Heterocyclic compound

Abstract

The present invention provides a heterocyclic compound having an orexin type 2 receptor agonist activity. A compound represented by the formula ( I ) : (I) wherein each symbol is as described in the specification, or a salt thereof, is useful as an agent for the prophylaxis or treatment of narcolepsy.

Description

[0001] [Document] Description [Title of the Invention] HETEROCYCLIC COMPOUND [Technical Field] 5 The present invention relates to a heterocyclic compound, particularly, a heterocyclic compound having an orexin type 2 receptor agonist activity. [Background of the Invention] 10 Orexin is a neuropeptide specifically produced in particular neurons located sparsely in the lateral hypothalamus and its surrounding area, and consists of two subtypes, orexin A and orexin B. Both orexin A and orexin B are endogenous ligands of the orexin receptors, which are G 15 protein-coupled receptors mainly present in the brain, and two types of subtypes, type 1 and type 2, are known for the orexin receptors (non-patent document 1). Since orexin-producing neurons (orexin neurons) are localized in the vicinity of the feeding center, and20intraventricular administration of orexin peptide results in an increase in food intake, orexin initially attracted attention as a neuropeptide having a feeding behavioral regulation. Thereafter, however, it was reported that the cause of dog narcolepsy is a genetic variation of orexin type252 receptor (non-patent document 2), and the role of orexin in controlling sleep and wakefulness also has been studied. From the studies using a transgenic mouse having denatured orexin neurons and a double transgenic mouse obtained by crossing this mouse with an orexin overexpressing 30 transgenic mouse, it was observed that narcolepsy-like symptoms that appear by degeneration of orexin neurons disappear due to sustained expression of orexin. Similarly, when orexin peptide was intraventricularly administered to a transgenic mouse having denatured orexin neuron, improvement 35 of narcolepsy-like symptoms was observed (non-patent document

[0002] 1

[0003] 3). Studies of orexin type 2 receptor knockout mice have suggested that orexin type 2 receptor is important for maintaining arousal (non-patent document 4, non-patent document 5). Such background suggests that orexin type 2 5 receptor agonists become therapeutic drugs for narcolepsy or therapeutic drugs for other sleep disorders exhibiting excessive sleepiness (non-patent document 6). In addition, it is suggested that a peptidic agonist that selectively acts on the orexin type 2 receptor improves 10 obesity due to high fat diet load in mice (non-patent document 7). In addition, it is suggested that intraventricular administration of orexin peptide shortens the systemic anesthetic time of rats (non-patent document 8). 15 In addition, it is suggested that patients with sleep apnea syndrome show a low orexin A concentration levels in plasma (non-patent document 9). In addition, it is suggested that intraventricular administration of orexin peptide improves memory retention of20senescence-accelerated model mouse (SAMP8) with cognitive dysfunction (non-patent document 10). In addition, it is suggested that an orexin type 2 receptor agonist will be a therapeutic drug for cardiac failure (patent document 1, non-patent document 11).25In addition, it is suggested that the daytime sleepiness of Parkinson’s disease patients is caused by orexin nerve fallout (non-patent document 12). In addition, it is suggested that orexin regulates bone formation and bone loss, and an orexin type 2 receptor agonist 30 will be a therapeutic drug for diseases related to bone loss such as osteoporosis, rheumatoid arthritis, and the like (patent document 2). In addition, it is suggested that an orexin receptor agonist is useful for the prophylaxis or treatment of sepsis, 35 severe sepsis and septic shock, since the mortality was

[0004] 2

[0005] significantly improved by mere continuous administration of orexin from the periphery in septic shock model mouse (patent document 3). Therefore, a compound having an orexin type 2 receptor 5 agonist activity is expected to be useful as a therapeutic drug for the treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, disturbance of consciousness, such as coma and the like, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome 10 accompanied by daytime hypersomnia (e.g., Parkinson’s disease, Guillain-Barre syndrome and Kleine Levin syndrome), Alzheimer, obesity, insulin resistance syndrome, cardiac failure, diseases related to bone loss, sepsis, and the like. Further, an orexin type 2 receptor agonist can be usedful as an 15 anesthetic antagonist or as a prophylactic or therapeutic drug for side effects and complications due to anesthesia. As sulfonamide derivatives, a compound represented by the formula , s as described in the document (Patent reported. In addition, as compounds having an orexin type 2 receptor agonist activity, the following compounds have been reported. 25 A compound represented by the formula

