Oxazepine derivatives

Abstract

The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The compound has superior orexin type-2 receptor agonist activity.

Description

[Technical Field]

[0001] The present invention relates to oxazepine derivatives and pharmaceutically acceptable salts thereof, and in particular to compounds which have orexin type 2 receptor agonist activity and are useful for the prevention or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, and the like. [Background technology]

[0002] Orexin is a neuropeptide produced by specific neurons located in the lateral hypothalamus. It is produced from preproorexin by a prohormone convertase, and there are two subtypes: orexin A and orexin B. In this specification, unless otherwise specified, the term "orexin" is used to encompass orexin A and orexin B.

[0003] Orexin binds to orexin receptors, which are endogenous ligands of G protein-coupled receptors expressed mainly in the brain. Two subtypes of orexin receptors are known: type 1 receptors (hereinafter sometimes abbreviated as OX1R) and type 2 receptors (hereinafter sometimes abbreviated as OX2R) (Non-Patent Document 1). In this specification, unless otherwise specified, the term "orexin receptor" is used to encompass OX1R and OX2R.

[0004] Known diseases associated with orexin or orexin type 2 receptor include, for example, narcolepsy, idiopathic hypersomnia, hypersomnia, and sleep apnea syndrome.

[0005] For example, narcolepsy-like symptoms that occur in transgenic mice lacking endogenous orexin through degeneration of orexin-producing neurons are improved by intracerebroventricular administration of orexin peptides (Non-Patent Document 2), and narcolepsy-like symptoms are induced in mice lacking preproorexin, a precursor of orexin (KO) (Non-Patent Document 3), suggesting that narcolepsy is caused by orexin deficiency.

[0006] Furthermore, it has been reported that dogs with OX2R mutations develop hereditary narcolepsy (Non-Patent Document 4), and narcolepsy-like symptoms are also induced in OX2R knockout mice (Non-Patent Document 5), strongly suggesting that stimulation of the orexin type 2 receptor is involved in the maintenance of wakefulness.

[0007] Narcolepsy type 1 and narcolepsy type 2 are known as diseases caused by abnormal orexin action. In this specification, unless otherwise specified, the term "narcolepsy" is used to encompass narcolepsy type 1 and narcolepsy type 2.

[0008] It has been reported that patients with narcolepsy type 1 have low orexin concentrations in cerebrospinal fluid (Non-Patent Document 6). It has also been suggested that patients with sleep apnea syndrome have low plasma orexin A concentrations (Non-Patent Document 7). Furthermore, it has been reported that patients with Parkinson's disease experience drowsiness, and the loss of orexin-producing neurons has been suggested as a cause (Non-Patent Document 8).

[0009] Given this background, it has been suggested that OX2R agonists may be promising therapeutic agents for narcolepsy and other sleep disorders that present with hypersomnia (Non-Patent Document 9).

[0010] Therefore, compounds having OX2R agonist activity are thought to be useful as preventive or therapeutic agents for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcoleptic symptoms, and hypersomnia syndrome accompanied by excessive daytime sleepiness (e.g., Parkinson's disease, dementia with Lewy bodies, Guillain-Barré syndrome, and Kleine-Levin syndrome).

[0011] In fact, it has been reported that compounds with OX2R agonist activity improve the symptoms of narcolepsy (Patent Document 1). Furthermore, clinical trials have been conducted on TAK-925 (intravenous administration), an existing compound with OX2R agonist activity, in healthy individuals and narcolepsy patients, and another compound, TAK-994 (oral administration), has been reported to cause side effects in clinical trials, but the details are unknown. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] WO2021 / 048822 A1 [Non-patent literature]

[0013] [Non-Patent Document 1] Cell, Vol.92, 573-585, 1998 [Non-patent document 2] Proc.Natl.Acad.Sci.USA,Vol.101,4649-4654,2004 [Non-patent document 3] Cell, Vol.98, 437-451, 1998 [Non-patent document 4] Cell, Vol.98, 365-376, 1999 [Non-Patent Document 5] Neuron, Vol.38, 715-730, 2003 [Non-patent document 6] THE LANCET,Vol.355,39-40,2000 [Non-Patent Document 7] Respiration,Vo.71,575-579,2004 [Non-patent document 8] Brain,Vol.130,1586-1595,2007 [Non-Patent Document 9] CNS Drugs, Vol.27, 83-90, 2013 Summary of the Invention [Problem to be solved by the invention]

[0014] An object of the present invention is to provide a compound having excellent orexin type 2 receptor agonist activity. [Means for solving the problem]

[0015] As a result of intensive research to achieve the above-mentioned object, the present inventors have discovered compounds having orexin type 2 receptor agonist activity, and further discovered that the compounds have therapeutic or preventive effects on diseases associated with orexin or the orexin type 2 receptor, thereby completing the present invention. That is, the present invention comprises the following:

[0016] [1] A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R 1 is a hydrogen atom, C 1-6 Alkyl group, C 3-8 Cycloalkyl group, 3- to 8-membered heterocyclyl group, hydroxy group, halogen, amino group, cyano group, carboxy group, C 6-10 Aryl group, 5- to 12-membered heteroaryl group, C 1-6 Alkoxy group, C 3-8 Cycloalkoxy group, 3- to 8-membered heterocyclyloxy group, C 6-10 Aryloxy group, 5-12 membered heteroaryloxy group, C 3-8 Cycloalkyl C 1-6Alkoxy group, 3-8 membered heterocyclyl C 1-6 Alkoxy group, C 6-10 Aryl C 1-6 Alkoxy group, or 5- to 12-membered heteroaryl C 1-6 represents an alkoxy group; R 1 is 1 to 6 [C optionally substituted with halogen, hydroxy group, carboxy group, oxo group, amino group, cyano group, 1 to 3 halogens] 1-6 C optionally substituted with an alkyl group or 1 to 3 halogens 1-6 alkoxy groups]; R 2 , R 3 and R 4 each independently represents a hydrogen atom, C optionally substituted with 1 to 6 halogen atoms, 1-6 C optionally substituted with alkyl group, 1 to 6 halogen atoms 3-8 represents a cycloalkyl group, a hydroxy group, or a halogen; R 2 , R 3 and R 4 each of which is C optionally substituted with 1 to 6 halogens, hydroxy groups, carboxy groups, oxo groups, amino groups, cyano groups, or 1 to 3 halogens; 1-6 C optionally substituted with an alkyl group or 1 to 3 halogens 1-6 alkoxy groups]; Adjacent R 1 and R 2 , R 2 and R 3 , and R 3 and R 4 may be linked to each other via a single bond to form a 5- to 8-membered ring; R 7 is a hydrogen atom, a halogen atom, or C optionally substituted with 1 to 6 halogen atoms 1-6 represents an alkyl group; R a is a hydrogen atom, C optionally substituted with 1 to 6 halogen atoms 1-6 represents an alkyl group, a hydroxy group, or a halogen; X is -O- or -CRb R c - represents R b and R c each independently represents a hydrogen atom, C optionally substituted with 1 to 6 halogen atoms, 1-6 represents an alkyl group or a halogen; Y represents -CH2- or -CO-; n represents 1 or 2; m represents 0 or 1; L represents -O- or -NH-; Q is 1 to 4 R 11 a 3- to 10-membered heterocyclyl group optionally substituted with 1 to 4 R 12 C optionally substituted with 6-10 an aryl group or 1 to 4 R 13 represents a 5- to 12-membered heteroaryl group optionally substituted by R 11 , R 12 and R 13 each independently represents a halogen, a hydroxy group, an oxo group, or C optionally substituted with 1 to 6 halogens 1-6 C optionally substituted with alkyl group, 1 to 6 halogen atoms 3-8 C optionally substituted with a cycloalkyl group or 1 to 6 halogen atoms 1-6 represents an alkoxy group.] [2] R 1 C 1-6 Alkyl group, C 3-8 Cycloalkyl group, 3- to 8-membered heterocyclyl group, hydroxy group, C 6-10 Aryl group, 5- to 12-membered heteroaryl group, C 1-6 Alkoxy group, C 3-8 Cycloalkoxy group, 3- to 8-membered heterocyclyloxy group, C 3-8 Cycloalkyl C 1-6 Alkoxy group, 3-8 membered heterocyclyl C 1-6 Alkoxy group or C 6-10 Aryl C 1-6 is an alkoxy group, R 1C optionally substituted with 1 to 3 halogens, hydroxy groups, oxo groups, 1 to 3 halogens 1-6 C optionally substituted with an alkyl group or 1 to 3 halogens 1-6 The compound according to [1], or a pharmaceutically acceptable salt thereof, optionally substituted with an alkoxy group. [3] R 2 is a hydrogen atom or a halogen atom, or a pharmaceutically acceptable salt thereof. [4] R 3 is a hydrogen atom, C optionally substituted with 1 to 6 halogen atoms 1-6 The compound according to any one of [1] to [3], wherein R is an alkyl group or a halogen atom, or a pharmaceutically acceptable salt thereof. [5] R 4

[0022]

[0023] The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [4], wherein is a hydrogen atom or a halogen. [6] R a

[0022]

[0023] The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [5], wherein is a hydrogen atom. [7] The compound according to any one of [1] to [6], wherein n is 1, or a pharmaceutically acceptable salt thereof. [8] The compound according to any one of [1] to [7], wherein m is 0, or a pharmaceutically acceptable salt thereof. [9] The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [8], wherein L is -O-.

[10] The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [9], wherein Y is -CO-.

[11] Q is 1 to 4 R 13 The compound according to any one of [1] to

[10] , or a pharmaceutically acceptable salt thereof, wherein R is a bicyclic 5- to 12-membered heteroaryl group optionally substituted with R.

[12] The compound or pharmaceutically acceptable salt thereof according to any one of [1] to

[11] , wherein Q is a structure represented by any one selected from the group consisting of formulas (II-1), (II-2), (II-3) and (II-4). [ka] [ka] [ka] [ka] [In formulas (II-1), (II-2), (II-3) and (II-4), Z 21 is CR f or N, Ring A represents a monocyclic 6- to 8-membered heterocyclyl ring or a monocyclic 6- to 7-membered heteroaryl ring; R 2701 , R 2702 , R 2703 and R 2704 each independently represents a halogen atom or a C group optionally substituted with 1 to 3 halogen atoms; 1-6 represents an alkyl group, R d , R e , and R f are each independently a hydrogen atom, a halogen atom, or a C optionally substituted with 1 to 3 halogen atoms. 1-6 represents an alkyl group, R 2601 , R 2602 , R 2603 and R 2604 each independently represents a hydrogen atom or a C optionally substituted with 1 to 6 halogen atoms; 1-6 C optionally substituted with an alkyl group or 1 to 6 halogens 3-8 represents a cycloalkyl group, Each q independently represents an integer of 0 to 4.

[13] The compound or a pharmaceutically acceptable salt thereof according to [1], which is a compound represented by formula (III) or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R 1 is a hydrogen atom, C 1-6 Alkyl group, C 3-8 Cycloalkyl group, 3- to 8-membered heterocyclyl group, hydroxy group, halogen, C 6-10 Aryl group, 5- to 12-membered heteroaryl group, C 1-6 Alkoxy group, C 3-8 Cycloalkoxy group, 3- to 8-membered heterocyclyloxy group, C 6-10 Aryloxy group, 5- to 12-membered heteroaryloxy group, C 3-8 Cycloalkyl C 1-6 Alkoxy group, 3-8 membered heterocyclyl C 1-6 Alkoxy group, C 6-10 Aryl C 1-6 Alkoxy group, or 5- to 12-membered heteroaryl C 1-6 represents an alkoxy group; R 1 is 1 to 6 [C optionally substituted with halogen, hydroxy group, carboxy group, oxo group, amino group, cyano group, 1 to 3 halogens] 1-6 C optionally substituted with an alkyl group or 1 to 3 halogens 1-6 alkoxy groups]; R 2 , R 3 and R 4 each independently represents a hydrogen atom, C optionally substituted with 1 to 6 halogen atoms, 1-6 represents an alkyl group or a halogen; R 7 is a hydrogen atom, a halogen atom, or a C optionally substituted with 1 to 3 halogen atoms 1-6 represents an alkyl group; Q is 1 to 4 R 11 a 3- to 10-membered heterocyclyl group optionally substituted with 1 to 4 R 12 C optionally substituted with 6-10 an aryl group or 1 to 4 R13 represents a 5- to 12-membered heteroaryl group optionally substituted by R 11 , R 12 and R 13 each independently represents a halogen, an oxo group, or C optionally substituted with 1 to 3 halogens 1-6 represents an alkyl group.]

[14] The compound according to any one of [1] to

[13] , or a pharmaceutically acceptable salt thereof, wherein Q is any one selected from the group consisting of formulae (IV), (V) and (VI): [ka] [ka] [ka] [In formulas (IV), (V) and (VI), R 31 , R 32 , R 33 , R 35 and R 36 each independently represents a hydrogen atom, C optionally substituted with 1 to 6 halogen atoms, 1-6 represents an alkyl group, a hydroxy group, or a halogen; Z 31 , Z 32 and Z 33 each independently represents CH or N, Z a is O or CR g represents 2, R g each independently represents a hydrogen atom or C optionally substituted with 1 to 6 halogen atoms 1-6 represents an alkyl group.]

[15] At least one compound selected from the following (1) to (50) or a pharmaceutically acceptable salt thereof: (1) (2S,11aR)-6-Isopropoxy-8-methyl-2-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (2) (2S,11aR)-6-(cyclopentyloxy)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (3) (2S,11aR)-6-isopropoxy-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (4) (2S,11aR)-6-(((S)-1-fluoropropan-2-yl)oxy)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (5) (2S,11aR)-6-Isopropoxy-8-methyl-2-((2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (6) (2S,11aR)-6-(cyclopentyloxy)-8-methyl-2-((2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (7) (2S,11aR)-6-(cyclopentyloxy)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (8) (2S,11aR)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-6-(((S)-1,1,1-trifluoropropan-2-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (9) (2S,11aR)-6-cyclobutoxy-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (10) (2S,11aR)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-6-(((R)-1,1,1-trifluoropropan-2-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (11) (2S,11aR)-6-(((R)-1-fluoropropan-2-yl)oxy)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (12) (2S,11aR)-6-(((R)-1,1-difluoropropan-2-yl)oxy)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (13) (2S,11aR)-6-(2,6-difluorophenyl)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (14) (2S,11aR)-2-((8-fluoro-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-6-isopropoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (15) (2S,11aR)-2-((8-fluoro-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)-6-isopropoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (16) (2S,11aR)-7-Fluoro-6-isopropoxy-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (17) (2S,11aR)-6-isobutyl-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (18) (2S,11aR)-6-(cyclopentyloxy)-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (19) (2S,11aR)-8-methyl-2-((2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)oxy)-6-(((R)-1,1,1-trifluoropropan-2-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (20) (2S,11aR)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)-6-(((R)-1,1,1-trifluoropropan-2-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (21) (2S,11aR)-2-((8-fluoro-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-8-methyl-6-(((R)-1,1,1-trifluoropropan-2-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (22) (2S,11aR)-8-chloro-6-isopropoxy-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (23) (2S,11aR)-6-Isobutoxy-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (24) (2S,11aR)-6-((R)-sec-butoxy)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (25) (2S,11aR)-6-((S)-sec-butoxy)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (26) (2S,11aR)-6-((2,2-difluorocyclopentyl)oxy)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (27) (2S,11aR)-7,9-difluoro-6-isopropoxy-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (28) (2S,11aR)-7-Fluoro-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-6-(((R)-1,1,1-trifluoropropan-2-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (29) (2S,11aR)-6-(2-fluoro-2-methylpropoxy)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (30) (2S,11aR)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-6-(pyrrolidin-1-yl)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (31) (2S,11aR)-6-(cyclopropylmethoxy)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (32) (2S,11aR)-7-fluoro-6-(2-fluoro-2-methylpropoxy)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (33) (2S,11aR)-7-Fluoro-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-6-(pyrrolidin-1-yl)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (34) (2S,11aR)-6-Isopropoxy-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-8-(trifluoromethyl)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (35) (2S,11aR)-6-(cyclopropylmethoxy)-7-fluoro-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (36) (2S,11aR)-7-Fluoro-6-isobutoxy-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (37) (2S,11aR)-7-Fluoro-6-((1-fluorocyclopropyl)methoxy)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (38) (2S,11aR)-9-Fluoro-6-isopropoxy-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (39) (2S,11aR)-6-((R)-sec-butoxy)-7-fluoro-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (40) (2S,11aR)-6-((S)-sec-butoxy)-7-fluoro-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (41) (2S,11aR)-6-(cyclopentyloxy)-7-fluoro-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (42) (2S,11aR)-6-ethoxy-7-fluoro-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (43) (2S,11aR)-7-Fluoro-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-6-propoxy-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (44) (2S,11aR)-7-chloro-6-isopropoxy-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (45) (2S,11aR)-6-(((R)-1,1-difluoropropan-2-yl)oxy)-7-fluoro-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (46) (2S,11aR)-7-Fluoro-6-(((R)-1-fluoropropan-2-yl)oxy)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (47) (2S,11aR)-7-Fluoro-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-6-(2,2,2-trifluoroethoxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (48) (2S,11aR)-7-Fluoro-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-6-(((S)-tetrahydrofuran-3-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (49) (2S,11aR)-7-Fluoro-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-6-(((R)-tetrahydrofuran-3-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (50) (2S,11aR)-6-((1,3-difluoropropan-2-yl)oxy)-7-fluoro-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one

[16] An orexin type 2 receptor agonist comprising the compound according to any one of [1] to

[15] or a pharmaceutically acceptable salt thereof.

[17] A pharmaceutical composition comprising the compound according to any one of [1] to

[15] or a pharmaceutically acceptable salt thereof.

[18] [1] A preventive or therapeutic agent for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcoleptic symptoms, hypersomnia associated with Parkinson's disease, hypersomnia associated with Guillain-Barré syndrome, hypersomnia associated with Kleine-Levin syndrome, or hypersomnia associated with dementia with Lewy bodies, comprising the compound according to any one of [1] to

[15] or a pharmaceutically acceptable salt thereof.

[0017] The present invention may further include the following aspects.

[19] The compound according to any one of [1] to

[12] , wherein n is 1, m is 0, L is -O-, and Y is -CO-, or a pharmaceutically acceptable salt thereof.

[20] Use of the compound according to any one of [1] to

[15] or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a disease mediated by orexin type 2 receptor agonism. [twenty one] The use according to

[20] , wherein the disease mediated by orexin type 2 receptor agonist activity is selected from narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcoleptic symptoms, hypersomnia associated with Parkinson's disease, hypersomnia associated with Guillain-Barré syndrome, hypersomnia associated with Kleine-Levin syndrome, and hypersomnia associated with dementia with Lewy bodies. [twenty two] The compound according to any one of [1] to

[15] or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease mediated by orexin type 2 receptor agonism. [twenty three] The compound or a pharmaceutically acceptable salt thereof according to

[22] , wherein the disease mediated by orexin type 2 receptor agonism is selected from narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, hypersomnia associated with Guillain-Barré syndrome, hypersomnia associated with Kleine-Levin syndrome, and hypersomnia associated with dementia with Lewy bodies. [Effects of the Invention]

[0018] According to the present invention, it is possible to provide a compound having excellent orexin type 2 receptor agonist activity. DETAILED DESCRIPTION OF THE INVENTION

[0019] The present invention will be described below based on specific embodiments, but the present invention is not limited to these embodiments. In addition, all documents cited in this specification, including patent publications, patent application publications, and non-patent publications, are incorporated herein by reference in their entirety for all purposes.

[0020] The "pharmaceutically acceptable salt" in the present invention is not particularly limited as long as it is pharmacologically acceptable and can form a salt with the compound of the present invention. Specific examples include acid addition salts such as acetate, propionate, butyrate, formate, trifluoroacetate, maleate, fumarate, tartrate, citrate, stearate, succinate, ethylsuccinate, malonate, malate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, hydrochloride, hydrobromide, phosphate, nitrate, sulfate, hydroiodide, nicotinate, and oxalate; inorganic base addition salts such as lithium salt, sodium salt, potassium salt, and calcium salt; organic base addition salts such as triethylamine, pyridine, morpholine, and piperidine; and addition salts with amino acids such as aspartic acid and glutamic acid.

[0021] The compounds of the present invention also include anhydrates and solvates (including hydrates) thereof.

[0022] The compounds of the present invention also include isotope-labeled compounds. Specific examples of such isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, etc. The above isotopically labeled compounds can be uniformly prepared by using readily available isotopically labeled reagents instead of non-isotopically labeled reagents and carrying out operations similar to those disclosed in the Examples below.

[0023] The compound of the present invention may be used in the form of a prodrug. A prodrug is a compound that is converted into the compound of the present invention by a reaction with an enzyme, gastric acid, or the like under physiological conditions in a living body, i.e., a compound that is converted into the compound of the present invention by enzymatic oxidation, reduction, hydrolysis, or the like, or a compound that is converted into the compound of the present invention by hydrolysis, etc., with gastric acid, or the like.

[0024] In the definitions of substituents herein, the number of carbon atoms may be expressed as, for example, "C 1-6 " It can also be written as "C 1-6The term "alkyl" is synonymous with alkyl having 1 to 6 carbon atoms.

[0025] In this specification, any substituent not specifically labeled with the term "optionally substituted" refers to an "unsubstituted" substituent. In the case of the definition of "optionally substituted", when a substituent is present, the number of the substituent is not particularly limited as long as it is substitutable, and may be one or more. Furthermore, the bonding position of the substituent may be any scientifically acceptable position unless otherwise specified in this specification.

[0026] In this specification, "C 1-6 The term "alkyl" refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl.

[0027] In this specification, "C 3-8 "Cycloalkyl" means a cyclic non-aromatic hydrocarbon group having 3 to 8 carbon atoms. 3-8 The term "cycloalkyl" also includes those having a partially unsaturated bond and those that are bridged. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, etc.

[0028] As used herein, "3- to 10-membered heterocyclyl" refers to a monocyclic or bicyclic non-aromatic heterocycle composed of 3 to 10 atoms, which contains, in addition to carbon atoms, 1 to 4 identical or different heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms as ring-constituting atoms. The term "3- to 8-membered heterocyclyl" as used herein can be understood in the same manner based on the above. "3- to 10-membered heterocyclyl" and "3- to 8-membered heterocyclyl" include those having a partially unsaturated bond, a partially bridged structure, and a partially spiro-substituted heterocyclyl. Specific examples include pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl.

[0029] As used herein, the term "halogen" refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0030] In this specification, "C 6-10 "Aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group whose rings are composed of only 6 to 10 carbon atoms. In the case of a bicyclic aryl group, if one ring is aromatic, the other ring may have a non-aromatic ring structure. Specific examples include phenyl, 1-naphthyl, and 2-naphthyl.

[0031] As used herein, the term "5- to 12-membered heteroaryl" refers to a monocyclic or bicyclic 5- to 12-membered aromatic heterocycle containing, in addition to carbon atoms as ring-constituting atoms, 1 to 4 identical or different heteroatoms selected from the group consisting of oxygen atoms, nitrogen atoms, and sulfur atoms. In the case of a bicyclic heteroaryl group, when one ring is an aromatic ring or an aromatic heterocyclic ring, the other ring may be a non-aromatic ring structure. Specific examples include pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, azolyl, thiazolyl, indolyl, purinyl, tetrahydronaphthyridyl, 2-quinolyl, 4-quinolyl, and thiophenyl.

[0032] In this specification, "C1-6 "Alkoxy" refers to the above "C 1-6 Specific examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, and the like.

[0033] In this specification, "C 3-8 "Cycloalkoxy" refers to the above "C 3-8 Specific examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, and the like.

[0034] As used herein, "3- to 8-membered heterocyclyloxy" and "C 6-10 The terms "aryloxy" and "5- to 12-membered heteroaryloxy" refer to the same as the above-mentioned "3- to 8-membered heterocyclyl" and "C 6-10 "aryl" or "5- to 12-membered heteroaryl" means an oxy group substituted with "aryl" or "5- to 12-membered heteroaryl".

[0035] In this specification, "C 3-8 Cycloalkyl C 1-6 "Alkoxy" refers to the above "C 3-8 The "C" substituted with "cycloalkyl" 1-6 Specifically, for example, the above-mentioned "C 3-8 Specific examples of "cycloalkyl" and the above "C 1-6 Specific examples of "alkoxy" include those bonded to the alkyl group.

[0036] As used herein, the term "3- to 8-membered heterocyclyl C 1-6 "Alkoxy" refers to the "C alkoxy" substituted by the "3- to 8-membered heterocyclyl". 1-6 Specifically, for example, the specific examples of the "3- to 8-membered heterocyclyl" and the "C 1-6 Specific examples of "alkoxy" include those bonded to the alkyl group.

[0037] In this specification, "C 6-10 Aryl C 1-6 "Alkoxy" refers to the above "C 6-10 aryl" 1-6 Specifically, for example, the above-mentioned "C 6-10 Specific examples of "aryl" and the above "C 1-6 Specific examples of "alkoxy" include those bonded to the alkyl group.

[0038] In this specification, "C 5-12 Heteroaryl C 1-6 "Alkoxy" refers to the above "C 5-12 "C" substituted with "heteroaryl" 1-6 Specifically, for example, the above-mentioned "C 5-12 Specific examples of "heteroaryl" and the above "C 1-6 Specific examples of "alkoxy" include those bonded to the alkyl group.

[0039] R of the compound represented by formula (I) of the present invention 1 As for C 1-6 Alkyl group, C 3-8 Cycloalkyl group, 3- to 8-membered heterocyclyl group, hydroxy group, C 6-10 Aryl group, C substituted with 1 to 6 halogens 6-10 Aryl group, 1-6 [C substituted with 1-3 halogens 1-6 C substituted with alkyl group 6-10 Aryl groups, 5- to 12-membered heteroaryl groups, 5- to 12-membered heteroaryl groups substituted with 1 to 6 halogens, 1 to 6 C substituted with 1 to 3 halogens 1-6 5-12 membered heteroaryl group substituted with alkyl group, C 1-6 Alkoxy group, C substituted with 1 to 6 halogens 1-6 Alkoxy group, C substituted with 1 to 6 hydroxy groups 1-6 Alkoxy group, C 3-8 Cycloalkoxy group, C substituted with 1 to 6 halogens 3-8 Cycloalkoxy group, 3- to 8-membered heterocyclyloxy group, C3-8 Cycloalkyl C 1-6 Alkoxy group, C substituted with 1 to 6 halogens 3-8 Cycloalkyl C 1-6 Alkoxy group, 3-8 membered heterocyclyl C 1-6 Alkoxy group or C 6-10 Aryl C 1-6 Alkoxy groups are preferred.

[0040] R of the compound represented by formula (I) of the present invention 2 is a hydrogen atom, a C optionally substituted with 1 to 6 halogen atoms, 1-6 C optionally substituted with alkyl group, 1 to 6 halogen atoms 3-8 A cycloalkyl group, a hydroxy group, or a halogen is preferred, and a hydrogen atom or a halogen is more preferred.

[0041] R of the compound represented by formula (I) of the present invention 3 is a hydrogen atom, a C optionally substituted with 1 to 6 halogen atoms, 1-6 C optionally substituted with alkyl group, 1 to 6 halogen atoms 3-8 A cycloalkyl group, a hydroxy group, or a halogen is preferred, and a hydrogen atom, a halogen, C 1-6 C optionally substituted with an alkyl group or 1 to 6 halogens 1-6 Alkyl groups are more preferred.

[0042] R of the compound represented by formula (I) of the present invention 4 is a hydrogen atom, a C optionally substituted with 1 to 6 halogen atoms, 1-6 C optionally substituted with alkyl group, 1 to 6 halogen atoms 3-8 A cycloalkyl group, a hydroxy group, or a halogen is preferred, and a hydrogen atom or a halogen is more preferred.

[0043] In the formula (I) of the present invention, the above R 1 ~R 4 In the adjacent R 1 and R 2 , R 2 and R 3 , and R3 and R 4 may be linked to each other via a single bond to form a 5- to 8-membered ring. Specific examples of compounds of formula (I) having such a ring include, but are not limited to, the following:

[0044] [ka]

[0045] R of the compound represented by formula (I) of the present invention a is preferably a hydrogen atom.

[0046] R of the compound represented by formula (I) of the present invention 7 The group is a hydrogen atom or C 1-6 Alkyl groups are preferred.

[0047] X in the compound represented by formula (I) of the present invention is -CR b R c - or -O- is preferred, and -O- is more preferred. b and R c are preferably both hydrogen atoms.

[0048] Y in the compound of formula (I) of the present invention is preferably —CO—.

[0049] In the compound of the present invention represented by formula (I), n is preferably 1.

[0050] In the compound of the present invention represented by formula (I), m is preferably 0 or 1, and more preferably 0.

[0051] L in the compound represented by formula (I) of the present invention is preferably —O— or —NH—, more preferably —O—.

[0052] The compound represented by formula (I) of the present invention is more preferably, for example, a compound represented by the following formula (III).

[0053] [ka]

[0054] [In the formula, R 1 is a hydrogen atom, C 1-6 Alkyl group, C 3-8 Cycloalkyl group, 3- to 8-membered heterocyclyl group, hydroxy group, halogen, C 6-10 Aryl group, 5- to 12-membered heteroaryl group, C 1-6 Alkoxy group, C 3-8 Cycloalkoxy group, 3- to 8-membered heterocyclyloxy group, C 6-10 Aryloxy group, 5- to 12-membered heteroaryloxy group, C 3-8 Cycloalkyl C 1-6 Alkoxy group, 3-8 membered heterocyclyl C 1-6 Alkoxy group, C 6-10 Aryl C 1-6 Alkoxy group, or 5- to 12-membered heteroaryl C 1-6 represents an alkoxy group; R 1 is 1 to 6 [C optionally substituted with halogen, hydroxy group, carboxy group, oxo group, amino group, cyano group, 1 to 3 halogens] 1-6 C optionally substituted with an alkyl group or 1 to 3 halogens 1-6 alkoxy groups]; R 2 , R 3 and R 4 each independently represents a hydrogen atom, C optionally substituted with 1 to 6 halogen atoms, 1-6 represents an alkyl group or a halogen; R 7 is a hydrogen atom, a halogen atom, or a C optionally substituted with 1 to 3 halogen atoms 1-6 represents an alkyl group; Q is 1 to 4 R 11 a 3- to 10-membered heterocyclyl group optionally substituted with 1 to 4 R 12 C optionally substituted with 6-10 an aryl group or 1 to 4 R 13represents a 5- to 12-membered heteroaryl group optionally substituted by R 11 , R 12 and R 13 each independently represents a halogen, an oxo group, or C optionally substituted with 1 to 3 halogens 1-6 represents an alkyl group.]

[0055] Specific examples, preferred examples, etc. of the compound represented by formula (III) of the present invention are the same as the examples of the compound represented by formula (I) of the present invention described above and below.

[0056] R of the compound represented by formula (I) of the present invention 1 "C 1-6 In the case of "C alkyl group", 1-6 The alkyl group is preferably isopropyl, isobutyl or pentyl.

[0057] R of the compound represented by formula (I) of the present invention 1 "C 3-8 In the case of "cycloalkyl group", such "C 3-8 The "cycloalkyl group" is preferably cyclohexyl or cyclopentyl.

[0058] R of the compound represented by formula (I) of the present invention 1 When is a "3- to 8-membered heterocyclyl group", such a "3- to 8-membered heterocyclyl group" is preferably pyrrolidine.

[0059] R of the compound represented by formula (I) of the present invention 1 "C 6-10 In the case of "aryl group", such "C 6-10 The "aryl group" is preferably phenyl. Furthermore, the substituents that such phenyl may have are preferably one or more fluorine atoms, or one or more methyls each substituted with one or more fluorine atoms.

[0060] R of the compound represented by formula (I) of the present invention 1When is "5- to 12-membered heteroaryl", the "5- to 12-membered heteroaryl" is preferably pyridyl or thienyl. Furthermore, the substituents that may be substituted on the pyridyl are preferably one or more fluorine atoms.

[0061] R of the compound represented by formula (I) of the present invention 1 "C 1-6 In the case of "alkoxy", such "C 1-6 As the "alkoxy", methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, sec-butoxy, pentyloxy or neopentyloxy is preferred. 1-6 The substituents which may be substituted on alkoxy (eg, ethoxy, propoxy, isopropoxy, isobutoxy) are preferably one or more fluorine atoms or one or more hydroxy groups.

[0062] R of the compound represented by formula (I) of the present invention 1 "C 3-8 In the case of "cycloalkoxy", such "C 3-8 The "cycloalkoxy" is preferably cyclobutyloxy, cyclopentyloxy or bicycloheptyloxy. Furthermore, the substituents which the cyclopentyloxy may have are preferably one or more fluorine atoms.

[0063] R of the compound represented by formula (I) of the present invention 1 When is "3- to 8-membered heterocyclyloxy", such "3- to 8-membered heterocyclyloxy" is preferably tetrahydrofuranyloxy.

[0064] R of the compound represented by formula (I) of the present invention 1 "C 3-8 Cycloalkyl C 1-6 In the case of "alkoxy", such "C 3-8 Cycloalkyl C 1-6The "alkoxy" is preferably cyclopropylmethoxy. Furthermore, the substituents which the cyclopropylmethoxy may have are preferably one or more fluorine atoms.

[0065] R of the compound represented by formula (I) of the present invention 1 "3-8 membered heterocyclyl C 1-6 In the case of "alkoxy", such "3- to 8-membered heterocyclyl C 1-6 As the "alkoxy", tetrahydrofuranylmethoxy or pyrrolidinylethoxy is preferred.

[0066] R of the compound represented by formula (I) of the present invention 1 "C 6-10 Aryl C 1-6 In the case of "alkoxy", such "C 6-10 Aryl C 1-6 As the "alkoxy", benzyloxy is preferred.

[0067] R of the compound represented by formula (I) of the present invention 2 When is a "halogen", the "halogen" is preferably a fluorine atom or a chlorine atom.

[0068] R of the compound represented by formula (I) of the present invention 2 "C 1-6 In the case of "C alkyl group", 1-6 The alkyl group is preferably propyl.

[0069] R of the compound represented by formula (I) of the present invention 3 When is a "halogen", the "halogen" is preferably a chlorine atom.

[0070] R of the compound represented by formula (I) of the present invention 3 "C optionally substituted with 1 to 6 halogens" 1-6 In the case of "an alkyl group," the "C optionally substituted with 1 to 6 halogen atoms" is 1-6 The "alkyl group" is preferably methyl or trifluoromethyl.

[0071] R of the compound represented by formula (I) of the present invention 4 When is a "halogen", the "halogen" is preferably a fluorine atom or a chlorine atom.

[0072] R of the compound represented by formula (I) of the present invention 7 "C optionally substituted with 1 to 6 halogens" 1-6 In the case of "an alkyl group," the "C optionally substituted with 1 to 6 halogen atoms" is 1-6 The "alkyl group" is preferably an unsubstituted methyl group.

[0073] Q of the compound represented by formula (I) of the present invention is 1 to 4 R 12 C optionally substituted with 6-10 an aryl group or 1 to 4 R 13 and optionally substituted 5- to 12-membered heteroaryl groups, each of which is a bicyclic C 6-10 An aryl group or a 5- to 12-membered heteroaryl group is more preferred.

[0074] R in Q of the compound represented by formula (I) of the present invention 12 and R 13 are each preferably an oxo group.

[0075] Q of the compound represented by formula (I) of the present invention is more preferably a structure represented by any one selected from the group consisting of the following formulae (II-1), (II-2), (II-3) and (II-4):

[0076] [ka] [ka] [ka] [ka]

[0077] [In formulas (II-1), (II-2), (II-3) and (II-4), Z 21 is CR f or N, Ring A represents a monocyclic 6- to 8-membered heterocyclyl ring or a monocyclic 6- to 7-membered heteroaryl ring; R 2701 , R 2702 , R 2703 and R 2704 each independently represents a halogen atom or a C group optionally substituted with 1 to 3 halogen atoms; 1-6 represents an alkyl group, R d , R e , and R f are each independently a hydrogen atom, a halogen atom, or a C optionally substituted with 1 to 3 halogen atoms. 1-6 represents an alkyl group, R 2601 , R 2602 , R 2603 and R 2604 each independently represents a hydrogen atom or a C optionally substituted with 1 to 6 halogen atoms; 1-6 C optionally substituted with an alkyl group or 1 to 6 halogens 3-8 represents a cycloalkyl group, Each q independently represents an integer of 0 to 4.

