reaction temperature is −78° C. to 30° C., preferably −78° C. to −40° C. The reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.As the reaction solvent, tetrahydrofuran or the like can be used. (In the formula, X １is a leaving group such as a chlorine atom, a bromine atom, or an iodine atom; PG″ is a suitable protecting group for an amino group (e.g., Boc, Cbz, etc.); other symbols are as defined in (1) above, etc.) [Step 5] Compound g8 can be obtained by allowing compound g7 to act on compound a3 in the presence of a base, a metal catalyst, and a ligand. 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, which can be used in an amount of 0.001 to 0.5 molar equivalents relative to compound a3. Examples of the ligand that can be used include BINAP and DPPF. Examples of bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, and potassium hydrogen phosphate, and can be used in an amount of 1 to 10 molar equivalents relative to compound a3. The reaction is carried out at a temperature between 20°C and the reflux temperature of the solvent, and optionally 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. [Step 6] Compound g9 can be obtained by appropriately deprotecting compound g8. [Step 7] Compound g11 can be obtained by sequentially treating compound g9 with compound g10 and a reducing agent in the presence of an acid. Examples of acids that can be used include acetic acid and tosylic acid. Examples of reducing agents include sodium triacetoxyborohydride, sodium cyanoborohydride, and 2-picoline borane, and can be used in an amount of 1 to 5 molar equivalents relative to compound g9. The reaction temperature is -10°C to 80°C, preferably 10°C to 40°C. The reaction time is 0.5 hours to 48 hours, preferably 1 to 24 hours. Examples of reaction solvents include dichloromethane, tetrahydrofuran, dioxane, and acetonitrile, and these can be used alone or in combination.

[0112] General synthesis method 8 [H method] (In the formula, X １ is a leaving group such as a chlorine atom, a bromine atom, or an iodine atom, and R ４７ and R ４８ are each independently a hydrogen atom or alkyl, and R ４７ and R ４８may form a substituted or unsubstituted non-aromatic heterocycle together with the oxygen atom to which they are bonded, and other symbols are as defined above in (1), etc.) [Step 1] Compound a3 can be reacted with compound h1 in the presence of a metal catalyst and a base to obtain compound h2. Examples of metal catalysts include palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, and bis(tri-tert-butylphosphine)palladium, which can be used in an amount of 0.001 to 0.5 molar equivalents relative to compound a3. Examples of bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, and potassium hydrogen phosphate, which can be used in an amount of 1 to 10 molar equivalents relative to compound a3. The reaction temperature is 20°C to the reflux temperature of the solvent, and optionally, is performed 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, and the like, which can be used alone or in combination. [Step 2] Compound h4 can be obtained by reacting compound h3 with a base and then compound h2. Examples of bases include n-butyllithium. The reaction temperature is −78°C to 30°C, preferably −78°C to −40°C. The reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours. Tetrahydrofuran and the like can be used as the reaction solvent. [Step 3] Compound h5 can be obtained by reacting compound h4 with triethylsilane in the presence of an acid. Examples of acids that can be used include trifluoroacetic acid and the like. Triethylsilane can be used in an amount of 1 to 10 molar equivalents relative to compound h4. The reaction temperature is from 20° C. to the reflux temperature of the solvent, and the reaction time is from 0.1 to 48 hours, preferably from 0.5 to 12 hours.Examples of reaction solvents include dichloroethane, toluene, etc., which can be used alone or in combination.

[0113] General synthesis method 9 [Method I] (In the formula, X １ is a leaving group such as a chlorine atom, a bromine atom, or an iodine atom, and X ４is a leaving group such as a bromine atom or an iodine atom, and other symbols are as defined above in (1), etc.) [Step 1] Compound i2 can be obtained by reacting compound a3 with compound i1 in the presence of a base, a metal catalyst, and a ligand. Examples of metal catalysts include palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, and bis(tri-tert-butylphosphine)palladium, which can be used in an amount of 0.001 to 0.5 molar equivalents relative to compound a3. Examples of ligands that can be used include BINAP and DPPF. Examples of bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, and potassium hydrogen phosphate, which can be used in an amount of 1 to 10 molar equivalents relative to compound a3. The reaction temperature is 20°C to the reflux temperature of the solvent, and optionally, is performed 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. [Step 2] Compound i3 can be obtained by, for example, reacting compound i2 with carbon tetrabromide or triphenylphosphine. The reaction temperature is −30°C to 80°C, preferably −10°C to 30°C. The reaction time is 0.1 to 24 hours, preferably 1 to 12 hours. Examples of reaction solvents that can be used include dichloromethane and tetrahydrofuran. [Step 3] Compound i4 can be obtained by reacting compound i3 with triphenylphosphine. Triphenylphosphine can be used in an amount of 1 to 10 molar equivalents relative to compound i3. The reaction temperature is 10°C to 150°C, preferably 20°C to 100°C. The reaction time is 0.1 to 48 hours, preferably 0.5 to 24 hours. As the reaction solvent, toluene, dioxane, dimethylformamide, tetrahydrofuran, etc. can be used.[Step 4] Compound i5 can be obtained by reacting compound g10 with compound i4 in the presence of a base. Examples of bases include LHMDS, KHMDS, potassium tert-butoxide, sodium tert-butoxide, n-butyllithium, lithium hydroxide, sodium hydroxide, and potassium hydroxide compounds, and can be used in an amount of 1 to 5 molar equivalents relative to compound i4. The reaction temperature is −30°C to 80°C, preferably −10°C to 30°C. The reaction time is 0.1 hours to 48 hours, preferably 0.5 hours to 24 hours. Examples of reaction solvents that can be used include toluene, dioxane, dimethylformamide, and tetrahydrofuran. [Step 5] Compound i6 can be obtained by reacting compound i5 with trimethylsulfoxonium iodide in the presence of a base. Examples of bases include potassium tert-butoxide and sodium hydride, and can be used in an amount of 1 to 5 molar equivalents relative to compound i5. The reaction temperature is −10° C. to 80° C., preferably 0° C. to 60° C. The reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours. Examples of reaction solvents include dimethyl sulfoxide, dichloromethane, tetrahydrofuran, dioxane, etc., which can be used alone or in combination.

[0114] General synthesis method 10 [J method] (In the formula, X ６ is a leaving group such as a chlorine atom, a bromine atom, or an iodine atom, and R ４２is alkyl, and other symbols are as defined above in (1), etc.) [Step 1] Compound j3 can be obtained by reacting compound j2 with compound j1 in the presence of a base. Examples of the base include sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, calcium carbonate, cesium carbonate, pyridine, triethylamine, etc., and can be used in an amount of 1 to 5 molar equivalents relative to compound j1. The reaction temperature is −10°C to 80°C, preferably 10°C to 60°C. The reaction time is 0.5 hours to 24 hours, preferably 1 to 12 hours. Examples of the reaction solvent include dichloromethane, tetrahydrofuran, dioxane, acetonitrile, toluene, etc., and these can be used alone or in combination. [Step 2] Compound j4 can be obtained by reacting compound j3 with diphosphorus pentoxide and phosphoryl chloride, etc. The reaction temperature is −10°C to 80°C, preferably 10°C to 60°C. The reaction time is 0.5 hours to 24 hours, preferably 1 to 12 hours. Toluene or the like can be used as a reaction solvent. [Step 3] Compound j5 can be obtained by reacting compound j4 with formic acid and an amine in the presence of a ruthenium catalyst. Examples of ruthenium catalysts include [(R,R)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamido]chloro(p-cymene)ruthenium and [(S,S)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamido]chloro(p-cymene)ruthenium, which can be used in an amount of 0.05 to 1 molar equivalent relative to compound j4. Examples of amines include triethylamine, which can be used in an amount of 1 to 3 molar equivalents relative to compound j4. The reaction temperature is −10°C to 80°C, preferably 10°C to 60°C. The reaction time is 0.5 hours to 24 hours, preferably 1 to 12 hours. Acetonitrile or the like can be used as a reaction solvent. As an alternative to Step 3, Step 3' can be performed. [Step 3'] Compound j5 can be obtained by reacting compound j4 with a reducing agent. Examples of the reducing agent include sodium borohydride, which can be used in an amount of 1 to 5 molar equivalents relative to compound j4.The reaction temperature is −10°C to 80°C, preferably 0°C to 30°C. The reaction time is 0.5 hours to 24 hours, preferably 1 to 12 hours. Methanol or the like can be used as a reaction solvent. [Step 4] Compound j6 can be obtained by reacting compound j5 with trifluoroacetic anhydride. The reaction temperature is −10°C to 80°C, preferably 10°C to 40°C. The reaction time is 0.5 hours to 24 hours, preferably 1 to 12 hours. Examples of reaction solvents include dichloromethane, tetrahydrofuran, dioxane, acetonitrile, and the like, which can be used alone or in combination. [Step 5] Compound j7 can be obtained by reacting compound j6 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 hours to 24 hours, preferably 1 to 12 hours. Examples of reaction solvents that can be used include dichloromethane, tetrahydrofuran, dioxane, acetonitrile, and the like. [Step 6] Compound j9 can be obtained by reacting compound j8 with compound j7 in the presence of a base. The reaction temperature is 0°C to the reflux temperature of the solvent. The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours. Potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, etc. can be used as the base. Examples of reaction solvents include methanol, ethanol, acetonitrile, tetrahydrofuran, dimethylformamide, etc., and these can be used alone or in combination. [Step 7] Compound j10 can be obtained by reacting compound j9 with a base. The reaction temperature is 0°C to 80°C, preferably 10 to 60°C. The reaction time is 0.5 to 12 hours, preferably 1 to 10 hours. Examples of bases that can be used include sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. Examples of reaction solvents include methanol, ethanol, water, acetone, acetonitrile, and tetrahydrofuran, and these can be used alone or in combination.[Step 8] Compound j11 can be obtained by sequentially reacting compound g10 and a reducing agent with compound j10 in the presence of an acid. Examples of the acid that can be used include acetic acid and tosylic acid. Examples of the reducing agent include sodium triacetoxyborohydride, sodium cyanoborohydride, and 2-picoline borane, and these can be used in an amount of 1 to 5 molar equivalents relative to compound j10. The reaction temperature is −10° C. to 80° C., preferably 10° C. to 40° C. The reaction time is 0.5 hours to 48 hours, preferably 1 to 24 hours. Examples of the reaction solvent include dichloromethane, tetrahydrofuran, dioxane, and acetonitrile, and these can be used alone or in combination.

[0115] General synthesis method 11 [K method] (In the formula, X ８ is a leaving group such as a chlorine atom, a bromine atom, or an iodine atom; other symbols are as defined in (1) or [Method A] above.) [Step 1] Compound k3 can be obtained by reacting compound k2 with compound k1 in the presence of an acid. The reaction temperature is 30°C to the reflux temperature of the solvent, preferably 90°C to the reflux temperature of the solvent. The reaction time is 1 hour to 48 hours, preferably 10 hours to 30 hours. Examples of acids that can be used include paratoluenesulfonic acid hydrate and camphorsulfonic acid. Examples of reaction solvents include toluene, DMF, DMA, and NMP, which can be used alone or in combination. [Step 2] Compound k4 can be obtained by treating compound k1 in the same manner as in [Step 2] of Method A above. [Step 3] Compound k5 can be obtained by treating compound k4 in the same manner as in [Step 3] of Method A above. [Step 4] Compound k6 can be obtained by treating compound k5 in the same manner as in [Step 4] of Method A above. [Step 5] Compound k6 can be obtained by subjecting compound k6 to the same procedure as in the above Method A [Step 9].

[0116] General synthesis method 12 [L method] (wherein each symbol has the same meaning as in the above (1), [Method G] or [Method K].) [Step 1] Compound k3 can be subjected to the same procedure as in the above Method G [Step 5] to obtain compound l1. [Step 2] Compound l1 can be subjected to the same procedure as in the above Method G [Step 6] to obtain compound l2. [Step 3] Compound l2 can be subjected to the same procedure as in the above Method G [Step 7] to obtain compound l3.