[0006] 3

[0007] is as described in the document (Patent Document 5). A compound represented by the formula 5 , y e document (Patent Document 6). A compound represented by the formula ,10 document (Patent Document 7). A compound represented by the formula

[0008] 4

[0009] O , w herein each symbol is as described in the document (Patent Document 8). A compound represented by the formula OO5 , described in the document (Patent Document 9). A compound represented by the formula O , 10 w ocument (Patent Document 10). A compound represented by the formula

[0010] 5

[0011] O , w ere n eac sym o s as escr e n the document (Patent Document 11). A compound represented by the formula 5 , w e e eac sy o s as esc ibed in the document (Patent Document 12). A compound represented by the formula

[0012] 6

[0013] , wherein each symbol is as described in the document (Patent Document 13). A compound represented by the formula O O 5 , w herein each symbol is as described in the document (Patent Document 14). A compound represented by the formula , 10 wherein each symbol is as described in the document (Patent

[0014] 7

[0015] Document 15). A compound represented by the formula , wherein each symbol is as described in the document (Patent 5 Document 16). A compound represented by the formula wh in the document (Patent Document 17).10A compound represented by the formula w y nt (Patent Document 18).

[0016] 8

[0017] A compound represented by the formula the document (Patent Document 19). 5 A compound represented by the formula (Patent Document 20). However, these compounds are considered to be insufficient in 10 terms of activity, pharmacokinetics or safety, and development of compounds having an orexin type 2 receptor agonist activity is still desired. [Document List] [Patent Document]15[Patent Document 1] WO 2015 / 073707 A1 [Patent Document 2] WO 2015 / 048091 A1 [Patent Document 3] WO 2015 / 147240 A1 [Patent Document 4] WO 2012 / 137982 A9 [Patent Document 5] WO 2017 / 135306 A1 20 [Patent Document 6] WO 2018 / 164191 A1 [Patent Document 7] WO 2018 / 164192 A1 [Patent Document 8] WO 2019 / 027003 A1 [Patent Document 9] WO 2019 / 027058 A1 [Patent Document 10] WO 2020 / 004536 A1

[0018] 9

[0019] [Patent Document 11] WO 2020 / 004537 A1 [Patent Document 12] WO 2020 / 122092 A1 [Patent Document 13] WO 2020 / 122093 A1 [Patent Document 14] WO 2020 / 158958 A1 5 [Patent Document 15] WO 2020 / 167701 A1 [Patent Document 16] WO 2020 / 167706 A1 [Patent Document 17] WO 2021 / 106975 A1 [Patent Document 18] WO 2024 / 095133 A1 [Patent Document 19] WO 2023 / 199091 A1 10 [Patent Document 20] WO 2024 / 116086 A1 [Non-Patent Document] [Non-Patent Document 1] Cell, Vol.92, 573-585, 1998) [Non-Patent Document 2] Cell, Vol.98, 365-376, 1999) [Non-Patent Document 3] Proc. Natl. Acad. Sci. USA, Vol.101, 15 4649-4654, 2004) [Non-Patent Document 4] Cell, Vol.98, 437-451, 1999) [Non-Patent Document 5] Neuron, Vol.38, 715-730, 2003) [Non-Patent Document 6] CNS Drugs, Vol.27, 83-90, 2013) [Non-Patent Document 7] Cell Metabolism, Vol.9, 64-76, 2009)20[Non-Patent Document 8] Neuroscience, Vol.121, 855-863, 2003) [Non-Patent Document 9] Respiration, Vol.71, 575-579, 2004) [Non-Patent Document 10] Peptides, Vol.23, 1683-1688, 2002) [Non-Patent Document 11] Journal of the American College of Cardiology. Vol. 66, 2015, Pages 2522-2533)25[Non-Patent Document 12] Brain. Vol. 130, 2007, Pages 1586- 1595) [Summary of the Invention] [Problems to be Solved by the Invention] The present invention aims to provide a heterocyclic 30 compound having an orexin type 2 receptor agonist activity. [Means of Solving the Problems] The present inventors have found that a compound represented by the following formula (I) or a salt thereof 35 (sometimes to be referred to as compound (I) in the present