[0078] In addition, R in the compounds represented by formulas (II-1), (II-2), (II-3) and (II-4) of the present invention 2701 , R 2702 , R 2703 and R 2704 In the case of the ring A, the hydrogen atoms bonded to the carbon atoms constituting the ring A are 1 to 4 R 2701 , R 2702 , R 2703 or R 2704 Here, it means that ring A may be substituted with 1 to 4 R 2701 , R 2702 , R 2703 or R 2704 When R is substituted with 2701 , R 2702 , R 2703 and R2704 represents an oxo group in the ring A, NR 2601 , N.R. 2602 , N.R. 2603 , N.R. 2604 It is clear that hydrogen atoms bonded to carbon atoms other than the condensed portion are substituted. 2701 ), (R 2702 ), (R 2703 ) and (R 2704 ) is an integer of 0 to 4 means that the group is unsubstituted or has 1 to 4 (R 2701 ), (R 2702 ), (R 2703 ) or (R 2704 ) is replaced by

[0079] R of the compounds represented by formula (II-1), (II-2), (II-3) and II-4) of the present invention 2601 , R 2602 , R 2603 and R 2604 In addition, R in the compounds represented by formulas (II-1), (II-2), (II-3) and (II-4) of the present invention is preferably a hydrogen atom. 2701 , R 2702 , R 2703 and R 2704 The group may be a hydrogen atom, a halogen atom, or C 1-6 An alkyl group is preferred. As the "halogen", a fluorine atom is preferred, and as the "C 1-6 The alkyl group is preferably methyl.

[0080] R of the compound represented by formula (II-1) of the present invention d As for R, halogen is preferred, and as such "halogen", a fluorine atom or a chlorine atom is preferred. e In addition, R of the compound represented by formula (II-1) of the present invention is preferably a hydrogen atom. f As the "halogen", halogen is preferred, and as such "halogen", a fluorine atom is preferred.

[0081] The "monocyclic 6- to 8-membered heterocyclyl ring or monocyclic 6- to 7-membered heteroaryl ring" in A of the compound represented by formula (II-1), (II-2), (II-3), or (II-4) of the present invention is preferably a tetrahydropyridine ring, a dihydropyridine ring, a dihydrooxazine ring, or a tetrahydroazepine ring.

[0082] Furthermore, as Q of the compound represented by formula (I) of the present invention, a compound represented by the following formula (IV), (V), or (VI) is particularly preferred.

[0083] [ka] [ka] [ka]

[0084] [In formulas (IV), (V) and (VI), R 31 , R 32 , R 33 , R 35 and R 36 each independently represents a hydrogen atom, C optionally substituted with 1 to 6 halogen atoms, 1-6 represents an alkyl group, a hydroxy group, or a halogen atom; Z 31 , Z 32 and Z 33 each independently represents CH or N, Z a is O or CR g represents 2, R g each independently represents a hydrogen atom or C optionally substituted with 1 to 6 halogen atoms 1-6 represents an alkyl group.]

[0085] R of the compound represented by formula (IV) of the present invention 31 is preferably a hydrogen atom or a halogen.

[0086] R of the compound represented by formula (IV) of the present invention 35 and R 36 are hydrogen atoms and C 1-6 An alkyl group or a halogen atom is preferred. 1-6 The "alkyl group" is preferably methyl, and the "halogen" is preferably a fluorine atom.

[0087] Z of the compound represented by formula (IV) of the present invention a As for CR g 2 is preferred. g is preferably a hydrogen atom.

[0088] R of the compound represented by formula (V) of the present invention 32 is preferably a hydrogen atom.

[0089] R of the compound represented by formula (VI) of the present invention 33 is preferably a hydrogen atom.

[0090] R of the compound represented by formula (IV) of the present invention 31 When is a "halogen", the "halogen" is preferably a fluorine atom or a chlorine atom.

[0091] As the overall Q of the compound represented by formula (I) of the present invention, structures represented by Q1 to Q19 below can be mentioned, and structures represented by Q1 to Q8 are preferred.

[0092] [ka]

[0093] As described above, the definitions, specific examples, preferred examples, etc. of each substituent in the compound represented by formula (I) of the present invention have been described. However, as the compound represented by formula (I) of the present invention, compounds in which the specific examples and preferred examples of each of the above groups are arbitrarily combined with each other are also preferred.

[0094] A general method for synthesizing the compound of the present invention represented by formula (I) will be explained below.

[0095] The compound represented by formula (I) of the present invention (hereinafter sometimes abbreviated as the compound of the present invention) can be synthesized by a combination of methods known in this field, including the synthesis method described below.

[0096] The compounds of the present invention represented by formula (I) and pharmaceutically acceptable salts thereof (hereinafter, these may be collectively referred to as the compounds of the present invention) can be synthesized by a combination of conventional methods known in the art, including the synthesis methods described below.

[0097] In each step, the compounds in the reaction scheme may form salts, and examples of such salts include those similar to the salts of the compound represented by formula (I) of the present invention.

[0098] These salts can be converted into free forms or other desired salts by known methods. Conversely, when the compound obtained in each step is in a free form, it can be converted into the desired salt by known methods.

[0099] In each step, the protection or removal of a functional group can be carried out in accordance with a protecting group for each substituent commonly used in this field and a known method, for example, the method described in "Protective Groups in Organic Synthesis (5th Edition)" by T.W. Greene and P.G.W. Uts, 2014, John Wiley & Sons Inc., or the method described in the Examples.

[0100] In addition, in the cases where raw materials and reagent compounds are commercially available in each step, the commercially available products can be used as they are.

[0101] Furthermore, in each step, the compound obtained may be isolated and purified by a method such as column chromatography, recrystallization, distillation, etc., or may be used in the next step as is without isolation.

[0102] In addition, when the reaction scheme of each step contains optical isomers, stereoisomers, or rotational isomers, these are also included in the same reaction scheme, and each can be obtained as a single product by a synthesis method or separation method known per se that is usually performed in this field. For example, when an optical isomer exists in the compound represented by formula (I) of the present invention, the optical isomer resolved from the compound is also included in the compound represented by formula (I) of the present invention.

[0103] Representative methods for synthesizing the compounds of the present invention are described below, in which the symbols in each formula are defined as in formula (I).

[0104] Manufacturing Method 1: The compound represented by formula (I-1) can be produced, for example, by the following method.

[0105] [ka] [In the formula, each symbol has the same meaning as defined above. 1 and P 2 indicates a suitable protecting group.]

[0106] (Process 1) This step is a step of producing compound (3) by subjecting compound (1) and compound (2) to a general dehydration condensation reaction in the presence of a phosphine compound and an azo compound, or in the presence of a phosphorane compound.

[0107] The reaction in this step can be carried out by a known method known as the Mitsunobu reaction. Examples of the phosphine compound used include triphenylphosphine and tributylphosphine. Examples of the azo compound used include diethyl azodicarboxylate and diisopropyl azodicarboxylate. Examples of the phosphorane compound used include cyanomethylenetrimethylphosphorane and cyanomethylenetributylphosphorane. The reaction is usually carried out in an inert solvent, such as tetrahydrofuran, dichloromethane, benzene, toluene, or a mixture of these solvents. The reaction time is usually 1 hour to 24 hours, and the reaction temperature is from -20°C to the boiling point of the solvent.

[0108] (Process 2) In this step, the protecting group P of compound (3) is removed by a known method. 2 This is a process for producing compound (4) by removing

[0109] (Step 3) In this step, the protecting group P of compound (4) is removed by a known method. 1 This is a process for producing compound (5) by removing

[0110] (Step 4) This step is a step of producing compound (I-1) according to the present invention by subjecting compound (5) to general amide bond forming conditions. This reaction can be carried out using a condensing agent well known to those skilled in the art, or by an ester activation method, mixed acid anhydride method, acid chloride method, carbodiimide method, etc., which are available to those skilled in the art. Examples of such amide bond-forming reagents include thionyl chloride, oxalyl chloride, N,N'-dicyclohexylcarbodiimide, 1-methyl-2-chloropyridinium iodide, N,N'-carbonyldiimidazole, diphenylphosphoryl chloride, diphenylphosphoryl azide, N,N'-disuccinimidyl carbonate, N,N'-disuccinimidyl oxalate, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, and 2-(5-norbornene-2,3-dicarboximide)-1,1,3,3-tetramethyluronium. Examples of suitable amide bond-forming reagents include tetrafluoroborate, O-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate, bromotripyrrolidinophosphonium hexafluorophosphate, ethyl chloroformate, isobutyl chloroformate, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, and propylphosphonic anhydride. Among these, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate are preferred. In the amide bond-forming reaction, a base and / or a condensation auxiliary may be used together with the amide bond-forming reagent. The base to be used is not particularly limited as long as it is an organic base, but among them, for example, tertiary aliphatic amines and the like are preferred, and particularly, for example, triethylamine, N,N-diisopropylethylamine and the like are suitable.Examples of the condensation promoter include 1-hydroxybenzotriazole hydrate and N-hydroxysuccinimide. The base, amide-forming reagent, and condensation promoter used in this reaction can be used alone or in combination. The reaction is usually carried out in an inert solvent, such as tetrahydrofuran, acetonitrile, N,N-dimethylformamide, ethyl acetate, 1,4-dioxane, benzene, toluene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, pyridine, or a mixture of these solvents. The reaction time is usually 0.5 to 96 hours, preferably 1 to 24 hours. The reaction temperature is usually -78 to 100°C, preferably -20°C to the boiling point of the solvent.

[0111] Manufacturing Method 2: The compound represented by the formula (I-1) can also be produced, for example, by the following method.

[0112] [ka] [In the formula, each symbol has the same meaning as defined above. 3 represents a suitable protecting group, and LG 1 indicates an appropriate leaving group.]

[0113] (Step 5) In this step, the protecting group P of compound (6) is removed by a known method. 3 This is a process for producing compound (7) by removing

[0114] (Step 6) This step produces compound (8) by subjecting the hydroxy group of compound (7) to general reaction conditions for converting it to a leaving group. Examples of reaction conditions for this reaction include those using methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, and the like. A base can also be used in this reaction. Examples of bases that can be used include organic bases such as triethylamine, N,N-diisopropylethylamine, pyridine, and 1,8-diazabicyclo[5.4.0]undec-7-ene; alkali metal hydrides such as sodium hydride and potassium hydride; inorganic bases such as sodium bicarbonate, sodium carbonate, and potassium carbonate; metal alkoxides such as sodium methoxide and potassium tert-butoxide; organometallic reagents such as n-butyllithium and isopropylmagnesium chloride; and metal amide reagents such as LDA and LHMDS. The reaction is usually carried out in an inert solvent, such as tetrahydrofuran, acetonitrile, N,N-dimethylformamide, ethyl acetate, 1,4-dioxane, benzene, toluene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, pyridine, etc., or a mixture of these solvents. The reaction time is usually 1 hour to 24 hours, and the reaction temperature is from -78°C to the boiling point of the solvent.

[0115] (Step 7) This step produces the compound (I-1) of the present invention by reacting the leaving group of compound (8) with a hydroxy compound, an amine compound, an organoboron compound, an alkenyl compound, an alkynyl compound, an organic cyanide compound, or the like in the presence of a base and a metal catalyst, and optionally in the presence of a phosphine ligand. The hydroxy compound, amine compound, organoboron compound, alkenyl compound, alkynyl compound, organic cyanide compound, or the like used may be commercially available or synthesized by known methods or methods similar thereto. Examples of the base used include inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, and sodium hydroxide; organic salts such as ammonium acetate; metal alkoxides such as sodium methoxide and sodium tert-butoxide; and organic bases such as triethylamine, N,N-diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, and pyridine. Depending on the type of coupling, a base may not be used. Examples of metal catalysts include bis(tri-o-tolylphosphine)palladium(0), tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, and XPhos Pd G3. For palladium acetate, etc., appropriate ligands may be selected from those listed in John Wiley & Sons Inc.'s "Palladium Reagents and Catalysts" (2004) or their related ligands. Examples of phosphine ligands include tri(o-tolyl)phosphine, SPhos, XPhos, DPPF, BINAP, and XantPhos. Depending on the type of coupling, a phosphine ligand may not be used.The reaction is usually carried out in an inert solvent, such as tetrahydrofuran, acetonitrile, N,N-dimethylformamide, 1,4-dioxane, toluene, 1,2-dimethoxyethane, water, or a mixture of these solvents. The reaction time is usually 0.5 to 96 hours, preferably 1 to 24 hours. The reaction temperature is usually 0 to 200°C, preferably room temperature to 100°C.

[0116] Manufacturing Method 3: The compound represented by formula (I-2) can be produced, for example, by the following method.

[0117] [ka] [In the formula, each symbol has the same meaning as defined above. 1 , P 2 and P 4 each independently represents a suitable protecting group, LG 2 indicates an appropriate leaving group. R 5 is optionally substituted C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 Aryl group, C 5-12 represents a heteroaryl group.]

[0118] (Step 8) This step is a step of producing compound (11) by subjecting compound (9) and compound (10) to the same conditions as in step 1 of production method 1.

[0119] (Step 9) In this step, compound (11) is reacted with an alcohol represented by general formula (12) in the presence of a base to produce compound (13). Examples of the base to be used include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate; alkali metal hydrogencarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate; metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; tertiary aliphatic amines such as trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,5-azabicyclo[4.3.0]non-5-ene; and aromatic amines such as pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline and isoquinoline. Examples of alcohols represented by general formula (12) include methanol, ethanol, 2-propanol, and benzyl alcohol, which are usually used as solvents. The reaction time is usually 1 to 24 hours, and the reaction temperature is from -20°C to the boiling point of the solvent.

[0120] (Step 10) In this step, compound (16) is produced by subjecting compound (13) and an alcohol represented by general formula (14) to the same conditions as in step 1 of production method 1. The alcohol represented by general formula (14) may be a commercially available product, or may be synthesized by a known method or a method analogous thereto. Examples of the alcohol include methanol, ethanol, 2-propanol, butanol, neopentyl alcohol, and benzyl alcohol.

[0121] (Step 11) In this step, compound (13) and a compound having a leaving group represented by general formula (15) are subjected to general nucleophilic substitution reaction conditions in the presence of a base to produce compound (16). The compound represented by general formula (15) can be a commercially available product, or one synthesized by a known method or a method analogous thereto. Examples of suitable compounds include alkyl halides such as iodomethane, iodoethane, 2-iodopropane, benzyl bromide, (iodomethyl)cyclopropane, 1-chloro-2-methyl-2-propanol, and bromocyclopentane; and alkylsulfonic acid esters such as 1,1,1-trifluoropropan-2-yl trifluoromethanesulfonate. Examples of the base to be used include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate; alkali metal hydrogencarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate; metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; tertiary aliphatic amines such as trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,5-azabicyclo[4.3.0]non-5-ene; and aromatic amines such as pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline and isoquinoline. The reaction is usually carried out in an inert solvent, such as tetrahydrofuran, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, 1,4-dioxane, benzene, toluene, acetone, methyl ethyl ketone, ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, pyridine, etc., or a mixture of these solvents. The reaction time is usually 1 hour to 24 hours, and the reaction temperature is from -20°C to the boiling point of the solvent.

[0122] (Step 12) In this step, the protecting group P of compound (16) is removed by a known method. 4 by removing the compound (17).

[0123] (Step 13) In this step, compound (17) and compound (18) are subjected to the same conditions as in step 1 of production method 1 to produce compound (19).

[0124] (Step 14) In this step, compound (19) is subjected to the same conditions as in step 2 of production method 1 to produce compound (20).

[0125] (Step 15) In this step, compound (20) is subjected to the same conditions as in step 3 of production method 1 to produce compound (21).

[0126] (Step 16) In this step, compound (21) is subjected to the same conditions as in step 4 of production method 1 to produce compound (I-2) of the present invention.

[0127] Manufacturing Method 4: The compound represented by the formula (19) can also be produced, for example, by the following method.

[0128] [ka] [In the formula, each symbol has the same meaning as defined above. 1 and P 2 each independently represents a suitable protecting group, LG 2 indicates an appropriate leaving group. R 5 is optionally substituted C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, 3- to 8-membered heterocyclyl groups, C 6-10 Aryl group, C 5-12 represents a heteroaryl group.]

[0129] (Step 17) This step is a step of producing a compound (22) by subjecting the compound (1) and the compound (10) to the same conditions as in step 1 of production method 1.

[0130] (Step 18) In this step, compound (22) is subjected to the same conditions as in step 9 of production method 3 to produce compound (23).

[0131] (Step 19) This step is a step for producing the compound (19) by subjecting the compound (23) to the same conditions as in step 10 of production method 3.

[0132] (Step 20) This step is a step of producing the compound (19) by subjecting the compound (23) to the same conditions as in step 11 of production method 3.

[0133] Manufacturing Method 5: The compound represented by formula (I-3) can be produced, for example, by the following method.

[0134] [ka] [In the formula, each symbol has the same meaning as defined above.] 3 indicates an appropriate leaving group. R 6 is a hydrogen atom, optionally substituted C 1-6 alkyl group, optionally substituted C 3-8 It represents a cycloalkyl group, an optionally substituted 3- to 8-membered heterocyclyl group, a hydroxy group, or a halogen.]

[0135] (Step 21) In this step, compound (24) and compound (25) are subjected to the same conditions as in step 1 of production method 1 to produce compound (I-3) of the present invention.

[0136] (Step 22) In this step, compound (25) is subjected to general reaction conditions for conversion to a leaving group, similar to step 6 of production method 2, to produce compound (26).

[0137] (Step 23) This step is a step for producing compound (I-3) of the present invention by subjecting compound (24) and compound (26) having a leaving group to general nucleophilic substitution reaction conditions in the presence of a base. Examples of the base to be used include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate; alkali metal hydrogencarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate; metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; tertiary aliphatic amines such as trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,5-diazabicyclo[4.3.0]non-5-ene; and aromatic amines such as pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline and isoquinoline. The reaction is usually carried out in an inert solvent, such as tetrahydrofuran, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, 1,4-dioxane, benzene, toluene, acetone, methyl ethyl ketone, ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, pyridine, etc., or a mixture of these solvents. The reaction time is usually 1 hour to 24 hours, and the reaction temperature is from -20°C to the boiling point of the solvent.

[0138] Manufacturing Method 6: The compounds represented by formula (I-4) and formula (I-5) can be produced, for example, by the following method.

[0139] [ka] [In the formula, each symbol has the same meaning as defined above. 5 represents a suitable protecting group, and LG 4 indicates an appropriate leaving group. R 6 is a hydrogen atom, optionally substituted C 1-6 alkyl group, optionally substituted C 3-8 It represents a cycloalkyl group, an optionally substituted 3- to 8-membered heterocyclyl group, a hydroxy group, or a halogen.]

[0140] (Step 24) In this step, compound (27) having a leaving group and compound (25) are subjected to general nucleophilic substitution reaction conditions, similar to step 23 of production method 5, to produce compound (28).

[0141] (Step 25) In this step, the protecting group P of compound (28) is removed by a known method. 5 This is a process for producing the compound (I-4) of the present invention by removing

[0142] (Step 26) In this step, compound (I-4) is subjected to typical catalytic hydrogenation conditions, optionally under a hydrogen atmosphere, to produce compound (I-5) of the present invention. Examples of reaction conditions include those using palladium on carbon, palladium (II) hydroxide, Raney nickel, etc. The reaction solvent used is not particularly limited as long as it does not interfere with the reaction, and specific examples include methanol, ethanol, acetic acid, ethyl acetate, benzene, toluene, xylene, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dichloromethane, acetonitrile, etc., or mixtures of these solvents. The reaction time is usually 1 to 14 days, and the reaction temperature is from room temperature to 100°C.

[0143] Manufacturing Method 7: The compound represented by the formula (28) can also be produced, for example, by the following method.

[0144] [ka] [In the formula, each symbol has the same meaning as defined above. 1 , P 2 and P 5 each independently represents a suitable protecting group, LG 4 indicates an appropriate leaving group. R 6 is a hydrogen atom, optionally substituted C 1-6 alkyl group, optionally substituted C 3-8 It represents a cycloalkyl group, an optionally substituted 3- to 8-membered heterocyclyl group, a hydroxy group, or a halogen.]

[0145] (Step 27) In this step, compound (27) having a leaving group and compound (29) are subjected to general nucleophilic substitution reaction conditions, similar to step 23 of production method 5, to produce compound (30).

[0146] (Step 28) In this step, compound (30) is subjected to the same conditions as in step 2 of production method 1 to produce compound (31).

[0147] (Step 29) This step is a step of producing compound (32) by subjecting compound (31) to the same conditions as in step 3 of production method 1.

[0148] (Step 30) This step is a step for producing the compound (28) by subjecting the compound (32) to the same conditions as in step 4 of production method 1.

[0149] Manufacturing Method 8: The compound represented by formula (I-6) can be produced, for example, by the following method.

[0150] [ka] [In the formula, each symbol has the same meaning as defined above. 6 represents a suitable protecting group, and LG 4 indicates an appropriate leaving group. R 6 is a hydrogen atom, optionally substituted C 1-6 alkyl group, optionally substituted C 3-8 It represents a cycloalkyl group, an optionally substituted 3- to 8-membered heterocyclyl group, a hydroxy group, or a halogen.]

[0151] (Step 31) In this step, compound (33) having a leaving group and compound (34) are subjected to general nucleophilic substitution reaction conditions in the presence of a base to produce compound (35). Examples of the base to be used include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate; alkali metal hydrogencarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate; metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; tertiary aliphatic amines such as trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,5-diazabicyclo[4.3.0]non-5-ene; and aromatic amines such as pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline and isoquinoline. The reaction is usually carried out in an inert solvent, such as tetrahydrofuran, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, 1,4-dioxane, benzene, toluene, acetone, methyl ethyl ketone, ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, pyridine, or a mixture of these solvents. The reaction time is usually 1 hour to 96 hours, preferably 1 hour to 24 hours. The reaction temperature is usually -20°C to 200°C, preferably room temperature to the boiling point of the solvent.

[0152] (Step 32) In this step, compound (35) is subjected to general catalytic hydrogenation reaction conditions, if necessary under a hydrogen atmosphere, in the same manner as in step 26 of production method 6, to produce compound (36).

[0153] (Step 33) In this step, compound (36) is subjected to typical intramolecular cyclization conditions in the presence of an acid, and optionally in the presence of a solvent, to produce compound (I-6) of the present invention. Examples of the acid used include acetic acid, formic acid, sulfuric acid, trifluoroacetic acid, and p-toluenesulfonic acid. The reaction solvent used is not particularly limited as long as it does not interfere with the reaction, and specific examples include methanol, ethanol, acetic acid, ethyl acetate, benzene, toluene, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dichloromethane, acetonitrile, water, and mixtures of these solvents. The reaction time is usually 1 hour to 24 hours, and the reaction temperature is from 0°C to the boiling point of the solvent.

[0154] Manufacturing Method 9: The compound represented by the formula (25) can be produced, for example, by the following method.

[0155] [ka] [In the formula, each symbol has the same meaning as defined above. 1 ,P 2 and P 4 each independently represents a suitable protecting group.

[0156] (Step 34) This step is a step of producing compound (39) by subjecting compound (37) and compound (38) to the same conditions as in step 1 of production method 1.

[0157] (Step 35) In this step, compound (39) is subjected to the same conditions as in step 2 of production method 1 to produce compound (40).

[0158] (Step 36) In this step, compound (40) is subjected to the same conditions as in step 3 of production method 1 to produce compound (41).

[0159] (Step 37) This step is a step of producing compound (42) by subjecting compound (41) to the same conditions as in step 4 of production method 1.

[0160] (Step 38) In this step, the protecting group P of compound (42) is removed by a known method. 4 by removing the compound (25).

[0161] Manufacturing Method 10: The compound represented by the formula (42) can also be produced, for example, by the following method.

[0162] [ka] [In the formula, each symbol has the same meaning as defined above. 3 and P 4 each independently represents a suitable protecting group, LG 1 indicates an appropriate leaving group.]

[0163] (Step 39) In this step, the protecting group P of the compound (43) is removed by a known method. 4 to produce compound (44).

[0164] (Step 40) In this step, compound (44) is subjected to general reaction conditions for conversion to a leaving group, similar to step 6 of production method 2, to produce compound (45).

[0165] (Step 41) This step is a step of producing the compound (42) by subjecting the compound (45) to the same conditions as in step 7 of production method 2.

[0166] Manufacturing Method 11: The compounds represented by the formulas (27) and (33) can be produced, for example, by the following method.

[0167] [ka] [In the formula, each symbol has the same meaning as defined above. 5 and P 6 represents a suitable protecting group, and LG 4 indicates a suitable leaving group, and W 3 R represents the appropriate halogen atom. 6 is a hydrogen atom, optionally substituted C 1-6 alkyl group, optionally substituted C 3-8 It represents a cycloalkyl group, an optionally substituted 3- to 8-membered heterocyclyl group, a hydroxy group, or a halogen.]

[0168] (Step 42) This step produces compound (47) by subjecting compound (46) to general halogenation reaction conditions. Examples of halogenating reagents include chlorinating agents such as N-chlorosuccinimide, brominating agents such as N-bromosuccinimide, and iodinating agents such as N-iodosuccinimide. The reaction is typically carried out in an inert solvent, such as tetrahydrofuran, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, 1,4-dioxane, acetone, methyl ethyl ketone, ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, water, or a mixture of these solvents. The reaction time is typically 1 hour to 96 hours, preferably 1 hour to 24 hours. The reaction temperature is typically −78°C to 100°C, preferably −20°C to the boiling point of the solvent.

[0169] (Step 43) In this step, halogen W contained in compound (47) is reacted with 3This is a process for producing compound (33) by reacting an alkenyl compound or the like with the above compound (33) in the presence of a base and a metal catalyst, and optionally in the presence of a phosphine ligand. The alkenyl compound used may be a commercially available product, or may be synthesized by a known method or a method similar thereto. Examples include ethyl acrylate and t-butyl acrylate. Examples of the base used include inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, and sodium hydroxide; organic salts such as ammonium acetate; metal alkoxides such as sodium methoxide and potassium tert-butoxide; and organic bases such as triethylamine, N,N-diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, and pyridine. Depending on the type of coupling, a base may not be used. Examples of metal catalysts include bis(tri-o-tolylphosphine)palladium(0), tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, and XPhos Pd G3. For palladium acetate, etc., appropriate ligands can be selected from those listed in John Wiley & Sons Inc.'s "Palladium Reagents and Catalysts" (2004) or their related ligands. Examples of phosphine ligands include tri(o-tolyl)phosphine, SPhos, XPhos, DPPF, BINAP, and XantPhos. Depending on the type of coupling, phosphine ligands may not be used. The reaction is usually carried out in an inert solvent, such as tetrahydrofuran, acetonitrile, N,N-dimethylformamide, 1,4-dioxane, toluene, 1,2-dimethoxyethane, water, etc., and mixtures of these solvents. The reaction time is usually 0.5 to 96 hours, preferably 1 to 24 hours.The reaction temperature is usually from 0°C to 200°C, preferably from room temperature to 100°C.

[0170] (Step 44) In this step, compound (33) is subjected to general intramolecular cyclization reaction conditions in the presence of an acid, similar to step 33 of production method 8, to produce compound (48).

[0171] (Step 45) In this step, a suitable protecting group P is attached to the amide group of compound (48) by a known method. 5 to produce the compound (27).

[0172] The compounds of the present invention have orexin type 2 receptor agonist activity and are therefore useful for the treatment or prevention of diseases mediated by orexin type 2 receptor agonist activity. Specifically, for example, the compounds of the present invention are useful for the treatment or prevention of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcoleptic symptoms, hypersomnia associated with Parkinson's disease, hypersomnia associated with Guillain-Barré syndrome, hypersomnia associated with Kleine-Levin syndrome, and hypersomnia associated with dementia with Lewy bodies, and are particularly useful for the treatment or prevention of narcolepsy.

[0173] Furthermore, the compounds of the present invention preferably have selectivity for orexin type 2 receptor agonism. For example, the compounds of the present invention preferably have significantly higher orexin type 2 receptor agonism than orexin type 1 receptor agonism. In fact, among the compounds of the present invention represented by formula (I), certain compounds have significantly higher orexin type 2 receptor agonism than orexin type 1 receptor agonism.

[0174] Therapeutic or prophylactic agents containing the compounds of the present invention or pharmaceutically acceptable salts or solvates thereof as active ingredients can be prepared into pharmaceutical compositions using carriers, bases, excipients, and other additives commonly used in formulations. Such carriers, bases, and excipients may be solid or liquid, and specific examples include lactose, magnesium stearate starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol, medium-chain fatty acid triglycerides, and other commonly used carriers, bases, and excipients.

[0175] The compound or pharmaceutical composition of the present invention may be administered orally in the form of tablets, pills, capsules, soft capsules, granules, powders, liquids, etc., or parenterally in the form of injections such as intravenous injections and intramuscular injections, suppositories, transdermal or nasal routes.

[0176] The compounds of the present invention or pharmaceutically acceptable salts or solvates thereof may be in the form of orexin type 2 receptor agonists containing them as active ingredients. The term "agonist" includes the forms commonly used in this field, i.e., activators, agonists, stimulants, etc.

[0177] The therapeutically effective amount of the active ingredient in a therapeutic agent, prophylactic agent, pharmaceutical composition, or activator containing the compound of the present invention as an active ingredient varies depending on the route of administration, the age, sex, and severity of the disease of the patient, but is usually about 1 to 1500 mg / day, and the frequency of administration is usually 1 to 3 times / day or 1 to 3 times / week. It is preferable to prepare a formulation that satisfies these conditions. However, since the dosage varies depending on various conditions, there are cases where a dosage less than the above-mentioned dosage is sufficient, and there are also cases where a dosage exceeding the above-mentioned range is required. [Example]

[0178] The present invention will be explained in more detail below with reference to examples, but the scope of the present invention is not limited to these examples.

[0179] In the present examples, the example number and the compound number of the compound produced in that example are the same. Unless otherwise specified, reagents, starting materials, and solvents were purchased from commercial suppliers (e.g., Sigma-Aldrich, Fujifilm Wako Pure Chemical Industries, Tokyo Chemical Industry, Fluka, Sigma, etc.) and used without further purification.

[0180] In the following Reference Examples and Examples, "room temperature" generally refers to a temperature between about 10°C and about 35°C. The ratios shown for mixed solvents are by volume unless otherwise specified. "%" indicates percent by weight unless otherwise specified. However, yields are expressed in mol / mol%.

[0181] In the Reference Examples and Examples, column chromatography was performed using a silica gel column and an amino silica gel column manufactured by Yamazen Corp. For TLC observation, a 60F TLC plate (silica gel) manufactured by Merck was used. 254 The TLC plate (NH silica gel) used was NH2 silica gel 60F254 plate-Wako manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.

[0182] The structure of the isolated novel compound is: 1 Confirmation was achieved by 1 H-NMR and / or mass spectrometry using LC / MS.

[0183] 1 For those for which H-NMR spectra (400 MHz, DMS0-d6, CDCl3, or CD3OD) were measured, the chemical shifts (δ: ppm) and coupling constants (J: Hz) are shown.

[0184] The LC / MS results are [M+H] observed using one of the following instruments and analytical conditions. + The value of (measured molecular weight: that is, the molecular mass (M) of the compound plus the proton (H + ) and retention time Rt (min).

[0185] Method A Mass spectrometer: Agilent Technologies LC / MS 6130 HPLC:LC-1260 Column: Phenomenex Gemini C1 3μm 4.6mm x 30mm UV: PDA detection (254 nM) Column temperature: 40℃ Detection voltage: 70V

[0186] Method B Mass spectrometer: Agilent Technologies LC / MS 6130 HPLC:LC-1260 Column: L-column2 3μm 3.0mm x 50mm UV: PDA detection (254 nM) Column temperature: 40℃ Detection voltage: 70V

[0187] [Gradient conditions (volume ratio)] Method A solvent: A: H2O / acetonitrile = 95 / 5 0.05% TFA B: H2O / acetonitrile = 5 / 95 0.05% TFA Flow rate: 1.0mL / min gradient: 0 min, Solvent B: 2% Solvent A: 98% 0-0.3 min, Solvent B: 2% → 10%, Solvent A: 98% → 90% 0.3-1.5 min: Solvent B: 10% → 100% Solvent A: 90% → 0% 1.5-3.5 min, Solvent B: 100% Solvent A: 0% 3.5–3.51 min: Solvent B: 100% → 2% Solvent A: 0% → 98% 3.51-4.5 min, Solvent B: 2% Solvent A: 98%

[0188] Method B solvent: A: 100% HO 0.05% TFA B: 100% acetonitrile 0.05% TFA Flow rate: 1.5mL / min gradient: 0-0.3 min, Solvent B: 2% Solvent A: 98% 0.3–2.3 min: Solvent B: 2% → 95% Solvent A: 98% → 5% 2.3-3.5 min, Solvent B: 95% Solvent A: 5% 3.5–3.51 min: Solvent B: 95% → 2% Solvent A: 5% → 98% 3.51-4.0 min, Solvent B: 2% Solvent A: 98%

[0189] Unless otherwise specified below, analysis was performed using Method A.

[0190] In the following examples, the following abbreviations may be used: 1 H-NMR: proton nuclear magnetic resonance LC / MS: Liquid chromatograph mass spectrometer MS: Mass spectrum Rt: retention time min:minutes s:singlet d: doublet t: triplet q:Quartet dd: double doublet ddd: double doublet dt: double triplet m: multiplet J: Coupling constant Hz: Hertz M: Molar concentration DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide THF: tetrahydrofuran LHMDS: lithium bis(trimethylsilyl)amide DIAD: Diisopropyl azodicarboxylate WSC-HCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride HOBt: 1-hydroxybenzotriazole Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2·CH2Cl2:[1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene Selectfluor®: 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) tBu: tert-butyl Boc: tert-butoxycarbonyl TBDPS: tert-butyldiphenylsilyl TFA: Trifluoroacetic acid CDCl3: deuterated chloroform DMSO-d6: deuterated dimethyl sulfoxide CD3OD: deuterated methanol

[0191] <Reference Example 1: Methyl 2-hydroxy-6-isopropoxybenzoate>

[0192] [Step 1] 5-Isopropoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one 5-Hydroxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (583 mg, 3.00 mmol) was dissolved in DMF (10 mL), and 2-iodopropane (447 μL, 4.50 mmol) and potassium carbonate (622 mg, 4.50 mmol) were added, followed by stirring at 50° C. overnight. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted twice with heptane / ethyl acetate (1 / 1). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (512 mg). LCMS: 237.2 [M+H] + (Rt = 2.207 min).

[0193] [Step 2] Methyl 2-hydroxy-6-isopropoxybenzoate The compound obtained in Step 1 (512 mg, 2.17 mmol) was dissolved in methanol (6.6 mL), potassium carbonate (898 mg, 6.50 mmol) was added, and the mixture was stirred at room temperature overnight. Water (30 mL) and 2 M aqueous hydrochloric acid solution (8 mL) were added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to obtain the title compound (440 mg). 1 H-NMR (CDCl3) δ: 11.37 (1H, s), 7.29 (1H, t, J = 8.5 Hz), 6.56 (1H, dd, J = 8.2, 0.9 Hz), 6.43 (1H, d, J = 8.2 Hz), 4.60-4.51 (1H, m), 3.93 (3H, s), 1.36 (6H, d, J = 6.4 Hz). LCMS: 211.2 [M+H] + (Rt = 2.169 min).