[0117] General synthesis method 13 [M method] (wherein each symbol has the same meaning as in the above (1), [Method K] or [Method H].) [Step 1] Compound m1 can be obtained by subjecting compound k3 to the same procedure as in the above Method H [Step 1]. [Step 2] Compound m1 can be obtained by subjecting compound m1 to the same procedure as in the above Method H [Step 2]. [Step 3] Compound m3 can be obtained by subjecting compound m2 to the same procedure as in the above Method H [Step 3].

[0118] General synthesis method 14 [N method] (In the formula, X ９ is a leaving group such as a bromine atom or an iodine atom, and other symbols are as defined in (1) or [Method K] above.) [Step 1] Compound n1 can be obtained by subjecting compound k3 to a procedure similar to that in Method I [Step 1] above. [Step 2] Compound n2 can be obtained by subjecting compound n1 to a procedure similar to that in Method I [Step 2] above. [Step 3] Compound n3 can be obtained by subjecting compound n2 to a procedure similar to that in Method I [Step 3] above. [Step 4] Compound n4 can be obtained by subjecting compound n3 to a procedure similar to that in Method I [Step 4] above. [Step 3] Compound n4 can be obtained by subjecting compound n5 to a procedure similar to that in Method I [Step 5] above.

[0119] General synthesis method 15 [O method] (wherein each symbol has the same meaning as in the above [Method A]) [Step 1] Compound d1 is reacted with oxalyl chloride in the presence of a catalytic amount of DMF, followed by sequential reaction with TMS diazomethane and aqueous hydrobromic acid to obtain compound o1. In both reactions, the reaction temperature is −20°C to 50°C, preferably −10°C to 30°C. Examples of reaction solvents include dichloromethane and tetrahydrofuran, which can be used alone or in combination. [Step 2] Compound o3 can be obtained by reacting compound o2 with compound o1 in the presence of a base. Examples of bases that can be used include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate, and can be used in an amount of 1 to 5 mol equivalents relative to compound o1. The reaction temperature is −20°C to 50°C, preferably −10°C to 30°C. Examples of reaction solvents include dimethylformamide and tetrahydrofuran, which can be used alone or in combination. [Step 3] Compound o4 can be obtained by reacting compound o3 with a base. Examples of the base that can be used include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, and triethylamine. The reaction temperature is −20° C. to 100° C., preferably −10° C. to 80° C. Examples of the reaction solvent include tetrahydrofuran, methanol, ethanol, and water, and these can be used alone or in combination.

[0120] General synthesis method 16 [P method] (wherein each symbol has the same meaning as in the above [Method A]) [Step 1] Compound p2 can be obtained by reacting compound o1 with compound p1 in aqueous hydrochloric acid. The reaction temperature is 0°C to 100°C, preferably 20°C to 100°C. Reaction solvents include ethanol, water, etc., and these can be used alone or in combination.

[0121] General synthesis method 17 [Q method] (wherein each symbol has the same meaning as in the above [Method A].) [Step 1] Compound q1 can be obtained by reacting compound d2 with Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide). The reaction temperature is −20° C. to the reflux temperature of the solvent, preferably 20° C. to the reflux temperature of the solvent. The reaction time is 0.1 to 48 hours, preferably 1 to 24 hours. Reaction solvents include toluene, dioxane, etc., which can be used alone or in combination. [Step 2] Compound q2 can be obtained by reacting compound q1 with carbonyldiimidazole. The reaction temperature is −20° C. to 50° C., preferably 0° C. to 30° C. The reaction time is 0.1 to 48 hours, preferably 1 to 24 hours. Reaction solvents include dichloromethane, acetonitrile, tetrahydrofuran, etc., which can be used alone or in combination. [R method] (In the formula, R ４３ is alkyl, and X ５ is a leaving group such as a chlorine atom, a bromine atom, or an iodine atom, and X ６is a leaving group such as a bromine atom or an iodine atom, M is Li, MgCl, MgBr, or the like, and the other symbols are as defined in (1) above.) [Step 1] Compound r2 can be obtained by reacting compound r1 with a basic aqueous solution. The reaction temperature is 0°C to 70°C, preferably 0°C to 50°C. The reaction time is 0.5 hours to 12 hours, preferably 1 hour to 6 hours. Usable bases include sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like. Reaction solvents include methanol, ethanol, water, acetone, acetonitrile, tetrahydrofuran, and the like, which can be used alone or in combination. [Step 2] Compound r4 can be obtained by reacting compound r2 with compound r3 in the presence of a condensing agent. Condensing agents include dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, EDC, HATU, etc., and can be used in an amount of 1 to 5 molar equivalents relative to compound r2. Bases include triethylamine, diisopropylethylamine, p-dimethylaminopyridine, etc. The reaction temperature is −20°C to 80°C, preferably 10°C to 70°C. The reaction time is 0.1 hours to 24 hours, preferably 1 hour to 12 hours. Reaction solvents include tetrahydrofuran, dichloromethane, DMF, etc., and can be used alone or in combination. [Step 3] Compound r6 can be obtained by reacting compound r4 with compound r5. Examples of r5 include Grignard reagents, organolithium reagents, etc., and can be used in an amount of 1 to 10 molar equivalents relative to compound r4. 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 the reaction solvent include tetrahydrofuran, diethyl ether, and dioxane, which can be used alone or in combination. [Step 4] Compound r7 can be obtained by reacting compound r6 with formic acid and an amine in the presence of a ruthenium catalyst.Examples of ruthenium catalysts include [(R,R)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamido]chloro(p-cymene)ruthenium and [(S,S)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamido]chloro(p-cymene)ruthenium, which can be used in an amount of 0.05 to 1 molar equivalent relative to compound r6. Examples of amines include triethylamine, which can be used in an amount of 1 to 5 molar equivalents relative to compound r6. The reaction temperature is −10°C to 80°C, preferably 10°C to 60°C. The reaction time is 0.5 hours to 24 hours, preferably 1 to 12 hours. Acetonitrile or the like can be used as the reaction solvent. [Step 5] Compound r9 can be obtained by reacting compound r7 with compound r8 in the presence of a metal catalyst and a base, optionally with tetrabutylammonium bromide or the like. Examples of metal catalysts 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 r7. Examples of bases 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 r7. The reaction temperature ranges from 20°C to the reflux temperature of the solvent, and may be performed under microwave irradiation in some cases. The reaction time ranges from 0.1 to 48 hours, preferably 0.5 to 12 hours. Examples of reaction solvents include tetrahydrofuran, toluene, DMF, dioxane, and water, and can be used alone or in combination. [Step 6] Compound r10 can be obtained by reacting compound r9 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% by weight based on the compound r9. 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 0°C to the reflux temperature of the solvent, preferably 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, and water, which can be used alone or in combination. [Step 7] Compound r11 can be obtained by reacting compound r10 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. Ethanol, etc. can be used as the reaction solvent. [Step 8] Compound r12 can be obtained by reacting compound r11 with trifluoroacetic anhydride. The reaction temperature is −10° C. to 80° C., preferably 0° C. to 40° C. The reaction time is 0.5 hours to 24 hours, preferably 1 to 12 hours. Examples of reaction solvents include dichloromethane, tetrahydrofuran, dioxane, acetonitrile, etc., and these can be used alone or in combination. [Step 9] Compound r13 can be obtained by reacting compound r12 with triphenylphosphine and a condensing agent. Examples of condensing agents include DEAD and DIAD, and these can be used in an amount of 1 to 5 molar equivalents relative to compound r12. The reaction temperature is 0° C. to 60° C., preferably 10° C. to 40° C. The reaction time is 0.1 hours to 12 hours, preferably 0.2 hours to 6 hours. Examples of reaction solvents include tetrahydrofuran, dioxane, ethyl acetate, toluene, acetonitrile, etc., and these can be used alone or in combination. [Step 10] Compound r14 can be obtained by reacting compound r13 with boron tribromide, aluminum chloride, etc. 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. Dichloromethane, toluene, etc. can be used as the reaction solvent.[Step 11] Compound r15 can be obtained by reacting compound j8 with compound r14 in the presence of a base. The reaction temperature is 0°C to the reflux temperature of the solvent. The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours. Potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, etc. can be used as the base. Examples of reaction solvents include methanol, ethanol, acetonitrile, tetrahydrofuran, and dimethylformamide, and these can be used alone or in combination. [Step 12] Compound r16 can be obtained by reacting compound r15 with a base. The reaction temperature is 0°C to 80°C, preferably 10 to 60°C. The reaction time is 0.5 to 12 hours, preferably 1 to 10 hours. Examples of bases that can be used include sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, and potassium hydroxide. Examples of reaction solvents include methanol, ethanol, water, acetone, acetonitrile, tetrahydrofuran, etc., and these can be used alone or in combination. [Step 13] Compound r17 can be obtained by sequentially treating compound g10 and a reducing agent with compound r16 in the presence of an acid. Examples of acids that can be used include acetic acid and tosylic acid. Examples of reducing agents include sodium triacetoxyborohydride, sodium cyanoborohydride, and 2-picoline borane, and these can be used in an amount of 1 to 5 molar equivalents relative to compound r16. The reaction temperature is −10° C. to 80° C., preferably 10° C. to 40° C. The reaction time is 0.5 to 48 hours, preferably 1 to 24 hours. Examples of reaction solvents include dichloromethane, tetrahydrofuran, dioxane, acetonitrile, etc., and these can be used alone or in combination.

[0122] 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 preventive agent" also encompasses agents for improving symptoms.

[0123] 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.

[0124] In the present invention, "diabetes" means a disease or condition in which the body is unable to maintain an appropriate blood glucose level, 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).

[0125] "Hyperglycemia" refers to a state in which plasma glucose levels are higher than normal (for example, 80 to 110 mg / dL in humans when fasting) either in the fasting state or after glucose administration, and is one of the typical symptoms of diabetes.

[0126] "Impaired glucose tolerance" includes insulin-resistant impaired glucose tolerance and insulin secretion disorders.

[0127] "Diabetic complications" refers 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, 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.

[0128] Examples of "dementia" include Alzheimer's disease, vascular dementia, and diabetic dementia. The compound of the present invention not only has GLP-1 receptor agonist activity but also has pharmaceutical utility and possesses any or all of the following excellent characteristics: a) weak inhibitory effect on CYP enzymes (e.g., CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.); b) exhibits favorable pharmacokinetics such as high bioavailability and moderate clearance; c) high metabolic stability; d) does not exhibit irreversible inhibitory effect on CYP enzymes (e.g., CYP3A4) within the concentration range of the measurement conditions described herein; e) is not mutagenic; f) has low cardiovascular risk; g) has low risk of hematotoxicity; h) exhibits high solubility; and i) exhibits high brain penetration.

[0129] 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.

[0130] For oral administration, the composition may be prepared and administered in any of the commonly used dosage forms, such as solid preparations for internal use (e.g., tablets, powders, granules, capsules, pills, films, etc.) and liquid preparations for internal use (e.g., suspensions, emulsions, elixirs, syrups, lemonades, spirits, 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.

[0131] In the case of 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.

[0132] Pharmaceutical compositions 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, as needed. Furthermore, by appropriately modifying the effective amount of the compound of the present invention, the dosage form, and / or the 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 of age, 28 days to 23 months of age, 2 to 11 years of age, or 12 to 17 or 18 years of age. Elderly pharmaceutical compositions are preferably administered to patients 65 years of age or older.

[0133] 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 in divided doses several times a day.

[0134] 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.

[0135] The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention to the concomitant drug can be appropriately selected depending on the 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.

[0136] 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.

[0137] 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.