[0020] 10

[0021] specification) has an orexin type 2 receptor agonist activity. As a result of further studies, they have completed the present invention. Accordingly, the present invention provides the 5 following. [1] A compound represented by the formula (I): ) 10 each is independently a single or a double bond as defined by X1, X2, X3, X4, and X5such that all valences are satisfied; X1is selected from –CR3-, =C-, and –N-; X2is selected from –CR4R5-, =CR4-, =N-, -NR6-, -O-, and –S-; and X3is selected from –CR7R8-, =CR7-, =N-, -NR9-, -O-, and –S-; 15 wherein when X2is =N-, X3is selected from =CR7-, -O-, and –S-; and when X3is =N-, X2is selected from =CR4-, -O-, and –S-; and when one of X2and X3is –O- or –S-, the other is not –O- or –S-;20X4and X5are each =C-; or one of X4and X5is –N- and the other is =C-; X6is selected from CR10and N; X7is selected from CR11and N; X8is selected from CR12and N; 25 R1is selected from an optionally substituted C1-6alkyl group, an optionally substituted C3-10cycloalkyl group and an optionally substituted mono- or di-C1-6alkylamino group; R2is an optionally substituted 5- or 6-membered monocyclic group;

[0022] 11

[0023] R3is selected from a hydrogen atom, a halogen atom, a hydroxy, an optionally substituted C1-6alkyl group, and an optionally substituted C1-6alkoxy group; R4, R5, R7, and R8are independently selected from a hydrogen 5 atom, a halogen atom, a hydroxy, an optionally substituted C1-6alkyl group, an optionally substituted C1-6alkoxy group, and an optionally substituted C3-6cycloalkyl group; R6and R9are independently selected from a hydrogen atom and an optionally substituted C1-6alkyl group; 10 R10, R11, and R12are independently selected from a hydrogen atom, a halogen atom, a hydroxy, an optionally substituted C1-6alkyl group, an optionally substituted C1-6alkoxy group, and an optionally substituted C3-6cycloalkyl group; L is selected from a bond, -CRbRc-, -NRa-, and –O-; 15 Rais selected from a hydrogen atom and an optionally substituted C1-6alkyl group; Rband Rcare independently selected from a hydrogen atom, a halogen atom, and an optionally substituted C1-6alkyl group; Ring B is selected from an optionally substituted C5-7cycloalkyl20group, an optionally substituted 4-, 5-, 6-, 7-, or 8-membered nitrogen-containing monocyclic heterocyclic group, and an optionally substituted 6-, 7-, or 8-membered nitrogen-containing fused heterocyclic group; W is selected from a bond and -CRdRe-; and25Rdand Reare independently selected from a hydrogen atom and an optionally substituted C1-6alkyl group; or a salt thereof. [2] The compound according to the above-mentioned [1], wherein: 30 X6is CR10; X7is CR11; and X8is CR12; or a salt thereof. 35 [3] The compound according to the above-mentioned [1], wherein:

[0024] 12

[0025]

[0026] 13

[0027] -6alkyl group optionally substituted with 1 to 3 halogen atoms, a C3-10cycloalkyl group, and a mono- or di-C1-6alkylamino group; 5 R2is a 6-membered monocyclic group optionally substituted with 1 to 3 halogen atoms; R3is a hydrogen atom; R4, R5, R7, and R8are independently selected from a hydrogen atom, a halogen atom, and a C1-6alkyl group; 10 R10, R11, and R12are independently selected from a hydrogen atom, a halogen atom, and a C1-6alkyl group optionally substituted with 1 to 3 halogen atoms; L is selected from a bond, -CRbRc-, -NRa-, and –O-; Rais a hydrogen atom; 15 Rband Rcare independently selected from a hydrogen atom, a halogen atom, and a C1-6alkyl group; Ring B is selected from: a C5-7cycloalkyl group; an 4-, 5-, 6-, or 7-membered nitrogen-containing monocyclic20heterocyclic group optionally substituted with 1 to 3 groups selected from a halogen atom, a hydroxy group, a C1-6alkyl group optionally substituted with a C1-6alkoxy group, and a halogenated C1-6alkyl group; and a 6-, 7-, or 8-membered nitrogen-containing fused 25 heterocyclic group; W is selected from a bond and -CRdRe-; and Rdand Reare independently selected from a hydrogen atom and a C1-6alkyl group; or a salt thereof.