[0194] <Reference Example 2: Methyl 2-(benzyloxy)-6-hydroxy-4-methylbenzoate>

[0195] [Step 1] 5-hydroxy-2,2,7-trimethyl-4H-benzo[d][1,3]dioxin-4-one 2,6-Dihydroxy-4-methylbenzoic acid (7.78 g, 46.3 mmol) was dissolved in 1,2-dimethoxyethane (46 mL), and acetone (4.1 mL, 55.5 mmol) and 4-dimethylaminopyridine (283 mg, 2.31 mmol) were added. Thionyl chloride (4.03 mL, 55.5 mmol) was added dropwise at 0°C, and the mixture was warmed to room temperature. After stirring at room temperature for 20 hours, the reaction mixture was cooled to 0°C, and 2 M aqueous sodium hydroxide and saturated aqueous sodium bicarbonate were added. The mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (7.40 g). 1 H-NMR (CDCl3) δ: 10.24 (1H, s), 6.46 (1H, s), 6.27 (1H, s), 2.31 (3H, s), 1.73 (6H, s). LCMS: 209.2 [M+H] + (Rt = 2.276 min).

[0196] [Step 2] 5-(benzyloxy)-2,2,7-trimethyl-4H-benzo[d][1,3]dioxin-4-one The compound obtained in Step 1 (300 mg, 1.44 mmol) and potassium carbonate (299 mg, 2.16 mmol) were dissolved in DMF (2.88 mL), and benzyl bromide (205 μL, 1.73 mmol) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 hours, and then saturated aqueous sodium bicarbonate solution was added and extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (427 mg). 1H-NMR (CDCl3) δ: 7.56 (2H, d, J = 7.3 Hz), 7.41-7.38 (2H, m), 7.30 (1H, t, J = 7.3 Hz), 6.47 (1H, s), 6.38 (1H, s), 5.23 (2H, s), 2.32 (3H, s), 1.70 (6H, s). LCMS: 299.1 [M+H] + (Rt = 2.370 min).

[0197] [Step 3] Methyl 2-(benzyloxy)-6-hydroxy-4-methylbenzoate The compound obtained in Step 2 (427 mg, 1.43 mmol) was dissolved in methanol (4.77 mL), potassium carbonate (593 mg, 4.29 mmol) was added, and the mixture was stirred at 50°C for 1 hour. The reaction mixture was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (363 mg). LCMS: 273.1 [M+H] + (Rt = 2.393 min).

[0198] <Reference Example 3: Methyl 2-ethoxy-6-hydroxy-4-methylbenzoate> The compound obtained in Step 1 of Reference Example 2 (200 mg, 0.96 mmol) and iodoethane (100 μL, 1.25 mmol) were used as starting materials, and the same operations as in Steps 2 and 3 of Reference Example 2 were carried out to obtain the title compound (194 mg). LCMS: 211.1 [M+H] + (Rt = 2.256 min).

[0199] <Reference Example 4: Methyl 2-hydroxy-6-isopropoxy-4-methylbenzoate>

[0200] [Step 1] 5-Isopropoxy-2,2,7-trimethyl-4H-benzo[d][1,3]dioxin-4-one The compound obtained in Step 1 of Reference Example 2 (500 mg, 2.40 mmol) and 2-iodopropane (310 μL, 3.12 mmol) were used as starting materials for the same procedure as in Step 2 of Reference Example 2 to give the title compound (726 mg). 1 H-NMR (CDCl3) δ: 6.43 (1H, s), 6.33 (1H, s), 4.67-4.58 (1H, m), 2.32 (3H, s), 1.68 (6H, s), 1.43 (6H, d, J = 5.9 Hz). LCMS: 251.1 [M+H] + (Rt = 2.301 min).

[0201] [Step 2] Methyl 2-hydroxy-6-isopropoxy-4-methylbenzoate The compound obtained in Step 1 (726 mg, 2.90 mmol) was used as a starting material, and the same procedure as in Step 3 of Reference Example 2 was carried out to give the title compound (598 mg). 1 H-NMR (CDCl3) δ: 11.44 (1H, s), 6.40 (1H, s), 6.24 (1H, s), 4.58-4.49 (1H, m), 3.91 (3H, s), 2.28 (3H, s), 1.35 (6H, d, J = 5.9 Hz). LCMS: 225.1 [M+H] + (Rt = 2.310 min).

[0202] <Reference Example 5: Methyl (S)-2-((1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)oxy)-6-hydroxy-4-methylbenzoate>

[0203] [Step 1] (R)-1-((tert-butyldiphenylsilyl)oxy)propan-2-ol (R)-(-)-Propane-1,2-diol (1.00 g, 13.1 mmol) and imidazole (1.34 g, 19.7 mmol) were dissolved in DMF (13.1 mL), and tert-butyldiphenylchlorosilane (3.7 mL, 14.5 mmol) was added dropwise. After the addition was complete, the mixture was stirred overnight at room temperature, followed by the addition of saturated aqueous sodium bicarbonate and extraction with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (3.93 g). 1 H-NMR (CDCl3) δ: 7.68-7.65 (4H, m), 7.44-7.37 (6H, m), 3.96-3.86 (1H, m), 3.62 (1H, dd, J = 10.1, 3.2 Hz), 3.45 (1H, dd, J = 10.1, 7.8 Hz), 2.52 (1H, d, J = 3.2 Hz), 1.10 (3H, d, J = 6.4 Hz), 1.07 (9H, s). LCMS: 315.1 [M+H] + (Rt = 2.577 min).

[0204] [Step 2] (S)-5-((1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)oxy)-2,2,7-trimethyl-4H-benzo[d][1,3]dioxin-4-one The compound obtained in Step 1 (725 mg, 2.31 mmol), the compound obtained in Step 1 of Reference Example 2 (400 mg, 1.92 mmol), and triphenylphosphine (655 mg, 2.50 mmol) were dissolved in THF (5.77 mL), and DIAD (486 μL, 2.50 mmol) was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 1 hour, and then saturated aqueous sodium bicarbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (935 mg). 1H-NMR (CDCl3) δ: 7.68-7.64 (4H, m), 7.42-7.34 (6H, m), 6.47 (1H, s), 6.32 (1H, s), 4.65-4.58 (1H, m), 3.95 (1H, dd, J = 10.5, 5.9 Hz), 3.73 (1H, dd, J = 10.5, 5.5 Hz), 2.27 (3H, s), 1.67 (3H, s), 1.64 (3H, s), 1.41 (3H, d, J = 5.9 Hz), 1.01 (9H, s). LCMS: 505.2 [M+H] + (Rt = 2.844 min).

[0205] [Step 3] Methyl (S)-2-((1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)oxy)-6-hydroxy-4-methylbenzoate The compound obtained in Step 2 (935 mg, 1.85 mmol) was dissolved in methanol (6.18 mL), potassium carbonate (768 mg, 5.56 mmol) was added, and the mixture was stirred at room temperature for 15 hours. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (846 mg). 1 H-NMR (CDCl3) δ: 11.43 (1H, s), 7.66-7.63 (4H, m), 7.42-7.34 (6H, m), 6.38 (1H, s), 6.24 (1H, s), 4.55-4.47 (1H, m), 3.85 (1H, dd, J = 10.5, 5.5 Hz), 3.79 (3H, s), 3.71 (1H, dd, J = 10.5, 5.0 Hz), 2.23 (3H, s), 1.35 (3H, d, J = 6.4 Hz), 1.03 (9H, s). LCMS: 479.2 [M+H] + (Rt = 2.919 min).

[0206] <Reference Example 6: Methyl (R)-2-((1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)oxy)-6-hydroxy-4-methylbenzoate> Using (S)-(+)-propane-1,2-diol (231 mg, 3.04 mmol) as a starting material, the same procedure as in Reference Example 5 was carried out to obtain the title compound (939 mg). 1 H-NMR (CDCl3) δ: 11.45 (1H, s), 7.65-7.64 (4H, m), 7.44-7.34 (6H, m), 6.39 (1H, s), 6.24 (1H, s), 4.53-4.50 (1H, m), 3.85 (1H, dd, J = 10.3, 5.1 Hz), 3.80 (3H, s), 3.71 (1H, dd, J = 10.5, 5.3 Hz), 2.23 (3H, s), 1.35 (3H, d, J = 5.9 Hz), 1.03 (9H, s). LCMS: 479.2 [M+H] + (Rt = 2.900 min).

[0207] <Reference Example 7: Methyl 2-hydroxy-4-methyl-6-((1,1,1-trifluoropropan-2-yl)oxy)benzoate>

[0208] [Step 1] 2,2,7-trimethyl-5-((1,1,1-trifluoropropan-2-yl)oxy)-4H-benzo[d][1,3]dioxin-4-one 1,1,1-Trifluoropropan-2-ol (200 mg, 1.75 mmol) and pyridine (149 μL, 1.84 mmol) were dissolved in dichloromethane (3.5 mL), and trifluoromethanesulfonic anhydride (288 μL, 1.75 mmol) was added dropwise at 0°C. After the addition was complete, the mixture was stirred overnight at room temperature, and then the reaction mixture was filtered. The filtrate was poured into a mixture of the compound obtained in Step 1 of Reference Example 2 (183 mg, 0.89 mmol), potassium carbonate (485 mg, 3.51 mmol), and DMF (3.51 mL), and the mixture was stirred at 60°C for 31 hours. After cooling to room temperature, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (heptane / ethyl acetate) to give the title compound (106 mg). 1 H-NMR (CDCl3) δ: 6.52 (1H, s), 6.50 (1H, s), 4.75-4.66 (1H, m), 2.35 (3H, s), 1.69 (6H, d, J = 2.7 Hz), 1.59 (3H, d, J = 6.4 Hz). LCMS: 305.1 [M+H] + (Rt = 2.320 min).

[0209] [Step 2] Methyl 2-hydroxy-4-methyl-6-((1,1,1-trifluoropropan-2-yl)oxy)benzoate The compound obtained in step 1 (106 mg, 0.35 mmol) was dissolved in methanol (1.74 mL), potassium carbonate (240 mg, 1.74 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (91.7 mg). 1H-NMR (CDCl3) δ: 11.46 (1H, s), 6.51 (1H, s), 6.23 (1H, s), 4.71-4.62 (1H, m), 3.92 (3H, s), 2.30 (3H, s), 1.52 (3H, d, J = 6.4 Hz). LCMS: 279.1 [M+H] + (Rt = 2.319 min).

[0210] <Reference Example 8: Methyl (R)-2-hydroxy-4-methyl-6-((1,1,1-trifluoropropan-2-yl)oxy)benzoate>

[0211] [Step 1] (R)-2,2,7-trimethyl-5-((1,1,1-trifluoropropan-2-yl)oxy)-4H-benzo[d][1,3]dioxin-4-one Using (S)-1,1,1-trifluoro-2-propanol (10.0 g, 87.7 mmol) as a starting material, the same procedure as in Step 1 of Reference Example 7 was carried out to give the title compound (6.02 g). 1 H-NMR (CDCl3) δ: 6.52 (1H, s), 6.50 (1H, s), 4.75-4.66 (1H, m), 2.35 (3H, s), 1.70 (3H, s), 1.69 (3H, s), 1.59 (3H, d, J = 6.4 Hz). LCMS: 305.1 [M+H] + (Rt = 2.330 min). [Step 2] Methyl (R)-2-hydroxy-4-methyl-6-((1,1,1-trifluoropropan-2-yl)oxy)benzoate The compound obtained in Step 1 (9.08 g, 29.9 mmol) was used as a starting material, and the same procedure as in Step 2 of Reference Example 7 was carried out to give the title compound (8.05 g). 1H-NMR (CDCl3) δ: 11.46 (1H, s), 6.52 (1H, s), 6.23 (1H, s), 4.71-4.62 (1H, m), 3.92 (3H, s), 2.30 (3H, s), 1.52 (3H, d, J = 6.4 Hz). LCMS: 279.1 [M+H] + (Rt = 2.312 min).

[0212] <Reference Example 9: Methyl 2-(((2R)-bicyclo[2.2.1]heptan-2-yl)oxy)-6-hydroxy-4-methylbenzoate> The compound obtained in Step 1 of Reference Example 2 (150 mg, 0.72 mmol) and exo-norborneol (105 mg, 0.94 mmol) were used as starting materials, and the same operations as in Steps 2 and 3 of Reference Example 5 were carried out to obtain the title compound (61.4 mg). LCMS: 277.1 [M+H] + (Rt = 2.543 min).

[0213] <Reference Example 10: Methyl 2-hydroxy-4-methyl-6-(neopentyloxy)benzoate> The compound obtained in Step 1 of Reference Example 2 (300 mg, 1.44 mmol) and neopentyl alcohol (165 mg, 1.87 mmol) were used as starting materials, and the same operations as in Steps 2 and 3 of Reference Example 5 were carried out to obtain the title compound (262 mg). LCMS: 253.1 [M+H] + (Rt = 2.540 min).

[0214] <Reference Example 11: Methyl 2-hydroxy-4-methyl-6-((tetrahydrofuran-2-yl)methoxy)benzoate> The compound obtained in Step 1 of Reference Example 2 (150 mg, 0.72 mmol) and tetrahydrofurfuryl alcohol (91.1 μL, 0.94 mmol) were used as starting materials, and the same operations as in Steps 2 and 3 of Reference Example 5 were carried out to obtain the title compound (138 mg). LCMS: 267.1 [M+H] +(Rt = 2.215 min).

[0215] <Reference Example 12: Methyl 2-hydroxy-6-isobutyl-4-methylbenzoate>

[0216] [Step 1] 2,2,7-trimethyl-4-oxo-4H-benzo[d][1,3]dioxin-5-yl trifluoromethanesulfonate The compound obtained in Step 1 of Reference Example 2 (1.50 g, 7.20 mmol) and triethylamine (1.21 mL, 8.65 mmol) were dissolved in dichloromethane (14.4 mL), and trifluoromethanesulfonic anhydride (1.30 mL, 7.92 mmol) was added dropwise at 0°C. After the addition was complete, the mixture was stirred at room temperature for 30 minutes, and then saturated aqueous sodium bicarbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (2.42 g). 1 H-NMR (CDCl3) δ: 6.85 (1H, s), 6.80 (1H, s), 2.43 (3H, s), 1.74 (6H, s). LCMS: 341.1 [M+H] + (Rt = 2.375 min).

[0217] [Step 2] 2,2,7-trimethyl-5-(2-methyl-1-propen-1-yl)-4H-benzo[d][1,3]dioxin-4-one The compound obtained in Step 1 (200 mg, 0.59 mmol), isopropenylboronic acid pinacol ester (214 mg, 1.18 mmol), and 2 M aqueous sodium carbonate solution (882 μL, 1.76 mmol) were dissolved in 1,4-dioxane (1.77 mL), and XPhos Pd G3 (24.9 mg, 0.03 mmol) was added. The mixture was stirred at 85° C. for 2 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (120 mg). 1 H-NMR (CDCl3) δ: 6.75 (2H, s), 6.63 (1H, s), 2.35 (3H, s), 1.95 (3H, d, J = 0.9 Hz), 1.77 (3H, d, J = 0.9 Hz), 1.69 (6H, s). LCMS: 247.1 [M+H] + (Rt = 2.433 min).

[0218] [Step 3] 5-Isobutyl-2,2,7-trimethyl-4H-benzo[d][1,3]dioxin-4-one The compound obtained in Step 2 (115 mg, 0.47 mmol) was dissolved in ethyl acetate (1.56 mL), and 10% palladium-activated carbon (11.5 mg) was added, followed by stirring at room temperature for 1 hour under a hydrogen atmosphere at atmospheric pressure. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (116 mg). 1 H-NMR (CDCl3) δ: 6.69 (1H, s), 6.62 (1H, s), 2.95 (2H, d, J = 7.3 Hz), 2.33 (3H, s), 1.94-1.84 (1H, m), 1.68 (6H, s), 0.91 (6H, d, J = 6.9 Hz). LCMS: 249.1 [M+H] + (Rt = 2.537 min).

[0219] [Step 4] Methyl 2-hydroxy-6-isobutyl-4-methylbenzoate The compound obtained in Step 3 (120 mg, 0.48 mmol) was dissolved in methanol (1.61 mL), potassium carbonate (200 mg, 1.45 mmol) was added, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (115 mg). 1 H-NMR (CDCl3) δ: 11.23 (1H, s), 6.67 (1H, s), 6.49 (1H, s), 3.94 (3H, s), 2.74 (2H, d, J = 6.9 Hz), 2.28 (3H, s), 1.80-1.69 (1H, m), 0.88 (6H, d, J = 6.9 Hz). LCMS: 223.2 [M+H] + (Rt = 2.484 min).

[0220] <Reference Example 13: Methyl 2-cyclohexyl-6-hydroxy-4-methylbenzoate> The compound obtained in Step 1 of Reference Example 12 (150 mg, 0.44 mmol) and 1-cyclohexene pinacol boronic acid (138 mg, 0.66 mmol) were used as starting materials, and operations similar to those in Steps 2 to 4 of Reference Example 12 were carried out to obtain the title compound (89.2 mg). LCMS: 249.1 [M+H] + (Rt = 2.460 min).

[0221] <Reference Example 14: Methyl 2'-fluoro-3-hydroxy-5-methyl-[1,1'-biphenyl]-2-carboxylate> The compound obtained in Step 1 of Reference Example 12 (150 mg, 0.44 mmol) and 2-fluorophenylboronic acid (123 mg, 0.88 mmol) were used as starting materials, and the same operations as in Steps 2 and 4 of Reference Example 12 were carried out to obtain the title compound (97.1 mg). LCMS: 261.1 [M+H]+ (Rt = 2.391 min).

[0222] <Reference Example 15: Methyl 2',6'-difluoro-3-hydroxy-5-methyl-[1,1'-biphenyl]-2-carboxylate>

[0223] [Step 1] 2,2,7-trimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-benzo[d][1,3]dioxin-4-one The compound obtained in Step 1 of Reference Example 12 (500 mg, 1.47 mmol), bis(pinacolato)diboron (485 mg, 1.91 mmol), and potassium acetate (433 mg, 4.41 mmol) were dissolved in 1,4-dioxane (7.35 mL), and Pd(dppf)Cl.CHCl (538 mg, 0.74 mmol) was added, followed by stirring at 100°C for 3 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to yield the title compound (359 mg). 1 H-NMR (CDCl3) δ: 6.96 (1H, s), 6.74 (1H, s), 2.36 (3H, s), 1.71 (6H, s), 1.42 (12H, s). LCMS: 319.2 [M+H] + (Rt = 2.390 min).

[0224] [Step 2] 5-(2,6-difluorophenyl)-2,2,7-trimethyl-4H-benzo[d][1,3]dioxin-4-one The compound obtained in Step 1 (180 mg, 0.57 mmol), 1,3-difluoro-2-iodobenzene (204 mg, 0.85 mmol), and 2 M aqueous sodium carbonate solution (849 μL, 1.70 mmol) were dissolved in 1,4-dioxane (2.83 mL), and XPhos Pd G3 (23.9 mg, 0.03 mmol) was added. The mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (109 mg). 1 H-NMR (CDCl3) δ: 7.35-7.27 (1H, m), 7.00-6.92 (2H, m), 6.87 (2H, d, J = 9.6 Hz), 2.42 (3H, s), 1.74 (6H, s). LCMS: 305.1 [M+H] + (Rt = 2.397 min).

[0225] [Step 3] Methyl 2',6'-difluoro-3-hydroxy-5-methyl-[1,1'-biphenyl]-2-carboxylate The compound obtained in Step 2 (109 mg, 0.36 mmol) was dissolved in methanol (1.19 mL), potassium carbonate (148 mg, 1.07 mmol) was added, and the mixture was stirred at 40°C for 2 hours. The reaction mixture was returned to room temperature, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (97.3 mg). 1 H-NMR (CDCl3) δ: 11.17 (1H, s), 7.31-7.24 (1H, m), 6.95-6.90 (3H, m), 6.63 (1H, s), 3.55 (3H, s), 2.36 (3H, s). LCMS: 279.1 [M+H] + (Rt = 2.397 min).

[0226] <Reference Example 16: Methyl 2'-(difluoromethyl)-3-hydroxy-5-methyl-[1,1'-biphenyl]-2-carboxylate> The compound obtained in Step 1 of Reference Example 15 (174 mg, 0.55 mmol) and 1-bromo-2-(difluoromethyl)benzene (106 μL, 0.82 mmol) were used as raw materials, and the same operations as in Steps 2 and 3 of Reference Example 15 were carried out to obtain the title compound (87.1 mg). 1 H-NMR (CDCl3) δ: 11.17 (1H, s), 7.70-7.68 (1H, m), 7.45-7.44 (2H, m), 7.15-7.12 (1H, m), 6.88 (1H, s), 6.54 (1H, s), 6.32 (1H, t, J = 55.1 Hz), 3.40 (3H, s), 2.35 (3H, s). LCMS: 293.7 [M+H] + (Rt= 2.415 min)

[0227] <Reference Example 17: Methyl 2-(3-fluoropyridin-2-yl)-6-hydroxy-4-methylbenzoate> The compound obtained in Step 1 of Reference Example 15 (250 mg, 0.79 mmol) and 2-chloro-3-fluoropyridine (207 mg, 1.57 mmol) were used as starting materials, and the same operations as in Steps 2 and 3 of Reference Example 15 were carried out to obtain the title compound (99.5 mg). 1 H-NMR (CDCl3) δ: 10.95 (1H, s), 8.46 (1H, td, J = 3.2, 1.5 Hz), 7.44-7.39 (1H, m), 7.32-7.28 (1H, m), 6.93 (1H, d, J = 0.9 Hz), 6.77 (1H, d, J = 0.9 Hz), 3.54 (3H, s), 2.37 (3H, s). LCMS: 262.1 [M+H] + (Rt = 2.127 min).

[0228] <Reference Example 18: Methyl 2-hydroxy-4-methyl-6-(2-(trifluoromethyl)pyridin-3-yl)benzoate> The compound obtained in Step 1 of Reference Example 12 (150 mg, 0.44 mmol) and 2-(trifluoromethyl)pyridine-3-boronic acid (126 mg, 0.66 mmol) were used as starting materials, and the same operations as in Steps 2 and 4 of Reference Example 12 were carried out to obtain the title compound (9.9 mg). LCMS: 312.1 [M+H] + (Rt = 2.313 min).

[0229] <Reference Example 19: Methyl 2-hydroxy-4-methyl-6-(thiophen-2-yl)benzoate> The compound obtained in Step 1 of Reference Example 12 (200 mg, 0.59 mmol) and 2-thienylboronic acid (150 mg, 1.18 mmol) were used as starting materials, and operations similar to those in Steps 2 and 4 of Reference Example 12 were carried out to obtain the title compound (136 mg). LCMS: 249.1 [M+H] + (Rt = 2.242 min).

[0230] <Reference Example 20: tert-butyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate>

[0231] [Step 1] tert-Butyl (2R,4R)-2-((benzoyloxy)methyl)-4-hydroxypyrrolidine-1-carboxylate tert-Butyl (2R,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (2.17 g, 10.0 mmol) and pyridine (25.0 mL, 310 mmol) were dissolved in dichloromethane (60 mL), and a dichloromethane solution (20 mL) of benzoyl chloride (1.28 mL, 11.0 mmol) was added dropwise over 10 minutes at -78°C. After the addition was complete, the mixture was warmed to room temperature and stirred overnight. Water was then added, and the mixture was extracted with dichloromethane. The organic layer was washed twice with 1 M aqueous hydrochloric acid and then saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (2.74 g). LCMS: 222.1 [M+H-Boc] + (Rt = 2.198 min).

[0232] [Step 2] tert-Butyl (2R,4R)-2-((benzoyloxy)methyl)-4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1-carboxylate The compound obtained in Step 1 (508 mg, 1.58 mmol) was dissolved in DMF (5.27 mL), and imidazole (269 mg, 3.95 mmol) and tert-butyldiphenylchlorosilane (486 μL, 1.90 mmol) were added, followed by stirring at room temperature overnight. Water was added to the reaction mixture, which was then extracted with heptane / ethyl acetate (2 / 1). The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound as a crude product. LCMS: 460.3 [M+H-Boc] + (Rt = 3.073 min).

[0233] [Step 3] tert-Butyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate The crude product of the compound obtained in Step 2 was dissolved in methanol (6.32 mL), potassium carbonate (655 mg, 4.74 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed twice with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (286 mg). LCMS: 400.2 [M+H-tBu] + (Rt = 2.766 min).

[0234] <Reference Example 21: tert-butyl (2S,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate> The title compound (1.87 g) was obtained by the same procedure as in Reference Example 20 using tert-butyl (2S,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.09 g, 5.00 mmol) as a starting material. LCMS: 400.2 [M+H-tBu] + (Rt = 2.735 min).

[0235] <Reference Example 22: tert-Butyl (2R,4S)-4-((tert-butyldiphenylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate>

[0236] [Step 1] (2R,4S)-1-(tert-butylcarbonyl)-4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-2-carboxylic acid (2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (2.31 g, 10.0 mmol) was dissolved in a mixed solvent of dichloromethane (50.0 mL) and DMF (10.0 mL). Imidazole (3.40 g, 50.0 mmol) and tert-butyldiphenylchlorosilane (5.63 mL, 22.0 mmol) were added and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (50.0 mL), and 4 M aqueous lithium hydroxide solution (4.00 mL, 16.0 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized with 1 M aqueous hydrochloric acid and extracted twice with dichloromethane. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to obtain the title compound (4.45 g). LCMS: 370.2 [M+H-Boc]+ (Rt= 2.601 min).

[0237] [Step 2] tert-Butyl (2R,4S)-4-((tert-butyldiphenylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate The compound obtained in step 1 (4.45 g, 9.47 mmol) was dissolved in THF (19.0 mL), and 0.9 M borane-THF / THF solution (11.4 mL, 12.6 mmol) was added dropwise at 0°C. After the addition was complete, the mixture was warmed to room temperature and stirred for 2 hours, after which a saturated aqueous solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (4.12 g). LCMS: 400.2 [M+H-tBu] + (Rt = 2.754 min).

[0238] <Reference Example 23: ((2R,4R)-4-((tert-butyldiphenylsilyl)oxy)pyrrolidin-2-yl)methylbenzoate> The compound obtained in Step 2 of Reference Example 20 (1.68 g, 3.00 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (6 mL) was added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (heptane / ethyl acetate) to give the title compound (1.35 g). LCMS: 460.15 [M+H] + (Rt = 2.138 min).

[0239] <Reference Example 24: (2R,11aR)-6-isopropoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-2-ol>

[0240] [Step 1] 2-Hydroxy-6-isopropoxy-4-methylbenzaldehyde The compound obtained in Step 1 of Reference Example 4 (1.25 g, 4.98 mmol) was dissolved in dichloromethane (25 mL), and 1.5 M diisobutylaluminum hydride (9.96 mL, 15.0 mmol) was added dropwise over 20 minutes at −78°C. After the addition was complete, the mixture was stirred for 3 hours at −78°C, and then methanol (5 mL) and then 1 M aqueous hydrochloric acid (40 mL) were added dropwise. The reaction mixture was warmed to room temperature, stirred for 1 hour, and extracted with dichloromethane. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in THF (10 mL), and 2 M aqueous hydrochloric acid (5 mL) was added. The mixture was stirred overnight, and then extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (466 mg). LCMS: 195.1 [M+H] +(Rt = 2.398 min).

[0241] [Step 2] ((2R,4R)-4-((tert-butyldiphenylsilyl)oxy)-1-(2-hydroxy-6-isopropoxy-4-methylbenzyl)pyrrolidin-2-yl)methylbenzoate The compound obtained in Step 1 (466 mg, 2.40 mmol) and the compound obtained in Reference Example 23 (1.04 g, 2.27 mmol) were dissolved in dichloromethane (11.4 mL), and acetic acid (156 μL, 2.72 mmol) was added, followed by stirring at room temperature for 1 hour. Sodium triacetoxyborohydride (577 mg, 2.72 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. After stirring at room temperature overnight, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (1.10 g). LCMS: 638.4 [M+H] + (Rt = 2.242 min).

[0242] [Step 3] 2-(((2R,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-(hydroxymethyl)pyrrolidin-1-yl)methyl-3-isopropoxy-5-methylphenol The compound obtained in step 2 (1.10 g, 1.73 mmol) and potassium carbonate (955 mg, 6.91 mmol) were dissolved in a mixed solvent of methanol (8.64 mL) and dichloromethane (8.64 mL) and stirred at room temperature for 4 hours. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (875 mg). LCMS: 534.3 [M+H] + (Rt = 2.154 min).

[0243] [Step 4] (2R,11aR)-2-((tert-butyldiphenylsilyl)oxy)-6-isopropoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepine The compound obtained in Step 3 (820 mg, 1.54 mmol) and triphenylphosphine (806 mg, 3.07 mmol) were dissolved in THF (15.4 mL), and DIAD (598 μL, 3.07 mmol) was added dropwise at 0°C. After the addition was complete, the mixture was stirred overnight at room temperature, and then saturated aqueous sodium bicarbonate solution was added and extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (68.0 mg). LCMS: 516.3 [M+H] + (Rt = 2.170 min).

[0244] [Step 5] (2R,11aR)-6-isopropoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-2-ol The compound obtained in step 4 (68.0 mg, 0.13 mmol) was dissolved in THF (527 μL), and 1 M tetrabutylammonium fluoride / THF solution (0.264 mL, 0.26 mmol) was added, followed by stirring at room temperature overnight. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted five times with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (heptane / ethyl acetate) to obtain the title compound (25.0 mg). LCMS: 278.2 [M+H] + (Rt = 1.723 min).

[0245] <Reference Example 25: tert-Butyl (2R,4S)-4-(benzyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate>

[0246] [Step 1] (2R,4S)-4-(benzyloxy)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.00 g, 4.32 mmol) was dissolved in THF (13 mL), and 50% sodium hydride (457 mg, 9.51 mmol) was added at 0°C. The mixture was warmed to room temperature and stirred for 20 minutes. The reaction mixture was cooled to 0°C again, and benzyl bromide (565 μL, 4.76 mmol) was added. The mixture was stirred at 50°C for 15 hours. After cooling to room temperature, water and 2M aqueous hydrochloric acid were added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (1.19 g). 1 H-NMR (CDCl3) δ: 7.38-7.30 (5H, m), 4.57-4.49 (3H, m), 4.17-4.15 (1H, m), 3.75-3.44 (2H, m), 2.57-2.47 (1H, m), 2.30-2.12 (1H, m), 1.49-1.43 (9H, m). LCMS: 222.1 [M+H-Boc] + (Rt = 2.144 min).

[0247] [Step 2] tert-Butyl (2R,4S)-4-(benzyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate The compound obtained in step 1 (1.19 g, 3.70 mmol) was dissolved in THF (11.1 mL), and 0.9 M borane-THF / THF solution (10.3 mL, 9.25 mmol) was added dropwise over 10 minutes at 0°C. After the addition was complete, the mixture was warmed to room temperature and stirred for 1 hour, after which a saturated aqueous solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (922 mg). 1H-NMR (CDCl3) δ: 7.37-7.28 (5H, m), 4.92 (1H, d, J = 8.2 Hz), 4.54-4.47 (2H, m), 4.17-4.05 (2H, m), 3.73-3.39 (3H, m), 2.22-2.17 (1H, m), 1.66-1.59 (1H, m), 1.47 (9H, s). LCMS: 252.1 [M+H-tBu] + (Rt = 2.202 min).

[0248] <Reference Example 26: tert-Butyl (2R,4R)-4-(benzyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate> The title compound was obtained by the same procedure as in Reference Example 25 using (2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid as a starting material. LCMS: 252.1 [M+H-tBu] + (Rt = 2.221 min).

[0249] <Reference Example 27: (2S,11aR)-6-(cyclopentyloxy)-2-hydroxy-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0250] [Step 1] Methyl 2-(cyclopentyloxy)-6-hydroxybenzoate Using 5-hydroxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (500 mg, 2.58 mmol) and cyclopentanol (288 mg, 3.35 mmol), the same procedures as in Steps 2 and 3 of Reference Example 5 were carried out to obtain the title compound (382 mg). 1H-NMR (CDCl3) δ: 11.44 (1H, s), 7.29 (1H, t, J = 8.5 Hz), 6.55-6.53 (1H, m), 6.40 (1H, d, J = 8.7 Hz), 4.83-4.79 (1H, m), 3.92 (3H, s), 1.91-1.76 (6H, m), 1.69-1.59 (2H, m). LCMS: 237.1 [M+H] + (Rt = 2.351 min).

[0251] [Step 2] tert-Butyl (2R,4S)-4-(benzyloxy)-2-((3-(cyclopentyloxy)-2-(methoxycarbonyl)phenoxy)methyl)pyrrolidine-1-carboxylate The compound obtained in Step 1 (190 mg, 0.80 mmol), the compound obtained in Reference Example 25 (297 mg, 0.96 mmol), and triphenylphosphine (274 mg, 1.05 mmol) were dissolved in THF (2.4 mL), and DIAD (203 μL, 1.05 mmol) was added dropwise. After the addition was completed, the mixture was stirred at 40° C. for 1 hour, and then the reaction mixture was cooled to room temperature. A saturated aqueous solution of sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (389 mg). LCMS: 426.3 [M+H-Boc] + (Rt = 2.646 min).

[0252] [Step 3] 2-(((2R,4S)-4-(benzyloxy)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-6-(cyclopentyloxy)benzoic acid The compound obtained in Step 2 (389 mg, 0.74 mmol) was dissolved in a mixed solvent of methanol (2.22 mL), THF (0.74 mL), and water (1.48 mL), and potassium hydroxide (208 mg, 3.70 mmol) was added, followed by stirring at 85°C for 6 days. The reaction mixture was cooled to room temperature, and 1 M aqueous hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (392 mg). LCMS: 412.2 [M+H-Boc] + (Rt = 2.458 min).

[0253] [Step 4] 2-(((2R,4S)-4-(benzyloxy)pyrrolidin-2-yl)methoxy)-6-(cyclopentyloxy)benzoic acid hydrochloride The compound obtained in Step 3 (392 mg, 0.77 mmol) was dissolved in dioxane (2.3 mL), and a 4 M hydrochloric acid / 1,4-dioxane solution (580 μL, 2.30 mmol) was added dropwise. After the addition was completed, the mixture was stirred at 40° C. for 20 hours, and then the reaction mixture was concentrated under reduced pressure. The residue was azeotroped with 1,4-dioxane to give the title compound (297 mg). LCMS: 412.2 [M+H] + (Rt = 1.891 min).

[0254] [Step 5] (2S,11aR)-2-(benzyloxy)-6-(cyclopentyloxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 4 (297 mg, 0.66 mmol) and N,N-diisopropylethylamine (1.14 mL, 6.64 mmol) were dissolved in DMF (2 mL), and WSC-HCl (191 mg, 1 mmol) and HOBt (152 mg, 1 mmol) were added, followed by stirring at 40°C for 2 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (209 mg). 1 H-NMR (CDCl3) δ: 7.37-7.23 (6H, m), 6.76 (1H, d, J = 8.7 Hz), 6.62 (1H, d, J = 8.2 Hz), 4.78 (1H, s), 4.58 (1H, d, J = 11.9 Hz), 4.48 (1H, d, J = 11.9 Hz), 4.33-4.28 (1H, m), 4.13-4.02 (2H, m), 3.97-3.92 (3H, m), 2.27-2.20 (1H, m), 2.00-1.96 (1H, m), 1.91-1.76 (6H, m), 1.60-1.51 (2H, m). LCMS: 394.2 [M+H] + (Rt = 2.368 min).

[0255] [Step 6] (2S,11aR)-6-(cyclopentyloxy)-2-hydroxy-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 5 (209 mg, 0.53 mmol) was dissolved in ethyl acetate (2.66 mL), and 20% palladium hydroxide on activated carbon (20.9 mg) was added, followed by stirring at room temperature for 1 hour under a hydrogen atmosphere at atmospheric pressure. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (153 mg). LCMS: 304.2 [M+H] + (Rt = 1.948 min).

[0256] <Reference Example 28: (2R,11aR)-6-(cyclopropylmethoxy)-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0257] [Step 1] Methyl 2-(cyclopropylmethoxy)-6-hydroxy-4-methylbenzoate The compound obtained in Step 1 of Reference Example 2 (5.00 g, 24.0 mmol) and (bromomethyl)cyclopropane (3.03 mL, 31.2 mmol) were used as starting materials, and the same operations as in Steps 2 and 3 of Reference Example 2 were carried out to obtain the title compound (2.91 g). 1 H-NMR (CDCl3) δ: 11.51 (1H, s), 6.41 (1H, s), 6.19 (1H, s), 3.93 (3H, s), 3.88 (2H, d, J = 6.4 Hz), 2.27 (3H, s), 1.31-1.22 (1H, m), 0.64-0.59 (2H, m), 0.43-0.39 (2H, m). LCMS: 237.1 [M+H] + (Rt = 2.356 min).