[0138] The abbreviations used in this specification have the following meanings: CHCl ３ : Chloroform CDCl3: Deuterated chloroform MeOH: Methanol DMSO-d ６: Deuterated dimethyl sulfoxide DMSO: Dimethyl sulfoxide DMF: Dimethylformamide Boc: tert-butoxycarbonyl Cbz: Benzyloxycarbonyl TBS: tert-butyldimethylsilyl DEAD: Diethyl azodicarboxylate DIAD: Diisopropyl azodicarboxylate DMAP: 4-dimethylaminopyridine DBU: 1,8-diazabicyclo[5.4.0]-7-undecene BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl DPPF: 1,1'-bis(diphenylphosphino)ferrocene TBAF: Tetrabutylammonium fluoride EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HATU: 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HOBt: 1-hydroxybenzotriazole NaBH(OAc) ３ : Sodium triacetoxyborohydride

[0139] (Method for identifying compounds) NMR analysis obtained in each example was carried out at 400 MHz, and DMSO-d ６ or CDCl ３ Measurement was performed using a method similar to that described above. When NMR data is presented, not all measured peaks may be listed. In the specification, RT represents the retention time in LC / MS (liquid chromatography / mass spectrometry), and was measured under the following conditions. In the specification, [M+H] represents the value observed by mass spectrometry.

[0140] (Measurement Condition 1) Column: ACQUITY UPLC BEH C18 (1.7 μm i.d. 2.1×50 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, followed by maintaining 100% solvent [B] for 0.5 minutes.

[0141] Example 1 Step 1: Compound 1 (5.51 g, 39.3 mmol), compound 2 (9.80 g, 59.0 mmol), and potassium carbonate (8.15 g, 59.0 mmol) were added to N,N-dimethylformamide (37 mL) and stirred at 70°C for 5 hours. Water was added to the reaction solution, followed by extraction with chloroform. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give compound 3 (1.70 g, yield 19%). [M+H] = 211.5, measurement condition 1: retention time 0.69 minutes 1 H-NMR (CDCl) δ: 1.36 (3H, t, J = 7.2 Hz), 2.26-2.35 (1H, m), 2.66-2.75 (1H, m), 4.28-4.37 (3H, m), 4.52 (1H, dd, J = 14.4, 2.9 Hz), 4.59-4.72 (2H, m), 5.06-5.12 (1H, m), 7.77 (2H, s). Step 2: Lithium aluminum hydride (0.41 g, 10.7 mmol) was added to tetrahydrofuran (7.5 mL) and cooled to 0 °C. A solution of compound 3 (1.50 g, 7.13 mmol) in tetrahydrofuran (7.5 mL) was added dropwise to the reaction mixture, which was then washed with tetrahydrofuran (3 mL). After stirring at 0°C for 1 hour, sodium sulfate decahydrate (1.5 g) was added to quench the reaction mixture. Insoluble matter was removed by filtration, and the filtrate was concentrated to obtain a crude product of compound 4 (0.92 g, yield 77%). [M+H] = 169.2, Measurement Condition 1: Retention time 0.25 min. 1H-NMR (CDCl3) δ: 2.41-2.49 (1H, m), 2.71-2.79 (1H, m), 3.51 (1H, t, J = 6.1 Hz), 4.22 (2H, d, J = 4.3 Hz), 4.34-4.39 (1H, m), 4.55-4.70 (3H, m), 5.08-5.14 (1H, m), 7.05 (1H, s), 7.54 (1H, s). Process 3 Compound 4 (1.35 g, 8.03 mmol) was dissolved in N,N-dimethylformamide (14 mL), and imidazole (1.20 g, 17.66 mmol) and tert-butyldimethylsilyl chloride (2.42 g, 16.05 mmol) were added, followed by stirring at room temperature for 1 hour and 10 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The solvent was then evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate-methanol) to give compound 5 (2.04 g, yield 90%). [M+H] = 283.4, Measurement Condition 1: Retention time 1.69 minutes 1 H-NMR (CDCl) δ: 0.05 (3H, s), 0.06 (3H, s), 0.88 (9H, s), 2.31-2.39 (1H, m), 2.62-2.70 (1H, m), 4.16-4.26 (2H, m), 4.34-4.39 (1H, m), 4.60-4.66 (1H, m), 4.67 (2H, s), 5.06-5.12 (1H, m), 6.94 (1H, s), 7.63 (1H, s). Step 4: Compound 5 (0.96 g, 3.41 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to −60° C. A 2.6 mol / L n-butyllithium n-hexane solution (2.6 mL, 6.82 mmol) was added dropwise, and the mixture was stirred at -60°C for 30 minutes. Then, N,N-dimethylformamide (1.4 mL) was added, and the mixture was stirred at -60°C for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure. The crude product obtained in another reaction was combined and purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 6 (1.19 g). [M+H] = 311.7, measurement condition 1: retention time 2.40 minutes 1H-NMR (CDCl3) δ: 0.09 (3H, s), 0.11 (3H, s), 0.92 (9H, s), 2.33-2.41 (1H, m), 2.70-2.78 (1H, m), 4.38 (1H, dt, J = 11.0, 4.6 Hz), 4.57-4.63 (1H, m), 4.67 (1H, dd, J = 14.4, 2.9 Hz), 4.77-4.82 (2H, m), 4.89 (1H, d, J = 13.3 Hz), 5.09 (1H, ddd, J = 14.4, 7.0, 2.9 Hz), 7.22 (1H, s), 9.78 (1H, s). Step 5: Compound 6 (200 mg, 0.62 mmol) was dissolved in acetonitrile (2 mL), N-chlorosuccinimide (86 mg, 0.65 mmol) was added, and the mixture was stirred for 90 minutes at 70° C. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The solvent was then evaporated under reduced pressure, and the resulting residue was purified by column chromatography (hexane-ethyl acetate) to give compound 7 (138 mg, yield 65%). 1H-NMR (CDCl3) δ: 0.09 (3H, s), 0.13 (3H, s), 0.90 (9H, s), 2.33-2.42 (1H, m), 2.72-2.80 (1H, m), 4.43 (1H, dt, J = 11.1, 4.5 Hz), 4.59-4.65 (1H, m), 4.74 (1H, dd, J = 14.2, 2.9 Hz), 4.79-4.89 (3H, m), 5.08 (1H, ddd, J = 14.4, 7.2, 2.9 Hz), 9.68 (1H, s). Step 6 Compound 8 (WO2018109607) (131 mg, 0.197 mmol) was separated into ethyl acetate and a 5% aqueous solution of sodium bicarbonate, and the organic layer was washed with 10% saline. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The concentrated residue was dissolved in tetrahydrofuran (1.5 mL), and compound 7 (68 mg, 0.197 mmol), acetic acid (23 μL, 0.394 mmol), and anhydrous magnesium sulfate (23.6 mg, 0.197 mmol) were added, followed by stirring at room temperature for 2 hours. Sodium triacetoxyborohydride (63.1 mg, 0.296 mmol) was then added, and the mixture was stirred at room temperature for 90 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 9 (95.4 mg, yield 75%). [M+H] = 649.6, Measurement Condition 1: retention time 2.94 minutes 1H-NMR (CDCl3) δ: 0.05 (3H, s), 0.08 (3H, s), 0.87 (9H, s), 1.67-1.89 (2H, m), 2.10-2.23 (2H, m), 2.42-2.49 (1H, m), 2.55-2.62 (1H, m), 2.69-2.75 (1H, m), 2.88-2.96 (2H, m), 3.61 (1H, d, J = 13.7 Hz), 3.74 (1H, d, J = 13.7 Hz), 4.38-4.74 (8H, m), 5.11-5.17 (1H, m), 5.41 (2H, s), 6.60 (1H, d, J = 8.2 Hz), 6.73 (1H, d, J = 7.2 Hz), 7.09-7.13 (2H, m), 7.43-7.52 (2H, m). Step 7: Compound 9 (94 mg, 0.145 mmol) was dissolved in tetrahydrofuran (1.9 mL), and a 1 mol / L tetrabutylammonium fluoride tetrahydrofuran solution (159 μL, 0.159 mmol) was added under ice-cooling, followed by stirring for 1 hour and 10 minutes under ice-cooling. Water was added to the reaction solution, which was extracted with ethyl acetate, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give crude compound 10 (79.4 mg). 1H-NMR (CDCl3) δ: 1.69-1.80 (2H, m), 1.84-1.89 (2H, m), 2.09-2.27 (2H, m), 2.46-2.63 (2H, m), 2.75-2.93 (3H, m), 3.53 (1H, d, J = 13.8 Hz), 3.61 (1H, d, J = 13.7 Hz), 4.36-4.44 (2H, m), 4.55-4.64 (3H, m), 4.71 (1H, dd, J = 14.2, 8.0 Hz), 5.19 (1H, ddd, J = 14.2, 7.1, 3.4 Hz), 5.38-5.46 (2H, m), 6.62 (1H, d, J = 8.2 Hz), 6.73 (1H, d, J = 7.3 Hz), 7.09-7.14 (2H, m), 7.45 (1H, t, J = 8.1 Hz), 7.50 (1H, t, J = 8.0 Hz). Step 8: The crude product of compound 10 (79 mg, 0.145 mmol) was dissolved in dichloromethane (1.5 mL), and manganese dioxide (381 mg, 4.38 mmol) was added. The mixture was stirred at room temperature for 80 minutes. Manganese dioxide (383 mg, 4.41 mmol) was then added and the mixture was stirred for 3 hours. Insoluble matter was removed by filtration and washed with dichloromethane and ethyl acetate. The solvent in the filtrate was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 11 (42.7 mg, 48% yield). [M+H]=533.3, measurement condition 1: retention time 2.08 minutes 1H-NMR (CDCl3) δ: 1.76-1.90 (4H, m), 2.17-2.30 (2H, m), 2.38-2.43 (1H, m), 2.57-2.62 (1H, m), 2.74-2.80 (1H, m), 2.89-3.00 (2H, m), 3.75 (1H, d, J = 13.8 Hz), 3.87 (1H, d, J = 13.8 Hz), 4.44 (1H, dt, J = 11.1, 4.5 Hz), 4.60-4.65 (1H, m), 4.77 (1H, dd, J = 14.2, 2.5 Hz), 4.98-5.10 (2H, m), 5.41 (2H, s), 6.61 (1H, d, J = 8.2 Hz), 6.73 (1H, d, J = 7.3 Hz), 7.09-7.13 (2H, m), 7.44 (1H, t, J = 8.2 Hz), 7.50 (1H, t, J = 8.1 Hz), 9.78 (1H, s). Step 9: Compound 11 (42 mg, 0.069 mmol) was dissolved in dichloromethane (1 mL), and compound 12 (115 mg, 0.344 mmol) was added. The mixture was stirred at room temperature for 6 hours and 30 minutes and then allowed to stand at 5°C for 14 hours and 30 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 give compound 13 (33.1 mg, yield 79%). [M+H]=589.4, measurement condition 1: retention time 2.22 minutes 1H-NMR (CDCl3) δ: 1.75-1.89 (4H, m), 2.14-2.25 (2H, m), 2.40-2.48 (1H, m), 2.55-2.62 (1H, m), 2.71-2.79 (1H, m), 2.86-2.96 (2H, m), 3.70 (2H, dd, J = 19.8, 13.7 Hz), 3.80 (3H, s), 4.43-4.51 (2H, m), 4.57-4.66 (2H, m), 5.06-5.12 (1H, m), 5.41 (2H, s), 6.61 (1H, d, J = 7.9 Hz), 6.69 (1H, d, J = 16.1 Hz), 6.73 (3H, d, J = 7.2 Hz), 7.09-7.13 (2H, m), 7.09 (2H, s), 7.44 (1H, t, J = 8.2 Hz), 7.50 (1H, t, J = 8.1 Hz), 7.58 (1H, d, J = 16.1 Hz). Step 10: Compound 13 (32 mg, 0.069 mmol) was dissolved in methanol (0.5 mL) and tetrahydrofuran (0.5 mL), and 1 mol / L aqueous sodium hydroxide solution (271 μL, 0.217 mmol) was added, followed by stirring at 40°C for 1 hour. Dilute sulfuric acid was added to the reaction solution until the pH reached approximately 4, and the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound I-006 (17.0 mg, yield 53%). [M+H] = 575.4, Measurement Condition 1: Retention time 1.98 minutes 1H-NMR (DMSO-d6) δ: 1.64-1.78 (4H, m), 2.05-2.18 (2H, m), 2.33-2.45 (1H, m), 2.54-2.61 (1H, m), 2.66-2.73 (1H, m), 2.80 (1H, d, J = 10.9 Hz), 2.94 (1H, d, J = 11.3 Hz), 3.50 (1H, d, J = 13.6 Hz), 3.71 (1H, d, J = 13.7 Hz), 4.35-4.40 (1H, m), 4.44-4.49 (2H, m), 4.60 (1H, dd, J = 15.5, 7.5 Hz), 4.97 (1H, q, J = 7.0 Hz), 5.38 (2H, s), 6.48 (1H, d, J = 16.1 Hz), 6.68 (1H, d, J = 8.2 Hz), 6.87 (1H, d, J = 7.3 Hz), 7.30 (1H, dd, J = 8.3, 1.7 Hz), 7.47 (1H, dd, J = 10.0, 2.0 Hz), 7.54-7.65 (3H, m).