[0028] 15

[0029] [4] The compound according to the above-mentioned [1], wherein Ring B is selected from:

[0030] 16

[0031] , wherein the bond marked with “*” is attached to W; or a salt thereof. 5 [5] The compound according to the above-mentioned [1] represented by the formula (Ia): ) w ere n: X2is selected from –CR4R5-, =CR4-, and =N-; and 10 X3is selected from –CR7R8-, -O-, and –S-; wherein when X2is =N-, X3is selected from –O- and –S-; R1is selected from a C1-6alkyl group, a C3-10cycloalkyl group, and a mono- or di-C1-6alkylamino group; R2is 6-membered monocyclic group optionally substituted with 1 to 15 3 halogen atoms; R4, R5, R7, and R8are each a hydrogen atom; R11is selected from a hydrogen atom, a halogen atom, and a C1-6alkyl group; and Ring B is selected from:20a C5-7cycloalkyl group; and a 5-, 6-, or 7-membered nitrogen-containing monocyclic

[0032] 18

[0033] heterocyclic group optionally substituted with 1 to 3 groups selected from a halogen atom and a C1-6alkyl group; or a salt thereof. 5 [6] The The compound according to the above-mentioned [5], wherein Ring B is selected from: , o a sa e eo . 10 [7] The compound The compound according to the above-mentioned [5], wherein: elected from the group consisting of:

[0034] 19

[0035] -C1-65 alkylamino group; R2is a phenyl group substituted with 1 to 3 halogen atoms; and R11is a hydrogen atom, a halogen atom, or a C1-6alkyl group; or a salt thereof.10[8] The compound according to the above-mentioned [1], wherein the compound is selected from the group consisting of: (4S)-N-[(1RS)-7-(2,6-difluorophenyl)-2,3-dihydro-1H-inden-1- yl]-4-(methanesulfonamido)azepane-1-carboxamide; (3S)-N-[(1R*)-7-(2,6-difluorophenyl)-2,3-dihydro-1H-inden-1- 15 yl]-3-(methanesulfonamido)pyrrolidine-1-carboxamide; (4S)-N-[4-(2,6-difluorophenyl)-1-benzothiophen-3-yl]-4- (methanesulfonamido)azepane-1-carboxamide; (4S)-N-[4-(2,6-difluorophenyl)-1-benzofuran-3-yl]-4- (methanesulfonamido)azepane-1-carboxamide; 20 (5R*)-N-[4-(2,6-difluorophenyl)-1-benzofuran-3-yl]-4,4-