[0258] [Step 2] (2R,11aR)-6-(cyclopropylmethoxy)-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 1 (147 mg, 0.62 mmol) and the compound obtained in Reference Example 26 (220 mg, 0.72 mmol) were used as starting materials, and the same operations as in Steps 2 to 6 of Reference Example 27 were carried out to obtain the title compound (84.7 mg). 1H-NMR (CDCl3) δ: 6.57 (1H, s), 6.51 (1H, s), 4.66-4.60 (2H, m), 4.06-3.81 (6H, m), 2.30 (3H, s), 2.28-2.21 (1H, m), 1.87-1.79 (2H, m), 1.35-1.28 (1H, m), 0.64-0.57 (2H, m), 0.41-0.33 (2H, m). LCMS: 304.2 [M+H] + (Rt = 1.974 min).

[0259] <Reference Example 29: (2S,11aR)-2-Hydroxy-6-isobutoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Step 1 of Reference Example 2 (250 mg, 1.20 mmol) and 2-methyl-1-propanol (140 μL, 1.56 mmol) were used as starting materials, and the same operations as in Steps 1 to 6 of Reference Example 27 were carried out to obtain the title compound (70.2 mg). LCMS: 306.2 [M+H] + (Rt = 2.006 min).

[0260] <Reference Example 30: (2S,11aR)-2-hydroxy-6-(2-hydroxy-2-methylpropoxy)-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0261] [Step 1] tert-Butyl (2R,4S)-4-(benzyloxy)-2-(((2,2,7-trimethyl-4-oxo-4H-benzo[d][1,3]dioxin-5-yl)oxy)methyl)pyrrolidine-1-carboxylate The compound obtained in Step 1 of Reference Example 2 (325 mg, 1.56 mmol), the compound obtained in Reference Example 25 (400 mg, 1.30 mmol), and triphenylphosphine (444 mg, 1.69 mmol) were dissolved in THF (3.91 mL), and DIAD (329 μL, 1.69 mmol) was added dropwise. After the addition was completed, the mixture was stirred at 40° C. for 1 hour, and then saturated aqueous sodium bicarbonate solution was added and extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) followed by amino silica gel column chromatography (heptane / ethyl acetate) to give the title compound (565 mg). LCMS: 398.2 [M+H-Boc] + (Rt = 2.595 min).

[0262] [Step 2] tert-Butyl (2R,4S)-4-(benzyloxy)-2-((3-hydroxy-2-(methoxycarbonyl)-5-methylphenoxy)methyl)pyrrolidine-1-carboxylate The compound obtained in Step 1 (565 mg, 1.14 mmol) was dissolved in methanol (10 mL), potassium carbonate (471 mg, 3.41 mmol) was added, and the mixture was stirred at 40°C for 1.5 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (542 mg). LCMS: 372.2 [M+H-Boc] + (Rt = 2.560 min).

[0263] [Step 3] tert-Butyl (2R,4S)-4-(benzyloxy)-2-((3-(2-hydroxy-2-methylpropoxy)-2-(methoxycarbonyl)-5-methylphenoxy)methyl)pyrrolidine-1-carboxylate The compound obtained in Step 2 (180 mg, 0.38 mmol) and potassium carbonate (316 mg, 2.30 mmol) were dissolved in DMF (1.91 mL), and 1-chloro-2-methyl-2-propanol (156 μL, 1.53 mmol) was added. The mixture was stirred at 100° C. for 2 days. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) followed by amino silica gel column chromatography (heptane / ethyl acetate) to give the title compound (124 mg). LCMS: 444.2 [M+H-Boc] + (Rt = 2.471 min).

[0264] [Step 4] (2S,11aR)-2-hydroxy-6-(2-hydroxy-2-methylpropoxy)-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 3 (124 mg, 0.23 mmol) was used as a starting material, and operations similar to those in Steps 3 to 6 of Reference Example 27 were carried out to give the title compound (30.2 mg). LCMS: 322.1 [M+H-Boc] + (Rt = 1.841 min).

[0265] <Reference Example 31: (2S,11aR)-2-Hydroxy-6-isopropoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Reference Example 4 (938 mg, 4.19 mmol) and the compound obtained in Reference Example 25 (1.01 g, 3.27 mmol) were used as starting materials, and the same operations as in Steps 2 to 6 of Reference Example 27 were carried out to obtain the title compound (375 mg). 1H-NMR (CDCl3) δ: 6.60 (1H, s), 6.47 (1H, s), 4.64-4.58 (1H, m), 4.56-4.48 (1H, m), 4.14-3.86 (4H, m), 3.80 (1H, dd, J = 12.6, 4.3 Hz), 2.30 (3H, s), 2.18-2.11 (2H, m), 1.86 (1H, dt, J = 13.0, 4.9 Hz), 1.37 (3H, d, J = 5.9 Hz), 1.33 (3H, d, J = 5.9 Hz). LCMS: 292.1 [M+H] + (Rt = 1.890 min).

[0266] <Reference Example 32: (2R,11aR)-8-chloro-2-hydroxy-6-isopropoxy-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0267] [Step 1] 4-chloro-2,6-dimethoxybenzoic acid Methyl 4-chloro-2,6-difluorobenzoate (1.03 g, 5.00 mmol) was dissolved in methanol (10.0 mL), and 5 M sodium methoxide / methanol solution (2.4 mL, 12.0 mmol) was added, followed by stirring overnight at 80°C. The reaction mixture was cooled to room temperature, and 2 M aqueous sodium hydroxide solution (10.0 mL, 20.0 mmol) was added, followed by stirring overnight at 60°C. After cooling to room temperature, the reaction mixture was added with 2 M aqueous hydrochloric acid solution (50 mL), followed by extraction twice with dichloromethane. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (1.05 g). 1 H-NMR (CDCl3) δ: 6.60 (2H, s), 3.87 (6H, s). LCMS: 217.1 [M+H] + (Rt = 1.955 min).

[0268] [Step 2] 4-chloro-2,6-dihydroxybenzoic acid The compound obtained in step 1 (627 mg, 2.89 mmol) was dissolved in dichloromethane (5.79 mL), and 1 M boron tribromide / dichloromethane solution (11.6 mL, 11.6 mmol) was added dropwise at -78°C. After the addition was completed, the reaction mixture was warmed to room temperature and stirred overnight, then added to ice water and stirred for 30 minutes. The reaction mixture was filtered, and the resulting solid was washed with water to obtain the title compound (427 mg). LCMS: 189.0 [M+H] + (Rt = 2.411 min).

[0269] [Step 3] 7-chloro-5-hydroxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one The compound obtained in Step 2 (427 mg, 2.26 mmol), 4-dimethylaminopyridine (27.7 mg, 0.23 mmol), and acetone (333 μL, 4.53 mmol) were dissolved in 1,2-dimethoxyethane (11.3 mL), and thionyl chloride (329 μL, 4.53 mmol) was added dropwise at 0°C. After the addition was complete, the reaction mixture was heated to 50°C and stirred for 6 hours. After cooling to room temperature, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate) to give the title compound (55.0 mg). LCMS: 229.1 [M+H] + (Rt = 2.345 min).

[0270] [Step 4] tert-Butyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-(((7-chloro-2,2-dimethyl-4-oxo-4H-benzo[d][1,3]dioxin-5-yl)oxy)methyl)pyrrolidine-1-carboxylate The compound obtained in Step 3 (151 mg, 0.66 mmol), the compound obtained in Reference Example 20 (286 mg, 0.63 mmol), and triphenylphosphine (198 mg, 0.75 mmol) were dissolved in THF (3.14 mL), and DIAD (147 μL, 0.75 mmol) was added dropwise at 0° C. After the addition was complete, the mixture was stirred overnight at room temperature, and then saturated aqueous sodium bicarbonate solution was added and extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) followed by amino silica gel column chromatography (heptane / ethyl acetate) to give the crude title compound. LCMS: 566.3 [M+H-Boc] + (Rt = 3.118 min).

[0271] [Step 5] tert-Butyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-((5-chloro-3-hydroxy-2-(methoxycarbonyl)phenoxy)methyl)pyrrolidine-1-carboxylate The crude product of the compound obtained in Step 4 was used as a starting material, and the same procedure as in Step 2 of Reference Example 30 was carried out to give the title compound (259 mg). LCMS: 540.3 [M+H-Boc] + (Rt = 3.149 min).

[0272] [Step 6] tert-Butyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-((5-chloro-3-isopropoxy-2-(methoxycarbonyl)phenoxy)methyl)pyrrolidine-1-carboxylate The compound obtained in Step 5 (259 mg, 0.40 mmol) and 2-iodopropane (121 μL, 1.21 mmol) were used as starting materials for the same procedure as in Step 3 of Reference Example 30 to give the title compound (273 mg). LCMS: 582.3 [M+H-Boc] + (Rt = 3.123 min).

[0273] [Step 7] 2-(((2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidin-2-yl)methoxy)-4-chloro-6-isopropoxybenzoic acid The compound obtained in Step 6 (273 mg, 0.40 mmol) was dissolved in ethanol (1.6 mL), and 2 M aqueous sodium hydroxide solution (0.8 mL, 1.6 mmol) was added, followed by stirring at 80°C overnight. The reaction solution was cooled to room temperature, and 2 M aqueous hydrochloric acid solution was added, followed by extraction twice with dichloromethane. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound as a crude product. LCMS: 330.1 [M+H-Boc] + (Rt = 2.229 min).

[0274] [Step 8] 4-chloro-2-(((2R,4R)-4-hydroxypyrrolidin-2-yl)methoxy)-6-isopropoxybenzoic acid The crude product of the compound obtained in Step 7 was dissolved in 1,4-dioxane (2 mL), and 4 M hydrochloric acid / 1,4-dioxane solution (2 mL, 8 mmol) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was azeotroped with 1,4-dioxane to obtain the crude product of the title compound. LCMS: 330.1 [M+H] + (Rt = 1.718 min).

[0275] [Step 9] (2R,11aR)-8-chloro-2-hydroxy-6-isopropoxy-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The crude product of the compound obtained in Step 8 and N,N-diisopropylethylamine (0.697 mL, 4 mmol) were dissolved in DMF (4 mL), and WSC-HCl (115 mg, 0.6 mmol) and HOBt (91.9 mg, 0.6 mmol) were added, followed by stirring at 40°C for 3 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (89.0 mg). LCMS: 312.1 [M+H] + (Rt = 2.007 min).

[0276] <Reference Example 33: (2R,11aR)-2-Hydroxy-6-isopropoxy-8-(trifluoromethyl)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0277] [Step 1] 1-(benzyloxy)-3-fluoro-5-(trifluoromethyl)benzene 3-Fluoro-5-(trifluoromethyl)phenol (1.00 g, 5.55 mmol) and potassium carbonate (1.00 g, 7.22 mmol) were dissolved in DMF (11.0 mL), and benzyl bromide (0.80 mL, 6.67 mmol) was added. The mixture was stirred at room temperature overnight. Water (20 mL) was added to the reaction mixture, and the mixture was extracted three times with heptane / ethyl acetate (2 / 1). The organic layer was collected, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (1.50 g). 1 H-NMR (CDCl3) δ: 7.43-7.34 (5H, m), 7.04 (1H, s), 6.94 (1H, d, J = 8.2 Hz), 6.85 (1H, dt, J = 10.2, 2.2 Hz), 5.08 (2H, s). LCMS: 271.4 [M+H]+ (Rt = 2.542 min).

[0278] [Step 2] 2-(benzyloxy)-6-fluoro-4-(trifluoromethyl)benzoic acid The compound obtained in step 1 (1.50 g, 5.55 mmol) was dissolved in THF (20.0 mL), and a 2 M diisopropylamide lithium / THF-heptane solution (3.30 mL, 6.60 mmol) was added dropwise at -78°C. After the addition was complete, the mixture was stirred for 2 hours, and then dry ice was added. The reaction mixture was warmed to room temperature and stirred overnight. Ethyl acetate was added to the reaction mixture, and the mixture was extracted with water. A 1 M aqueous hydrochloric acid solution was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title compound (923 mg). 1 H-NMR (CDCl3) δ: 7.44-7.34 (5H, m), 7.07 (2H, d, J = 7.3 Hz), 5.23 (2H, s).

[0279] [Step 3] Isopropyl 2-(benzyloxy)-6-fluoro-4-(trifluoromethyl)benzoate The compound obtained in Step 2 (923 mg, 2.94 mmol) and potassium carbonate (1.53 g, 11.1 mmol) were dissolved in DMF (19 mL), and 2-iodopropane (0.58 mL, 5.83 mmol) was added, followed by stirring at room temperature overnight. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (994 mg). 1 H-NMR (CDCl3) δ: 7.42-7.32 (5H, m), 7.02-7.01 (2H, m), 5.33-5.23 (1H, m), 5.15 (2H, s), 1.30 (6H, d, J = 6.4 Hz). LCMS: 357.1 [M+H] + (Rt= 2.569 min) [Step 4] Isopropyl 2-(benzyloxy)-6-isopropoxy-4-(trifluoromethyl)benzoate The compound obtained in Step 3 (994 mg, 2.79 mmol) was dissolved in 2-propanol (15 mL), and 50% sodium hydride (250 mg, 5.73 mmol) was added, followed by stirring at room temperature overnight. 2M aqueous hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to obtain the title compound (227 mg). LCMS: 397.2 [M+H] + (Rt = 2.600 min).

[0280] [Step 5] Isopropyl 2-hydroxy-6-isopropoxy-4-(trifluoromethyl)benzoate The compound obtained in step 4 (227 mg, 0.57 mmol) was dissolved in methanol (5.70 mL), and 10% palladium-activated carbon (22.7 mg) was added. The mixture was stirred overnight at room temperature under a hydrogen atmosphere at atmospheric pressure. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (100 mg). 1 H-NMR (CDCl3) δ: 11.53 (1H, s), 6.79 (1H, d, J = 1.4 Hz), 6.59 (1H, s), 5.33-5.27 (1H, m), 4.67-4.61 (1H, m), 1.40-1.37 (12H, m). LCMS: 307.1 [M+H] + (Rt = 2.447 min).

[0281] [Step 6] tert-Butyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-((3-isopropoxy-2-(isopropoxycarbonyl)-5-(trifluoromethyl)phenoxy)methyl)pyrrolidine-1-carboxylate The compound obtained in Step 5 (100 mg, 0.33 mmol) and the compound obtained in Reference Example 20 (157 mg, 0.34 mmol) were dissolved in toluene (4 mL), and cyanomethylenetributylphosphorane (0.200 mL, 0.76 mmol) was added, followed by stirring overnight at 100° C. The reaction solution was cooled to room temperature and purified directly by silica gel column chromatography (heptane / ethyl acetate) to obtain the title compound (222 mg). LCMS: 644.3 [M+H-Boc] + (Rt = 3.227 min).

[0282] [Step 7] 2-(((2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidin-2-yl)methoxy)-6-isopropoxy-4-(trifluoromethyl)benzoic acid The compound obtained in Step 6 (222 mg, 0.3 mmol) was dissolved in ethanol (3 mL), and 2 M aqueous sodium hydroxide solution (0.6 mL, 1.19 mmol) was added, followed by stirring at 60°C overnight. The reaction mixture was cooled to room temperature, and 2 M aqueous hydrochloric acid solution was added, followed by extraction with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound as a crude product. LCMS: 406.2 [M+H-tBu] + (Rt = 2.488 min).

[0283] [Step 8] 2-(((2R,4R)-4-hydroxypyrrolidin-2-yl)methoxy)-6-isopropoxy-4-(trifluoromethyl)benzoic acid The crude product of the compound obtained in Step 7 was dissolved in dichloromethane (1.49 mL), and trifluoroacetic acid (1.49 mL) was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 1 hour, and then the reaction mixture was azeotroped with toluene to obtain the crude product of the title compound. LCMS: 406.2 [M+H] + (Rt = 1.901 min).

[0284] [Step 9] (2R,11aR)-2-hydroxy-6-isopropoxy-8-(trifluoromethyl)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The crude product of the compound obtained in Step 8 was used as a starting material, and the same procedure as in Step 9 of Reference Example 32 was carried out to give the title compound (52.3 mg). 1 H-NMR (CDCl3) δ: 6.98 (1H, s), 6.93 (1H, s), 4.75-4.60 (3H, m), 4.11-3.84 (4H, m), 2.33-2.26 (1H, m), 2.01 (1H, br s), 1.87-1.83 (1H, m), 1.42 (3H, d, J = 5.9 Hz), 1.38 (3H, d, J = 5.9 Hz). LCMS: 346.1 [M+H] + (Rt = 2.062 min).

[0285] <Reference Example 34: (2R,11aR)-2-Hydroxy-6-isopropoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Reference Example 4 (355 mg, 1.58 mmol) and the compound obtained in Reference Example 26 (584 mg, 1.90 mmol) were used as starting materials, and the same operations as in Steps 2 to 6 of Reference Example 27 were carried out to obtain the title compound (268 mg). LCMS: 292.2 [M+H] + (Rt= 1.930 min)

[0286] <Reference Example 35: (7aS,9S)-9-Hydroxy-1-isopropoxy-3-methyl-6,7,7a,8,9,10-hexahydro-12H-benzo[b]pyrrolo[1,2-e][1,5]oxazocin-12-one>

[0287] [Step 1] tert-Butyl (2R,4S)-4-((tert-butyldiphenylsilyl)oxy)-2-formylpyrrolidine-1-carboxylate The compound obtained in Reference Example 22 (2.00 g, 4.39 mmol) was dissolved in dichloromethane (22 mL), Dess-Martin periodinane (1.86 g, 4.39 mmol) was added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate and an aqueous solution of sodium thiosulfate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (1.80 g). 1 H-NMR (CDCl3) δ: 9.48-9.35 (1H, m), 7.62-7.58 (4H, m), 7.44-7.35 (6H, m), 4.44-4.25 (2H, m), 3.61-3.27 (2H, m), 2.08-2.02 (1H, m), 1.80-1.72 (1H, m), 1.45-1.43 (9H, m), 1.03 (9H, s). LCMS: 354.9 [M+H-Boc] + (Rt = 2.946 min).

[0288] [Step 2] tert-Butyl (2R,4S)-4-((tert-butyldiphenylsilyl)oxy)-2-((E)-2-methoxyvinyl)pyrrolidine-1-carboxylate (Methoxymethyl)triphenylphosphonium chloride (2.87 g, 8.38 mmol) was dissolved in THF (6 mL), and 1 M sodium bis(trimethylsilyl)amide / THF solution (7.96 mL, 7.96 mmol) was added at 0°C. The mixture was stirred at 0°C for 10 minutes. To the reaction mixture was added dropwise a THF solution (7 mL) of the compound obtained in Step 1 (1.90 g, 4.19 mmol). After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (1.9 g). LCMS: 382.2 [M+H-Boc] + (Rt = 3.170 min).

[0289] [Step 3] tert-Butyl (2R,4S)-4-((tert-butyldiphenylsilyl)oxy)-2-(2-oxoethyl)pyrrolidine-1-carboxylate The compound obtained in step 2 (2.16 g, 4.48 mmol) was dissolved in a mixed solvent of acetonitrile (30 mL) and water (7.5 mL), and trifluoroacetic acid (0.374 mL, 4.88 mmol) was added and stirred at room temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude product of the title compound. LCMS: 368.2 [M+H-Boc] + (Rt = 2.966 min).

[0290] [Step 4] tert-Butyl (2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-2-(2-hydroxyethyl)pyrrolidine-1-carboxylate The crude product of the compound obtained in Step 3 was dissolved in methanol (14.9 mL), sodium borohydride (339 mg, 8.97 mmol) was added, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (1.95 g). LCMS: 370.2 [M+H-Boc] + (Rt = 2.927 min).

[0291] [Step 5] tert-Butyl (2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-2-(2-((2,2,7-trimethyl-4-oxo-4H-benzo[d][1,3]dioxin-5-yl)oxy)ethyl)pyrrolidine-1-carboxylate The compound obtained in Step 4 (113 mg, 0.24 mmol) and the compound obtained in Step 1 of Reference Example 2 (55.1 mg, 0.26 mmol) were used as starting materials, and the same procedure as in Step 4 of Reference Example 32 was carried out to obtain the title compound (141 mg). LCMS: 660.4 [M+H] + (Rt = 3.440 min).

[0292] [Step 6] tert-Butyl (2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-2-(2-(3-isopropoxy-2-(methoxycarbonyl)-5-methylphenoxy)ethyl)pyrrolidine-1-carboxylate The compound obtained in Step 5 (140 mg, 0.21 mmol) was used as a starting material, and operations similar to those in Steps 5 and 6 of Reference Example 32 were carried out to give the title compound (132 mg). LCMS: 676.3 [M+H] + (Rt = 3.484 min).

[0293] [Step 7] (7aS,9S)-9-Hydroxy-1-isopropoxy-3-methyl-6,7,7a,8,9,10-hexahydro-12H-benzo[b]pyrrolo[1,2-e][1,5]oxazocin-12-one The compound obtained in Step 6 (132 mg, 0.20 mmol) was used as a starting material, and operations similar to those in Steps 7 to 9 of Reference Example 32 were carried out to give the title compound (6.3 mg). LCMS: 306.2 [M+H] + (Rt = 1.899 min).

[0294] <Reference Example 36: (2S,11aR)-6-(((R)-1-fluoropropan-2-yl)oxy)-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0295] [Step 1] tert-Butyl (2R,4S)-4-(benzyloxy)-2-((3-(((R)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)oxy)-2-(methoxycarbonyl)-5-methylphenoxy)methyl)pyrrolidine-1-carboxylate The compound obtained in Reference Example 25 (724 mg, 2.35 mmol) and the compound obtained in Reference Example 6 (939 mg, 1.96 mmol) were used as starting materials, and the same procedure as in Step 2 of Reference Example 27 was carried out to obtain the title compound (1.18 g). LCMS: 668.4 [M+H-Boc] + (Rt = 3.135 min).

[0296] [Step 2] tert-Butyl (2R,4S)-4-(benzyloxy)-2-((3-(((R)-1-hydroxypropan-2-yl)oxy)-2-(methoxycarbonyl)-5-methylphenoxy)methyl)pyrrolidine-1-carboxylate The compound obtained in step 1 (1.18 g, 1.54 mmol) was dissolved in THF (5 mL), and 1 M tetrabutylammonium fluoride / THF solution (2.3 mL, 2.31 mmol) was added dropwise at 0°C. After the addition was completed, the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (797 mg). LCMS: 430.2 [M+H-Boc] + (Rt = 2.413 min).

[0297] [Step 3] tert-Butyl (2R,4S)-4-(benzyloxy)-2-((3-(((R)-1-fluoropropan-2-yl)oxy)-2-(methoxycarbonyl)-5-methylphenoxy)methyl)pyrrolidine-1-carboxylate The compound obtained in step 2 (297 mg, 0.56 mmol) was dissolved in dichloromethane (9.2 mL), and bis(2-methoxyethyl)aminosulfur trifluoride (197 μL, 1.12 mmol) was added dropwise at −78° C., followed by stirring at room temperature for 21 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to obtain the title compound (157 mg). 1 H-NMR (CDCl3) δ: 7.33-7.28 (5H, m), 6.43-6.36 (2H, m), 4.61-4.20 (8H, m), 4.07-3.36 (6H, m), 2.32-2.30 (3H, m), 2.28-2.13 (2H, m), 1.47-1.44 (9H, m), 1.31 (3H, dd, J = 6.2, 1.1 Hz). LCMS: 432.3 [M+H-Boc] + (Rt = 2.513 min).

[0298] [Step 4] (2S,11aR)-6-(((R)-1-fluoropropan-2-yl)oxy)-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 3 (157 mg, 0.30 mmol) was used as a starting material, and operations similar to those in Steps 3 to 6 of Reference Example 27 were carried out to give the title compound (63.3 mg). 1 H-NMR (CDCl3) δ: 6.69 (1H, s), 6.55 (1H, s), 4.66-4.38 (4H, m), 4.16-4.05 (2H, m), 4.00-3.94 (1H, m), 3.84 (2H, d, J = 4.6 Hz), 2.31 (3H, s), 2.19-2.12 (1H, m), 1.97 (1H, s), 1.85 (1H, dt, J = 13.3, 5.3 Hz), 1.38 (3H, dd, J = 6.2, 1.6 Hz). LCMS: 310.2 [M+H] + (Rt = 1.881 min).

[0299] <Reference Example 37: (2S,11aR)-6-(((R)-1,1-difluoropropan-2-yl)oxy)-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0300] [Step 1] tert-Butyl (2R,4S)-4-(benzyloxy)-2-((2-(methoxycarbonyl)-5-methyl-3-(((R)-1-oxopropan-2-yl)oxy)phenoxy)methyl)pyrrolidine-1-carboxylate The compound obtained in Step 2 of Reference Example 36 (500 mg, 0.94 mmol) was dissolved in dichloromethane (4.72 mL), Dess-Martin periodinane (481 mg, 1.13 mmol) was added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate and an aqueous solution of sodium thiosulfate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (434 mg). LCMS: 428.2 [M+H-Boc] + (Rt = 2.366 min).

[0301] [Step 2] tert-Butyl (2R,4S)-4-(benzyloxy)-2-((3-(((R)-1,1-difluoropropan-2-yl)oxy)-2-(methoxycarbonyl)-5-methylphenoxy)methyl)pyrrolidine-1-carboxylate The compound obtained in step 1 (434 mg, 0.82 mmol) was dissolved in dichloromethane (8.2 mL), and bis(2-methoxyethyl)aminosulfur trifluoride (0.43 mL, 2.47 mmol) was added. The mixture was stirred at 0°C for 1 hour, then warmed to room temperature and stirred for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to obtain the title compound (348 mg). LCMS: 450.2 [M+H-Boc] + (Rt = 2.519 min).

[0302] [Step 3] (2S,11aR)-6-(((R)-1,1-difluoropropan-2-yl)oxy)-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 2 (348 mg, 0.63 mmol) was used as a starting material, and operations similar to those in Steps 3 to 6 of Reference Example 27 were carried out to give the title compound (127 mg). LCMS: 328.1 [M+H] + (Rt = 1.938 min).

[0303] <Reference Example 38: (2S,11aR)-2-Hydroxy-8-methyl-6-(((R)-1,1,1-trifluoropropan-2-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Reference Example 8 (7.70 g, 27.7 mmol) and the compound obtained in Reference Example 25 (10.2 g, 33.2 mmol) were used as starting materials, and the same operations as in Steps 2 to 6 of Reference Example 27 were carried out to obtain the title compound (5.60 g). 1 H-NMR (CDCl3) δ: 6.70 (1H, s), 6.62 (1H, s), 4.72-4.63 (1H, m), 4.63-4.57 (1H, m), 4.15 (1H, dd, J = 9.1, 4.1 Hz), 4.10-3.95 (2H, m), 3.88-3.79 (2H, m), 2.32 (3H, s), 2.20-2.13 (1H, m), 1.94 (1H, s), 1.86 (1H, dt, J = 13.4, 5.3 Hz), 1.59-1.57 (3H, m). LCMS: 346.1 [M+H] + (Rt = 1.996 min).

[0304] <Reference Example 39: (2R,11aR)-2-Hydroxy-8-methyl-6-(((R)1,1,1-trifluoropropan-2-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Reference Example 8 (300 mg, 1.08 mmol) and the compound obtained in Reference Example 26 (398 mg, 1.29 mmol) were used as starting materials, and the same operations as in Steps 2 to 6 of Reference Example 27 were carried out to obtain the title compound (245 mg). 1 H-NMR (CDCl3) δ: 6.70 (1H, s), 6.64 (1H, s), 4.74-4.61 (3H, m), 4.04 (1H, dd, J = 10.1, 5.0 Hz), 3.98-3.89 (2H, m), 3.84 (1H, dd, J = 13.3, 4.6 Hz), 2.32 (3H, s), 2.30-2.23 (1H, m), 1.89 (1H, d, J = 1.8 Hz), 1.81 (1H, dd, J = 14.2, 1.4 Hz), 1.59-1.57 (3H, m). LCMS: 346.1 [M+H] + (Rt = 2.010 min).

[0305] <Reference Example 40: (2S,11aR)-2-Hydroxy-8-methyl-6-(((S)-1,1,1-trifluoropropan-2-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0306] [Step 1] Methyl (S)-2-hydroxy-4-methyl-6-((1,1,1-trifluoropropan-2-yl)oxy)benzoate Using (R)-1,1,1-trifluoro-2-propanol (1.00 g, 8.77 mmol) as a starting material, the same procedure as in Reference Example 7 was carried out to obtain the title compound (547 mg). 1 H-NMR (CDCl3) δ: 11.46 (1H, s), 6.51 (1H, s), 6.23 (1H, s), 4.71-4.62 (1H, m), 3.92 (3H, s), 2.30 (3H, s), 1.52 (3H, d, J = 6.9 Hz). LCMS: 279.1 [M+H]+ (Rt = 2.316 min).

[0307] [Step 2] (2S,11aR)-2-hydroxy-8-methyl-6-(((S)-1,1,1-trifluoropropan-2-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 1 (274 mg, 0.98 mmol) and the compound obtained in Reference Example 25 (275 mg, 0.89 mmol) were used as starting materials, and the same operations as in Steps 2 to 6 of Reference Example 27 were carried out to obtain the title compound (153 mg). 1 H-NMR (CDCl3) δ: 6.68 (1H, s), 6.64 (1H, s), 4.65-4.58 (2H, m), 4.18 (1H, dd, J = 9.6, 4.1 Hz), 4.08-3.97 (2H, m), 3.90-3.85 (1H, m), 3.81 (1H, dd, J = 12.6, 4.8 Hz), 2.32 (3H, s), 2.21-2.14 (1H, m), 1.87 (1H, dt, J = 13.3, 5.5 Hz), 1.79 (1H, d, J = 4.1 Hz), 1.46 (3H, d, J = 6.4 Hz). LCMS: 346.1 [M+H] + (Rt = 2.001 min).

[0308] <Reference Example 41: Benzyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate>

[0309] [Step 1] (2R,4R)-1-((benzyloxy)carbonyl)-4-hydroxypyrrolidine-2-carboxylic acid Cis-4-hydroxy-D-proline (5.30 g, 40.4 mmol) was dissolved in a mixed solvent of saturated aqueous sodium bicarbonate (120 mL) and THF (20 mL), and a solution of benzyloxycarbonyl chloride (7.58 g, 44.5 mmol) in THF (20 mL) was added dropwise at 0°C. After the addition was complete, the mixture was stirred at 0°C for 2 hours, and then 3 M aqueous hydrochloric acid was added and extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to give the title compound (9.93 g). 1 H-NMR (CDCl3) δ: 7.37-7.33 (5H, m), 5.24-5.11 (2H, m), 4.53-4.45 (2H, m), 3.74-3.54 (2H, m), 2.43-2.23 (2H, m). LCMS: 266.1 [M+H] + (Rt = 1.833 min).

[0310] [Step 2] (2R,4R)-1-((benzyloxy)carbonyl)-4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-2-carboxylic acid The compound obtained in Step 1 (9.93 g, 37.4 mmol) and imidazole (12.7 g, 187 mmol) were dissolved in a mixed solvent of dichloromethane (187 mL) and DMF (37.4 mL), and tert-butyldiphenylchlorosilane (21.1 mL, 82.3 mmol) was added and stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and concentrated under reduced pressure. The resulting residue was dissolved in a mixed solvent of methanol (125 mL) and water (46.8 mL), and 4 M aqueous lithium hydroxide solution (15 mL) was added, and the mixture was stirred at room temperature for 2 hours. 1 M aqueous hydrochloric acid solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to obtain the title compound (17.5 g). LCMS: 504.2 [M+H] + (Rt = 2.572 min).

[0311] [Step 3] Benzyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate The compound obtained in step 2 (17.5 g, 34.8 mmol) was dissolved in THF (69.7 mL), and 1 M borane-THF / THF solution (46.5 mL, 46.5 mmol) was added dropwise at 0°C. The reaction mixture was returned to room temperature and stirred for 4 hours. Methanol was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and then saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (14.0 g). LCMS: 490.3 [M+H] + (Rt = 2.700 min).

[0312] <Reference Example 42: (2R,11aR)-6-((R)-sec-butoxy)-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0313] [Step 1] Benzyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-(((2,2,7-trimethyl-4-oxo-4H-benzo[d][1,3]dioxin-5-yl)oxy)methyl)pyrrolidine-1-carboxylate The compound obtained in Step 1 of Reference Example 2 (1.08 g, 5.2 mmol) and the compound obtained in Reference Example 41 (1.96 g, 4.00 mmol) were used as starting materials, and the same procedure as in Step 1 of Reference Example 30 was carried out to obtain a crude product of the title compound. LCMS: 680.3 [M+H] + (Rt = 2.953 min).

[0314] [Step 2] Benzyl (2R,4R)-2-((2-((benzyloxy)carbonyl)-3-hydroxy-5-methylphenoxy)methyl)-4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1-carboxylate To a mixture of 50% sodium hydride (640 mg, 16.0 mmol) and THF (20 mL) was added dropwise benzyl alcohol (2.16 g, 20.0 mmol) at 0°C, followed by stirring at room temperature for 1 hour. The reaction mixture was cooled again to 0°C, and a solution of the crude compound obtained in step 1 in THF (5 mL) was added dropwise. After stirring at 0°C for 1 hour, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (1.56 g). LCMS: 730.3 [M+H] + (Rt = 3.187 min).

[0315] [Step 3] Benzyl (2R,4R)-2-((2-((benzyloxy)carbonyl)-3-((R)-sec-butoxy)-5-methylphenoxy)methyl)-4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1-carboxylate The compound obtained in step 2 (438 mg, 0.60 mmol) and (S)-(+)-2-butanol (88.9 mg, 1.20 mmol) were dissolved in toluene (6 mL), and cyanomethylenetributylphosphorane (290 mg, 1.20 mmol) was added, followed by stirring overnight at 100° C. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane / ethyl acetate) to obtain the title compound (462 mg). LCMS: 786.4 [M+H] + (Rt = 3.235 min).

[0316] [Step 4] 2-((R)-sec-butoxy)-6-(((2R,4R)-4-((tert-butyldiphenylsilyl)oxy)pyrrolidin-2-yl)methoxy)-4-methylbenzoic acid The compound obtained in Step 3 (462 mg, 0.59 mmol) was dissolved in ethanol (5.88 mL), and 10% palladium-activated carbon (46.2 mg) was added thereto, followed by stirring overnight at room temperature under a hydrogen atmosphere at atmospheric pressure. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound as a crude product. LCMS: 562.4 [M+H] + (Rt = 2.172 min).

[0317] [Step 5] (2R,11aR)-6-((R)-sec-butoxy)-2-((tert-butyldiphenylsilyl)oxy)-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The crude product of the compound obtained in Step 4 and triethylamine (328 μL, 2.35 mmol) were dissolved in THF (5.88 mL), and a 1.7 M propylphosphonic anhydride / ethyl acetate solution (519 μL, 0.88 mmol) was added, followed by stirring at room temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (220 mg). LCMS: 544.3 [M+H] + (Rt = 2.838 min).

[0318] [Step 6] (2R,11aR)-6-((R)-sec-butoxy)-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in step 5 (220 mg, 0.40 mmol) was dissolved in THF (1.62 mL), and 1 M tetrabutylammonium fluoride / THF solution (809 μL, 0.81 mmol) was added, followed by stirring at room temperature for 4 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to give the title compound (111 mg). LCMS: 306.1 [M+H] + (Rt= 2.007 min)

[0319] <Reference Example 43: (2R,11aR)-6-((S)-sec-butoxy)-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Step 2 of Reference Example 42 (438 mg, 0.60 mmol) and (R)-(-)-2-butanol (88.9 mg, 1.20 mmol) were used as starting materials, and the same operations as in Steps 3 to 6 of Reference Example 42 were carried out to obtain the title compound (109 mg). LCMS: 306.1 [M+H] + (Rt = 2.024 min).