[0142] Example 2 Step 1: Compound 10 (87 mg, 0.162 mmol) was dissolved in dichloromethane (0.87 mL), manganese dioxide (141 mg, 1.625 mmol) was added, and the mixture was left standing at room temperature for 24 hours. The reaction mixture was filtered, the solids were removed, and the solvent was evaporated under reduced pressure. The resulting residue and sodium cyanide (11.9 mg, 0.244 mmol) were dissolved in methanol (0.87 mL), manganese dioxide (141 mg, 1.625 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, the solids were removed, and water was added, followed by extraction with chloroform. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by column chromatography (hexane-ethyl acetate) to give compound 14 (50.1 mg, yield 55%). 1H-NMR (CDCl3) δ: 1.67-1.78 (4H, m), 2.09-2.19 (2H, m), 2.56-2.61 (1H, m), 2.80 (1H, d, J = 12.3 Hz), 2.94 (1H, d, J = 11.3 Hz), 3.56 (1H, d, J = 13.6 Hz), 3.78 (1H, d, J = 13.4 Hz), 3.79 (3H, s), 4.34 (1H, m), 4.46 (1H, q, J = 7.5 Hz), 4.64 (1H, d, J = 14.4 Hz), 4.85-4.96 (2H, m), 5.36 (2H, s), 6.68 (1H, d, J = 8.3 Hz), 6.87 (1H, d, J = 7.2 Hz), 7.30 (1H, dd, J = 8.4 Hz, 2.0 Hz), 7.46 (1H, dd, J = 9.9 Hz, 1.9 Hz), 7.57 (1H, t, J = 8.2 Hz), 7.63 (1H, t, J = 7.7 Hz). [M+H] = 563.15, Measurement condition 1: Retention time 2.12 minutes. Step 2: Compound 14 (50 mg, 0.089 mmol) was dissolved in tetrahydrofuran (0.5 mL) and methanol (0.5 mL), and 1 mol / L aqueous sodium hydroxide solution (0.300 mL, 0.300 mmol) was added, followed by stirring at 50°C for 1 hour. The reaction mixture was cooled on ice, and 0.1 g / mL aqueous citric acid solution (0.210 mL, 0.100 mmol) and water were added, followed by extraction with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was evaporated to give compound 15 (48.2 mg, yield 99%). 1H-NMR (CDCl3) δ: 1.66-1.78 (4H, m), 2.12-2.19 (2H, m), 2.56-2.61 (1H, m), 2.82 (1H, d, J = 11.2 Hz), 2.94 (1H, d, J = 11.4 Hz), 3.56 (1H, d, J = 12.8 Hz), 3.78 (1H, d, J = 13.8 Hz), 4.33-4.38 (1H, m), 4.47 (1H, dd, J = 14.6 Hz, 6.6 Hz), 4.67 (1H, d, J = 13.8 Hz), 4.87-4.96 (2H, m), 5.37 (2H, s), 6.68 (1H, d, J = 8.0 Hz), 6.87 (1H, d, J = 7.3 Hz), 7.30 (1H, dd, J = 8.3 Hz, 1.9 Hz), 7.46 (1H, dd, J = 9.9 Hz, 2.0 Hz), 7.57 (1H, t, J = 8.2 Hz), 7.63 (1H, t, J = 7.8 Hz), 13.22-13.42 (1H, br). [M+H] = 549.10, measurement conditions 1: holding time 1.90 minutes Step 3 Compound 15 (8 mg, 0.015 mmol) was dissolved in tetrahydrofuran (0.40 mL), carbonyldiimidazole (4.7 mg, 0.029 mmol) was added, and the mixture was stirred at 60°C for 1 hour. Hydrazine monohydrate (3.5 μL, 0.073 mmol) was then added, and the mixture was stirred at 60°C for 1 hour. Water was 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 sodium sulfate. The solvent was evaporated to obtain compound 16 (8.0 mg, 98% yield). Step 4: Compound 16 (8.0 mg, 0.015 mmol) was dissolved in tetrahydrofuran (0.5 mL), carbonyldiimidazole (4.7 mg, 0.029 mmol) was added, and the mixture was allowed to stand at room temperature overnight. Water was 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 sodium sulfate. The solvent was evaporated and the resulting residue was purified by column chromatography (chloroform-methanol) to obtain Compound I-005 (6.1 mg, yield 71%). 1H-NMR (CDCl3) δ: 1.65-1.79 (4H, m), 2.09-2.22 (2H, m), 2.58-2.64 (1H, m), 2.83 (1H, d, J = 11.7 Hz), 2.96 (1H, d, J = 10.2 Hz), 3.57 (1H, d, J = 13.6 Hz), 3.81 (1H, d, J = 13.6 Hz), 4.30-4.35 (1H, m), 4.46 (1H, dd, J = 14.7 Hz, 6.2 Hz), 4.56 (1H, d, J = 14.9 Hz), 4.81 (1H, d, J = 14.9 Hz, 7.6 Hz), 5.00 (1H, q, J = 7.5 Hz), 5.37 (2H, s), 6.68 (1H, d, J = 8.2 Hz), 6.88 (1H, d, J = 7.2 Hz), 7.30 (1H, dd, J = 8.2 Hz, 1.8 Hz), 7.46 (1H, dd, J = 10.0 Hz, 1.9 Hz), 7.60 (2H, dt, J = 27.1 Hz, 7.9 Hz), 12.72 (1H, br).

[0143] Example 3 Step 1: Compound 17 (132 mg, 0.255 mmol), synthesized by the synthetic method described in WO2019239319A1, was suspended in ethyl acetate, followed by the addition of saturated aqueous sodium bicarbonate and stirring at room temperature for 3 minutes. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (1.5 mL), and then compound 7 (83.6 mg, 0.242 mmol), acetic acid (28 μL, 0.485 mmol), and magnesium sulfate (29 mg, 0.242 mmol) were added in that order. After stirring at room temperature for 2 hours, sodium triacetoxyborohydride (77 mg, 0.364 mmol) was added to the reaction solution. After stirring at room temperature again for 1 hour, water was added to the reaction solution, and the mixture was extracted 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 18 (98 mg, yield 60%). 1H-NMR (CDCl3) δ: 0.05 (3H, s), 0.08 (3H, s), 0.88 (9H, s), 1.69-1.85 (4H, m), 2.05 (3H, s), 2.12-2.25 (2H, m), 2.40-2.49 (1H, m), 2.64-2.77 (2H, m), 2.88 (1H, d, J = 11.2 Hz), 2.96 (1H, d, J = 10.3 Hz), 3.61 (1H, d, J = 13.6 Hz), 3.75 (1H, d, J = 13.6 Hz), 4.40 (1H, dd, J = 14.9, 2.9 Hz), 4.47 (1H, dt, J = 11.0, 4.6 Hz), 4.61-4.74 (4H, m), 5.11-5.18 (1H, m), 6.67-6.71 (2H, m), 6.75-6.79 (1H, m), 7.09-7.14 (2H, m), 7.49-7.53 (1H, m). Step 2: To a solution of compound 18 (98 mg, 0.145 mmol) in tetrahydrofuran (1 mL), 1 mol / L TBAF tetrahydrofuran solution (159 μL, 0.159 mmol) was added under ice-cooling, followed by stirring for 1 hour under ice-cooling. Water was added to the reaction mixture, which was extracted with ethyl acetate and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give crude compound 19. Step 3: The entire amount of the crude product of compound 19 was dissolved in acetonitrile (1 mL), and then 2-hydroxy-2-azaadamantane (1.1 mg, 0.007 mmol), 2,2'-bipyridine (1.1 mg, 0.007 mmol), DMAP (1.7 mg, 0.015 mmol), and copper(I) chloride (0.7 mg, 0.007 mmol) were added in that order, and the mixture was stirred at room temperature under an air atmosphere for 3 days. Aqueous sodium bicarbonate and aqueous sodium thiosulfate were added to the reaction mixture, and the mixture was stirred vigorously for 5 minutes, followed by extraction with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to obtain crude product of compound 20. Step 4: The crude product of compound 20 was dissolved in dichloromethane (1.5 mL), and then methyl (triphenylphosphoranylidene)acetate (242 mg, 0.725 mmol) was added, and the mixture was stirred at room temperature for 5.5 hours.Aqueous sodium bicarbonate solution was added to the reaction mixture, which was then extracted 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 21 (78 mg, yield 87%). 1 H-NMR (CDCl3) δ: 1.73-1.85 (4H, m), 2.15-2.28 (2H, m), 2.40-2.49 (1H, m), 2.64-2.80 (2H, m), 2.91 (2H, dd, J = 25.9, 11.4 Hz), 3.70 (2H, dd, J = 22.6, 13.7 Hz), 3.80 (3H, s), 4.43-4.49 (2H, m), 4.58-4.66 (2H, m), 5.08 (1H, ddd, J = 14.2, 7.0, 2.7 Hz), 6.63-6.69 (2H, m), 6.71 (1H, s), 6.74-6.79 (1H, m), 7.09-7.15 (2H, m), 7.50 (1H, t, J = 8.3 Hz), 7.58 (1H, d, J = 16.1 Hz). Step 5: To a solution of compound 21 (78 mg, 0.127 mmol) in methanol (0.75 mL) and tetrahydrofuran (0.75 mL), 2 mol / L aqueous sodium hydroxide solution (316 μL, 0.633 mmol) was added, and the mixture was stirred at 45°C for 3 hours. Water was added to the reaction solution, and then dilute sulfuric acid was added until the pH was approximately 4, and 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 (chloroform-methanol) to obtain compound I-007 (50 mg, yield 66%). 1H-NMR (DMSO-D6) δ: 1.63-1.75 (4H, m), 1.99-2.19 (5H, m), 2.37-2.45 (1H, m), 2.58-2.73 (2H, m), 2.80 (1H, d, J = 11.0 Hz), 2.96 (1H, d, J = 10.0 Hz), 3.49 (1H, d, J = 13.4 Hz), 3.72 (1H, d, J = 13.7 Hz), 4.35-4.50 (3H, m), 4.59 (1H, dd, J = 15.6, 7.3 Hz), 4.94-4.99 (1H, m), 6.48 (1H, d, J = 16.1 Hz), 6.73-6.80 (3H, m), 7.34 (1H, d, J = 8.4 Hz), 7.54-7.60 (3H, m).