[0320] <Reference Example 44: (2S,11aR)-6-Cyclobutoxy-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0321] [Step 1] Methyl 2-cyclobutoxy-6-hydroxy-4-methylbenzoate The compound obtained in Step 1 of Reference Example 2 (250 mg, 1.20 mmol) and cyclobutanol (104 mg, 1.44 mmol) were used as starting materials, and the same procedures as in Steps 2 and 3 of Reference Example 5 were carried out to give the title compound (216 mg). 1H-NMR (CDCl3) δ: 11.53 (1H, s), 6.39 (1H, s), 6.04 (1H, s), 4.69-4.62 (1H, m), 3.93 (3H, s), 2.51-2.43 (2H, m), 2.27 (3H, s), 2.24-2.16 (2H, m), 1.92-1.83 (1H, m), 1.76-1.64 (1H, m). LCMS: 237.1 [M+H] + (Rt = 2.371 min).

[0322] [Step 2] (2S,11aR)-6-cyclobutoxy-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 1 (211 mg, 0.89 mmol) and the compound obtained in Reference Example 25 (250 mg, 0.81 mmol) were used as starting materials, and the same operations as in Steps 2 to 6 of Reference Example 27 were carried out to obtain the title compound (88.4 mg). 1 H-NMR (CDCl3) δ: 6.46 (1H, s), 6.41 (1H, s), 4.69-4.60 (2H, m), 4.15-4.05 (2H, m), 3.99-3.80 (3H, m), 2.45-2.10 (8H, m), 1.91-1.79 (3H, m), 1.71-1.60 (1H, m). LCMS: 304.2 [M+H] + (Rt = 1.949 min).

[0323] <Reference Example 45: (2R,11aR)-6-((2,2-difluorocyclopentyl)oxy)-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0324] [Step 1] Methyl 2-(benzyloxy)-6-((2-hydroxycyclopentyl)oxy)-4-methylbenzoate The compound obtained in Reference Example 2 (817 mg, 3.00 mmol) and potassium carbonate (829 mg, 6.00 mmol) were dissolved in DMF (10.0 mL), and 1,2-epoxycyclopentane (757 mg, 9.00 mmol) was added, followed by stirring at 100°C overnight. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (565 mg). LCMS: 357.2 [M+H] + (Rt = 2.320 min).

[0325] [Step 2] Methyl 2-(benzyloxy)-4-methyl-6-((2-oxocyclopentyl)oxy)methylbenzoate The compound obtained in Step 1 (709 mg, 1.99 mmol) was dissolved in dichloromethane (10 mL), Dess-Martin periodinane (1.01 g, 2.39 mmol) was added at 0°C, and the mixture was stirred overnight at room temperature. 1 M aqueous sodium thiosulfate solution and saturated aqueous sodium bicarbonate solution were added to the reaction mixture, and the mixture was stirred for an additional 30 minutes, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to obtain the title compound (653 mg). LCMS: 355.2 [M+H] + (Rt = 2.342 min).

[0326] [Step 3] Methyl 2-(benzyloxy)-6-((2,2-difluorocyclopentyl)oxy)-4-methylbenzoate The compound obtained in step 2 (653 mg, 1.84 mmol) was dissolved in dichloromethane (9.2 mL), and bis(2-methoxyethyl)aminosulfur trifluoride (1.7 mL, 9.21 mmol) was added, followed by stirring at room temperature for 6 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to obtain the title compound (616 mg). LCMS: 377.2 [M+H] + (Rt = 2.453 min).

[0327] [Step 4] Methyl 2-((2,2-difluorocyclopentyl)oxy)-6-hydroxy-4-methylbenzoate The compound obtained in Step 3 (616 mg, 1.64 mmol) was dissolved in ethanol (8.18 mL), and 10% palladium-activated carbon (61.6 mg) was added. The mixture was stirred overnight at room temperature under a hydrogen atmosphere at atmospheric pressure. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (403 mg). 1 H-NMR (CDCl3) δ: 11.47 (1H, s), 6.46 (1H, s), 6.24 (1H, s), 4.60-4.56 (1H, m), 3.91 (3H, s), 2.35-2.11 (6H, m), 2.03-1.92 (2H, m), 1.86-1.74 (1H, m). LCMS: 287.1 [M+H] + (Rt = 2.341 min).

[0328] [Step 5] (2R,11aR)-6-((2,2-difluorocyclopentyl)oxy)-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 4 (391 mg, 1.84 mmol) and the compound obtained in Reference Example 41 (637 mg, 1.30 mmol) were used as starting materials, and operations similar to those in Steps 2 to 3 of Reference Example 27 and Steps 4 to 5 of Reference Example 42 were carried out to obtain the title compound (222 mg). LCMS: 354.1 [M+H] + (Rt= 2.027 min)

[0329] <Reference Example 46: (2S,11aR)-2-Hydroxy-6-isobutyl-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0330] [Step 1] Methyl 2-hydroxy-4-methyl-6-(2-methyl-1-propen-1-yl)benzoate The compound obtained in Step 2 of Reference Example 12 (165 mg, 0.67 mmol) was used as a starting material, and the same procedure as in Step 4 of Reference Example 12 was carried out to give the title compound (142 mg). 1 H-NMR (CDCl3) δ: 11.23 (1H, s), 6.69 (1H, s), 6.49 (1H, s), 6.43 (1H, s), 3.88 (3H, s), 2.30 (3H, s), 1.88 (3H, s),1.65 (3H, s). LCMS: 221.1 [M+H] + (Rt = 2.423 min).

[0331] [Step 2] (2S,11aR)-2-hydroxy-6-isobutyl-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 1 (142 mg, 0.65 mmol) and the compound obtained in Reference Example 25 (238 mg, 0.77 mmol) were used as starting materials, and the same operations as in Steps 2 to 6 of Reference Example 27 were carried out to obtain the title compound (78.6 mg). 1H-NMR (CDCl3) δ: 6.83 (1H, s), 6.72 (1H, s), 4.63-4.61 (1H, m), 4.16 (1H, dd, J = 8.5, 3.0 Hz), 4.04-3.93 (2H, m), 3.85-3.84 (2H, m), 3.19 (1H, dd, J = 13.0, 7.5 Hz), 2.39 (1H, dd, J = 13.3, 6.9 Hz), 2.31 (3H, s), 2.18-2.12 (1H, m), 1.88 (1H, dt, J = 13.4, 5.1 Hz), 1.82-1.76 (1H, m), 1.64 (1H, s), 0.85 (6H, t, J = 6.2 Hz). LCMS: 290.1 ​​[M+H] + (Rt = 2.089 min).

[0332] <Reference Example 47: (2S,11aR)-6-(2,6-difluorophenyl)-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Reference Example 15 (131 mg, 0.47 mmol) and the compound obtained in Reference Example 25 (173 mg, 0.56 mmol) were used as starting materials, and the same operations as in Steps 2 to 6 of Reference Example 27 were carried out to obtain the title compound (77.4 mg). 1 H-NMR (CDCl3) δ: 7.29-7.22 (1H, m), 7.02-6.95 (3H, m), 6.87-6.82 (1H, m), 4.58-4.55 (1H, m), 4.28 (1H, dd, J = 9.8, 4.8 Hz), 4.25-4.17 (1H, m), 4.08-4.03 (1H, m), 3.82-3.77 (1H, m), 3.72 (1H, dd, J = 12.8, 4.6 Hz), 2.39 (3H, s), 2.26-2.19 (1H, m), 1.87 (1H, dt, J = 13.3, 5.7 Hz), 1.71 (1H, d, J = 4.1 Hz). LCMS: 346.1 [M+H] + (Rt = 2.061 min).

[0333] <Reference Example 48: (2S,11aR)-2-Hydroxy-8-methyl-6-(pyrrolidin-1-yl)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0334] [Step 1] (2S,11aR)-2-(benzyloxy)-6-(cyclopropylmethoxy)-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 1 of Reference Example 28 (110 mg, 0.47 mmol) and the compound obtained in Reference Example 25 (157 mg, 0.51 mmol) were used as starting materials, and the same operations as in Steps 2 to 5 of Reference Example 27 were carried out to obtain the title compound (101 mg). 1 H-NMR (CDCl3) δ: 7.37-7.28 (5H, m), 6.56 (1H, s), 6.47 (1H, s), 4.59 (1H, d, J = 11.4 Hz), 4.49 (1H, d, J = 11.9 Hz), 4.33-4.27 (1H, m), 4.12-4.02 (2H, m), 3.96-3.91 (4H, m), 3.81 (1H, dd, J = 10.1, 6.9 Hz), 2.30 (3H, s), 2.26-2.19 (1H, m), 1.88 (1H, ddd, J = 13.3, 5.9, 4.1 Hz), 1.32-1.29 (1H, m), 0.60-0.56 (2H, m), 0.37-0.34 (2H, m). LCMS: 394.2 [M+H] + (Rt = 2.344 min).

[0335] [Step 2] (2S,11aR)-2-(benzyloxy)-6-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in step 1 (138 mg, 0.35 mmol) was dissolved in ethanol (1.75 mL), and a 4 M hydrochloric acid / 1,4-dioxane solution (437 μL, 1.75 mmol) was added, followed by stirring at 50° C. overnight. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to obtain the title compound (102 mg). 1 H-NMR (CDCl3) δ: 7.37-7.28 (5H, m), 6.46 (1H, d, J = 0.9 Hz), 6.28 (1H, d, J = 1.4 Hz), 4.58 (1H, d, J = 11.9 Hz), 4.51 (1H, d, J = 11.9 Hz), 4.44 (1H, dd, J = 11.9, 1.8 Hz), 4.25-4.18 (2H, m), 4.01 (1H, d, J = 13.7 Hz), 3.95 (1H, dd, J = 11.9, 8.7 Hz), 3.81 (1H, dd, J = 13.7, 4.1 Hz), 2.34 (1H, tdd, J = 8.6, 4.3, 2.1 Hz), 2.24 (3H, s), 1.73 (1H, ddd, J = 14.2, 9.8, 3.4 Hz). LCMS: 340.2 [M+H] + (Rt = 2.418 min).

[0336] [Step 3] (2S,11aR)-2-(benzyloxy)-8-methyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-6-yl trifluoromethanesulfonate The compound obtained in Step 2 (102 mg, 0.30 mmol) was used as a starting material, and the same procedure as in Step 1 of Reference Example 12 was carried out to give the title compound (126 mg). 1 H-NMR (CDCl3) δ: 7.36-7.29 (5H, m), 6.90 (1H, s), 6.89 (1H, s), 4.60 (1H, d, J = 11.4 Hz), 4.45 (1H, d, J = 11.9 Hz), 4.29-4.24 (2H, m), 4.16-4.04 (3H, m), 3.76 (1H, dd, J = 12.8, 4.6 Hz), 2.37 (3H, s), 2.33-2.27 (1H, m), 1.86 (1H, dt, J = 13.3, 5.5 Hz). LCMS: 472.1 [M+H] + (Rt = 2.406 min).

[0337] [Step 4] (2S,11aR)-2-(benzyloxy)-8-methyl-6-(pyrrolidin-1-yl)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 3 (126 mg, 0.27 mmol), pyrrolidine (111 μL, 1.33 mmol), and cesium carbonate (175 mg, 0.53 mmol) were dissolved in 1,2-dimethoxyethane (1.33 mL), and XPhos (20.3 mg, 0.04 mmol) and Pd(dba) (9.75 mg, 0.01 mmol) were added. The mixture was stirred at 80°C for 4 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (48.0 mg). 1H-NMR (CDCl3) δ: 7.35-7.28 (5H, m), 6.35 (1H, s), 6.23 (1H, s), 4.56 (1H, d, J = 11.4 Hz), 4.47 (1H, d, J = 11.4 Hz), 4.33-4.26 (2H, m), 4.15-4.07 (2H, m), 3.90 (1H, t, J = 11.0 Hz), 3.80 (1H, dd, J = 12.8, 4.6 Hz), 3.44-3.38 (2H, m), 3.02-2.98 (2H, m), 2.34-2.28 (1H, m), 2.26 (3H, s), 1.92-1.73 (5H, m). LCMS: 393.2 [M+H] + (Rt = 1.950 min).

[0338] [Step 5] (2S,11aR)-2-hydroxy-8-methyl-6-(pyrrolidin-1-yl)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 4 (48.0 mg, 0.12 mmol) was used as a starting material, and the same procedure as in Step 6 of Reference Example 27 was carried out to give the title compound (30.1 mg). LCMS: 303.2 [M+H] + (Rt = 1.627 min).

[0339] <Reference Example 49: (2S,11aR)-7-Fluoro-2-hydroxy-6-methoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0340] [Step 1] Methyl 2-(cyclopropylmethoxy)-3-fluoro-6-hydroxy-4-methylbenzoate The compound obtained in Step 1 of Reference Example 28 (10.3 g, 43.4 mmol) was dissolved in acetonitrile (86.0 mL), and Selectfluor (registered trademark) (23.1 g, 65.1 mmol) was added at 0°C over 20 minutes. The reaction mixture was then warmed to room temperature and stirred for 14 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (heptane / ethyl acetate) to give the title compound (5.51 g). 1 H-NMR (CDCl3) δ: 10.88 (1H, s), 6.55 (1H, dd, J = 5.9, 0.9 Hz), 3.97 (3H, s), 3.86 (2H, d, J = 6.9 Hz), 2.26 (3H, d, J = 2.3 Hz), 1.34-1.24 (1H, m), 0.64-0.59 (2H, m), 0.34-0.30 (2H, m). LCMS: 255.1 [M+H] + (Rt = 2.343 min).

[0341] [Step 2] tert-Butyl (2R,4S)-4-(benzyloxy)-2-((3-(cyclopropylmethoxy)-4-fluoro-2-(methoxycarbonyl)-5-methylphenoxy)methyl)pyrrolidine-1-carboxylate The compound obtained in Step 1 (5.51 g, 21.7 mmol), the compound obtained in Reference Example 25 (8.00 g, 26.0 mmol), and triphenylphosphine (7.39 g, 28.2 mmol) were dissolved in THF (54.2 mL), and DIAD (5.49 mL, 28.2 mmol) was added dropwise at 0°C. After the addition was complete, the mixture was stirred overnight at 40°C, and then the reaction mixture was cooled to room temperature. A saturated aqueous solution of sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) followed by aminosilica gel column chromatography (heptane / ethyl acetate) to give the title compound (9.80 g). 1 H-NMR (CDCl3) δ: 7.37-7.28 (5H, m), 6.47-6.39 (1H, m), 4.56-4.46 (2H, m), 4.24-4.20 (3H, m), 4.02-3.97 (1H, m), 3.90 (2H, d, J = 7.3 Hz), 3.86 (3H, s), 3.50-3.40 (2H, m), 2.25-2.14 (5H, m), 1.45 (9H, d, J = 8.7 Hz), 1.23-1.18 (1H, m), 0.59-0.54 (2H, m), 0.30-0.26 (2H, m). LCMS: 444.3 [M+H-Boc] + (Rt = 2.673 min).

[0342] [Step 3] (2S,11aR)-2-(benzyloxy)-6-(cyclopropylmethoxy)-7-fluoro-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 2 (9.80 g, 18.0 mmol) was used as a starting material, and operations similar to those in Steps 3 to 5 of Reference Example 27 were carried out to give the title compound (7.18 g). 1H-NMR (CDCl3) δ: 7.35-7.31 (5H, m), 6.60 (1H, d, J = 5.9 Hz), 4.47-4.58 (2H, m), 4.31-4.25 (1H, m), 4.08-4.01 (3H, m), 3.94-3.84 (4H, m), 2.24-2.19 (4H, m), 1.87 (1H, dt, J = 13.0, 5.0 Hz), 1.31-1.29 (1H, m), 0.57-0.46 (2H, m), 0.33-0.25 (2H, m). LCMS: 412.2 [M+H] + (Rt = 2.391 min).

[0343] [Step 4] (2S,11aR)-2-(benzyloxy)-7-fluoro-6-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 3 (7.18 g, 17.4 mmol) was dissolved in ethanol (58 mL), and a 4 M hydrochloric acid / ethyl acetate solution (21.8 mL) was added, followed by stirring for 22 hours at 50° C. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane / ethyl acetate) to obtain the title compound (5.07 g). 1 H-NMR (CDCl3) δ: 7.37-7.28 (5H, m), 6.24 (1H, d, J = 5.9 Hz), 4.60-4.50 (2H, m), 4.44 (1H, dd, J = 11.9, 1.8 Hz), 4.23-4.20 (2H, m), 3.99-3.85 (3H, m), 2.35 (1H, dd, J = 13.0, 6.2 Hz), 2.24 (3H, d, J = 1.8 Hz), 1.73 (1H, td, J = 14.2, 10.1 Hz). LCMS: 358.2 [M+H] + (Rt = 2.439 min).

[0344] [Step 5] (2S,11aR)-2-(benzyloxy)-7-fluoro-6-methoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 4 (50.0 mg, 0.14 mmol) and potassium carbonate (38.7 mg, 0.28 mmol) were dissolved in DMF (700 μL), iodomethane (13.1 μL, 0.21 mmol) was added, and the mixture was stirred at room temperature for 19 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (52.1 mg). 1 H-NMR (CDCl3) δ: 7.37-7.28 (5H, m), 6.60 (1H, d, J = 5.9 Hz), 4.57 (1H, d, J = 11.9 Hz), 4.50 (1H, d, J = 11.9 Hz), 4.31-4.25 (1H, m), 4.15-4.00 (2H, m), 3.99 (3H, d, J = 1.4 Hz), 3.96-3.90 (2H, m), 3.85 (1H, dd, J = 12.3, 5.5 Hz), 2.26-2.20 (4H, m), 1.87 (1H, dt, J = 13.3, 5.0 Hz). LCMS: 372.2 [M+H] + (Rt = 2.282 min).

[0345] [Step 6] (2S,11aR)-7-fluoro-2-hydroxy-6-methoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 5 (52.1 mg, 0.14 mmol) was dissolved in ethyl acetate (1.4 mL), and 20% palladium hydroxide on activated carbon (2.61 mg) was added, followed by stirring at room temperature for 4 hours under a hydrogen atmosphere at atmospheric pressure. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (40.6 mg). 1 H-NMR (CDCl3) δ: 6.62 (1H, d, J = 5.5 Hz), 4.64-4.58 (1H, m), 4.17-3.94 (6H, m), 3.89 (1H, dd, J = 12.6, 3.9 Hz), 3.82 (1H, dd, J = 12.6, 4.8 Hz), 2.27 (3H, d, J = 1.8 Hz), 2.20-2.14 (1H, m), 1.86 (1H, dt, J = 13.4, 5.3 Hz), 1.81 (1H, br s). LCMS: 282.1 [M+H] + (Rt = 1.880 min).

[0346] <Reference Example 50: (2S,11aR)-6-ethoxy-7-fluoro-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Step 4 of Reference Example 49 (50.0 mg, 0.14 mmol) and iodoethane (16.9 μL, 0.21 mmol) were used as starting materials, and the same operations as in Steps 5 and 6 of Reference Example 49 were carried out to obtain the title compound (40.2 mg). 1 H-NMR (CDCl3) δ: 6.61 (1H, d, J = 5.9 Hz), 4.62-4.59 (1H, m), 4.30-4.02 (4H, m), 3.98-3.93 (1H, m), 3.84 (2H, d, J = 4.6 Hz), 2.26 (3H, d, J = 2.3 Hz), 2.19-2.13 (1H, m), 1.97 (1H, br s), 1.86 (1H, dt, J = 13.3, 5.3 Hz), 1.40 (3H, t, J = 6.9 Hz). LCMS: 296.1 [M+H] + (Rt = 1.926 min).

[0347] <Reference Example 51: (2S,11aR)-7-fluoro-2-hydroxy-8-methyl-6-propoxy-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0348] [Step 1] (2S,11aR)-2-(benzyloxy)-7-fluoro-8-methyl-6-propoxy-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 4 of Reference Example 49 (120 mg, 0.34 mmol), 1-propanol (30.2 μL, 0.40 mmol), and triphenylphosphine (115 mg, 0.44 mmol) were dissolved in THF (1 mL), and DIAD (85 μL, 0.44 mmol) was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 2 hours, and then saturated aqueous sodium bicarbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed twice with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (187 mg). 1 H-NMR (CDCl3) δ: 7.37-7.28 (5H, m), 6.59 (1H, d, J = 5.9 Hz), 5.01-4.95 (1H, m), 4.57 (1H, d, J = 11.9 Hz), 4.49 (1H, d, J = 11.4 Hz), 4.31-4.26 (1H, m), 4.16-3.89 (5H, m), 3.86 (1H, dd, J = 12.6, 5.3 Hz), 2.26-2.20 (4H, m), 1.87 (1H, dt, J = 13.1, 5.1 Hz), 1.78 (2H, ddd, J = 14.4, 7.1, 2.3 Hz), 0.98 (3H, t, J = 7.5 Hz). LCMS: 400.2 [M+H] + (Rt= 2.422 min) [Step 2] (2S,11aR)-7-fluoro-2-hydroxy-8-methyl-6-propoxy-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 1 (187 mg, 0.47 mmol) was used as a starting material, and the same procedure as in Step 6 of Reference Example 49 was carried out to give the title compound (164 mg). 1 H-NMR (CDCl3) δ: 6.61 (1H, d, J = 5.9 Hz), 5.01-4.95 (1H, m), 4.63-4.59 (1H, m), 4.21-4.12 (2H, m), 4.09-3.92 (2H, m), 3.84 (2H, d, J = 4.6 Hz), 2.26 (3H, d, J = 1.8 Hz), 2.19-2.13 (1H, m), 1.90-1.76 (4H, m), 1.00 (3H, t, J = 7.3 Hz). LCMS: 310.2 [M+H] + (Rt= 2.023 min)

[0349] <Reference Example 52: (2S,11aR)-6-butoxy-7-fluoro-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Step 4 of Reference Example 49 (100 mg, 0.28 mmol) and 1-butanol (38.0 μL, 0.42 mmol) were used as starting materials for the same procedure as in Reference Example 51 to give the title compound (135 mg). LCMS: 324.2 [M+H] + (Rt = 2.106 min).

[0350] <Reference Example 53: (2S,11aR)-7-Fluoro-2-hydroxy-8-methyl-6-(pentyloxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Step 4 of Reference Example 49 (100 mg, 0.28 mmol) and 1-bromopentane (51.5 μL, 0.42 mmol) were used as starting materials, and the same operations as in Steps 5 and 6 of Reference Example 49 were carried out to obtain the title compound (85.3 mg). LCMS: 338.2 [M+H] + (Rt = 2.203 min).

[0351] <Reference Example 54: (2S,11aR)-7-fluoro-6-(3-fluoropropoxy)-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Step 4 of Reference Example 49 (75.0 mg, 0.21 mmol) and 3-fluoro-1-propanol (23.7 μL, 0.31 mmol) were used as starting materials for the same procedure as in Reference Example 51 to give the title compound (50.8 mg). LCMS: 328.8 [M+H] + (Rt = 1.956 min).

[0352] <Reference Example 55: (2S,11aR)-7-Fluoro-2-hydroxy-6-isopropoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0353] [Step 1] Methyl 3-fluoro-6-hydroxy-2-isopropoxy-4-methylbenzoate The compound obtained in Reference Example 4 (53.0 mg, 0.24 mmol) was used as a starting material, and the same procedure as in Step 1 of Reference Example 49 was carried out to give the title compound (18.2 mg). 1H-NMR (CDCl3) δ: 10.93 (1H, s), 6.53 (1H, d, J = 5.5 Hz), 4.46-4.37 (1H, m), 3.96 (3H, s), 2.26 (3H, d, J = 2.3 Hz), 1.31 (6H, dd, J = 5.9, 0.9 Hz). LCMS: 243.1 [M+H] + (Rt = 2.317 min).

[0354] [Step 2] (2S,11aR)-7-fluoro-2-hydroxy-6-isopropoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 1 (252 mg, 1.04 mmol) and the compound obtained in Reference Example 25 (384 mg, 1.25 mmol) were used as starting materials, and the same operations as in Steps 2 to 6 of Reference Example 27 were carried out to obtain the title compound (122 mg). 1 H-NMR (CDCl3) δ: 6.61 (1H, d, J = 5.9 Hz), 4.61 (1H, s), 4.53-4.47 (1H, m), 4.14 (1H, dd, J = 9.6, 4.6 Hz), 4.07-3.92 (2H, m), 3.88-3.80 (2H, m), 2.26 (3H, d, J = 2.3 Hz), 2.19-2.13 (1H, m), 1.89-1.83 (1H, m), 1.35 (3H, d, J = 5.9 Hz), 1.28 (3H, d, J = 6.4 Hz). LCMS: 310.2 [M+H] + (Rt = 1.971 min).

[0355] <Reference Example 56: (2S,11aR)-9-Fluoro-2-hydroxy-6-isopropoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0356] [Step 1] 8-Fluoro-5-isopropoxy-2,2,7-trimethyl-4H-benzo[d][1,3]dioxin-4-one The compound (5.05 g, 20.2 mmol) obtained in Step 1 of Reference Example 4 was used as a starting material, and the same procedure as in Step 1 of Reference Example 49 was carried out. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to obtain the title compound (290 mg). LCMS: 269.1 [M+H] + (Rt = 2.331 min).

[0357] [Step 2] Methyl 3-fluoro-2-hydroxy-6-isopropoxy-4-methylbenzoate The compound obtained in Step 1 (290 mg, 1.08 mmol) was used as a starting material, and the same procedure as in Step 3 of Reference Example 2 was carried out to give the title compound (246 mg). 1 H-NMR (CDCl3) δ: 11.49 (1H, s), 6.21 (1H, d, J = 5.5 Hz), 4.51-4.42 (1H, m), 3.93 (3H, s), 2.28 (3H, d, J = 2.3 Hz), 1.33 (6H, d, J = 5.9 Hz). LCMS: 243.1 [M+H] + (Rt = 2.300 min). [Step 3] (2S,11aR)-9-fluoro-2-hydroxy-6-isopropoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 2 (246 mg, 1.01 mmol) and the compound obtained in Reference Example 25 (374 mg, 1.22 mmol) were used as starting materials, and the same operations as in Steps 2 to 6 of Reference Example 27 were carried out to obtain the title compound (236 mg). LCMS: 310.2 [M+H] + (Rt = 1.970 min).

[0358] <Reference Example 57: (2S,11aR)-7,9-difluoro-2-hydroxy-6-isopropoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0359] [Step 1] 6,8-Difluoro-5-isopropoxy-2,2,7-trimethyl-4H-benzo[d][1,3]dioxin-4-one The compound (1 g, 4.00 mmol) obtained in Step 1 of Reference Example 4 was dissolved in acetonitrile (7.99 mL), and Selectfluor (registered trademark) (3.54 g, 9.99 mmol) was added at 0°C, followed by stirring at 60°C for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (223 mg). 1 H-NMR (CDCl3) δ: 4.55-4.46 (1H, m), 2.28 (3H, t, J = 2.3 Hz), 1.73 (6H, s), 1.36 (6H, dd, J = 5.9, 0.9 Hz). LCMS: 287.1 [M+H] + (Rt = 2.404 min).

[0360] [Step 2] (2S,11aR)-7,9-difluoro-2-hydroxy-6-isopropoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 1 (223 mg, 0.78 mmol) was used as a starting material, and operations similar to those in Steps 2 and 3 of Reference Example 56 were carried out to give the title compound (106 mg). 1H-NMR (CDCl3) δ: 4.65-4.59 (1H, m), 4.47-4.41 (1H, m), 4.24 (1H, dd, J = 9.1, 3.2 Hz), 4.08-3.98 (2H, m), 3.88 (1H, dd, J = 12.8, 3.2 Hz), 3.82 (1H, dd, J = 12.8, 5.0 Hz), 2.23 (3H, t, J = 2.1 Hz), 2.21-2.15 (1H, m), 1.89 (1H, dt, J = 13.4, 5.1 Hz), 1.80 (1H, d, J = 4.1 Hz), 1.35 (3H, d, J = 5.9 Hz), 1.26 (3H, d, J = 5.9 Hz). LCMS: 328.1 [M+H] + (Rt = 2.006 min).

[0361] <Reference Example 58: (2R,11aR)-7-chloro-6-ethoxy-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0362] [Step 1] 8-chloro-5-hydroxy-2,2,7-trimethyl-4H-benzo[d][1,3]dioxin-4-one The compound obtained in Step 1 of Reference Example 2 (700 mg, 3.36 mmol) was dissolved in acetonitrile (16.8 mL), and N-chlorosuccinimide (584 mg, 4.37 mmol) was added thereto, followed by stirring for 5 hours at 50° C. The reaction solution was concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (heptane / ethyl acetate) to obtain the title compound (523 mg). LCMS: 243.1 [M+H] + (Rt = 2.395 min).

[0363] [Step 2] tert-Butyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-(((8-chloro-2,2,7-trimethyl-4-oxo-4H-benzo[d][1,3]dioxin-5-yl)oxy)methyl)pyrrolidine-1-carboxylate The compound obtained in Step 1 (547 mg, 1.20 mmol), the compound obtained in Reference Example 20 (320 mg, 1.32 mmol), and triphenylphosphine (378 mg, 1.44 mmol) were dissolved in THF (6 mL), and DIAD (280 μL, 1.44 mmol) was added dropwise at 0° C. After the addition was complete, the mixture was stirred overnight at room temperature, and then saturated aqueous sodium bicarbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed twice with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (460 mg). LCMS: 580.3 [M+H-Boc] + (Rt = 3.120 min).

[0364] [Step 3] tert-Butyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-((4-chloro-3-hydroxy-2-(methoxycarbonyl)-5-methylphenoxy)methyl)pyrrolidine-1-carboxylate The compound obtained in Step 2 (460 mg, 0.68 mmol) was used as a starting material, and the same procedure as in Step 2 of Reference Example 30 was carried out to give the title compound as a crude product. [Step 4] tert-Butyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-((4-chloro-3-ethoxy-2-(methoxycarbonyl)-5-methylphenoxy)methyl)pyrrolidine-1-carboxylate The crude product of the compound obtained in Step 3 and iodoethane (81.5 μL, 1.01 mmol) were used as starting materials for the same procedure as in Step 3 of Reference Example 30 to give the title compound (407 mg). LCMS: 582.3 [M+H-Boc] + (Rt = 3.235 min).

[0365] [Step 5] (2R,11aR)-7-chloro-6-ethoxy-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 4 (407 mg, 0.60 mmol) was used as a starting material, and operations similar to those in Steps 7 to 9 of Reference Example 32 were carried out to give the title compound (100 mg). 1 H-NMR (CDCl3) δ: 6.77 (1H, s), 4.66-4.64 (2H, m), 4.34-4.30 (1H, m), 4.18-4.15 (1H, m), 4.03 (1H, dd, J = 10.3, 5.3 Hz), 3.95-3.92 (2H, m), 3.88-3.82 (1H, m), 2.37 (3H, s), 2.26-2.19 (1H, m), 1.83-1.80 (1H, m), 1.43 (3H, t, J = 6.9 Hz).

[0366] <Reference Example 59: (2R,11aR)-7-chloro-2-hydroxy-6-isopropoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0367] [Step 1] 6-chloro-5-isopropoxy-2,2,7-trimethyl-4H-benzo[d][1,3]dioxin-4-one The compound obtained in Step 1 of Reference Example 4 (800 mg, 3.20 mmol) was used as a starting material, and the same procedure as in Step 1 of Reference Example 58 was carried out to give the title compound (275 mg). LCMS: 285.1 [M+H] + (Rt = 2.391 min).

[0368] [Step 2] Methyl 3-chloro-6-hydroxy-2-isopropoxy-4-methylbenzoate The compound obtained in Step 1 (300 mg, 1.05 mmol) was used as a starting material, and the same procedure as in Step 3 of Reference Example 2 was carried out to give the title compound (358 mg). 1 H-NMR (CDCl3) δ: 6.02 (1H, s), 4.29-4.23 (1H, m), 3.57 (3H, s), 2.02 (3H, s), 1.15 (6H, d, J = 5.9 Hz). LCMS: 259.1 [M+H] + (Rt=2.362 min).

[0369] [Step 3] (2S,11aR)-2-(benzyloxy)-7-chloro-6-isopropoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 2 (273 mg, 1.05 mmol) and the compound obtained in Reference Example 25 (389 mg, 1.27 mmol) were used as starting materials, and the same operations as in Steps 2 to 5 of Reference Example 27 were carried out to obtain the title compound (128 mg). LCMS: 416.2 [M+H] + (Rt = 2.453 min).

[0370] [Step 4] (2S,11aR)-7-chloro-2-hydroxy-6-isopropoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 3 (100 mg, 0.24 mmol) was dissolved in methanol (12 mL), and 10% palladium-activated carbon (25.6 mg) was added, followed by stirring at room temperature for 1 hour under a hydrogen atmosphere at atmospheric pressure. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (81.2 mg). LCMS: 326.1 [M+H] + (Rt = 2.014 min).

[0371] [Step 5] (2R,11aR)-7-chloro-2-hydroxy-6-isopropoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 4 (81.2 mg, 0.25 mmol), acetic acid (21.4 μL, 0.374 mmol), and triphenylphosphine (85 mg, 0.324 mmol) were dissolved in THF (1.25 mL), and DIAD (63.1 μL, 0.324 mmol) was added dropwise at 0°C. After the addition was complete, the mixture was stirred at room temperature for 3 hours, and then saturated aqueous sodium bicarbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed twice with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate). The obtained compound was dissolved in methanol (1.07 mL), potassium carbonate (59.4 mg, 0.43 mmol) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (69.2 mg). LCMS: 326.1 [M+H] + (Rt = 2.014 min).

[0372] <Reference Example 60: (2R,11aR)-7,9-dichloro-2-hydroxy-6-isopropoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0373] [Step 1] 6,8-Dichloro-5-hydroxy-2,2,7-trimethyl-4H-benzo[d][1,3]dioxin-4-one The compound obtained in Step 1 of Reference Example 2 (700 mg, 3.36 mmol) was used as a starting material, and the same procedure as in Step 1 of Reference Example 58 was carried out to obtain the title compound. LCMS: 277.0 [M+H] + (Rt = 2.493 min).

[0374] [Step 2] tert-Butyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-((2,4-dichloro-5-hydroxy-6-(methoxycarbonyl)-3-methylphenoxy)methyl)pyrrolidine-1-carboxylate The crude product of the compound obtained in Step 1 and the compound obtained in Reference Example 20 (547 mg, 1.20 mmol) were used as starting materials, and the same operations as in Steps 2 and 3 of Reference Example 58 were carried out to obtain the crude product of the title compound. LCMS: 632.3 [M+H-tBu] + (Rt = 3.629 min).

[0375] [Step 3] tert-Butyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-((2,4-dichloro-5-isopropoxy-6-(methoxycarbonyl)-3-methylphenoxy)methyl)pyrrolidine-1-carboxylate The crude product of the compound obtained in Step 2 and 2-iodopropane (18.1 μL, 0.18 mmol) were used as starting materials for the same procedure as in Step 3 of Reference Example 30 to give the title compound (99.4 mg). [Step 4] (2R,11aR)-7,9-dichloro-2-hydroxy-6-isopropoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 3 (99.4 mg, 0.14 mmol) was used as a starting material, and operations similar to those in Steps 7 to 9 of Reference Example 32 were carried out to give the title compound (27.4 mg). LCMS: 360.1 [M+H] + (Rt = 2.190 min).

[0376] <Reference Example 61: (2R,11aR)-6-(cyclopropylmethoxy)-7-fluoro-8-methyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-2-yl 4-methylbenzenesulfonate>

[0377] [Step 1] (2S,11aR)-6-(cyclopropylmethoxy)-7-fluoro-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 3 of Reference Example 49 (150 mg, 0.36 mmol) was dissolved in ethyl acetate (1.80 mL), and 20% palladium hydroxide on activated carbon (15.0 mg) was added, followed by stirring at room temperature for 1 hour under a hydrogen atmosphere at atmospheric pressure. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (116 mg). LCMS: 322.2 [M+H] + (Rt = 2.020 min).