[0144] Reference example 1 Step 1: Compound 22 (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 solution, 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 give compound 23 (2.25 g, 74% yield). [M+H] = 274.2, Measurement Condition 1: Retention time 2.28 minutes 1H-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: Compound 23 (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 evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 24 (2.00 g, yield 70%). [M+H] = 400.2, Measurement Condition 1: Retention time 2.55 minutes 1H-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: Compound 24 (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. The mixture was stirred at 100°C under a nitrogen atmosphere for 3 hours, after which 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 then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 25 (1.56 g, yield 94%). [M+H]=342.2, measurement condition 1: retention time 2.51 minutes 1H-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: Compound 25 (1.55 g, 4.41 mmol) was dissolved in dichloromethane (7.8 mL). Under ice-cooling, a 1 mol / L solution of boron tribromide in dichloromethane (13.2 mL, 13.2 mmol) was added, followed by stirring at room temperature for 2 hours and 30 minutes. Under ice-cooling, methanol (7.8 mL) was added, followed by water, 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 give compound 26 (1.20 g, yield 78%). [M-H] = 326.2, Measurement Condition 1: Retention time 2.18 minutes. Step 5: N,N-Dimethylformamide (1.1 mL) was added to compound 26 (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), and the mixture was 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 evaporated under reduced pressure, and the resulting residue was purified by column chromatography (hexane-ethyl acetate) to give compound 27 (142 mg, yield 92%). 1H-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: Compound 27 (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 28 (104 mg, yield 94%) 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).

[0145] Example 4 Step 1: Compound 6 (503 mg, 1.55 mmol) was dissolved in acetonitrile (5 mL), and N-bromosuccinimide (304 mg, 1.71 mmol) was added under ice-cooling, followed by stirring at room temperature for 3 hours. Sodium thiosulfate and aqueous sodium bicarbonate solution were added to the reaction solution, followed by extraction with ethyl acetate, and the solvent was evaporated under reduced pressure. Crude products obtained from separate reactions were combined and purified by column chromatography (hexane-ethyl acetate) to give compound 29 (611 mg, yield 90%). 1 H-NMR (CDCl) δ: 0.10 (3H, s), 0.14 (3H, s), 0.91 (9H, s), 2.33-2.42 (1H, m), 2.73-2.80 (1H, m), 4.40-4.46 (1H, m), 4.59-4.66 (1H, m), 4.73-4.91 (4H, m), 5.07 (1H, ddd, J = 14.4, 7.2, 2.9 Hz), 9.70 (1H, s). Step 2: Compound 30 (30 mg, 24% yield) was obtained from compound 28 (61 mg, 0.164 mmol) and compound 29 (64 mg, 0.164 mmol) in the same manner as in Step 1 of Example 3. 1H-NMR (CDCl3) δ: 0.07 (3H, s), 0.08 (3H, s), 0.87 (9H, s), 1.32 (3H, d, J = 6.7 Hz), 2.33-2.42 (1H, m), 2.59-2.75 (4H, m), 2.79-2.87 (1H, m), 2.99-3.05 (1H, m), 3.87 (1H, q, J = 6.7 Hz), 3.93 (2H, s), 4.36-4.45 (2H, m), 4.62 (1H, td, J = 7.8, 6.1 Hz), 4.67 (2H, s), 4.72 (1H, dd, J = 15.1, 7.3 Hz), 5.07-5.18 (3H, m), 6.72 (1H, s), 7.12 (1H, dd, J = 9.8, 2.0 Hz), 7.19 (1H, dd, J = 8.3, 1.5 Hz), 7.31 (1H, s), 7.52 (1H, t, J = 8.1 Hz). Step 3: Compound 31 was obtained from compound 30 (68 mg, 0.091 mmol) in the same manner as in Step 2 of Example 3. Step 4: Compound 32 was obtained from compound 31 in the same manner as in Step 3 of Example 3. Step 5: Compound 33 (45 mg, three-step yield 72%) was obtained from compound 32 in the same manner as in Step 4 of Example 3. 1H-NMR (CDCl3) δ: 1.35 (3H, d, J = 6.7 Hz), 2.32-2.41 (1H, m), 2.60-2.75 (3H, m), 2.83-2.90 (1H, m), 3.01-3.08 (1H, m), 3.81-3.85 (4H, m), 3.91 (1H, d, J = 13.8 Hz), 4.01 (1H, d, J = 13.7 Hz), 4.36-4.41 (1H, m), 4.48 (1H, dd, J = 15.6, 2.5 Hz), 4.57-4.64 (2H, m), 5.02-5.07 (1H, m), 5.14 (2H, dd, J = 16.5, 12.7 Hz), 6.72 (1H, s), 6.78 (1H, d, J = 16.1 Hz), 7.12 (1H, dd, J = 9.8, 1.9 Hz), 7.19 (1H, d, J = 8.4 Hz), 7.31 (1H, s), 7.49-7.53 (2H, m). Engineering 6 Compound 33 (45mg, 0.127mmol) Example 3 Project 5. The same compound I-008 (37 mg, yield 84%) was obtained. 1 H-NMR (DMSO-D6) δ: 1.31 (3H, d, J = 6.8 Hz), 2.28-2.37 (1H, m), 2.58-2.63 (2H, m), 2.67-2.73 (1H, m), 2.77-2.85 (1H, m), 2.93-2.99 (1H, m), 3.80-3.91 (3H, m), 4.30-4.36 (1H, m), 4.44-4.53 (2H, m), 4.62 (1H, dd, J = 15.6, 7.3 Hz), 4.92-4.98 (1H, m), 5.25 (2H, dd, J = 16.9, 12.4 Hz), 6.59 (1H, d, J = 16.1 Hz), 7.20 (1H, s), 7.36-7.38 (2H, m), 7.49-7.59 (3H, m).