[0378] [Step 2] (2R,11aR)-6-(cyclopropylmethoxy)-7-fluoro-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in step 1 (116 mg, 0.36 mmol), benzoic acid (52.8 mg, 0.43 mmol), and triphenylphosphine (113 mg, 0.43 mmol) were dissolved in THF (1.08 mL), and DIAD (84.2 μL, 0.43 mmol) was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 1 hour, and then saturated aqueous sodium bicarbonate solution was added and extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (heptane / ethyl acetate). The obtained compound was dissolved in ethanol (1.9 mL), and 2 M aqueous sodium hydroxide solution (0.380 mL, 0.76 mmol) was added. The mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to obtain the title compound (77.9 mg). 1H-NMR (CDCl3) δ: 6.64 (1H, d, J = 5.9 Hz), 4.64-4.58 (2H, m), 4.13-4.11 (1H, m), 4.02 (1H, dd, J = 10.1, 5.0 Hz), 3.92-3.87 (4H, m), 2.24-2.20 (4H, m), 1.86-1.79 (2H, m), 1.42-1.33 (1H, m), 0.59-0.55 (2H, m), 0.40-0.35 (2H, m). LCMS: 322.2 [M+H] + (Rt = 2.027 min).

[0379] [Step 3] (2R,11aR)-6-(cyclopropylmethoxy)-7-fluoro-8-methyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-2-yl 4-methylbenzenesulfonate The compound obtained in Step 2 (147 mg, 0.46 mmol), pyridine (73.7 μL, 0.92 mmol), and 4-dimethylaminopyridine (11.2 mg, 0.09 mmol) were dissolved in dichloromethane (2.29 mL), p-toluenesulfonyl chloride (131 mg, 0.69 mmol) was added, and the mixture was stirred at 40° C. for 5 days. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (heptane / ethyl acetate) to give the title compound (109 mg). 1H-NMR (CDCl3) δ: 7.81 (2H, d, J = 8.2 Hz), 7.37 (2H, d, J = 7.8 Hz), 6.64 (1H, d, J = 5.9 Hz), 5.22-5.20 (1H, m), 4.38 (1H, dd, J = 11.7, 10.3 Hz), 4.06 (1H, dd, J = 9.6, 7.3 Hz), 4.01 (1H, dd, J = 10.3, 5.3 Hz), 3.98-3.84 (3H, m), 3.78 (1H, dd, J = 14.4, 4.8 Hz), 2.47 (3H, s), 2.38-2.31 (1H, m), 2.25 (3H, d, J = 1.8 Hz), 2.14-2.10 (1H, m), 1.37-1.30 (1H, m), 0.57-0.54 (2H, m), 0.39-0.31 (2H, m). LCMS: 476.2 [M+H] + (Rt = 2.375 min).

[0380] <Reference Example 62: (2S,11aR)-7-Fluoro-2-hydroxy-8-methyl-6-(2,2,2-trifluoroethoxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Step 4 of Reference Example 49 (100 mg, 0.28 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (80.7 μL, 0.56 mmol) were used as starting materials, and the same operations as in Steps 5 and 6 of Reference Example 49 were carried out to obtain the title compound (99.3 mg). LCMS: 350.1 [M+H] + (Rt = 2.051 min).

[0381] <Reference Example 63: (2R,11aR)-7-Fluoro-6-((1-fluorocyclopropyl)methoxy)-8-methyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-2-yl 4-methylbenzenesulfonate>

[0382] [Step 1] (2S,11aR)-2-(benzyloxy)-7-fluoro-6-((1-fluorocyclopropyl)methoxy)-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 4 of Reference Example 49 (147 mg, 0.41 mmol), (1-fluorocyclopropyl)methanol (44.6 mg, 0.50 mmol), and triphenylphosphine (130 mg, 0.50 mmol) were dissolved in THF (1.24 mL), and DIAD (96.3 μL, 0.50 mmol) was added dropwise. After the addition was completed, the mixture was stirred at 40° C. overnight. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (224 mg). LCMS: 430.2 [M+H] + (Rt = 2.357 min).

[0383] [Step 2] (2S,11aR)-7-fluoro-6-((1-fluorocyclopropyl)methoxy)-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 1 (224 mg, 0.52 mmol) was used as a starting material, and the same procedure as in Step 1 of Reference Example 61 was carried out to give the title compound (188 mg). LCMS: 340.1 [M+H] + (Rt = 2.008 min).

[0384] [Step 3] (2R,11aR)-7-Fluoro-6-((1-fluorocyclopropyl)methoxy)-8-methyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-2-yl 4-methylbenzenesulfonate The compound obtained in Step 2 (49.5 mg, 0.15 mmol) was used as a starting material, and operations similar to those in Steps 2 and 3 of Reference Example 61 were carried out to give the title compound (40.5 mg). 1 H-NMR (CDCl3) δ: 7.81 (2H, d, J = 8.2 Hz), 7.38 (2H, d, J = 8.2 Hz), 6.68 (1H, d, J = 5.9 Hz), 5.22-5.20 (1H, m), 4.51-4.30 (3H, m), 4.04-3.92 (2H, m), 3.87 (1H, d, J = 14.2 Hz), 3.77 (1H, dd, J = 14.4, 5.3 Hz), 2.47 (3H, s), 2.40-2.32 (1H, m), 2.27 (3H, s), 2.14-2.11 (1H, m), 1.13-1.09 (2H, m), 0.99-0.76 (2H, m). LCMS: 494.2 [M+H] + (Rt = 2.370 min).

[0385] <Reference Example 64: (2S,11aR)-7-Fluoro-2-hydroxy-6-isobutoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Step 4 of Reference Example 49 (150 mg, 0.42 mmol) and 1-bromo-2-methylpropane (67.9 μL, 0.63 mmol) were used as starting materials, and the same operations as in Steps 5 and 6 of Reference Example 49 were carried out to obtain the title compound (132 mg). LCMS: 324.2 [M+H] + (Rt = 2.102 min).

[0386] <Reference Example 65: (2S,11aR)-7-fluoro-6-(2-fluoro-2-methylpropoxy)-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Step 4 of Reference Example 49 (200 mg, 0.56 mmol) and 2-fluoro-2-methyl-1-propanol (79.9 μL, 0.84 mmol) were used as starting materials for the same procedure as in Reference Example 51 to give the title compound (92.3 mg). LCMS: 342.1 [M+H] + (Rt = 2.030 min).

[0387] <Reference Example 66: (2R,11aR)-6-((1,3-difluoropropan-2-yl)oxy)-7-fluoro-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0388] [Step 1] (2S,11aR)-6-((1,3-difluoropropan-2-yl)oxy)-7-fluoro-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 4 of Reference Example 49 (200 mg, 0.56 mmol) and 1,3-difluoropropan-2-ol (65.0 μL, 0.84 mmol) were used as starting materials for the same procedure as in Reference Example 51 to give the title compound (109 mg). LCMS: 346.2 [M+H] + (Rt = 1.960 min).

[0389] [Step 2] (2R,11aR)-6-((1,3-difluoropropan-2-yl)oxy)-7-fluoro-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 1 (42.3 mg, 0.12 mmol) was used as a starting material, and the same procedure as in Step 2 of Reference Example 61 was carried out to give the title compound (25.2 mg). 1H-NMR (CDCl3) δ: 6.71 (1H, d, J = 5.9 Hz), 4.92-4.86 (1H, m), 4.81-4.59 (6H, m), 4.03 (1H, dd, J = 10.1, 5.0 Hz), 3.93-3.87 (2H, m), 3.82 (1H, dd, J = 13.3, 4.6 Hz), 2.28-2.21 (4H, m), 1.84-1.80 (1H, m). LCMS: 346.2 [M+H] + (Rt = 1.977 min).

[0390] <Reference Example 67: (2S,11aR)-6-((R)-sec-butoxy)-7-fluoro-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Step 4 of Reference Example 49 (100 mg, 0.28 mmol) and (S)-(+)-2-butanol (33.0 μL, 0.36 mmol) were used as starting materials to carry out the same procedure as in Reference Example 51 to obtain the title compound (103 mg). LCMS: 324.2 [M+H] + (Rt = 2.036 min).

[0391] <Reference Example 68: (2S,11aR)-6-((S)-sec-butoxy)-7-fluoro-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Step 4 of Reference Example 49 (100 mg, 0.28 mmol) and (R)-(-)-2-butanol (67.0 μL, 0.73 mmol) were used as starting materials to carry out the same procedure as in Reference Example 51 to obtain the title compound (73.5 mg). 1H-NMR (CDCl3) δ: 6.61 (1H, d, J = 5.9 Hz), 4.60 (1H, dd, J = 8.2, 4.1 Hz), 4.27-4.21 (1H, m), 4.01-3.90 (5H, m), 2.25 (3H, d, J = 1.8 Hz), 2.21-2.13 (1H, m), 1.88-1.76 (3H, m), 1.69-1.62 (1H, m), 1.20 (3H, d, J = 6.4 Hz), 0.97 (3H, t, J = 7.3 Hz). LCMS: 324.2 [M+H] + (Rt = 2.037 min).

[0392] <Reference Example 69: (2S,11aR)-7-fluoro-6-(((R)-1-fluoropropan-2-yl)oxy)-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0393] [Step 1] Methyl (R)-2-((1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)oxy)-3-fluoro-6-hydroxy-4-methylbenzoate The compound obtained in Reference Example 6 (1.62 g, 3.39 mmol) was dissolved in acetonitrile (11 mL), and Selectfluor (registered trademark) (1.80 g, 5.09 mmol) was added at 0°C, followed by stirring at room temperature overnight. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed twice with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to obtain the title compound (832 mg). LCMS: 497.3 [M+H] + (Rt = 2.928 min).

[0394] [Step 2] tert-Butyl (2R,4S)-4-(benzyloxy)-2-((3-(((R)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)oxy)-4-fluoro-2-(methoxycarbonyl)-5-methylphenoxy)methyl)pyrrolidine-1-carboxylate The compound obtained in Step 1 (832 mg, 1.68 mmol), the compound obtained in Reference Example 25 (618 mg, 2.01 mmol), and triphenylphosphine (571 mg, 2.18 mmol) were dissolved in THF (4.2 mL), and DIAD (424 μL, 2.18 mmol) was added dropwise. After the addition was completed, the mixture was stirred at 45° C. for 4 hours, and then saturated aqueous sodium bicarbonate solution was added and extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (1.21 g). LCMS: 686.4 [M+H-Boc] + (Rt = 3.296 min).

[0395] [Step 3] tert-Butyl (2R,4S)-4-(benzyloxy)-2-((4-fluoro-3-(((R)-1-hydroxypropan-2-yl)oxy)-2-(methoxycarbonyl)-5-methylphenoxy)methyl)pyrrolidine-1-carboxylate The compound obtained in step 2 (1.21 g, 1.54 mmol) was dissolved in THF (5 mL), and 1 M tetrabutylammonium fluoride / THF solution (2.31 mL, 2.31 mmol) was added dropwise at 0°C. After the addition was complete, the mixture was stirred at room temperature for 2.5 hours, and then saturated aqueous ammonium chloride solution was added and extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (818 mg). 1H-NMR (CDCl3) δ: 7.35-7.26 (5H, m), 6.46-6.38 (1H, m), 4.51-4.46 (3H, m), 4.25-3.55 (11H, m), 3.39-3.41 (1H, m), 2.24-2.18 (5H, m), 1.47-1.45 (9H, m), 1.32 (3H, d, J = 6.4 Hz).

[0396] [Step 4] tert-Butyl (2R,4S)-4-(benzyloxy)-2-((4-fluoro-3-(((R)-1-fluoropropan-2-yl)oxy)-2-(methoxycarbonyl)-5-methylphenoxy)methyl)pyrrolidine-1-carboxylate The compound obtained in step 3 (400 mg, 0.73 mmol) was dissolved in dichloromethane (7.3 mL), and bis(2-methoxyethyl)aminosulfur trifluoride (257 μL, 1.46 mmol) was added, followed by stirring at room temperature overnight. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to obtain the title compound (150 mg). 1 H-NMR (CDCl3) δ: 7.32-7.29 (5H, m), 6.49-6.42 (1H, m), 4.59-4.46 (4H, m), 4.40 (1H, d, J = 4.1 Hz), 4.25-3.96 (4H, m), 3.85 (3H, s), 3.84-3.34 (2H, m), 2.23-2.18 (5H, m), 1.47-1.45 (9H, m), 1.32 (3H, d, J = 6.4 Hz).

[0397] [Step 5] (2S,11aR)-7-fluoro-6-(((R)-1-fluoropropan-2-yl)oxy)-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 4 (146 mg, 0.35 mmol) was used as a starting material, and operations similar to those in Steps 3 to 6 of Reference Example 27 were carried out to give the title compound (115 mg). LCMS: 328.2 [M+H] + (Rt = 1.937 min).

[0398] <Reference Example 70: (2S,11aR)-6-(((R)-1,1-difluoropropan-2-yl)oxy)-7-fluoro-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0399] [Step 1] tert-Butyl (2R,4S)-4-(benzyloxy)-2-((4-fluoro-2-(methoxycarbonyl)-5-methyl-3-(((R)-1-oxopropan-2-yl)oxy)phenoxy)methyl)pyrrolidine-1-carboxylate The compound obtained in Step 3 of Reference Example 69 (400 mg, 0.73 mmol) was dissolved in dichloromethane (3.7 mL), Dess-Martin periodinane (372 mg, 0.88 mmol) was added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate and an aqueous solution of sodium thiosulfate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (257 mg). 1 H-NMR (CDCl3) δ: 9.85 (1H, s), 7.35-7.26 (5H, m), 6.54-6.45 (1H, m), 4.57-4.46 (3H, m), 4.25-3.79 (7H, m), 3.56-3.37 (2H, m), 2.25-2.05 (5H, m), 1.47-1.45 (9H, m), 1.32 (3H, d, J = 6.4 Hz).

[0400] [Step 2] tert-Butyl (2R,4S)-4-(benzyloxy)-2-((3-(((R)-1,1-difluoropropan-2-yl)oxy)-4-fluoro-2-(methoxycarbonyl)-5-methylphenoxy)methyl)pyrrolidine-1-carboxylate The compound obtained in step 1 (257 mg, 0.47 mmol) was dissolved in dichloromethane (4.70 mL), and bis(2-methoxyethyl)aminosulfur trifluoride (248 μL, 1.41 mmol) was added at 0°C. The mixture was stirred at 0°C for 1 hour, then warmed to room temperature and stirred for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to obtain the title compound (218 mg). 1 H-NMR (CDCl3) δ: 7.35-7.30 (5H, m), 6.52-6.44 (1H, m), 5.88 (1H, td, J = 55.6, 2.7 Hz), 4.56-4.39 (3H, m), 4.27-4.18 (3H, m), 4.02-3.99 (1H, m), 3.83-3.53 (4H, m), 3.42-3.36 (1H, m), 2.27-2.25 (3H, m), 2.21-2.15 (2H, m), 1.45 (9H, d, J = 8.7 Hz), 1.37 (3H, d, J = 6.4 Hz).

[0401] [Step 3] (2S,11aR)-6-(((R)-1,1-difluoropropan-2-yl)oxy)-7-fluoro-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 2 (217 mg, 0.38 mmol) was used as a starting material, and operations similar to those in Steps 3 to 6 of Reference Example 27 were carried out to give the title compound (116 mg). 1H-NMR (CDCl3) δ: 6.67 (1H, d, J = 5.9 Hz), 5.84 (1H, td, J = 55.9, 4.9 Hz), 4.60-4.57 (1H, m), 4.39-4.32 (1H, m), 4.16 (1H, dd, J = 9.1, 3.7 Hz), 4.06-3.94 (2H, m), 3.88 (1H, dq, J = 12.6, 1.6 Hz), 3.79 (1H, dd, J = 12.6, 4.8 Hz), 2.27 (3H, d, J = 1.8 Hz), 2.20-2.15 (1H, m), 1.89-1.82 (2H, m), 1.48 (3H, d, J = 6.4 Hz). LCMS: 346.1 [M+H] + (Rt = 2.022 min).

[0402] <Reference Example 71: (2S,11aR)-7-Fluoro-2-hydroxy-8-methyl-6-(((R)-1,1,1-trifluoropropan-2-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0403] [Step 1] (R)-6-Fluoro-2,2,7-trimethyl-5-((1,1,1-trifluoropropan-2-yl)oxy)-4H-benzo[d][1,3]dioxin-4-one The compound obtained in Step 1 of Reference Example 8 (400 mg, 1.31 mmol) was dissolved in acetonitrile (6.57 mL), and Selectfluor (registered trademark) (931 mg, 2.63 mmol) was added at 0°C, followed by stirring at room temperature for 48 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (258 mg). 1H-NMR (CDCl3) δ: 6.60 (1H, d, J = 5.5 Hz), 4.72-4.62 (1H, m), 2.32-2.32 (3H, m), 1.69 (6H, d, J = 7.8 Hz), 1.62 (3H, d, J = 6.4 Hz). LCMS: 323.1 [M+H] + (Rt = 2.387 min). [Step 2] Methyl (R)-3-fluoro-6-hydroxy-4-methyl-2-((1,1,1-trifluoropropan-2-yl)oxy)benzoate The compound obtained in Step 1 (258 mg, 0.80 mmol) was used as a starting material, and the same procedures as in Step 2 of Reference Example 7 were carried out to give the title compound (177 mg). 1 H-NMR (CDCl3) δ: 11.01 (1H, s), 6.60 (1H, d, J = 5.9 Hz), 4.62-4.52 (1H, m), 3.95 (3H, s), 2.28 (3H, d, J = 2.3 Hz), 1.54 (3H, d, J = 6.4 Hz). LCMS: 297.0 [M+H] + (Rt= 2.352 min) [Step 3] (2S,11aR)-7-Fluoro-2-hydroxy-8-methyl-6-(((R)-1,1,1-trifluoropropan-2-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 2 (2.25 g, 7.59 mmol) and the compound obtained in Reference Example 25 (2.80 mg, 9.11 mmol) were used as starting materials, and the same operations as in Steps 2 to 6 of Reference Example 27 were carried out to obtain the title compound (1.57 g). LCMS: 364.1 [M+H] + (Rt = 2.050 min).

[0404] <Reference Example 72: (2S,11aR)-6-(cyclopentyloxy)-7-fluoro-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Step 4 of Reference Example 49 (50.0 mg, 0.14 mmol) and bromocyclopentane (30.0 μL, 0.28 mmol) were used as starting materials, and the same operations as in Steps 5 and 6 of Reference Example 49 were carried out to obtain the title compound (41.4 mg). LCMS: 336.2 [M+H] + (Rt= 2.075 min)

[0405] <Reference Example 73: (2S,11aR)-7-Fluoro-2-hydroxy-8-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Step 4 of Reference Example 49 (70.0 mg, 0.20 mmol) and (R)-3-hydroxytetrahydrofuran (23.3 μL, 0.29 mmol) were used as starting materials for the same procedure as in Reference Example 51 to give the title compound (33.8 mg). 1 H-NMR (CDCl3) δ: 6.65 (1H, d, J = 5.9 Hz), 5.04-5.01 (1H, m), 4.61-4.59 (1H, m), 4.20-4.16 (2H, m), 4.06-3.75 (7H, m), 2.27-2.14 (5H, m), 2.03-1.98 (2H, m), 1.87-1.83 (1H, m). LCMS: 338.2 [M+H] + (Rt = 1.853 min).

[0406] <Reference Example 74: (2S,11aR)-7-Fluoro-2-hydroxy-8-methyl-6-(((R)-tetrahydrofuran-3-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Step 4 of Reference Example 49 (100 mg, 0.28 mmol) and (S)-3-hydroxytetrahydrofuran (33.3 μL, 0.42 mmol) were used as starting materials to carry out the same procedure as in Reference Example 51 to give the title compound (59.6 mg). LCMS: 338.2 [M+H] + (Rt= 1.871 min)

[0407] <Reference Example 75: (2R,11S,11aR)-7-fluoro-2-hydroxy-6-isopropoxy-8,11-dimethyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0408] [Step 1] tert-Butyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-formylpyrrolidine-1-carboxylate The compound obtained in Reference Example 20 (4.56 g, 10.0 mmol) was used as a starting material, and the same procedure as in Step 1 of Reference Example 35 was carried out to give the title compound (4.34 g). LCMS: 454.7 [M+H] + (Rt = 2.808 min).

[0409] [Step 2] tert-Butyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-((R)-1-hydroxyethyl)pyrrolidine-1-carboxylate The compound obtained in step 1 (4.34 g, 9.57 mmol) was dissolved in THF (32 mL), and a 3 M methylmagnesium bromide / diethyl ether solution (3.83 mL, 11.5 mmol) was added dropwise at -78°C. After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (1.49 g). 1H-NMR (CDCl3) δ: 7.66-7.62 (4H, m), 7.47-7.38 (6H, m), 5.60-5.25 (1H, m), 4.49-4.05 (2H, m), 3.73-3.18 (3H, m), 1.99 (1H, br s), 1.71-1.67 (1H, m), 1.43 (9H, s), 1.16-1.15 (3H, m), 1.07-1.06 (9H, m). LCMS: 414.2 [M+H-tBu] + (Rt= 2.848 min) [Step 3] (2R,11S,11aR)-7-fluoro-2-hydroxy-6-isopropoxy-8,11-dimethyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 2 (564 mg, 1.20 mmol) was used as a starting material, and operations similar to those in Steps 6 to 9 of Reference Example 33 were carried out to give the title compound (155 mg). LCMS: 324.2 [M+H] + (Rt= 2.033 min)

[0410] <Reference Example 76: (2R,11R,11aR)-7-fluoro-2-hydroxy-6-isopropoxy-8,11-dimethyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0411] [Step 1] tert-Butyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-((S)-1-hydroxyethyl)pyrrolidine-1-carboxylate The compound obtained in Step 1 of Reference Example 75 (4.34 g, 9.57 mmol) was used as a starting material, and the same procedure as in Step 2 of Reference Example 75 was carried out to give the title compound (1.28 g). 1H-NMR (CDCl3) δ: 7.66 (4H, t, J = 6.4 Hz), 7.48-7.38 (6H, m), 4.33-3.12 (5H, m), 2.06 (1H, br s), 1.79 (1H, br s), 1.42 (9H, s), 1.14 (3H, d, J = 6.4 Hz), 1.07 (9H, s). LCMS: 414.2 [M+H-tBu] + (Rt = 2.848 min).

[0412] [Step 2] (2R,11R,11aR)-7-fluoro-2-hydroxy-6-isopropoxy-8,11-dimethyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 1 (705 mg, 1.50 mmol) was used as a starting material, and the same procedure as in Step 3 of Reference Example 75 was carried out to give the title compound (13.0 mg). LCMS: 324.2 [M+H] + (Rt = 2.022 min).

[0413] <Reference Example 77: (2S,11aR)-7-Fluoro-2-hydroxy-8-methyl-6-(pyrrolidin-1-yl)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0414] [Step 1] (2S,11aR)-2-(benzyloxy)-7-fluoro-8-methyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-6-yl trifluoromethanesulfonate The compound obtained in Step 4 of Reference Example 49 (110 mg, 0.31 mmol) and triethylamine (64.4 μL, 0.47 mmol) were dissolved in dichloromethane (1.5 mL), and trifluoromethanesulfonic anhydride (65.4 μL, 0.40 mmol) was added dropwise at 0°C. After the addition was complete, the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (141 mg). 1 H-NMR (CDCl3) δ: 7.36-7.27 (5H, m), 6.93 (1H, d, J = 5.9 Hz), 4.60 (1H, d, J = 11.4 Hz), 4.45 (1H, d, J = 11.9 Hz), 4.30-4.22 (2H, m), 4.18-4.02 (3H, m), 3.74 (1H, dd, J = 12.8, 4.6 Hz), 2.33-2.28 (4H, m), 1.86 (1H, dt, J = 13.3, 5.7 Hz). LCMS: 490.1 [M+H] + (Rt = 2.450 min).

[0415] [Step 2] (2S,11aR)-2-(benzyloxy)-7-fluoro-8-methyl-6-(pyrrolidin-1-yl)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 1 (141 mg, 0.29 mmol) and pyrrolidine (120 μL, 1.45 mmol) were used as starting materials for the same procedure as in Step 4 of Reference Example 48 to give the title compound (62.5 mg). 1H-NMR (CDCl3) δ: 7.36-7.27 (5H, m), 6.23 (1H, d, J = 5.5 Hz), 4.56 (1H, d, J = 11.4 Hz), 4.47 (1H, d, J = 11.4 Hz), 4.33-4.29 (1H, m), 4.25-4.18 (1H, m), 4.08-4.02 (2H, m), 3.88-3.78 (2H, m), 3.70-3.63 (2H, m), 3.14-3.10 (2H, m), 2.34-2.28 (1H, m), 2.17 (3H, d, J = 2.7 Hz), 1.90-1.69 (5H, m). LCMS: 411.2 [M+H] + (Rt = 1.945 min).

[0416] [Step 3] (2S,11aR)-7-fluoro-2-hydroxy-8-methyl-6-(pyrrolidin-1-yl)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 2 (62.5 mg, 0.15 mmol) was used as a starting material, and the same procedure as in Step 6 of Reference Example 27 was carried out to give the title compound (42.1 mg). LCMS: 321.2 [M+H] + (Rt = 1.632 min).

[0417] <Reference Example 78: (2S,11aR)-7-Fluoro-2-hydroxy-6-isopropyl-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0418] [Step 1] (2S,11aR)-2-(benzyloxy)-7-fluoro-8-methyl-6-(propen-2-yl)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 1 of Reference Example 77 (130 mg, 0.27 mmol), isopropenylboronic acid pinacol ester (99.8 μL, 0.53 mmol), and 2 M aqueous sodium carbonate solution (398 μL, 0.80 mmol) were dissolved in 1,4-dioxane (1.06 mL), and XPhos Pd G3 (11.2 mg, 0.01 mmol) was added, followed by stirring at 90°C for 1 hour. The reaction solution was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (90.0 mg). 1 H-NMR (CDCl3) δ: 7.32-7.30 (5H, m), 6.78 (1H, d, J = 6.4 Hz), 5.17 (1H, s), 4.75 (1H, s), 4.55 (1H, d, J = 11.4 Hz), 4.45 (1H, d, J = 11.4 Hz), 4.29-4.25 (1H, m), 4.18-3.93 (4H, m), 3.71 (1H, dd, J = 12.6, 4.3 Hz), 2.31-2.25 (4H, m), 2.14 (3H, s), 1.87-1.84 (1H, m). LCMS: 382.2 [M+H] + (Rt = 2.414 min).

[0419] [Step 2] (2S,11aR)-7-fluoro-2-hydroxy-6-isopropyl-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in step 1 (90.0 mg, 0.24 mmol) was dissolved in ethyl acetate (1.18 mL), and 20% palladium hydroxide on activated carbon (4.50 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere at atmospheric pressure for 7 days. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (38.3 mg). 1 H-NMR (CDCl3) δ: 6.73 (1H, d, J = 6.4 Hz), 4.66-4.64 (1H, m), 4.11-3.99 (2H, m), 3.94-3.88 (2H, m), 3.77 (1H, dd, J = 12.3, 4.1 Hz), 3.53-3.42 (1H, m), 2.24 (3H, d, J = 2.7 Hz), 2.21-2.15 (1H, m), 1.93-1.90 (1H, m), 1.72 (1H, d, J = 4.6 Hz), 1.39 (3H, d, J = 6.9 Hz), 1.30-1.28 (3H, m). LCMS: 294.2 [M+H] + (Rt = 2.069 min).

[0420] <Reference Example 79: (2S,11aR)-6-Cyclopentyl-7-fluoro-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Step 1 of Reference Example 77 (130 mg, 0.27 mmol) and 1-cyclopentenylboronic acid (55.1 μL, 0.53 mmol) were used as starting materials for the same procedure as in Reference Example 78 to give the title compound (72.0 mg). LCMS: 320.2 [M+H] + (Rt = 2.165 min).

[0421] <Reference Example 80: tert-butyl (2R,4S)-4-((tert-butyldiphenylsilyl)oxy)-2-ethynylpyrrolidine-1-carboxylate> A mixture of potassium carbonate (305 mg, 2.20 mmol), dimethyl (1-diazo-2-oxopropyl)phosphonate (199 μL, 1.32 mmol), and methanol (3.68 mL) was stirred at room temperature for 10 minutes, and the compound obtained in Step 1 of Reference Example 35 (500 mg, 1.10 mmol) was added, followed by stirring at room temperature for 3 hours. Saturated brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (379 mg). 1 H-NMR (CDCl3) δ: 7.61 (4H, t, J = 5.9 Hz), 7.45-7.35 (6H, m), 4.62-4.50 (1H, m), 4.44-4.39 (1H, m), 3.42-3.34 (2H, m), 2.23-2.17 (2H, m), 1.97 (1H, br s), 1.25 (9H, s), 1.02 (9H, s). LCMS: 350.2 [M+H-Boc] + (Rt = 3.105 min).

[0422] <Reference Example 81: (2S,11aS)-7-Fluoro-2-hydroxy-6-isopropoxy-8-methyl-1,2,3,10,11,11a-hexahydro-5H-benzo[e]pyrrolo[1,2-a]azepin-5-one>

[0423] [Step 1] Methyl 3-fluoro-2-isopropoxy-4-methyl-6-(((trifluoromethyl)sulfonyl)oxy)benzoate The compound obtained in Step 1 of Reference Example 55 (580 mg, 2.39 mmol) and N,N-diisopropylethylamine (495 μL, 2.87 mmol) were dissolved in dichloromethane (3.19 mL), and trifluoromethanesulfonic anhydride (431 μL, 2.63 mmol) was added at 0°C. The mixture was stirred at 0°C for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (486 mg). LCMS: 375.1 [M+H] + (Rt = 2.583 min).

[0424] [Step 2] tert-Butyl (2R,4S)-4-((tert-butyldiphenylsilyl)oxy)-2-((4-fluoro-3-isopropoxy-2-(methoxycarbonyl)-5-methylphenyl)ethynyl)pyrrolidine-1-carboxylate The compound obtained in Step 1 (100 mg, 0.27 mmol), the compound obtained in Reference Example 80 (126 mg, 0.28 mmol), and diethylamine (84.0 μL, 0.80 mmol) were dissolved in DMF (1.07 mL), and copper iodide (10.2 mg, 0.05 mmol) and dichlorobis(triphenylphosphine)palladium(II) (18.8 mg, 0.03 mmol) were added, followed by stirring overnight at 80°C under a nitrogen atmosphere. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (113 mg). LCMS: 574.2 [M+H-Boc] + (Rt = 3.742 min).

[0425] [Step 3] tert-Butyl (2S,4S)-4-((tert-butyldiphenylsilyl)oxy)-2-(4-fluoro-3-isopropoxy-2-(methoxycarbonyl)-5-methylphenethyl)pyrrolidine-1-carboxylate The compound obtained in step 2 (113 mg, 0.17 mmol) was dissolved in methanol (3.35 mL), and 10% palladium-activated carbon (17.8 mg) was added, followed by stirring at room temperature for 5 hours under a hydrogen atmosphere at atmospheric pressure. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (112 mg). LCMS: 578.3 [M+H-Boc] + (Rt = 3.924 min).

[0426] [Step 4] (2S,11aS)-7-Fluoro-2-hydroxy-6-isopropoxy-8-methyl-1,2,3,10,11,11a-hexahydro-5H-benzo[e]pyrrolo[1,2-a]azepin-5-one The compound obtained in Step 3 (112 mg, 0.17 mmol) was used as a starting material, and operations similar to those in Steps 7 to 9 of Reference Example 32 were carried out to give the title compound (29.0 mg). 1 H-NMR (CDCl3) δ: 6.66 (1H, d, J = 6.9 Hz), 4.62-4.55 (1H, m), 4.49-4.40 (1H, m), 3.83 (1H, dd, J = 12.6, 5.3 Hz), 3.74 (1H, dd, J = 12.6, 4.8 Hz), 3.71-3.63 (1H, m), 2.79-2.69 (1H, m), 2.56 (1H, dd, J = 13.7, 6.4 Hz), 2.25 (3H, d, J = 2.3 Hz), 2.19-2.12 (1H, m), 2.04-1.94 (2H, m), 1.90-1.86 (1H, m), 1.84-1.75 (1H, m), 1.34 (3H, d, J = 5.9 Hz), 1.26 (3H, d, J = 6.4 Hz). LCMS: 308.2 [M+H] +(Rt = 2.024 min).

[0427] <Reference Example 82: (2S,11aR)-2-amino-7-fluoro-6-isopropoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0428] [Step 1] (2R,11aR)-7-fluoro-2-hydroxy-6-isopropoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Reference Example 20 (1.80 g, 3.96 mmol) was used as a starting material, and operations similar to those in Steps 6 to 9 of Reference Example 33 were carried out to give the title compound (894 mg). LCMS: 310.1 [M+H] + (Rt = 1.983 min).

[0429] [Step 2] (2S,11aR)-2-Azido-7-fluoro-6-isopropoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 1 (309 mg, 1.00 mmol) and triethylamine (181 μL, 1.30 mmol) were dissolved in dichloromethane (5.00 mL), and methanesulfonyl chloride (92.9 μL, 1.20 mmol) was added. The mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with 0.5 M aqueous hydrochloric acid and then with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in DMF (5.00 mL), and sodium azide (130 mg, 2.00 mmol) was added. The mixture was stirred at 80°C overnight. The reaction mixture was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (331 mg). LCMS: 335.2 [M+H] + (Rt = 2.259 min).

[0430] [Step 3] (2S,11aR)-2-amino-7-fluoro-6-isopropoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in step 2 (331 mg, 0.99 mmol) was dissolved in ethanol (4.95 mL), and 10% palladium-activated carbon (33.1 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere at atmospheric pressure for 4 days. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (heptane / ethyl acetate) to give the title compound (227 mg). LCMS: 309.2 [M+H] + (Rt = 1.693 min).

[0431] <Reference Example 83: tert-butyl (2R,4S)-2-(hydroxymethyl)-4-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)pyrrolidine-1-carboxylate>

[0432] [Step 1] tert-Butyl (2R,4R)-2-((benzoyloxy)methyl)-4-hydroxypyrrolidine-1-carboxylate tert-Butyl (2R,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (897 mg, 4.13 mmol) and pyridine (1.00 mL, 12.4 mmol) were dissolved in dichloromethane (20.7 mL), and benzoyl chloride (524 μL, 4.54 mmol) was added dropwise at −78°C. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 19 hours. A saturated aqueous solution of sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (737 mg). 1 H-NMR (CDCl3) δ: 8.06-8.04 (2H, m), 7.57 (1H, t, J = 7.3 Hz), 7.45 (2H, t, J = 7.5 Hz), 4.63-4.49 (3H, m), 4.31-4.20 (1H, m), 3.71-3.60 (1H, m), 3.45-3.42 (1H, m), 2.23 (1H, br s), 2.09-1.99 (1H, m), 1.46 (9H, s). LCMS: 222.1 [M+H-Boc] + (Rt = 2.202 min).

[0433] [Step 2] tert-Butyl (2R,4S)-2-((benzoyloxy)methyl)-4-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)pyrrolidine-1-carboxylate The compound obtained in Step 1 (643 mg, 2.00 mmol), 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (424 mg, 2.60 mmol), and triphenylphosphine (630 mg, 2.40 mmol) were dissolved in THF (10 mL), and DIAD (467 μL, 2.40 mmol) was added dropwise at 0°C. After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. A saturated aqueous solution of sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (767 mg). 1H-NMR (CDCl3) δ: 8.03 (2H, d, J = 7.8 Hz), 7.61-7.55 (2H, m), 7.46 (2H, t, J = 7.8 Hz), 7.04 (1H, d, J = 8.7 Hz), 6.46 (1H, dd, J = 8.2, 2.3 Hz), 6.25 (1H, d, J = 1.8 Hz), 4.94-4.87 (1H, m), 4.56-4.32 (3H, m), 3.92-3.70 (1H, m), 3.62-3.59 (1H, m), 2.90 (2H, t, J = 7.5 Hz), 2.61 (2H, t, J = 7.5 Hz), 2.39-2.24 (2H, br m), 1.49-1.46 (9H, m). LCMS: 367.1 [M+H-Boc] + (Rt = 2.337 min).