[0146] Example 5 Step 1: To a solution of commercially available compound 34 (3.42 g, 14.85 mmol) in acetonitrile (35 mL), formic acid (2.45 mL, 63.8 mmol), triethylamine (5.15 mL, 37.1 mmol), and [(R,R)—N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamido]chloro(p-cymene)ruthenium(II) (0.19 g, 0.30 mmol) were added, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate and then washed with aqueous sodium bicarbonate. 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 35 (3.44 g, 100% yield). 1 H-NMR (CDCl3) δ: 1.45 (3H, d, J = 6.4 Hz), 3.96 (3H, s), 4.03 (1H, d, J = 8.3 Hz), 5.01-5.08 (1H, m), 6.59 (1H, d, J = 8.7 Hz), 7.67 (1H, d, J = 8.7 Hz). [M+H] = 232, measurement condition 1: holding time 1.57 minutes Step 2 To a solution of compound 35 (3.44 g, 14.82 mmol) in N,N-dimethylformamide (27.5 mL) were added N-vinylphthalimide (2.62 g, 14.82 mmol), tetrabutylammonium bromide (4.78 g, 14.82 mmol), palladium acetate (0.33 g, 1.48 mmol), and N,N-dicyclohexyl-N-methylamine (4.72 mL, 22.23 mmol). After degassing under reduced pressure, the mixture was purged with nitrogen and stirred at 110°C for 1 hour. Water was added to the reaction solution, and the resulting solid was collected by filtration. The solid was then washed with diisopropyl ether to give compound 36 (3.87 g, 81% yield). 1H-NMR (CDCl3) δ: 1.45 (3H, d, J = 6.4 Hz), 3.99 (3H, s), 4.54 (1H, d, J = 7.7 Hz), 5.09-5.16 (1H, m), 6.71 (1H, d, J = 8.5 Hz), 7.17 (1H, d, J = 14.9 Hz), 7.72 (1H, d, J = 14.9 Hz), 7.77-7.81 (3H, m), 7.90-7.93 (2H, m). [M+H] = 325, measurement condition 1: retention time 1.98 minutes Step 3 To a solution of compound 36 (3.87 g, 11.9 mmol) in methanol (25 mL) and tetrahydrofuran (50 mL) was added 10% palladium-carbon (50% aqueous) (2.54 g, 1.2 mmol), and the mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) for 6 hours and 30 minutes. Insoluble matter was removed by filtration, and the solvent was evaporated under reduced pressure to give a crude product containing compound 37 (1.55 g, yield 40%). The resulting compound 37 was used directly in the next step without purification. 1 H-NMR (CDCl3) δ: 1.47 (3H, d, J = 6.4 Hz), 2.82-2.99 (2H, m), 3.84-3.89 (2H, m), 3.94 (3H, s), 4.27 (1H, d, J = 8.0 Hz), 5.04-5.11 (1H, m), 6.62 (1H, d, J = 8.4 Hz), 7.50 (1H, d, J = 8.4 Hz), 7.71-7.75 (2H, m), 7.83-7.87 (2H, m). [M+H] = 327, measurement conditions 1: retention time 1.68 minutes Step 4 Hydrazine monohydrate (1.15 mL, 23.75 mmol) was added to a solution of the entire crude product of compound 37 obtained in step 3 (1.55 g, 4.75 mmol) in ethanol (30 mL), followed by stirring at 80°C for 35 minutes. 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 (1.05 g) containing compound 38. The resulting compound 38 was used directly in the next step without purification. 1H-NMR (CDCl) δ: 1.45 (3H, d, J = 6.4 Hz), 2.62-2.78 (2H, m), 2.86-3.02 (2H, m), 3.95 (3H, s), 5.01 (1H, q, J = 6.4 Hz), 6.63 (1H, d, J = 8.4 Hz), 7.41 (1H, d, J = 8.4 Hz). [M+H] = 197, Measurement condition 1: Retention time 0.54 min. Step 5: To a solution of the entire crude product of compound 38 (4.75 mmol) obtained in Step 4 in dichloromethane (10 mL), trifluoroacetic anhydride (2.0 mL, 14.25 mmol) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 45 minutes. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in toluene, and the solvent was evaporated again under reduced pressure. The resulting residue was dissolved in ethyl acetate and slowly poured into aqueous sodium bicarbonate solution. The mixture was stirred at 35°C for 9 hours, and then extracted twice 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 silica gel column chromatography (hexane-ethyl acetate) to give compound 39 (952 mg, yield 69%). 1 H-NMR (CDCl3) δ: 1.48 (3H, d, J = 6.4 Hz), 2.80-2.92 (2H, m), 3.50-3.64 (2H, m), 3.82 (1H, d, J = 7.0 Hz), 3.95 (3H, s), 4.95-5.02 (1H, m), 6.67 (1H, d, J = 8.4 Hz), 6.77 (1H, s), 7.41 (1H, d, J = 8.4 Hz). [M+H] = 293, measurement conditions 1: holding time 1.29 minutes Step 6 To a solution of compound 39 (952 mg, 3.26 mmol) in tetrahydrofuran (30 mL) was added triphenylphosphine (1.28 g, 4.89 mmol), and then DIAD (0.95 mL, 4.89 mmol) was added dropwise under water cooling. After stirring at room temperature for 30 minutes, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 40 (776 mg, yield 87%). 1H-NMR (CDCl3) δ: 1.59 (2.1H, d, J = 6.9 Hz), 1.65 (0.9H, d, J = 6.9 Hz), 2.64-2.73 (1H, m), 2.87-2.98 (1H, m), 3.14-3.21 (0.3H, m), 3.44-3.51 (0.7H, m), 3.90 (2.1H, s), 3.90 (0.9H, s), 4.09-4.15 (0.7H, m), 4.69 (0.3H, dd, J = 13.2, 5.6 Hz), 5.01 (0.3H, q, J = 6.8 Hz), 5.43 (0.7H, q, J = 6.8 Hz), 6.57-6.61 (1H, m), 7.30-7.34 (1H, m). [M+H] = 275, Measurement Condition 1: Retention time 1.75 min. Step 7: Sodium iodide (1.27 g, 8.49 mmol) and trimethylsilyl chloride (1.085 mL, 8.49 mmol) were added to a solution of compound 40 (776 mg, 2.83 mmol) in acetonitrile (10 mL), and the mixture was stirred at 45 °C for 6 hours. Aqueous sodium bicarbonate and aqueous sodium thiosulfate were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give crude compound 41 (747 mg). The resulting compound 41 was used directly in the next step without purification. 1H-NMR (CDCl3) δ: 1.65 (2.4H, d, J = 6.8 Hz), 1.73 (0.6H, d, J = 6.8 Hz), 2.50-2.58 (1H, m), 2.73-2.84 (1H, m), 3.14-3.22 (0.2H, m), 3.44-3.52 (0.8H, m), 4.08-4.13 (0.8H, m), 4.68 (0.2H, dd, J = 13.4, 5.8 Hz), 4.96 (0.2H, q, J = 6.6 Hz), 5.43 (0.8H, q, J = 6.8 Hz), 6.48-6.52 (1H, m), 7.26-7.22 (1H, m), 12.82 (1H, s). [M+H] = 261, Measurement Condition 1: Retention time 1.10 min. Step 8: N-iodosuccinimide (519 mg, 2.31 mmol) was added to a solution of compound 41 (400 mg, 1.54 mmol) in N,N-dimethylformamide (6 mL), and the mixture was stirred at room temperature for 4 hours. Ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give crude compound 42 (764 mg). The obtained compound 42 was used directly in the next step without purification. 1H-NMR (CDCl3) δ: 1.67 (2.25H, d, J = 6.8 Hz), 1.75 (0.75H, d, J = 6.8 Hz), 2.51-2.59 (1H, m), 2.80-2.85 (1H, m), 3.12-3.19 (0.25H, m), 3.42-3.49 (0.75H, m), 4.07-4.12 (0.75H, m), 4.68 (0.25H, dd, J = 13.5, 5.7 Hz), 4.97-5.02 (0.25H, m), 5.46 (0.75H, q, J = 6.7 Hz), 7.87 (0.75H, s), 7.88 (0.25H, s). [M+H] = 387, Measurement Condition 1: Retention time 1.48 minutes. Step 9: To a solution of half (0.77 mmol) of the total amount of crude compound 42 in 1,4-dioxane (3 mL), silver carbonate (318 mg, 1.15 mmol) and 4-chloro-2-fluorobenzyl bromide (206 mg, 0.92 mmol) were added, and the mixture was stirred at 65°C for 2 hours. Silver carbonate (106 mg, 0.38 mmol) was further added, and the mixture was stirred at 65°C for 7 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 give compound 43 (361 mg, yield 89%). 1H-NMR (CDCl3) δ: 1.53 (2.1H, d, J = 6.9 Hz), 1.60 (0.9H, d, J = 6.9 Hz), 2.64-2.72 (1H, m), 2.86-2.96 (1H, m), 3.10-3.17 (0.3H, m), 3.39-3.47 (0.7H, m), 4.08-4.12 (0.7H, m), 4.68 (0.3H, dd, J = 13.2, 5.6 Hz), 4.98 (0.3H, q, J = 6.7 Hz), 5.36-5.46 (2.7H, m), 7.11-7.17 (2H, m), 7.47-7.53 (1H, m), 7.82 (0.7H, s), 7.84 (0.3H, s). [M+H] = 529, Measurement condition 1: retention time 3.12 minutes. Step 10: Palladium acetate (25.5 mg, 0.11 mmol), 2-di-tert-butylphosphinobiphenyl (45.2 mg, 0.15 mmol), sodium carbonate (100 mg, 0.95 mmol), triethylsilane (227 μL, 1.42 mmol), and tert-butyl isocyanide (107 μL, 0.95 mmol) were added to a solution of compound 43 (200 mg, 0.38 mmol) in N,N-dimethylformamide (2 mL). After degassing under reduced pressure, the atmosphere was replaced with nitrogen and the mixture was stirred at 65°C for 1 hour. Dilute hydrochloric acid was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 44 (39 mg, yield 19%). 1H-NMR (CDCl3) δ: 1.59 (2.25H, d, J = 7.0 Hz), 1.65 (0.75H, d, J = 7.0 Hz), 2.75-2.84 (1H, m), 2.92-3.03 (1H, m), 3.14-3.21 (0.25H, m), 3.44-3.51 (0.75H, m), 4.13-4.18 (0.75H, m), 4.73 (0.25H, dd, J = 12.9, 5.8 Hz), 5.06 (0.25H, q, J = 6.9 Hz), 5.46-5.57 (2.75H, m), 7.14-7.17 (2H, m), 7.42-7.46 (1H, m), 7.91 (0.75H, s), 7.93 (0.25H, s), 10.34 (1H, s). [M+H] = 431, Measurement Condition 1: Retention time 2.77 min. Step 11: To a solution of compound 44 (39 mg, 0.09 mmol) in dichloromethane (0.4 mL), (diethylamino)sulfur trifluoride (40 μL, 0.27 mmol) was added and the mixture was stirred at room temperature for 1.5 hours. (Diethylamino)sulfur trifluoride (20 μL, 0.14 mmol) was further added and the mixture was stirred at room temperature for 7.5 hours. Aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted 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 45 (30 mg, yield 73%). 1H-NMR (CDCl3) δ: 1.56 (2.25H, d, J = 6.8 Hz), 1.62 (0.75H, d, J = 6.8 Hz), 2.72-2.80 (1H, m), 2.91-3.02 (1H, m), 3.14-3.21 (0.25H, m), 3.43-3.51 (0.75H, m), 4.11-4.17 (0.75H, m), 4.72 (0.25H, dd, J = 12.9, 5.6 Hz), 5.03 (0.25H, q, J = 6.5 Hz), 5.40-5.51 (2.75H, m), 6.83 (1H, t, J = 55.2 Hz), 7.12-7.15 (2H, m), 7.37-7.41 (1H, m), 7.64 (0.75H, s), 7.65 (0.25H, s). [M+H] = 453, Measurement condition 1: retention time 2.92 min. Step 12: To a solution of compound 45 (30 mg, 0.07 mmol) in methanol (0.5 mL) and tetrahydrofuran (0.5 mL), potassium carbonate (18 mg, 0.13 mmol) was added and the mixture was stirred at 65 °C for 6 hours. The solvent was evaporated under reduced pressure, and water was added to the residue, followed by extraction twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give crude compound 46 (25 mg). The resulting compound 46 was used directly in the next step without purification. 1H-NMR (CDCl3) δ: 1.48 (3H, d, J = 6.8 Hz), 2.69 (1H, dt, J = 16.0, 4.0 Hz), 2.81-2.88 (1H, m), 2.97-3.04 (1H, m), 3.24-3.30 (1H, m), 4.01 (1H, q, J = 6.8 Hz), 5.45 (2H, dd, J = 18.2, 12.8 Hz), 6.83 (1H, t, J = 55.5 Hz), 7.09-7.14 (2H, m), 7.40 (1H, t, J = 8.1 Hz), 7.56 (1H, s). [M+H] = 357, Measurement Condition 1: Retention time 1.83 minutes. Step 13: Methanol (0.5 mL) was added to compound 7 (50 mg, 0.15 mmol), and a mixture of sodium borohydride (11 mg, 0.29 mmol) / methanol (0.5 mL) was added thereto, followed by stirring at room temperature for 15 minutes. Ammonium chloride was added to the reaction mixture, followed by 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 47 (48 mg, yield 95%). 1H-NMR (CDCl3) δ: 0.08 (6H, d, J = 5.8 Hz), 0.89 (9H, s), 2.43-2.51 (1H, m), 2.71-2.79 (1H, m), 3.72 (1H, dd, J = 7.7, 5.6 Hz), 4.25 (1H, dd, J = 15.2, 2.1 Hz), 4.42 (1H, dd, J = 15.3, 8.0 Hz), 4.53-4.74 (6H, m), 5.14 (1H, ddd, J = 15.3, 7.7, 2.4 Hz). [M+H]=348.1, measurement condition 1: retention time 2.27 minutes Step 14 Compound 47 (40 mg, 0.12 mmol) and diisopropylethylamine (40 μL, 0.23 mmol) were dissolved in dichloromethane (0.8 mL). Methanesulfonyl chloride (9.9 μL, 0.13 mmol) was added at 0°C and stirred at the same temperature for 2 hours. Methanesulfonyl chloride (1.8 μL, 0.02 mmol) was then added. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The solvent was evaporated under reduced pressure to give crude compound 48. [M+H] = 365.0, Measurement Condition 1: Retention time 2.88 minutes. Step 15: Acetonitrile (0.5 mL) was added to compound 46 (41 mg, 0.12 mmol), compound 48 (42 mg, 0.12 mmol), and potassium carbonate (32 mg, 0.23 mmol), and the mixture was stirred at 65°C for 2 hours. The mixture was cooled to room temperature, aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain compound 49 (38 mg, two-step yield: 48%). 1H-NMR (CDCl3) δ: 0.06 (6H, d, J = 11.8 Hz), 0.87 (9H, s), 1.39 (3H, d, J = 6.7 Hz), 2.34-2.43 (1H, m), 2.59-2.78 (4H, m), 2.92-2.99 (1H, m), 3.75-3.87 (2H, m), 4.02 (1H, d, J = 13.7 Hz), 4.40-4.45 (2H, m), 4.58-4.69 (4H, m), 5.10 (1H, dd, J = 14.3, 7.2 Hz), 5.44 (2H, dd, J = 27.7, 12.9 Hz), 6.83 (1H, t, J = 55.4 Hz), 7.09-7.14 (2H, m), 7.40 (1H, t, J = 8.2 Hz), 7.57 (1H, s). [M+H] = 685.3, Measurement condition 1: retention time 2.97 min. Step 16: Compound 49 (38 mg, 0.056 mmol) was reacted in the same manner as in Step 2 of Example 3, and purified by silica gel chromatography (hexane-ethyl acetate) to give compound 50 (27 mg, 85% yield). [M+H] = 571.1, Measurement condition 1: retention time 2.02 min. Step 17: Compound 50 (27 mg, 0.047 mmol) was used in the same manner as in Step 3 of Example 3 to give crude compound 51. [M+H]=569.05, measurement condition 1: retention time 2.54 minutes. Step 18: Compound 52 (22 mg, two-step yield 75%) was obtained from the whole amount of the crude product of Compound 51 in the same manner as in Step 4 of Example 3. 1H-NMR (CDCl3) δ: 1.41 (3H, d, J = 6.7 Hz), 2.35-2.42 (1H, m), 2.62-2.69 (3H, m), 2.76-2.82 (1H, m), 2.95-3.01 (1H, m), 3.72-3.86 (5H, m), 4.08-4.15 (1H, m), 4.37-4.41 (1H, m), 4.52-4.55 (2H, m), 4.62 (1H, dd, J = 14.0, 7.7 Hz), 5.03-5.08 (1H, m), 5.43 (2H, dd, J = 29.2, 12.9 Hz), 6.68-6.97 (2H, m), 7.08-7.15 (2H, m), 7.40 (1H, t, J = 8.2 Hz), 7.50-7.58 (2H, m). [M+H] = 625.1. Measurement condition 1: Holding time 2.58 points Engineering 19 Compound 52 (22 mg, 0.035 mmol) was obtained by using the same method as Compound I-012 (21 mg, yield 97%) in Example 1 of Project 10 of the same method. 1 H-NMR (CDCl3) δ: 1.41 (3H, d, J = 6.7 Hz), 2.31-2.43 (1H, m), 2.61-2.74 (3H, m), 2.75-2.86 (1H, m), 2.94-3.04 (1H, m), 3.81-3.72 (1H, m), 3.85 (1H, d, J = 13.6 Hz), 4.13 (1H, d, J = 13.6 Hz), 4.35-4.43 (1H, m), 4.57-4.50 (2H, m), 4.58-4.66 (1H, m), 5.07 (1H, br), 5.39 (1H, d, J = 12.8 Hz), 5.47 (1H, d, J = 12.8 Hz), 6.69 (1H, d, J = 15.6 Hz), 6.83 (1H, t, J = 55.2 Hz), 7.08-7.15 (1H, m), 7.36-7.43 (1H, m), 7.58 (1H, s), 7.60 (1H, d, J = 16.4 Hz).

[0147] Example 6 Step 1: Compound 41 (800 mg, 3.07 mmol) was dissolved in N,N-dimethylformamide (8 mL), and then N-chlorosuccinimide (452 ​​mg, 3.38 mmol) was added at 45°C, followed by stirring at the same temperature for 6 hours. N-chlorosuccinimide (45 mg, 0.34 mmol) was then added, and the mixture was stirred at 45°C for 4 hours. After cooling to room temperature, aqueous sodium thiosulfate solution and aqueous sodium hydrogencarbonate solution were added, and the resulting solid was collected by filtration to obtain compound 53 (527 mg, yield 58%). 1 H-NMR (DMSO-D6) δ: 1.46 (2.4H, d, J = 6.8 Hz), 1.55 (0.6H, d, J = 6.5 Hz), 2.58-2.67 (2H, m), 3.54-3.62 (1H, m), 3.93 (0.8H, d, J = 12.9 Hz), 4.39 (0.2H, dd, J = 13.8, 4.5 Hz), 4.85 (0.2H, q, J = 6.4 Hz), 5.17 (0.8H, dd, J = 6.7, 13.5 Hz), 7.62-7.65 (1H, m). [M+H]=295.1, measurement conditions 1: holding time 1.30 minutes Step 2 Compound 53 (86 mg, 0.29 mmol), silver carbonate (121 mg, 0.44 mmol), and 4-chloro-2-fluorobenzyl bromide (78 mg, 0.35 mmol) were added to 1,4-dioxane (0.86 mL) and stirred at 60°C for 2 hours. After cooling to room temperature, insoluble matter was removed by filtration and washed with ethyl acetate. The solvent in the filtrate was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 54 (101 mg, yield 79%). [M+H] = 437.2, Measurement Condition 1: Retention time 3.08 minutes. Step 3: Compound 54 (101 mg, 0.23 mmol) was dissolved in tetrahydrofuran (1 mL) and methanol (1 mL), potassium carbonate (64 mg, 0.46 mmol) was added, and the mixture was stirred at 50°C for 4 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, and the residue was added with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure to give a crude product (85 mg) of Compound 55. The obtained Compound 55 was used in the next step without further purification. 1H-NMR (CDCl3) δ: 1.44 (3H, d, J = 6.8 Hz), 2.59-2.67 (1H, m), 2.76-2.84 (1H, m), 2.94-3.01 (1H, m), 3.22-3.25 (1H, m), 3.96 (1H, q, J = 6.8 Hz), 5.46 (2H, dd, J = 19.2, 13.2 Hz), 7.09-7.14 (2H, m), 7.36 (1H, s), 7.47 (1H, t, J = 8.0 Hz). [M+H] = 341.2, measurement conditions 1: holding time 1.74 minutes Step 4 Compound 56 (57 mg, yield 48%) was obtained from compound 55 (56 mg, 0.16 mmol) and compound 29 (64 mg, 0.16 mmol) in the same manner as in Step 1 of Example 3. 1H-NMR (CDCl3) δ: 1.36 (3H, d, J = 6.7 Hz), 2.33-2.41 (1H, m), 2.55-2.71 (4H, m), 2.87-2.95 (1H, m), 3.74 (1H, q, J = 6.8 Hz), 3.84 (1H, d, J = 13.7 Hz), 4.02 (1H, d, J = 13.7 Hz), 4.38-4.48 (3H, m), 4.59-4.72 (3H, m), 5.09 (1H, ddd, J = 14.7, 7.0, 2.5 Hz), 5.44 (2H, q, J = 13.4 Hz), 7.10-7.15 (2H, m), 7.36 (1H, s), 7.42-7.53 (1H, m). [M+H] = 713.5, Measurement Condition 1: Retention time 3.45 min. Step 5: Compound 56 (55 mg, 0.077 mmol) was used to obtain crude compound 57 (48 mg) in the same manner as in Step 2 of Example 3. [M+H] = 599.3, Measurement Condition 1: Retention time 2.14. Step 6: Manganese dioxide (209 mg, 2.4 mmol) was added to a solution of crude compound 57 (48 mg) in dichloromethane (1 mL), and the mixture was stirred at room temperature for 2.5 hours. Manganese dioxide (500 mg, 5.8 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Insoluble matter was removed by filtration, and the solvent in the filtrate was evaporated under reduced pressure to obtain crude compound 58 (20 mg). [M+H]=597.3, measurement condition 1: retention time 2.58 minutes. Step 7 Compound 59 (8.6 mg, three-step yield 18%) was obtained from the crude product of compound 58 (19 mg) in the same manner as in Step 4 of Example 3. 11H-NMR (CDCl3) δ: 1.38 (3H, d, J = 6.7 Hz), 2.34 - 2.40 (1H, m), 2.56 - 2.76 (4H, m), 2.91 - 2.97 (1H, m), 3.71 (1H, dd, J = 13.1, 6.1 Hz), 3.80 (3H, s), 3.84 (1H, d, J = 13.3 Hz), 4.10 (1H, d, J = 13.8 Hz), 4.36 - 4.41 (1H, m), 4.52 - 4.55 (2H, m), 4.61 (1H, dd, J = 14.2, 7.8 Hz), 5.03 - 5.06 (1H, m), 5.44 (2H, dd, J = 27.7, 13.2 Hz), 6.78 (1H, d, J = 16.1 Hz), 7.09 - 7.15 (2H, m), 7.37 (1H, s), 7.45 - 7.54 (2H, m). [M+H]= 653.4, Measurement condition 1: Retention time 2.59 minutes Step 8 Using compound 59 (8.6 mg, 0.013 mmol), I - 010 (4.9 mg, yield 58%) was obtained in the same manner as in Step 10 of Example 1. 1H-NMR (DMSO-D6) δ: 1.30 (3H, d, J = 6.5 Hz), 2.30 - 2.34 (1H, m), 2.57 - 2.73 (4H, m), 2.86 - 2.90 (1H, m), 3.71 (1H, q, J = 6.3 Hz), 3.79 (1H, d, J = 12.8 Hz), 3.91 (1H, d, J = 13.7 Hz), 4.28 - 4.33 (1H, m), 4.45 - 4.57 (3H, m), 4.92 - 4.97 (1H, m), 5.38 (1H, d, J = 12.7 Hz), 5.45 (1H, d, J = 13.1 Hz), 6.58 (1H, d, J = 16.3 Hz), 7.32 (1H, dd, J = 8.4, 1.4 Hz), 7.47 - 7.55 (3H, m), 7.68 (1H, s).

[0148] Example 7 Step 1: To a dichloromethane (400 mL) suspension of compound 60 (51.3 g, 171 mmol), synthesized by the synthetic method described in WO2020146682, 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, followed by stirring at room temperature for 1 hour. Water was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was then 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, yield 77%). 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 min. Step 2: 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. The organic layer was dried over anhydrous magnesium 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 62 (29.1 g, yield 61%). 1H-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 min. Step 3: 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 solution, which was extracted with ethyl acetate and then washed with aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 63 (28.5 g, yield 97%). 1 H-NMR (CDCl) 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 min. Step 4: To a solution of compound 63 (32 g, 107 mmol) in N,N-dimethylformamide (250 mL) were added 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). After degassing under reduced pressure, the mixture was purged with nitrogen and stirred for 4 hours at 110° C. Water was added to the reaction mixture, and the resulting solid was collected by filtration and washed with diisopropyl ether to obtain Compound 64 (37 g, yield 88%). 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: holding time 2.35 minutes Step 5 To a solution of compound 64 (37 g, 94 mmol) in methanol (250 mL) and tetrahydrofuran (500 mL) was added 10% palladium-carbon (50% aqueous) (20 g, 9.4 mmol), and the mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) for 8 hours and 30 minutes. Insoluble matter was removed by filtration, and 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 purification. 1 H-NMR (CDCl) 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 min. Step 6: To a solution of the entire crude product of Compound 65 (94 mmol) obtained in Step 5 in ethanol (500 mL) was added hydrazine monohydrate (22.8 mL, 470 mmol), and the mixture was stirred at 80 °C for 1 hour. Insoluble matter was removed by filtration, and the solvent was evaporated under reduced pressure. Dichloromethane was added to the resulting residue. The precipitated insoluble matter was again removed by filtration, and the solvent was evaporated under reduced pressure to give a crude product (24.6 g) containing compound 66. The obtained compound 66 was used in the next step as it was without 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 min. Step 7: To a solution of the entire crude product of compound 66 (94 mmol) obtained in Step 6 in dichloromethane (200 mL), trifluoroacetic anhydride (40 mL, 282 mmol) was added dropwise under ice cooling and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in toluene. The solvent was evaporated again under reduced pressure. The resulting residue was dissolved in ethyl acetate and slowly poured into aqueous sodium bicarbonate solution. After stirring at 30°C for 6 hours, the mixture was extracted twice 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 silica gel column chromatography (hexane-ethyl acetate) to give Compound 67 (22.9 g, yield 68%). 1 H-NMR (CDCl) 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 min. Step 8: To a solution of compound 67 (21.5 g, 60 mmol) in tetrahydrofuran (500 mL) was added triphenylphosphine (23.5 g, 89 mmol), and then DIAD (17.4 mL, 89 mmol) was added dropwise over 20 min under ice-cooling. After stirring at room temperature for 1 hour and 30 minutes, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 68 (16.4 g, yield 81%). 1H-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 min. Step 9: To a solution of compound 68 (16.4 g, 48 mmol) in acetonitrile (200 mL), sodium iodide (21.6 g, 144 mmol) and trimethylsilyl chloride (18.4 mL, 144 mmol) were added, followed by stirring at 45 °C for 1 hour. Aqueous sodium bicarbonate and aqueous sodium thiosulfate were added to the reaction solution, followed by extraction twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and 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 purification. 1H-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: 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 insoluble matter was removed 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, yield 97%). 1H-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 min. Step 11: 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: Compound 71 (145 mg, 0.387 mmol), Compound 7 (134 mg, 0.387 mmol), and anhydrous magnesium sulfate (46.6 mg, 0.387 mmol) were added with tetrahydrofuran (2 mL) and acetic acid (44 μL, 0.775 mmol), and the mixture was stirred at room temperature for 2 hours. Subsequently, NaBH(OAc) ３ (164 mg, 0.775 mmol) was added and stirred for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give crude compound 72 (102 mg). [M+H] = 703.10, Measurement Condition 1: Retention time 3.19 minutes. Step 13: Tetrahydrofuran (1 mL) and TBAF (1 mol / L, 161 μL, 0.161 mol) were added to the crude compound 72, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 73 (19.2 mg, yield 22%). [M+H] = 589.05, Measurement Condition 1: Retention time 2.15 minutes 1H-NMR (CDCl3) δ: 1.38 (3H, d, J = 6.8 Hz), 2.35-2.50 (1H, m), 2.58-2.73 (3H, m), 2.73-2.83(1H, m), 2.91-3.00(1H, m), 3.57-3.63 (1H, m), 3.725 (1H, d, J = 14 Hz), 3.73-3.76 (1H, m), 3.92 (1H, d, J = 14hz), 4.33-4.41 (1H, m), 4.44-4.52 (1H, m), 4.52-4.65(3H, m), 4.65-4.74(1H, m), 5.07-5.16(1H, m), 5.43 (1H, d, J = 13.6 Hz), 5.51 (1H, d, J = 13.6 Hz), 7.16-7.07 (1H, m), 7.16-7.07 (1H, m), 7.41-7.47 (1H, m), 7.59 (1H, s). Step 14: Compound 73 (19 mg, 0.032 mmol) was dissolved in acetonitrile (380 μL), and 2-hydroxy-2-azaadamantane (0.494 mg, 3.22 μmol), 2,2′-bipyridine (0.503 mg, 3.22 μmol), and N-dimethylaminopyridine (0.788 mg, 6.45 μmol) were added and stirred. Finally, cuprous chloride (0.319 mg, 3.22 μmol) was added and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate and aqueous sodium thiosulfate were added to the reaction mixture, which was then extracted with ethyl acetate. The solvent was then evaporated under reduced pressure to give crude compound 74. Step 15: Dichloromethane (188 μL) and methyl triphenylphosphoranylideneacetate (53.5 mg, 0.160 mmol) were added to compound 74 obtained in step 14, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, which was then 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 give compound 75 (9.2 mg, yield 45%). [M+H] = 645.05, measurement condition 1: retention time 2.70 minutes 1H-NMR (CDCl3) δ: 7.59 (1H, s), 7.51 (1H, d, J = 16.1 Hz), 7.46-7.42 (1H, m), 7.16-7.12 (1H, m), 7.12-7.07 (1H, m), 6.70 (1H, d, J = 16.1 Hz), 5.52 (1H, d, J = 13.6 Hz), 5.44 (1H, d, J = 13.6 Hz), 5.06-5.04 (1H, br m), 4.62-4.60 (1H, m), 4.52-4.50 (2H, m), 4.40-4.38 (1H, m), 4.11 (1H, d, J = 14 Hz), 3.84 (1H, d, J = 14 Hz), 3.80 (3H, s), 3.77-3.75 (1H, m), 2.99-2.97 (1H, m), 2.78-2.76 (1H, m), 2.74-2.59 (3H, m), 2.38-2.36 (1H, m), 1.41 (3H, d, J = 6.7 Hz). Step 16: Compound 75 (9.2 mg, 0.014 mmol) was dissolved in a 1:1 mixture of tetrahydrofuran and methanol (368 μL), and 3 mol / L aqueous sodium hydroxide (42.9 μL, 0.043 mmol) was added, followed by stirring at 45° C. for 4 hours. 10% aqueous citric acid was added to the reaction mixture, followed by extraction with acetic acid. The solvent was evaporated under reduced pressure, and the resulting residue was purified by preparative thin-layer silica gel chromatography (chloroform-methanol) to obtain compound I-011 (9 mg, yield 100%). 1H-NMR (CDCl3) δ: 7.59 (1H, s), 7.57 (1H, d, J = 12.8 Hz), 7.45-7.43 (1H, m),7.16-7.11 (1H, m), 7.11-7.07 (1H, m), 6.69 (1H, d, J = 15.9 Hz), 5.52 (1H, d, J = 13.2 Hz), 5.44 (1H, d, J = 13.2 Hz), 5.06 (1H, br), 4.66-4.58 (1H, m), 4.55-4.48 (2H, m), 4.42-4.34 (1H, m), 4.10 (1H, d, J = 12.8 Hz), 3.85 (1H, d, J = 12.8 Hz), 3.81-3.73 (1H, m), 3.03-2.94 (1H, m), 2.85-2.74 (1H, m), 2.74-2.59 (3H, m), 2.43-2.30 (1H, m), 1.41 (3H, d, J = 6.8Hz)