[0434] [Step 3] tert-Butyl (2R,4S)-2-(hydroxymethyl)-4-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)pyrrolidine-1-carboxylate The compound obtained in step 2 (1.17 g, 2.51 mmol) was dissolved in methanol (8.38 mL), potassium carbonate (1.04 g, 7.54 mmol) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate / methanol) to obtain the title compound (846 mg). 1H-NMR (CDCl3) δ: 7.99 (1H, s), 7.06 (1H, d, J = 8.2 Hz), 6.48 (1H, dd, J = 8.2, 2.7 Hz), 6.30 (1H, d, J = 2.3 Hz), 4.83-4.76 (2H, m), 4.17 (1H, br s), 3.87-3.72 (2H, m), 3.63-3.55 (2H, m), 2.91 (2H, t, J = 7.5 Hz), 2.63 (2H, t, J = 7.3 Hz), 2.32-2.26 (1H, m), 1.81-1.75 (1H, m), 1.47 (9H, s). LCMS: 263.1 [M+H-tBu] + (Rt = 2.015 min).

[0435] <Reference Example 84: 7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-naphthyridin-2(1H)-one>

[0436] [Step 1] Ethyl (E)-3-(4-amino-6-chloropyridin-3-yl)acrylate 2-Chloro-5-iodopyridin-4-amine (2.00 g, 7.86 mmol), ethyl acrylate (941 μL, 8.65 mmol), and triethylamine (2.19 mL, 15.7 mmol) were dissolved in acetonitrile (26.2 mL), and palladium(II) acetate (70.6 mg, 0.31 mmol) and tri(o-tolyl)phosphine (191 mg, 0.63 mmol) were added, followed by stirring at 70° C. for 3 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) followed by amino silica gel column chromatography (heptane / ethyl acetate) to give the title compound (1.51 g). 1H-NMR (CDCl3) δ: 8.21 (1H, s), 7.62 (1H, d, J = 16.0 Hz), 6.60 (1H, s), 6.39 (1H, d, J = 16.0 Hz), 4.58 (2H, br s), 4.27 (2H, q, J = 7.2 Hz),1.34 (3H, t, J = 7.1 Hz). LCMS: 227.1 [M+H] + (Rt = 1.716 min).

[0437] [Step 2] 7-chloro-1,6-naphthyridin-2(1H)-one The compound obtained in Step 1 (1.45 g, 6.40 mmol) was dissolved in acetic acid (12.8 mL), tributylphosphine (1.6 mL, 6.40 mmol) was added, and the mixture was stirred at 100° C. for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting solid was washed with ethyl acetate to give the title compound (948 mg). 1 H-NMR (DMSO-d6) δ: 12.11 (1H, br s), 8.68 (1H, s), 7.99 (1H, d, J = 9.6 Hz), 7.20 (1H, s), 6.59 (1H, d, J = 9.6 Hz). LCMS: 181.0 [M+H] + (Rt = 1.660 min).

[0438] [Step 3] 7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-naphthyridin-2(1H)-one The compound obtained in step 2 (1.01 g, 5.59 mmol) was dissolved in DMF (56 mL), 50% sodium hydride (349 mg, 7.27 mmol) was added, and the mixture was stirred at room temperature for 1 hour. 2-(Trimethylsilyl)ethoxymethyl chloride (1.28 mL, 7.27 mmol) was then added, and the mixture was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with heptane / ethyl acetate (1 / 1). The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to obtain the title compound (776 mg). 1 H-NMR (CDCl3) δ: 8.55 (1H, s), 7.71 (1H, d, J = 9.6 Hz), 7.48 (1H, s), 6.69 (1H, d, J = 9.6 Hz), 5.66 (2H, s), 3.67 (2H, t, J = 8.2 Hz), 0.97-0.93 (2H, m), -0.02 (9H, s). LCMS: 311.1 [M+H] + (Rt = 2.413 min).

[0439] <Reference Example 85: 7-Hydroxy-3,4-dihydro-1,6-naphthyridin-2(1H)-one>

[0440] [Step 1] 5-iodo-2-methoxypyridin-4-amine 2-Chloro-5-iodopyridin-4-amine (2.54 g, 10.0 mmol) was added with 5 M sodium methoxide / methanol solution (10.0 mL, 50.0 mmol) and stirred at 80° C. overnight. After the reaction mixture was cooled to room temperature, brine was added and the mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (heptane / ethyl acetate) to give the title compound (1.17 g). LCMS: 251.0 [M+H] + (Rt = 0.826 min).

[0441] [Step 2] Ethyl (E)-3-(4-amino-6-methoxypyridin-3-yl)acrylate The compound obtained in Step 1 (773 mg, 3.09 mmol) and ethyl acrylate (404 μL, 3.71 mmol) were used as starting materials for the same procedure as in Step 1 of Reference Example 84 to give the title compound (506 mg). LCMS: 223.1 [M+H] + (Rt = 1.577 min).

[0442] [Step 3] Ethyl 3-(4-amino-6-methoxypyridin-3-yl)propanoate The compound obtained in Step 2 (506 mg, 2.28 mmol) was dissolved in methanol (11.4 mL), and 10% palladium-activated carbon (50.6 mg) was added thereto, followed by stirring overnight at room temperature under a hydrogen atmosphere at atmospheric pressure. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound as a crude product. LCMS: 225.1 [M+H] + (Rt = 1.506 min).

[0443] [Step 4] 7-Methoxy-3,4-dihydro-1,6-naphthyridin-2(1H)-one Acetic acid (7.60 mL) was added to the crude product of the compound obtained in Step 3, and the mixture was stirred at 100°C overnight. The reaction mixture was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to obtain the title compound (240 mg). 1 H-NMR (DMSO-d6) δ: 10.35 (1H, s), 7.86 (1H, s), 6.18 (1H, s), 3.76 (3H, s), 2.80 (2H, t, J = 7.5 Hz), 2.49-2.45 (2H, m). LCMS: 179.1 [M+H] + (Rt = 0.596 min).

[0444] [Step 5] 7-Hydroxy-3,4-dihydro-1,6-naphthyridin-2(1H)-one A mixture of the compound obtained in Step 4 (412 mg, 2.31 mmol), 6 M aqueous hydrochloric acid (2.31 mL), and 4 M hydrochloric acid / 1,4-dioxane solution (7.71 mL) was stirred at 100°C overnight. The reaction mixture was cooled to room temperature, dichloromethane was added, and the mixture was extracted with water. The aqueous layer was concentrated under reduced pressure, and the residue was suspended in methanol and filtered. The filtrate was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography to give the title compound (296 mg). 1 H-NMR (DMSO-d6) δ: 10.96 (1H, s), 7.77 (1H, s), 6.42 (1H, s), 2.82 (2H, t, J = 7.5 Hz), 2.52 (2H, t, J = 7.8 Hz). LCMS: 165.1 [M+H] + (Rt = 0.723 min).

[0445] <Reference Example 86: 8-Fluoro-7-hydroxy-3,4-dihydroquinolin-2(1H)-one>

[0446] [Step 1] 1-(benzyloxy)-4-bromo-2,3-difluorobenzene 4-Bromo-2,3-difluorophenol (2.09 g, 10.0 mmol) and potassium carbonate (2.07 g, 15.0 mmol) were dissolved in DMF (20.0 mL), and benzyl bromide (1.56 mL, 13.0 mmol) was added dropwise. The mixture was stirred at 80°C overnight. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with heptane / ethyl acetate (2 / 1). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (heptane / ethyl acetate) to give the title compound (2.98 g). 1H-NMR (CDCl3) δ: 7.43-7.32 (5H, m), 7.20-7.15 (1H, m), 6.72-6.68 (1H, m), 5.14 (2H, s).

[0447] [Step 2] 3-(benzyloxy)-6-bromo-N-(2,4-dimethoxybenzyl)-2-fluoroaniline The compound obtained in Step 1 (2.98 g, 9.96 mmol) was dissolved in N-methylpyrrolidone (16.6 mL), and 2,4-dimethoxybenzylamine (4.5 mL, 29.9 mmol) was added. The mixture was stirred at 130°C overnight. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with heptane / ethyl acetate (2 / 1). The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to obtain the title compound as a crude product. LCMS: 446.1 [M+H] + (Rt = 2.583 min).

[0448] [Step 3] 3-(benzyloxy)-6-bromo-2-fluoroaniline The crude product of the compound obtained in step 2 was dissolved in dichloromethane (10.0 mL), trifluoroacetic acid (10.0 mL) was added dropwise, and the mixture was stirred at room temperature overnight. Methanol (100 ml) was added to the reaction mixture, and the precipitate was filtered, and the filtrate was concentrated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to the residue, and the mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title compound (893 mg). LCMS: 296.0 [M+H] + (Rt = 2.389 min).

[0449] [Step 4] 3-(benzyloxy)-6-bromo-N-(1-ethoxycyclopropyl)-2-fluoroaniline The compound obtained in step 3 (296 mg, 1.00 mmol) and acetic acid (229 μL, 4.00 mmol) were dissolved in ethanol (5 mL), and (1-ethoxycyclopropoxy)trimethylsilane (402 μL, 2.00 mmol) was added. The mixture was heated under reflux overnight under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and then purified by silica gel column chromatography (heptane / ethyl acetate) to obtain the title compound (291 mg). LCMS: 380.1 [M+H] + (Rt = 2.555 min).

[0450] [Step 5] 7-(benzyloxy)-8-fluoro-3,4-dihydroquinolin-2(1H)-one The compound obtained in step 4 (291 mg, 0.77 mmol) and potassium carbonate (207 mg, 1.50 mmol) were dissolved in DMF (5.00 mL), and Pd(dba) (45.8 mg, 0.05 mmol) and XPhos (119 mg, 0.25 mmol) were added. The mixture was stirred overnight at 95°C under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, 1 M aqueous hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (heptane / ethyl acetate) to give the title compound (107 mg). LCMS: 272.1 [M+H] + (Rt = 2.163 min).

[0451] [Step 6] 8-Fluoro-7-hydroxy-3,4-dihydroquinolin-2(1H)-one The compound obtained in step 5 (107 mg, 0.39 mmol) was dissolved in a mixed solvent of ethanol (3.90 mL) and THF (3.90 mL), and 10% palladium on activated carbon (21.4 mg) was added. The mixture was stirred overnight at room temperature under a hydrogen atmosphere at atmospheric pressure. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (heptane / ethyl acetate) to give the title compound (61.0 mg). 1H-NMR (DMSO-d6) δ: 9.96 (1H, s), 9.67 (1H, s), 6.74 (1H, d, J = 7.8 Hz), 6.47 (1H, t, J = 8.2 Hz), 2.78 (2H, t, J = 7.3 Hz), 2.43-2.39 (2H, m). LCMS: 182.1 [M+H] + (Rt = 1.665 min).

[0452] <Reference Example 87: 8-Fluoro-7-hydroxy-3,4-dihydro-1,6-naphthyridin-2(1H)-one>

[0453] [Step 1] 2,3-Difluoro-5-iodopyridin-4-amine 2,3-Difluoropyridin-4-amine (500 mg, 3.84 mmol) and N-iodosuccinimide (1.04 g, 4.61 mmol) were dissolved in acetonitrile (7.69 mL), p-toluenesulfonic acid monohydrate (36.6 mg, 0.19 mmol) was added, and the mixture was stirred at 80°C for 16 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium sulfite solution and then with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (872 mg). 1 H-NMR (CDCl3) δ: 7.97 (1H, s), 4.87 (2H, br s). LCMS: 256.9 [M+H] + (Rt = 2.033 min).

[0454] [Step 2] 3-Fluoro-5-iodo-2-methoxypyridin-4-amine The compound obtained in Step 1 (383 mg, 1.50 mmol) was dissolved in methanol (3.74 mL), and 5 M sodium methoxide / methanol solution (598 μL, 2.99 mmol) was added, followed by stirring at 80° C. overnight. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with dichloromethane. The organic layer was washed twice with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (391 mg). LCMS: 269.0 [M+H] + (Rt = 2.058 min).

[0455] [Step 3] 8-Fluoro-7-methoxy-3,4-dihydro-1,6-naphthyridin-2(1H)-one The compound obtained in Step 2 (391 mg, 1.46 mmol) and ethyl acrylate (191 μL, 1.75 mmol) were used as starting materials for the same operations as in Steps 2 to 4 of Reference Example 85 to give the title compound (225 mg). LCMS: 197.1 [M+H] + (Rt = 1.756 min).

[0456] [Step 4] 8-Fluoro-7-hydroxy-3,4-dihydro-1,6-naphthyridin-2(1H)-one To the compound obtained in Step 3 (98.1 mg, 0.50 mmol), a 4 M solution of hydrochloric acid in 1,4-dioxane (2.0 mL) was added, followed by stirring at 90° C. overnight. The reaction mixture was cooled to room temperature, saturated brine was added, and the mixture was filtered with dichloromethane. The residue was washed with water and then dichloromethane, and dried under reduced pressure to obtain the title compound (60.0 mg). 1 H-NMR (DMSO-d6) δ: 11.56 (1H, br s), 10.45 (1H, br s), 7.08 (1H, s), 2.71 (2H, t, J = 7.2 Hz), 2.46 (2H, t, J = 7.2 Hz). LCMS: 183.1 [M+H] + (Rt = 0.720 min).

[0457] <Reference Example 88: 7-Hydroxy-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one>

[0458] [Step 1] Ethyl 4-(benzyloxy)-2-nitrobenzoate Ethyl 4-fluoro-2-nitrobenzoate (1.03 g, 4.83 mmol) and potassium carbonate (1.00 g, 7.25 mmol) were dissolved in DMF (9.67 mL), and benzyl alcohol (599 μL, 5.80 mmol) was added. The mixture was stirred at 60° C. overnight. The reaction mixture was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) followed by amino silica gel column chromatography (heptane / ethyl acetate) to give the title compound (791 mg). LCMS: 302.1 [M+H] + (Rt = 2.415 min).

[0459] [Step 2] (4-(benzyloxy)-2-nitrophenyl)methanol The compound obtained in step 1 (791 mg, 2.63 mmol) was dissolved in a mixed solvent of THF (7.5 mL) and methanol (0.88 mL), and 4 M lithium borohydride / THF solution (1.31 mL, 5.25 mmol) was added dropwise at 0°C. After the addition was complete, the mixture was stirred at room temperature for 4 hours, and then saturated aqueous ammonium chloride solution was added and extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (683 mg). 1H-NMR (DMSO-d6) δ: 7.69 (1H, d, J = 2.7 Hz), 7.58 (1H, d, J = 8.7 Hz), 7.44-7.36 (5H, m), 7.27-7.24 (1H, m), 5.14 (2H, s), 4.86 (2H, d, J = 6.4 Hz), 2.55 (1H, t, J = 6.6 Hz). LCMS: 242.1 [M+H-HO] + (Rt = 2.220 min).

[0460] [Step 3] (2-amino-4-(benzyloxy)phenyl)methanol The compound obtained in step 2 (683 mg, 2.64 mmol) and ammonium chloride (705 mg, 13.2 mmol) were dissolved in a mixed solvent of water (1.10 mL) and ethanol (4.40 mL), and iron (736 mg, 13.2 mmol) was added, followed by stirring at 50°C for 16 hours. The reaction mixture was cooled to room temperature, ethyl acetate was added, and the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (280 mg). LCMS: 212.1 [M+H-HO] + (Rt = 1.808 min).

[0461] [Step 4] 7-(benzyloxy)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one The compound obtained in step 3 (280 mg, 1.22 mmol) was dissolved in THF (3.70 mL), and a solution of triphosgene (435 mg, 1.47 mmol) in THF (2 mL) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 15 minutes, and then triethylamine (595 μL, 4.27 mmol) was added, followed by stirring at 0°C for 30 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (254 mg). LCMS: 256.1 [M+H] + (Rt = 2.143 min).

[0462] [Step 5] 7-Hydroxy-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one The compound obtained in step 4 (254 mg, 0.993 mmol) was dissolved in ethyl acetate (5.00 mL), and 10% palladium-activated carbon (50.7 mg) was added. The mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere at atmospheric pressure. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to give the title compound (79.7 mg). 1 H-NMR (DMSO-d6) δ: 9.98 (1H, s), 9.55 (1H, s), 6.95 (1H, d, J = 7.8 Hz), 6.37 (1H, dd, J = 8.2, 2.3 Hz), 6.33 (1H, d, J = 2.3 Hz), 5.12 (2H, s). LCMS: 166.1 [M+H] + (Rt = 1.597 min).

[0463] <Reference Example 89: 6-Hydroxy-2H-benzo[b][1,4]oxazin-3(4H)-one> 2H-Benzo[b][1,4]oxazin-3(4H)-one (500 mg, 3.35 mmol) was dissolved in trifluoroacetic acid (6.70 mL), and a solution of [bis(trifluoroacetoxy)iodo]benzene (1.73 g, 4.02 mmol) in trifluoroacetic acid (4.00 mL) was added, followed by stirring for 30 minutes at 80° C. Water was added to the reaction solution, which was then filtered. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (338 mg). 1 H-NMR (DMSO-d6) δ: 10.54 (1H, s), 9.15 (1H, s), 6.72 (1H, d, J = 8.7 Hz), 6.35 (1H, d, J = 2.7 Hz), 6.27 (1H, dd, J = 8.7, 2.7 Hz), 4.42 (2H, s). LCMS: 166.1 [M+H] + (Rt = 1.635 min).

[0464] <Reference Example 90: 8-Hydroxy-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]azepin-2-one>

[0465] [Step 1] tert-Butyl (E)-4-(4-amino-6-methoxypyridin-3-yl)-3-butenoate The compound obtained in Step 1 of Reference Example 85 (748 mg, 2.99 mmol) and tert-butyl 3-butenoate (970 μL, 5.98 mmol) were used as starting materials for the same procedure as in Step 2 of Reference Example 85 to obtain the title compound (486 mg). LCMS: 265.1 [M+H] + (Rt = 1.704 min).

[0466] [Step 2] tert-Butyl 4-(4-amino-6-methoxypyridin-3-yl)butanoate The compound obtained in Step 1 (486 mg, 1.84 mmol) was used as a starting material, and the same procedure as in Step 3 of Reference Example 85 was carried out to give the crude title compound. LCMS: 267.2 [M+H] + (Rt = 1.715 min).

[0467] [Step 3] 4-(4-amino-6-methoxypyridin-3-yl)butanoic acid The crude product of the compound obtained in Step 2 was dissolved in THF (9.19 mL), potassium tert-butoxide (247 mg, 2.20 mmol) was added, and the mixture was stirred at 50°C overnight. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (200 mg). LCMS: 211.6 [M+H] + (Rt = 0.524 min).

[0468] [Step 4] 8-Methoxy-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]azepin-2-one The compound obtained in Step 3 (200 mg, 0.95 mmol) and N,N-diisopropylethylamine (0.497 mL, 2.85 mmol) were dissolved in DMF (4.76 mL), and WSC-HCl (274 mg, 1.43 mmol) and HOBt (193 mg, 1.43 mmol) were added, followed by stirring at room temperature overnight. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (46.2 mg). LCMS: 193.2 [M+H] + (Rt = 1.605 min).

[0469] [Step 5] 8-Hydroxy-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]azepin-2-one The compound obtained in step 4 (46.2 mg) was dissolved in acetonitrile (2.40 mL), and potassium iodide (79.8 mg, 0.481 mmol) and trimethylchlorosilane (61 μL, 0.481 mmol) were added, followed by stirring at 80°C overnight. The reaction mixture was cooled to room temperature and filtered. Water was added to the filtrate, which was then washed three times with dichloromethane. The aqueous layer was concentrated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (ethyl acetate / methanol) to give the title compound (7.50 mg). LCMS: 179.5 [M+H] + (Rt = 1.072 min).

[0470] <Reference Example 91: tert-butyl (E)-3-(4-amino-5,6-difluoropyridin-3-yl)acrylate> The compound obtained in Step 1 of Reference Example 87 (1.28 g, 5.00 mmol) and tert-butyl acrylate (769 mg, 6.00 mmol) were used as starting materials for the same procedure as in Step 1 of Reference Example 84 to give the title compound (1.01 g). LCMS: 257.1 [M+H] + (Rt = 2.289 min).

[0471] <Reference Example 92: tert-butyl (2R,5S)-2-(hydroxymethyl)-5-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)piperidine-1-carboxylate>

[0472] [Step 1] 1-(tert-butyl) 2-methyl (2R,5S)-5-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)piperidine-1,2-dicarboxylate Using 1-(tert-butyl) 2-methyl (2R,5R)-5-hydroxypiperidine-1,2-dicarboxylate (58.5 mg, 0.23 mmol) and 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (44.2 mg, 0.27 mmol) as starting materials, the same procedure as in Step 2 of Reference Example 83 was carried out to obtain the title compound (33.9 mg). 1 H-NMR (CDCl3) δ: 7.31 (1H, s), 7.06 (1H, d, J = 8.2 Hz), 6.51 (1H, dd, J = 8.2, 2.3 Hz), 6.28 (1H, s), 4.92 (1H, d, J = 102.0 Hz), 4.37 (1H, s), 4.28 (1H, d, J = 14.6 Hz), 3.77 (3H, d, J = 13.7 Hz), 3.22 (1H, d, J = 12.8 Hz), 2.90 (2H, t, J = 7.5 Hz), 2.61 (2H, t, J = 7.3 Hz), 2.26-2.14 (1H, m), 2.02 (2H, d, J = 14.2 Hz), 1.38 (9H, d, J = 45.7 Hz). LCMS: 305.1 [M+H-Boc] + (Rt = 2.190 min).

[0473] [Step 2] tert-Butyl (2R,5S)-2-(hydroxymethyl)-5-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)piperidine-1-carboxylate The compound obtained in Step 1 (101 mg, 0.25 mmol) was used as a starting material, and the same procedure as in Step 4 of Reference Example 35 was carried out to give the title compound (39.7 mg). 1H-NMR (CDCl3) δ: 7.36 (1H, s), 7.06 (1H, d, J = 8.2 Hz), 6.52 (1H, dd, J = 8.2, 2.3 Hz), 6.28 (1H, d, J = 2.3 Hz), 4.38-4.32 (2H, m), 4.21 (1H, d, J = 14.6 Hz), 3.83-3.80 (1H, m), 3.70-3.64 (1H, m), 3.12 (1H, d, J = 13.7 Hz), 2.90 (2H, t, J = 7.5 Hz), 2.62-2.60 (2H, m), 2.13-2.03 (2H, m), 1.93-1.78 (2H, m), 1.53-1.50 (1H, m), 1.36 (9H, s). LCMS: 321.1 [M+H-tBu] + (Rt = 1.967 min).

[0474] <Reference Example 93: tert-butyl (2R,4R)-2-(hydroxymethyl)-4-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)piperidine-1-carboxylate> The same procedure as in Reference Example 92 was carried out using 1-(tert-butyl) 2-methyl (2R,4S)-4-hydroxypiperidine-1,2-dicarboxylate (200 mg, 0.77 mmol) and 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (151 mg, 0.93 mmol) as starting materials to obtain the title compound (62.4 mg). 1H-NMR (CDCl3) δ: 8.02 (1H, br s), 7.04 (1H, d, J = 8.2 Hz), 6.52 (1H, dd, J = 8.2, 2.3 Hz), 6.35 (1H, d, J = 2.3 Hz), 4.50-4.45 (2H, m), 4.13-4.11 (1H, m), 3.78-3.76 (2H, m), 3.07-3.04 (1H, m), 2.90 (2H, t, J = 7.5 Hz), 2.64-2.62 (2H, m), 2.58 (1H, br s), 2.27-2.23 (1H, m), 2.06-2.03 (1H, m), 1.71-1.60 (2H, m), 1.48 (9H, s). LCMS: 321.1 [M+H-tBu] + (Rt = 2.066 min).

[0475] <Reference Example 94: 7-Hydroxy-3,3-dimethyl-3,4-dihydroquinolin-2(1H)-one>

[0476] [Step 1] 7-(benzyloxy)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one 7-(Benzyloxy)-3,4-dihydroquinolin-2(1H)-one (500 mg, 1.97 mmol) was dissolved in DMF (9.87 mL), and 50% sodium hydride (114 mg, 2.37 mmol) was added at 0°C. The mixture was warmed to room temperature and stirred for 15 minutes. 4-Methoxybenzyl chloride (404 μL, 2.96 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic layer was collected, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting solid was washed with ethyl acetate to give the title compound (675 mg). 1H-NMR (CDCl3) δ: 7.37-7.29 (5H, m), 7.11 (2H, d, J = 8.7 Hz), 7.04 (1H, d, J = 9.1 Hz), 6.82 (2H, dt, J = 9.3, 2.5 Hz), 6.58-6.55 (2H, m), 5.05 (2H, s), 4.93 (2H, s), 3.78 (3H, s), 2.88 (2H, dd, J = 8.7, 5.9 Hz), 2.74 (2H, dd, J = 8.5, 5.7). LCMS: 374.2 [M+H] + (Rt = 2.448 min).

[0477] [Step 2] 7-(benzyloxy)-1-(4-methoxybenzyl)-3-methyl-3,4-dihydroquinolin-2(1H)-one The compound obtained in step 1 (496 mg, 1.33 mmol) was dissolved in THF (6.64 mL), and 1 M HMDS / toluene solution (1.46 mL, 1.46 mmol) was added at 0°C. The mixture was stirred at 0°C for 30 minutes. Iodomethane (99.2 μL, 1.59 mmol) was added to the reaction mixture, and the mixture was stirred at 0°C for 3 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic layer was collected, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (335 mg). LCMS: 388.2 [M+H] + (Rt = 2.551 min).

[0478] [Step 3] 7-(benzyloxy)-1-(4-methoxybenzyl)-3,3-dimethyl-3,4-dihydroquinolin-2(1H)-one The compound obtained in step 2 (468 mg, 1.21 mmol) was dissolved in THF (6.04 mL), and 1 M HMDS / toluene solution (1.33 mL, 1.33 mmol) was added at 0°C. The mixture was stirred at 0°C for 30 minutes. Iodomethane (90.3 μL, 1.45 mmol) was added to the reaction mixture, and the mixture was stirred at 0°C for 3 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic layer was collected, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (405 mg). 1 H-NMR (CDCl3) δ: 7.38-7.30 (5H, m), 7.08 (2H, d, J = 8.7 Hz), 7.04-6.99 (1H, m), 6.85-6.80 (2H, m), 6.59-6.52 (2H, m), 5.02 (2H, s), 4.92 (2H, s), 3.77 (3H, s), 2.74 (2H, s), 1.23 (6H, s). LCMS: 402.2 [M+H] + (Rt = 2.606 min).

[0479] [Step 4] 7-Hydroxy-3,3-dimethyl-3,4-dihydroquinolin-2(1H)-one The compound obtained in step 3 (180 mg, 0.45 mmol) was dissolved in trifluoroacetic acid (750 μL), and anisole (48.7 μL, 0.45 mmol) was added, followed by stirring at 70°C overnight. The reaction mixture was concentrated under reduced pressure, and triethylamine and saturated saline were added to the residue, followed by extraction with dichloromethane. The organic layer was washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The resulting solid was washed with dichloromethane to give the title compound (22.6 mg). 1H-NMR (CD3OD) δ: 6.93 (1H, d, J = 8.2 Hz), 6.40 (1H, dd, J = 8.0, 2.5 Hz), 6.33 (1H, d, J = 2.3 Hz), 2.67 (2H, s), 1.12 (6H, s). LCMS: 192.10 [M+H] + (Rt = 1.865 min).

[0480] <Reference Example 95: 7-Hydroxy-3-methyl-3,4-dihydro-1,6-naphthyridin-2(1H)-one> The compound obtained in Step 1 of Reference Example 85 (50.0 mg, 0.20 mmol) and methyl methacrylate (85.0 μL, 0.80 mmol) were used as starting materials, and the same operations as in Steps 2 to 5 of Reference Example 85 were carried out to obtain the title compound (17.1 mg). 1 H-NMR (CD3OD) δ: 7.90 (1H, s), 6.50 (1H, s), 3.10-3.08 (1H, m), 2.74-2.71 (2H, m), 1.26 (3H, d, J = 6.4 Hz). LCMS: 179.1 [M+H] + (Rt = 1.105 min).

[0481] <Reference Example 96: N-benzyl-3-chloro-2-fluoro-5-iodopyridin-4-amine>

[0482] [Step 1] tert-Butyl (3-chloro-2-fluoropyridin-4-yl)carbamate 3-Chloro-2-fluoro-4-iodopyridine (515 mg, 2.00 mmol) was dissolved in toluene (10.0 mL), and tert-butyl carbamate (281 mg, 2.40 mmol), cesium carbonate (1.30 g, 4.00 mmol), XantPhos (347 mg, 0.60 mmol), and Pd(dba) (275 mg, 0.30 mmol) were added. The mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (430 mg). LCMS: 247.0 [M+H] + (Rt = 2.478 min).

[0483] [Step 2] N-benzyl-3-chloro-2-fluoropyridin-4-amine The compound obtained in Step 1 (430 mg, 1.74 mmol) was used as a starting material, and operations similar to those in Step 2 of Reference Example 2 and Step 4 of Reference Example 27 were carried out to give the title compound (414 mg). LCMS: 237.0[M+H] + (Rt = 2.289 min).

[0484] [Step 3] N-benzyl-3-chloro-2-fluoro-5-iodopyridin-4-amine The compound obtained in Step 2 (414 mg, 1.75 mmol) was used as a starting material, and the same procedure as in Step 1 of Reference Example 87 was carried out to give the title compound (378 mg). 1 H-NMR (CDCl3) δ: 8.14 (1H, s), 7.42-7.30 (5H, m), 5.05 (1H, br s), 4.90 (2H, d, J = 5.9 Hz). LCMS: 363.0 [M+H] + (Rt = 2.538 min).

[0485] <Reference Example 97: 6-Fluoro-7-hydroxy-3,4-dihydroquinolin-2(1H)-one>

[0486] [Step 1] 6,7-Difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)quinolin-2(1H)-one Using 4,5-difluoro-2-iodoaniline (1.27 g, 5.00 mmol) and ethyl acrylate (601 mg, 6.00 mmol) as starting materials, the same procedure as in Reference Example 84 was carried out to obtain the title compound (682 mg). 1 H-NMR (CDCl3) δ: 7.57 (1H, d, J = 9.6 Hz), 7.45 (1H, dd, J = 12.3, 6.9 Hz), 7.33 (1H, dd, J = 9.8, 8.5 Hz), 6.65 (1H, d, J = 9.6 Hz), 5.69 (2H, s), 3.67 (2H, t, J = 8.2 Hz), 0.94 (2H, t, J = 8.2 Hz), -0.03 (9H, s). LCMS: 312.1 [M+H] + (Rt= 2.609 min) (Method B).

[0487] [Step 2] 7-(benzyloxy)-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)quinolin-2(1H)-one A DMF solution (1.50 mL) of benzyl alcohol (92.7 μL, 0.90 mmol) was added dropwise to a mixture of 50% sodium hydride (36.0 mg, 0.90 mmol) and THF (0.30 mL), and the mixture was stirred at room temperature for 1 hour. The compound obtained in Step 1 (93.4 mg, 0.30 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was collected, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (159 mg). 1H-NMR (CDCl3) δ: 7.54-7.21 (8H, m), 6.55 (1H, d, J = 9.6 Hz), 5.67 (2H, s), 5.25 (2H, s), 3.68-3.64 (2H, m), 0.93-0.89 (2H, m), -0.02 (9H, s). LCMS: 400.1 [M+H] + (Rt= 2.755 min) (Method B).

[0488] [Step 3] 7-(benzyloxy)-6-fluoroquinolin-2(1H)-one The compound obtained in Step 2 (294 mg, 0.74 mmol) was dissolved in THF (4.91 mL), and 6 M aqueous hydrochloric acid solution (2.45 mL) was added, followed by stirring at 50° C. overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting solid was washed with ethyl acetate to give the title compound (261 mg). 1 H-NMR (DMSO-d6) δ: 11.72 (1H, br s), 7.77 (1H, d, J = 9.6 Hz), 7.56 (1H, d, J = 11.4 Hz), 7.50-7.48 (2H, m), 7.43-7.36 (3H, m), 7.11 (1H, d, J = 7.3 Hz), 6.37 (1H, d, J = 9.6 Hz), 5.19 (2H, s). LCMS: 270.1 [M+H] + (Rt= 2.039 min) (Method B).

[0489] [Step 4] 6-Fluoro-7-hydroxy-3,4-dihydroquinolin-2(1H)-one The compound obtained in Step 3 (261 mg, 0.97 mmol) was used as a starting material, and the same procedure as in Step 6 of Reference Example 27 was carried out to give the title compound (28.0 mg). 1H-NMR (DMSO-d6) δ: 9.93 (1H, s), 9.69 (1H, s), 6.93 (1H, d, J = 11.0 Hz), 6.49 (1H, d, J = 7.8 Hz), 2.72 (2H, t, J = 7.3 Hz), 2.36 (2H, t, J = 7.5 Hz). LCMS: 182.10 [M+H] + (Rt= 1.507 min) (Method B).

[0490] <Reference Example 98: (2S,11aR)-7-Fluoro-2-hydroxy-8-methyl-6-pentyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Step 1 of Reference Example 77 (100 mg, 0.20 mmol) and 1-penten-1-ylboronic acid (46.6 mg, 0.41 mmol) were used as starting materials for the same procedure as in Reference Example 78 to give the title compound (40.2 mg). LCMS: 322.2 [M+H] + (Rt = 2.277 min).

[0491] <Reference Example 99: (2S,11aR)-7-fluoro-6-(2-fluorophenyl)-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Step 1 of Reference Example 77 (123 mg, 0.25 mmol) and 2-fluorophenylboronic acid (70.2 mg, 0.50 mmol) were used as starting materials for the same procedure as in Reference Example 78 to give the title compound (56.2 mg). LCMS: 346.1 [M+H] + (Rt = 2.049 min).

[0492] <Reference Example 100: (2S,11aR)-2-amino-6-isopropoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Reference Example 34 (437 mg, 1.50 mmol) was used as a starting material, and operations similar to those in Steps 2 and 3 of Reference Example 82 were carried out to give the title compound (337 mg). LCMS: 291.1 [M+H] + (Rt = 1.640 min).

[0493] <Reference Example 101: (2R,11aR)-7-Fluoro-6-isopropoxy-8-methyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-2-yl 4-methylbenzenesulfonate> The compound obtained in Step 1 of Reference Example 82 (100 mg, 0.32 mmol) was dissolved in THF (3.23 mL), and 50% sodium hydride (31.0 mg, 0.65 mmol) was added, followed by stirring at room temperature for 30 minutes. p-Toluenesulfonyl chloride (185 mg, 0.97 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. After stirring at room temperature for 3 hours, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (137 mg). 1H-NMR (CDCl3) δ: 7.80 (2H, d, J = 8.2 Hz), 7.37 (2H, d, J = 8.2 Hz), 6.63 (1H, d, J = 5.5 Hz), 5.23 (1H, t, J = 5.0 Hz), 4.63-4.55 (1H, m), 4.37 (1H, dd, J = 11.9, 10.1 Hz), 4.00 (1H, dd, J = 10.3, 5.3 Hz), 3.97-3.90 (1H, m), 3.87 (1H, d, J = 14.6 Hz), 3.77 (1H, dd, J = 14.6, 5.0 Hz), 2.47 (3H, s), 2.41-2.32 (1H, m), 2.25 (3H, d, J = 2.3 Hz), 2.13 (1H, d, J = 15.1 Hz), 1.33 (3H, d, J = 5.9 Hz), 1.28 (3H, d, J = 5.7 Hz). LCMS: 464.2 [M+H] + (Rt = 2.370 min).