[0149] The compounds shown below were similarly synthesized using the general synthesis methods described above or the synthesis methods described in the Examples.

[0150]

[0151]

[0152]

[0153]

[0154] The compounds shown below can be similarly synthesized using the general synthesis methods described above or the synthesis methods described in the Examples.

[0155] 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 following test examples. The compounds of formula (I), formula (IA) or formula (IB) according to the present invention 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.

[0156] 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 at 37°C, 5% CO ２ The 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) under the following conditions: 10 g / L trypsin / 5.3 mmol / L EDTA solution (Nacalai Tesque) diluted 10-fold, and then harvested 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, 0.1 mM IBMX (Sigma), and 0.2 mM RO20-1724 (Calbiochem). ４ The cells are suspended to 100 cells / mL, and the cell suspension is added at 6 μL / well. After incubation at 37°C for 1 hour, the intracellular cAMP concentration is measured using a cAMP Gs dynamic kit (Cisbio) according to the protocol provided with the product. Specifically, a total of 6 μL / well of a cAMP-d2 / Anti-cAMP-Cryptate (1 / 1) mixture is added and incubated at room temperature for 1 hour, and time-resolved fluorescence is measured using a PHERAstar (BMG Labtech). The cAMP concentration when human GLP-1 (7-36) is dispensed to a final concentration of 2 nM is defined as 100%, and the cAMP concentration when DMSO alone is dispensed is defined as 0%, and the 50% effective concentration (EC ５０The EC value (Emax) and maximum effect (Emax) are calculated using TIBCO Spotfire (TIBCO Software). The dilution concentration and dilution solvent are changed as necessary. The compounds of the present invention were tested essentially as described above. The EC value of each compound of the present invention was ５０ , Emax are shown in the table below.

[0157] 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.

[0158] Test Example 2: Metabolic stability test Commercially available pooled human liver microsomes are reacted with the compound of the present invention for a certain period of time, and the residual 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.

[0159] The reaction mixture was incubated in 0.2 mL of a buffer solution (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL of human liver microsomes 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. The dilution concentration and dilution solvent were varied as necessary. The compounds of the present invention can be tested essentially as described above.

[0160] 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 2 μL of the compound solution is added to 198 μL of the 17th Edition Japanese Pharmacopoeia Dissolution Test No. 2 Fluid. 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 / 2 (V / V / V), and the concentration in the filtrate is measured using LC / MS / MS with the absolute calibration curve method. The compounds of the present invention can be tested essentially as described above.

[0161] Test Example 4: CYP inhibition test Using commercially available pooled human liver microsomes, the extent to which the production of each metabolite is inhibited by the compound of the present invention is evaluated using as indicators the 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), which are typical substrate metabolic reactions of major human CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4). 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: 0.2 mg protein / mL pooled human liver microsomes; concentration of the compound of the present invention: 1, 5, 10, 20 μmol / L (4 points). A 96-well plate was prepared as a reaction solution, and five types of substrates, human liver microsomes, and the compound of the present invention were added to 50 mmol / L Hepes buffer in the above-mentioned compositions, followed by the addition of the coenzyme NADPH to initiate the metabolic reaction used as an indicator. After 15 minutes of reaction 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, resorufin (a CYP1A2 metabolite) in the supernatant was quantified using a fluorescent multilabel counter or LC / MS / MS, and tolbutamide hydroxylate (a CYP2C9 metabolite), mephenytoin 4'-hydroxylate (a CYP2C19 metabolite), dextrorphan (a CYP2D6 metabolite), and terfenadine alcohol (a CYP3A4 metabolite) were quantified using LC / MS / MS. A control (100%) was prepared by adding only DMSO, the solvent in which the drug was dissolved, to the reaction system. Residual activity (%) was calculated, and the IC was calculated by inverse estimation using a logistic model based on the concentration and inhibition rate. ５０ Compounds of the invention can be tested essentially as described above.

[0162] Test Example 5: BA Test Materials and Methods for Experiments to Examine Oral Absorbability (1) Animals Used: Mice or SD rats are used. (2) Breeding Conditions: Mice or SD rats are allowed free access to solid feed and sterilized tap water. (3) Dosage and Grouping: Oral and intravenous administration is administered at the specified dose. Groups are 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 Dosage Solution: Oral administration is administered as a solution or suspension. Intravenous administration is administered after solubilization. (5) Administration Method: Oral administration is administered by forced administration into the stomach using an oral probe. Intravenous administration is administered via the tail vein or femoral 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 area under the plasma concentration-time curve (AUC) of the compound of the present invention is calculated by moment analysis for the time course of the 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. The compound of the present invention can be tested essentially as described above.

[0163] Test Example 6: Clearance Evaluation Test Materials and Methods (1) Animals: SD rats were used. (2) Breeding Conditions: SD rats were allowed free access to solid feed and sterilized tap water. (3) Dose and Grouping: Intravenous administration was performed at a predetermined dose. Groups were set up as follows: Intravenous administration: 1 μmol / kg (n=2) (4) Preparation of Dosage Solution: Solubilized and administered using a dimethyl sulfoxide / propylene glycol = 1 / 1 solvent. (5) Administration Method: Administered via the tail vein using a syringe with an injection needle. (6) Evaluation Items: Blood was collected over time, and the plasma concentration of the compound of the present invention was measured using LC / MS / MS. (7) Statistical Analysis: The total body clearance (CLtot) was calculated using moment analysis based on the progression of the plasma concentration of the compound of the present invention. The dilution concentration and dilution solvent were changed as necessary. The compound of the present invention can be tested essentially as described above.

[0164] Test Example 7: CYP3A4 (MDZ) MBI Test This test evaluates the mechanism-based inhibition (MBI) ability of the compound of the present invention in terms of metabolic potentiation of CYP3A4 inhibition. Using pooled human liver microsomes, CYP3A4 inhibition was evaluated using the 1-hydroxylation reaction 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 for pre-reaction and 0.05 mg / mL (at 10-fold dilution) for reaction; and pre-reaction concentrations of the compound of the present invention, 0.83, 5, 10, and 20 μmol / L (4 points). Pooled human liver microsomes and a solution of the compound of the present invention were added to a 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) at the pre-reaction composition described above. 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 used as an indicator (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 used as an indicator was started. After the specified reaction time, the reaction was stopped by adding a 1 / 1 (V / V) methanol / acetonitrile solution. Each plate in which the indicator reaction was performed was centrifuged at 3000 rpm for 15 minutes, and 1-hydroxymidazolam in the supernatant was quantified by LC / MS / MS. A control (100%) was prepared by adding only DMSO, the solvent in which the compound of the present invention was dissolved, to the reaction system. 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 determined as the IC at 0 min preincubation / IC at 30 min preincubation, with a Shifted IC of 1.5 or higher being considered positive and a Shifted IC of 1.0 or lower being considered negative. The compounds of the present invention can be tested essentially as described above.

[0165] Formulation Examples 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, topically, e.g., in the form of lotions, gels, ointments, or creams, or intranasally or in the form of 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.

[0166] 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.

[0167] The compounds according to the present invention have GLP-1 receptor agonist activity and are believed to be useful as therapeutic and / or preventive agents for diseases or conditions involving the GLP-1 receptor.

Claims

1. Formula (IA): 【Chemistry 1】 (In the formula, R １ is a substituted or unsubstituted alkyl or a substituted or unsubstituted non-aromatic heterocyclic group; R ２ teeth, 【Chemistry 2】 (In the formula, R ４ is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; R ５ is a hydrogen atom or a substituted or unsubstituted alkyl; X is N or C(R ３ ) and R ３ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, difluoromethyl, trifluoromethyl or C1-C3 alkyl; L is, 【Transformation 3】 (In the formula, Atoms marked with a are: 【Chemistry 4】 is bonded to a group represented by The atom marked with b is 【Transformation 5】 is bonded to a group represented by R ８ is a hydrogen atom or substituted or unsubstituted alkyl; R ９ is halogen or substituted or unsubstituted alkyl; Z １ and Z ２ are each independently N or CH; W is N or CR １５ and R １１ is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, an aromatic carbocyclic group, a non-aromatic carbocyclic group, an aromatic heterocyclic group, or a non-aromatic heterocyclic group; R １２ and R １３ are each independently a hydrogen atom or a halogen; R １４ and R １５ are each independently a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy; R １１ and R １２ may be taken together to form a substituted or unsubstituted aromatic heterocycle or a substituted or unsubstituted non-aromatic heterocycle; R １１ and R １３ may be taken together to form a substituted or unsubstituted aromatic heterocycle or a substituted or unsubstituted non-aromatic heterocycle; R １３ and R １４ may be taken together to form a substituted or unsubstituted aromatic heterocycle or a substituted or unsubstituted non-aromatic heterocycle), or a pharmaceutically acceptable salt thereof.

2. R １ 2. The compound of claim 1, wherein 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.

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

4. R ２ but, 【Transformation 6】 2. The compound according to claim 1, which is a group represented by the formula: wherein each symbol has the same meaning as in claim 1, or a pharmaceutically acceptable salt thereof.

5. X is C(R ３ 2. The compound of claim 1, wherein R is 1 or 2; or a pharmaceutically acceptable salt thereof.

6. R ９ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is halogen or haloalkyl.

7. Z １ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is CH.

8. R １１ is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, an aromatic carbocyclic group, a non-aromatic carbocyclic group, an aromatic heterocyclic group, or a non-aromatic heterocyclic group; R １２ and R １３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each of the groups independently represents a hydrogen atom or a halogen atom.

9. R １１ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is halogen, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy.

10. R １２ and R １３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is a hydrogen atom.

11. R １４ and R １５ 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each of the groups independently represents a hydrogen atom or a halogen atom.

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.

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