[0494] <Reference Example 102: (2S,11aR)-7-Fluoro-2-hydroxy-6-(((S)-1-(methoxymethoxy)propan-2-yl)oxy)-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0495] [Step 1] (2S,11aR)-2-(benzyloxy)-6-(((S)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)oxy)-7-fluoro-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 4 of Reference Example 49 (200 mg, 0.56 mmol) and the compound obtained in Step 1 of Reference Example 5 (211 mg, 0.67 mmol) were used as starting materials, and the same procedure as in Step 2 of Reference Example 5 was carried out to obtain the title compound (318 mg). 1H-NMR (CDCl3) δ: 7.61 (2H, dd, J = 7.8, 1.8 Hz), 7.53 (2H, dd, J = 8.0, 1.6 Hz), 7.41-7.28 (11H, m), 6.57 (1H, d, J = 5.9 Hz), 5.01-4.95 (1H, m), 4.55 (1H, d, J = 11.9 Hz), 4.46 (1H, d, J = 11.9 Hz), 4.34-4.31 (1H, m), 4.27-4.23 (1H, m), 4.05 (1H, dd, J = 9.1, 4.6 Hz), 4.00-3.96 (3H, m), 3.94-3.86 (1H, m), 3.80 (1H, dd, J = 12.3, 5.0 Hz), 3.63 (1H, dd, J = 10.5, 5.0 Hz), 2.22 (3H, d, J = 1.8 Hz), 2.18-2.15 (1H, m), 1.83-1.79 (1H, m), 1.26-1.24 (3H, m), 0.95 (9H, s). LCMS: 654.3 [M+H] + (Rt = 3.085 min).

[0496] [Step 2] (2S,11aR)-2-(benzyloxy)-7-fluoro-6-(((S)-1-hydroxypropan-2-yl)oxy)-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 1 (318 mg, 0.49 mmol) was used as a starting material, and the same procedure as in Step 2 of Reference Example 36 was carried out to give the title compound (183 mg). 1H-NMR (CDCl3) δ: 7.38-7.29 (6H, m), 6.57 (1H, d, J = 5.5 Hz), 6.36 (1H, dd, J = 8.7, 5.5 Hz), 4.59-4.49 (3H, m), 4.33-4.27 (1H, m), 4.09-3.85 (5H, m), 3.69-3.63 (2H, m), 2.25 (3H, d, J = 2.3 Hz), 2.19 (1H, dd, J = 13.3, 6.9 Hz), 1.89 (1H, dq, J = 13.3, 3.2 Hz), 1.40 (3H, d, J = 6.4 Hz). LCMS: 416.2 [M+H] + (Rt = 2.343 min).

[0497] [Step 3] (2S,11aR)-2-(benzyloxy)-7-fluoro-6-(((S)-1-(methoxymethoxy)propan-2-yl)oxy)-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 2 (183 mg, 0.44 mmol) and N,N-diisopropylethylamine (152 μL, 0.88 mmol) were dissolved in dichloromethane (1.00 mL), and methoxymethyl chloride (66.8 μL, 0.88 mmol) was added at 0°C. The reaction mixture was warmed to room temperature and stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (200 mg). 1H-NMR (CDCl3) δ: 7.36-7.28 (5H, m), 6.60 (1H, d, J = 5.5 Hz), 4.62-4.55 (3H, m), 4.47-4.42 (2H, m), 4.30-4.25 (1H, m), 4.13-4.10 (1H, m), 4.03-4.00 (2H, m), 3.95-3.87 (1H, m), 3.81 (1H, dd, J = 12.3, 5.0 Hz), 3.75 (1H, dd, J = 10.3, 5.3 Hz), 3.61 (1H, dd, J = 10.5, 5.0 Hz), 3.31 (3H, s), 2.28-2.21 (4H, m), 1.85 (1H, dt, J = 13.3, 5.3 Hz), 1.28 (3H, d, J = 6.4 Hz). LCMS: 460.2 [M+H] + (Rt = 2.329 min).

[0498] [Step 4] (2S,11aR)-7-Fluoro-2-hydroxy-6-(((S)-1-(methoxymethoxy)propan-2-yl)oxy)-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 3 (200 mg, 0.44 mmol) was used as a starting material for the same procedure as in Step 6 of Reference Example 49 to give the title compound (143 mg). 1H-NMR (CDCl3) δ:6.62 (1H, d, J = 5.5 Hz), 4.62-4.59 (3H, m), 4.55-4.49 (1H, m), 4.16-4.11 (1H, m), 4.06-4.02 (1H, m), 3.96 (1H, q, J = 10.7 Hz), 3.85-3.81 (3H, m), 3.68 (1H, dd, J = 10.5, 5.5 Hz), 3.33 (3H, s), 2.25 (3H, d, J = 1.4 Hz), 2.17-2.15 (1H, m), 2.05-2.04 (1H, m), 1.86 (1H, dt, J = 13.3, 5.5 Hz), 1.33 (3H, d, J = 5.9 Hz). LCMS: 370.2 [M+H] + (Rt = 1.903 min).

[0499] <Reference Example 103: (2S,11aR)-7-Fluoro-2-hydroxy-6-(((R)-1-(methoxymethoxy)propan-2-yl)oxy)-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0500] [Step 1] (S)-1-((tert-butyldiphenylsilyl)oxy)propan-2-ol Using (S)-propane-1,2-diol (1.00 g, 13.1 mmol) as a starting material, the same procedure as in Step 1 of Reference Example 5 was carried out to give the title compound (3.13 g). 1 H-NMR (CDCl3) δ: 7.66 (4H, dt, J = 6.6, 1.1 Hz), 7.44-7.40 (6H, m), 3.95-3.87 (1H, m), 3.62 (1H, dd, J = 10.1, 3.7 Hz), 3.44 (1H, dd, J = 10.1, 7.8 Hz), 2.54 (1H, d, J = 3.2 Hz), 1.10 (3H, d, J = 6.4 Hz), 1.07 (9H, s).

[0501] [Step 2] (2S,11aR)-7-Fluoro-2-hydroxy-6-(((R)-1-(methoxymethoxy)propan-2-yl)oxy)-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 4 of Reference Example 49 (200 mg, 0.56 mmol) and the compound obtained in Step 1 (194 mg, 0.62 mmol) were used as starting materials, and the same procedure as in Reference Example 102 was carried out to obtain the title compound (175 mg). LCMS: 370.1 [M+H] + (Rt = 1.938 min).

[0502] <Reference Example 104: (2S,11aR)-6-(2,2-difluoropropoxy)-7-fluoro-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0503] [Step 1] (2S,11aR)-2-(benzyloxy)-7-fluoro-8-methyl-6-(2-oxopropoxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 4 of Reference Example 49 (200 mg, 0.56 mmol) and bromoacetone (70.5 μL, 0.84 mmol) were used as starting materials for the same procedure as in Step 5 of Reference Example 49 to give the title compound (235 mg). 1H-NMR (CDCl3) δ: 7.37-7.28 (5H, m), 6.65 (1H, d, J = 5.5 Hz), 4.86-4.82 (1H, m), 4.60-4.56 (2H, m), 4.50-4.47 (1H, m), 4.31-4.26 (1H, m), 4.15-4.02 (2H, m), 3.97-3.89 (2H, m), 3.84 (1H, dd, J = 12.6, 5.3 Hz), 2.29 (3H, s), 2.26-2.22 (4H, m), 1.87 (1H, dt, J = 13.1, 5.3 Hz). LCMS: 414.2 [M+H] + (Rt = 2.259 min).

[0504] [Step 2] (2S,11aR)-2-(benzyloxy)-6-(2,2-difluoropropoxy)-7-fluoro-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 1 (235 mg, 0.57 mmol) was used as a starting material, and the same procedure as in Step 2 of Reference Example 37 was carried out to give the title compound (161 mg). 1 H-NMR (CDCl3) δ: 7.37-7.28 (5H, m), 6.65 (1H, d, J = 5.5 Hz), 4.57 (1H, d, J = 11.9 Hz), 4.48 (1H, d, J = 11.4 Hz), 4.40-4.26 (2H, m), 4.22-4.09 (3H, m), 4.07-4.00 (1H, m), 3.97-3.92 (2H, m), 3.83 (1H, dd, J = 12.6, 5.3 Hz), 2.29-2.22 (4H, m), 1.89-1.83 (1H, m), 1.78 (3H, t, J = 19.2 Hz). LCMS: 436.2 [M+H] + (Rt = 2.417 min).

[0505] [Step 3] (2S,11aR)-6-(2,2-difluoropropoxy)-7-fluoro-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 2 (161 mg, 0.37 mmol) was used as a starting material, and the same procedure as in Step 6 of Reference Example 49 was carried out to give the title compound (129 mg). 1 H-NMR (CDCl3) δ: 6.67 (1H, d, J = 5.9 Hz), 4.63-4.58 (1H, m), 4.43-4.34 (1H, m), 4.20-4.12 (2H, m), 4.08-4.03 (1H, m), 3.97 (1H, dd, J = 11.2, 9.8 Hz), 3.86 (1H, dq, J = 12.8, 1.7 Hz), 3.80 (1H, dd, J = 12.6, 4.8 Hz), 2.27 (3H, d, J = 1.8 Hz), 2.21-2.15 (1H, m), 1.90-1.76 (5H, m). LCMS: 346.1 [M+H] + (Rt = 2.017 min).

[0506] <Reference Example 105: (2S,11aR)-7-Fluoro-2-hydroxy-8-methyl-6-(((S)-1,1,1-trifluoropropan-2-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> Using (R)-1,1,1-trifluoro-2-propanol (160 mg, 1.40 mmol) and the compound obtained in Step 4 of Reference Example 49 (200 mg, 0.56 mmol) as starting materials, the same operations as in Step 1 of Reference Example 7 and Step 6 of Reference Example 49 were carried out to obtain the title compound (153 mg). LCMS: 364.1 [M+H] + (Rt = 2.075 min).

[0507] <Reference Example 106: (2S,11aR)-6-Cyclobutoxy-7-fluoro-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Step 4 of Reference Example 49 (100 mg, 0.28 mmol) and bromocyclobutane (39.6 μL, 0.42 mmol) were used as starting materials, and the same operations as in Steps 5 and 6 of Reference Example 49 were carried out to obtain the title compound (79.4 mg). LCMS: 322.1 [M+H] + (Rt = 2.172 min).

[0508] <Reference Example 107: (2S,11aR)-6-((4,4-difluorocyclohexyl)oxy)-7-fluoro-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Step 4 of Reference Example 49 (100 mg, 0.28 mmol) and 4,4-difluorocyclohexanol (45.7 mg, 0.34 mmol) were used as starting materials for the same procedure as in Reference Example 51 to give the title compound (74.3 mg). 1 H-NMR (CDCl3) δ: 6.63 (1H, d, J = 5.9 Hz), 4.62-4.60 (1H, m), 4.48-4.48 (1H, br m), 4.17 (1H, dd, J = 9.6, 4.1 Hz), 4.08-3.94 (2H, m), 3.90-3.87 (1H, m), 3.77 (1H, dd, J = 12.8, 4.1 Hz), 2.36-2.29 (4H, m), 2.21-2.12 (3H, m), 2.00-1.77 (6H, m), 1.70 (1H, d, J = 3.7 Hz). LCMS: 386.1 [M+H] + (Rt = 2.077 min).

[0509] <Reference Example 108: (2S,11aR)-6-((3,3-difluorocyclobutyl)methoxy)-7-fluoro-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Step 4 of Reference Example 49 (100 mg, 0.28 mmol) and (3,3-difluorocyclobutyl)methanol (37.6 μL, 0.36 mmol) were used as starting materials for the same procedure as in Reference Example 51 to give the title compound (75.9 mg). 1 H-NMR (CDCl3) δ: 6.64 (1H, d, J = 5.9 Hz), 4.63-4.61 (1H, m), 4.30 (1H, dd, J = 8.9, 4.8 Hz), 4.16 (1H, dd, J = 9.8, 4.3 Hz), 4.09-4.05 (2H, m), 4.03-3.94 (1H, m), 3.83 (2H, d, J = 4.6 Hz), 2.72-2.45 (5H, m), 2.26 (3H, d, J = 2.3 Hz), 2.20-2.14 (1H, m), 1.87 (1H, dt, J = 13.4, 5.3 Hz), 1.73 (1H, d, J = 4.1 Hz). LCMS: 372.1 [M+H] + (Rt = 2.084 min).

[0510] <Reference Example 109: (2R,11aR)-6-(3,3-difluorocyclobutoxy)-7-fluoro-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one>

[0511] [Step 1] (2S,11aR)-6-(3,3-difluorocyclobutoxy)-7-fluoro-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 4 of Reference Example 49 (100 mg, 0.28 mmol) and 3,3-difluorocyclobutanol (35.7 μL, 0.42 mmol) were used as starting materials for the same procedure as in Reference Example 51 to give the title compound (57.8 mg). LCMS: 358.1 [M+H] + (Rt = 2.048 min).

[0512] [Step 2] (2R,11aR)-6-(3,3-difluorocyclobutoxy)-7-fluoro-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 1 (57.8 mg, 0.16 mmol) was used as a starting material, and the same procedure as in Step 2 of Reference Example 61 was carried out to give the title compound (41.3 mg). 1 H-NMR (CDCl3) δ: 6.68 (1H, d, J = 5.9 Hz), 4.79-4.76 (1H, br m), 4.64-4.61 (2H, m), 4.03 (1H, dd, J = 10.1, 5.5 Hz), 3.93-3.85 (3H, m), 3.13-2.91 (4H, m), 2.29-2.22 (4H, m), 1.83 (2H, d, J = 13.7 Hz). LCMS: 358.1 [M+H] + (Rt = 2.079 min).

[0513] <Reference Example 110: (2S,11aR)-7-Fluoro-2-hydroxy-6-(((R)-1-methoxypropan-2-yl)oxy)-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Step 4 of Reference Example 49 (75.0 mg, 0.21 mmol) and (S)-(+)-1-methoxy-2-propanol (31.0 μL, 0.31 mmol) were used as starting materials, and the same procedure as in Reference Example 51 was carried out to obtain the title compound (62.2 mg). LCMS: 340.1 [M+H] + (Rt = 1.897 min).

[0514] <Reference Example 111: (2S,11aR)-7-Fluoro-2-hydroxy-6-(((S)-1-methoxypropan-2-yl)oxy)-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Step 4 of Reference Example 49 (75.0 mg, 0.21 mmol) and (R)-(-)-1-methoxy-2-propanol (31.0 μL, 0.31 mmol) were used as starting materials, and the same procedure as in Reference Example 51 was carried out to obtain the title compound (64.0 mg). LCMS: 340.2 [M+H] + (Rt = 1.883 min).

[0515] <Reference Example 112: (2S,11aR)-7-fluoro-2-hydroxy-6-(2-methoxy-2-methylpropoxy)-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Step 4 of Reference Example 49 (100 mg, 0.28 mmol) and 2-methoxy-2-methyl-1-propanol (49.0 μL, 0.42 mmol) were used as starting materials for the same procedure as in Reference Example 51 to give the title compound (74.7 mg). LCMS: 354.2 [M+H] + (Rt = 1.951 min).

[0516] <Reference Example 113: (2S,11aR)-7-fluoro-2-hydroxy-6-(2-methoxyethoxy)-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Step 4 of Reference Example 49 (75.0 mg, 0.21 mmol) and 2-methoxyethanol (25.0 μL, 0.31 mmol) were used as starting materials for the same procedure as in Reference Example 51 to give the title compound (58.0 mg). LCMS: 326.1 [M+H] + (Rt = 1.856 min).

[0517] <Reference Example 114: (2S,11aR)-7-Fluoro-2-hydroxy-8-methyl-6-(2-(pyrrolidin-1-yl)ethoxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one> The compound obtained in Step 4 of Reference Example 49 (100 mg, 0.28 mmol) and 1-(2-hydroxyethyl)pyrrolidine (49.0 μL, 0.42 mmol) were used as starting materials for the same procedure as in Reference Example 51 to give the title compound (55.2 mg). LCMS: 365.2 [M+H] + (Rt = 1.652 min).

[0518] <Reference Example 115: (2R,11aR)-7-Fluoro-6-isopropoxy-8-methyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-2-yl methanesulfonate> The compound obtained in Step 1 of Reference Example 82 (100 mg, 0.32 mmol) and triethylamine (66.0 μL, 0.48 mmol) were dissolved in dichloromethane (1.08 mL), and methanesulfonyl chloride (30.0 μL, 0.39 mmol) was added at 0°C. The mixture was stirred at 0°C for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (110 mg). 1H-NMR (CDCl3) δ: 6.65 (1H, d, J = 5.9 Hz), 5.42 (1H, t, J = 4.8 Hz), 4.66-4.57 (1H, m), 4.38 (1H, t, J = 11.0 Hz), 4.17 (1H, d, J = 14.6 Hz), 4.03-3.98 (3H, m), 3.10 (3H, s), 2.47-2.40 (1H, m), 2.26-2.21 (4H, m), 1.37 (3H, d, J = 5.9 Hz), 1.31 (3H, d, J = 5.9 Hz). LCMS: 388.1 [M+H] + (Rt= 2.063 min) (Method B).

[0519] <Reference Example 116: (2R,11aR)-7-chloro-8-methyl-5-oxo-6-(2,2,2-trifluoroethoxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-2-yl methanesulfonate>

[0520] [Step 1] Methyl 3-chloro-2-(cyclopropylmethoxy)-6-hydroxy-4-methylbenzoate The compound obtained in Step 1 of Reference Example 28 (1.97 g, 8.34 mmol) was used as a starting material, and the same procedure as in Step 1 of Reference Example 58 was carried out to give the title compound (1.17 g). 1 H-NMR (CDCl3) δ: 11.14 (1H, s), 6.70 (1H, s), 3.99 (3H, s), 3.77 (2H, d, J = 6.9 Hz), 2.36 (3H, s), 1.39-1.29 (1H, m), 0.67-0.62 (2H, m), 0.36 (2H, q, J = 5.0 Hz). LCMS: 271.0 [M+H] + (Rt= 2.516 min) (Method B).

[0521] [Step 2] (2S,11aR)-2-(benzyloxy)-7-chloro-6-(cyclopropylmethoxy)-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 1 (1.29 g, 4.76 mmol) and the compound obtained in Reference Example 25 (1.90 g, 6.19 mmol) were used as starting materials, and the same operations as in Steps 2 to 5 of Reference Example 27 were carried out to obtain the title compound (1.53 g). 1 H-NMR (CDCl3) δ: 7.37-7.28 (5H, m), 6.72 (1H, s), 4.57 (1H, d, J = 11.4 Hz), 4.48 (1H, d, J = 11.4 Hz), 4.30-4.25 (1H, m), 4.13-4.10 (1H, m), 4.06-3.83 (6H, m), 2.36 (3H, s), 2.26-2.19 (1H, m), 1.86 (1H, td, J = 9.0, 4.3 Hz), 1.38-1.31 (1H, m), 0.58-0.50 (2H, m), 0.34-0.30 (2H, m). LCMS: 428.1 [M+H] + (Rt= 2.573 min) (Method B).

[0522] [Step 3] (2S,11aR)-2-(benzyloxy)-7-chloro-6-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 2 (1.53 g, 3.57 mmol) was used as a starting material, and the same procedure as in Step 4 of Reference Example 49 was carried out to give the title compound (1.19 g). 1H-NMR (CDCl3) δ: 7.37-7.28 (5H, m), 6.38 (1H, s), 4.58 (1H, d, J = 11.9 Hz), 4.51 (1H, d, J = 11.9 Hz), 4.46 (1H, dd, J = 11.9, 1.4 Hz), 4.25-4.19 (2H, m), 4.03 (1H, dd, J = 14.0, 1.6 Hz), 3.94 (1H, dd, J = 11.9, 8.7 Hz), 3.82 (1H, dd, J = 13.7, 4.1 Hz), 2.38-2.33 (4H, m), 1.74 (1H, ddd, J = 14.2, 10.1, 3.2 Hz). LCMS: 374.1 [M+H] + (Rt= 2.625 min) (Method B).

[0523] [Step 4] (2S,11aR)-2-(benzyloxy)-7-chloro-8-methyl-6-(2,2,2-trifluoroethoxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 3 (100 mg, 0.27 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (77.1 μL, 0.54 mmol) were used as starting materials for the same procedure as in Step 5 of Reference Example 49 to give the title compound (121 mg). 1 H-NMR (CDCl3) δ: 7.37-7.30 (5H, m), 6.81 (1H, s), 4.80-4.75 (1H, m), 4.57 (1H, d, J = 11.9 Hz), 4.48 (1H, d, J = 11.4 Hz), 4.43-4.38 (1H, m), 4.30-4.25 (1H, m), 4.17-4.13 (1H, m), 4.04-3.96 (3H, m), 3.81 (1H, dd, J = 12.8, 5.0 Hz), 2.38 (3H, s), 2.29-2.23 (1H, m), 1.86 (1H, dt, J = 13.3, 5.0 Hz). LCMS: 456.1 [M+H] + (Rt= 2.572 min) (Method B).

[0524] [Step 5] (2S,11aR)-7-chloro-2-hydroxy-8-methyl-6-(2,2,2-trifluoroethoxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 4 (121 mg, 0.27 mmol) was used as a starting material, and the same procedure as in Step 4 of Reference Example 59 was carried out to give the title compound (97.6 mg). LCMS: 366.1 [M+H] + (Rt= 2.058 min) (Method B).

[0525] [Step 6] (2R,11aR)-7-chloro-2-hydroxy-8-methyl-6-(2,2,2-trifluoroethoxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 5 (97.6 mg, 0.27 mmol) was used as a starting material, and the same procedure as in Step 2 of Reference Example 61 was carried out to give the title compound (93.5 mg). LCMS: 366.1 [M+H] + (Rt= 2.097 min) (Method B).

[0526] [Step 7] (2R,11aR)-7-chloro-8-methyl-5-oxo-6-(2,2,2-trifluoroethoxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-2-yl methanesulfonate The compound obtained in Step 6 (93.5 mg, 0.26 mmol) was used as a starting material, and the same procedure as in Reference Example 115 was carried out to give the title compound (92.8 mg). 1H-NMR (CDCl3) δ: 6.88 (1H, s), 5.43 (1H, t, J = 4.8 Hz), 4.91-4.86 (1H, m), 4.49-4.34 (2H, m), 4.16-4.11 (2H, m), 4.01-3.97 (2H, m), 3.11 (3H, s), 2.51-2.44 (1H, m), 2.40 (3H, s), 2.25 (1H, d, J = 14.6 Hz). LCMS: 444.1 [M+H] + (Rt= 2.270 min) (Method B).

[0527] <Reference Example 117: (2R,11aR)-7-chloro-6-((1-fluorocyclopropyl)methoxy)-8-methyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-2-yl methanesulfonate>

[0528] [Step 1] (2S,11aR)-7-chloro-6-(cyclopropylmethoxy)-2-hydroxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one The compound obtained in Step 2 of Reference Example 116 (542 mg, 1.27 mmol) was used as a starting material, and the same procedure as in Step 4 of Reference Example 59 was carried out to give the title compound (383 mg). LCMS: 338.1 [M+H] + (Rt= 2.006 min) (Method B).

[0529] [Step 2] (2R,11aR)-7-chloro-6-(cyclopropylmethoxy)-8-methyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-2-yl benzoate The compound obtained in Step 1 (383 mg, 1.14 mmol), benzoic acid (216 mg, 1.77 mmol), and triphenylphosphine (464 mg, 1.77 mmol) were dissolved in THF (3.78 mL), and DIAD (345 μL, 1.77 mmol) was added and stirred at room temperature for 3 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane / ethyl acetate) to give the title compound (669 mg). 1 H-NMR (CDCl3) δ: 8.04 (2H, d, J = 7.3 Hz), 7.61 (1H, t, J = 7.3 Hz), 7.48 (2H, t, J = 7.8 Hz), 6.77 (1H, s), 5.71 (1H, t, J = 5.0 Hz), 5.03-4.93 (2H, m), 4.47 (1H, dd, J = 11.7, 10.3 Hz), 4.11-3.93 (4H, m), 2.51-2.44 (1H, m), 2.38 (3H, s), 2.07-2.04 (1H, br m), 1.44-1.41 (1H, m), 0.60 (2H, dd, J = 8.0, 1.6 Hz), 0.43 (2H, t, J = 4.6 Hz). LCMS: 442.1 [M+H] + (Rt= 2.556 min) (Method B).

[0530] [Step 3] (2R,11aR)-7-chloro-6-hydroxy-8-methyl-5-oxo-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-2-yl benzoate The compound obtained in Step 2 (669 mg, 1.51 mmol) was used as a starting material, and the same procedure as in Step 4 of Reference Example 49 was carried out to give the title compound (310 mg). 1H-NMR (CDCl3) δ: 8.04-8.02 (2H, m), 7.61 (1H, t, J = 7.5 Hz), 7.48 (2H, t, J = 7.5 Hz), 6.48 (1H, s), 5.67-5.64 (1H, m), 4...

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 [In the formula, R １ is a hydrogen atom, C １－６ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, hydroxy group, halogen, amino group, cyano group, carboxy group, C ６－１０ aryl group, 5- to 12-membered heteroaryl group, C １－６ Alkoxy group, C ３－８ Cycloalkoxy group, 3- to 8-membered heterocyclyloxy group, C ６－１０ aryloxy group, 5- to 12-membered heteroaryloxy group, C ３－８ Cycloalkyl C １－６ Alkoxy group, 3- to 8-membered heterocyclyl C １－６ Alkoxy group, C ６－１０ Aryl C １－６ an alkoxy group, or a 5- to 12-membered heteroaryl C １－６ represents an alkoxy group; The R １ is C optionally substituted with 1 to 6 [halogen, hydroxy group, carboxy group, oxo group, amino group, cyano group, 1 to 3 halogens] １－６ C optionally substituted with an alkyl group or 1 to 3 halogen atoms １－６ alkoxy group]; R ２ , R ３ and R ４ each independently represents a hydrogen atom, C optionally substituted with 1 to 6 halogen atoms, １－６ alkyl group, C optionally substituted with 1 to 6 halogen atoms ３－８ represents a cycloalkyl group, a hydroxy group, or a halogen; The R ２ , R ３ and R ４ each of which is C optionally substituted with 1 to 6 [halogen, hydroxy group, carboxy group, oxo group, amino group, cyano group, 1 to 3 halogens] １－６ C optionally substituted with an alkyl group or 1 to 3 halogen atoms １－６ alkoxy group]; R ７ is a hydrogen atom, a halogen atom, or C optionally substituted with 1 to 6 halogen atoms １－６ represents an alkyl group; R ａ is a hydrogen atom, C optionally substituted with 1 to 6 halogen atoms １－６ represents an alkyl group, a hydroxy group, or a halogen; X is -O- or -CR ｂ R ｃ represents -, The R ｂ and R ｃ each independently represents a hydrogen atom, C optionally substituted with 1 to 6 halogen atoms, １－６ represents an alkyl group or a halogen; Y is -CH ２ - or -CO-, n represents 1 or 2; m represents 0 or 1; L represents —O— or —NH—; Q is a structure represented by any one selected from the group consisting of formulas (II-1), (II-2), (II-3) and (II-4), 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 【Transformation 5】 [In formulas (II-1), (II-2), (II-3) and (II-4), Z ２１ is CR ｆ or N, Ring A represents a monocyclic 6- to 8-membered heterocyclyl ring or a monocyclic 6- to 7-membered heteroaryl ring; R ２７０１ , R ２７０２ , R ２７０３ and R ２７０４ are each independently a halogen or a C optionally substituted with 1 to 3 halogens. １－６ represents an alkyl group, R d and R e each independently represent a hydrogen atom, a halogen atom, or a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms; R ｆ is a hydrogen atom, a halogen atom, or a C optionally substituted with 1 to 3 halogen atoms １－６ represents an alkyl group, When ring A is a 6- to 8-membered monocyclic heterocyclyl group, R ２６０１ , R ２６０２ , R ２６０３ and R ２６０４ are each independently a hydrogen atom, a C optionally substituted with 1 to 6 halogen atoms, １－６ C optionally substituted with an alkyl group or 1 to 6 halogen atoms ３－８ represents a cycloalkyl group, or When ring A is a 6- to 7-membered monocyclic heteroaryl, R ２６０１ , R ２６０２ , R2 ６０３ and R ２６０４ represent hydrogen atoms, and Each q independently represents an integer of 0 to 4.

2. R １ is C １－６ Alkyl group, C ３－８ a cycloalkyl group, a 3- to 8-membered heterocyclyl group, a hydroxy group, C ６－１０ aryl group, 5- to 12-membered heteroaryl group, C １－６ Alkoxy group, C ３－８ Cycloalkoxy group, 3- to 8-membered heterocyclyloxy group, C ３－８ Cycloalkyl C １－６ Alkoxy group, 3- to 8-membered heterocyclyl C １－６ an alkoxy group, or C ６－１０ Aryl C １－６ is an alkoxy group, The R １ is C optionally substituted with 1 to 3 halogens, hydroxy groups, oxo groups, 1 to 3 halogens １－６ C optionally substituted with an alkyl group or 1 to 3 halogen atoms １－６ 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, optionally substituted with an alkoxy group.

3. R ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is a hydrogen atom or a halogen.

4. R ３ is a hydrogen atom, C optionally substituted with 1 to 6 halogen atoms １－６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is an alkyl group or a halogen atom.

5. R ４ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is a hydrogen atom or a halogen.

6. R ａ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is a hydrogen atom.

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

8. 2. The compound of claim 1, wherein m is 0, or a pharmaceutically acceptable salt thereof.

9. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is -O-.

10. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is --CO--.

11. 2. The compound according to claim 1, which is a compound represented by formula (III) or a pharmaceutically acceptable salt thereof: 【Transformation 6】 [In the formula, R １ is a hydrogen atom, C １－６ Alkyl group, C ３－８ Cycloalkyl group, 3- to 8-membered heterocyclyl group, hydroxy group, halogen, C ６－１０ aryl group, 5- to 12-membered heteroaryl group, C １－６ Alkoxy group, C ３－８ Cycloalkoxy group, 3- to 8-membered heterocyclyloxy group, C ６－１０ aryloxy group, 5- to 12-membered heteroaryloxy group, C ３－８ Cycloalkyl C １－６ Alkoxy group, 3- to 8-membered heterocyclyl C １－６ Alkoxy group, C ６－１０ Aryl C １－６ an alkoxy group, or a 5- to 12-membered heteroaryl C １－６ represents an alkoxy group; The R １ is C optionally substituted with 1 to 6 [halogen, hydroxy group, carboxy group, oxo group, amino group, cyano group, 1 to 3 halogens] １－６ C optionally substituted with an alkyl group or 1 to 3 halogen atoms １－６ alkoxy group]; R ２ , R ３ and R ４ each independently represents a hydrogen atom, C optionally substituted with 1 to 6 halogen atoms, １－６ represents an alkyl group or a halogen; R ７ is a hydrogen atom, a halogen atom, or a C optionally substituted with 1 to 3 halogen atoms １－６ represents an alkyl group; Q is a structure represented by any one selected from the group consisting of formulas (II-1), (II-2), (II-3), and (II-4) defined in claim 1.

12. 2. The compound according to claim 1, wherein Q is any one selected from the group consisting of formulae (IV), (V) and (VI), or a pharmaceutically acceptable salt thereof. 【Transformation 7】 【Transformation 8】 【Chemistry 9】 [In formulas (IV), (V) and (VI), R ３１ , R ３２ , R ３３ , R ３５ and R ３６ each independently represents a hydrogen atom, C optionally substituted with 1 to 3 halogen atoms １－６ represents an alkyl group or a halogen; Z ３１ , Z ３２ and Z ３３ each independently represents CH or N, Z ａ is O or CR ｇ ２ represents The R ｇ Each independently represents a hydrogen atom or C optionally substituted with 1 to 6 halogen atoms. １－６ represents an alkyl group.]

13. At least one compound selected from the following (1) to (50) or a pharmaceutically acceptable salt thereof: (1) (2S,11aR)-6-isopropoxy-8-methyl-2-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (2) (2S,11aR)-6-(cyclopentyloxy)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (3) (2S,11aR)-6-isopropoxy-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (4) (2S,11aR)-6-(((S)-1-fluoropropan-2-yl)oxy)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (5) (2S,11aR)-6-isopropoxy-8-methyl-2-((2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (6) (2S,11aR)-6-(cyclopentyloxy)-8-methyl-2-((2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (7) (2S,11aR)-6-(cyclopentyloxy)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (8) (2S,11aR)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-6-(((S)-1,1,1-trifluoropropan-2-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (9) (2S,11aR)-6-cyclobutoxy-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (10) (2S,11aR)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-6-(((R)-1,1,1-trifluoropropan-2-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (11) (2S,11aR)-6-(((R)-1-fluoropropan-2-yl)oxy)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (12) (2S,11aR)-6-(((R)-1,1-difluoropropan-2-yl)oxy)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (13) (2S,11aR)-6-(2,6-difluorophenyl)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (14) (2S,11aR)-2-((8-fluoro-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-6-isopropoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (15) (2S,11aR)-2-((8-fluoro-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)-6-isopropoxy-8-methyl-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (16) (2S,11aR)-7-fluoro-6-isopropoxy-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (17) (2S,11aR)-6-isobutyl-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (18) (2S,11aR)-6-(cyclopentyloxy)-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (19) (2S,11aR)-8-methyl-2-((2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)oxy)-6-(((R)-1,1,1-trifluoropropan-2-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (20) (2S,11aR)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)-6-(((R)-1,1,1-trifluoropropan-2-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (21) (2S,11aR)-2-((8-fluoro-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-8-methyl-6-(((R)-1,1,1-trifluoropropan-2-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (22) (2S,11aR)-8-chloro-6-isopropoxy-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (23) (2S,11aR)-6-isobutoxy-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (24) (2S,11aR)-6-((R)-sec-butoxy)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (25) (2S,11aR)-6-((S)-sec-butoxy)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (26) (2S,11aR)-6-((2,2-difluorocyclopentyl)oxy)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (27) (2S,11aR)-7,9-difluoro-6-isopropoxy-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (28) (2S,11aR)-7-fluoro-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-6-(((R)-1,1,1-trifluoropropan-2-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (29) (2S,11aR)-6-(2-fluoro-2-methylpropoxy)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (30) (2S,11aR)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-6-(pyrrolidin-1-yl)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (31) (2S,11aR)-6-(cyclopropylmethoxy)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (32) (2S,11aR)-7-fluoro-6-(2-fluoro-2-methylpropoxy)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (33) (2S,11aR)-7-fluoro-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-6-(pyrrolidin-1-yl)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (34) (2S,11aR)-6-isopropoxy-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-8-(trifluoromethyl)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (35) (2S,11aR)-6-(cyclopropylmethoxy)-7-fluoro-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (36) (2S,11aR)-7-fluoro-6-isobutoxy-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (37) (2S,11aR)-7-fluoro-6-((1-fluorocyclopropyl)methoxy)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (38) (2S,11aR)-9-fluoro-6-isopropoxy-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (39) (2S,11aR)-6-((R)-sec-butoxy)-7-fluoro-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (40) (2S,11aR)-6-((S)-sec-butoxy)-7-fluoro-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (41) (2S,11aR)-6-(cyclopentyloxy)-7-fluoro-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (42) (2S,11aR)-6-ethoxy-7-fluoro-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (43) (2S,11aR)-7-fluoro-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-6-propoxy-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (44) (2S,11aR)-7-chloro-6-isopropoxy-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (45) (2S,11aR)-6-(((R)-1,1-difluoropropan-2-yl)oxy)-7-fluoro-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (46) (2S,11aR)-7-fluoro-6-(((R)-1-fluoropropan-2-yl)oxy)-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (47) (2S,11aR)-7-fluoro-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-6-(2,2,2-trifluoroethoxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (48) (2S,11aR)-7-fluoro-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-6-(((S)-tetrahydrofuran-3-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (49) (2S,11aR)-7-fluoro-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-6-(((R)-tetrahydrofuran-3-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one (50) (2S,11aR)-6-((1,3-difluoropropan-2-yl)oxy)-7-fluoro-8-methyl-2-((2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)oxy)-2,3,11,11a-tetrahydro-1H,5H-benzo[f]pyrrolo[2,1-c][1,4]oxazepin-5-one

14. An orexin type 2 receptor agonist comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

16. A preventive or therapeutic agent for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcoleptic symptoms, hypersomnia associated with Parkinson's disease, hypersomnia associated with Guillain-Barré syndrome, hypersomnia associated with Kleine-Levin syndrome, or hypersomnia associated with dementia with Lewy bodies, comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

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