[0036] 20

[0037] difluoro-5-(methanesulfonamido)azepane-1-carboxamide; (5R*)-N-[4-(2,6-difluorophenyl)-1-benzothiophen-3-yl]-4,4- difluoro-5-(methanesulfonamido)azepane-1-carboxamide; (4S)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-4- 5 (methanesulfonamido)azepane-1-carboxamide; (5R*)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-4,4- difluoro-5-(methanesulfonamido)azepane-1-carboxamide; (3S)-N-[4-(2,6-difluorophenyl)-6-methyl-1,2-benzoxazol-3-yl]- 3-(methanesulfonamido)pyrrolidine-1-carboxamide; 10 (5R*)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-5- (ethanesulfonamido)-4,4-difluoroazepane-1-carboxamide; (3S)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3- (dimethylsulfamamido)pyrrolidine-1-carboxamide; (2R,4S)-N-[4-(2,6-difluorophenyl)-6-methyl-1,2-benzoxazol-3- 15 yl]-4-(methanesulfonamido)-2-methylpyrrolidine-1-carboxamide; (4R*)-N-[6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]- 3,3-difluoro-4-(methanesulfonamido)pyrrolidine-1-carboxamide; (4R*)-N-[6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]- 4-(ethanesulfonamido)-3,3-difluoropyrrolidine-1-carboxamide;20(3S)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3- (ethanesulfonamido)pyrrolidine-1-carboxamide; (4R*)-N-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]- 4-(ethanesulfonamido)-3,3-difluoropyrrolidine-1-carboxamide; (3S)-3-(cyclopropanesulfonamido)-N-[4-(2,6-difluorophenyl)-251,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide; (4R*)-N-[6-bromo-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]- 3,3-difluoro-4-(methanesulfonamido)pyrrolidine-1-carboxamide; (4S)-N-[4-(2,6-difluorophenyl)-1,2-benzothiazol-3-yl]-4- (methanesulfonamido)azepane-1-carboxamide; and 30 (5R)-N-[4-(2,6-difluorophenyl)-1,2-benzothiazol-3-yl]-4,4- difluoro-5-(methanesulfonamido)azepane-1-carboxamide; or a salt thereof. [9] A pharmaceutical composition comprising the compound as 35 defined in any one of the above-mentioned [1] to [8] or a salt

[0038] 21

[0039] thereof, and a pharmacologically acceptable carrier.

[0010] A medicament comprising the compound as defined in any one of the above-mentioned [1] to [8] or a salt thereof. 5

[0011] The medicament according to the above-mentioned

[0010] , which is an orexin type 2 receptor agonist.

[0012] The medicament according to the above-mentioned

[0010] , which is an agent for the prophylaxis or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, 10 narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia, Alzheimer’s disease, obesity, insulin resistance syndrome, cardiac failure, diseases related to bone loss, sepsis, disturbance of consciousness, or side effects and complications due to 15 anesthesia.

[0013] The medicament according to the above-mentioned

[0010] , which is an agent for the prophylaxis or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, or sleep apnea syndrome.

[0014] The medicament according to the above-mentioned

[0010] , which20is an agent for the prophylaxis or treatment of narcolepsy.

[0015] A method for the prophylaxis or treatment of a disease or disorder associated with an orexin type 2 receptor in a mammal in need thereof comprising administering to the mammal a25therapeutically effective amount of the compound as defined in any one of the above-mentioned [1] to [8] or a salt thereof.

[0016] The method according to the above-mentioned

[0015] , wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea 30 syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia, Alzheimer’s disease, obesity, insulin resistance syndrome, cardiac failure, diseases related to bone loss, sepsis, disturbance of consciousness, and side effects and complications due to 35 anesthesia.

[0040] 22

[0041]

[0017] The method according to the above-mentioned

[0015] , wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, and sleep apnea syndrome. 5

[0018] The method according to the above-mentioned

[0015] , wherein the disease or disorder is narcolepsy.

[0019] The compound as defined in any one of the above-mentioned [1] to [8], or a salt thereof, for use in therapy. 10

[0020] The compound or salt according to the above-mentioned

[0019] , wherein the therapy comprises treatment of a disease or disorder associated with an orexin type 2 receptor.

[0021] The compound or salt according to the above-mentioned

[0020] , wherein the disease or disorder is selected from the group 15 consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia, Alzheimer’s disease, obesity, insulin resistance syndrome, cardiac failure, diseases related to bone20loss, sepsis, disturbance of consciousness, and side effects and complications due to anesthesia.

[0022] The compound or salt according to the above-mentioned

[0020] , wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, and25sleep apnea syndrome.

[0023] The compound or salt according to the above-mentioned

[0020] , wherein the disease or disorder is narcolepsy.

[0024] Use of the compound as defined in any one of the above- 30 mentioned [1] to [8] or a salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder associated with an orexin type 2 receptor.

[0025] Use according to the above-mentioned

[0024] , wherein the disease or disorder is selected from the group consisting of narcolepsy, 35 idiopathic hypersomnia, hypersomnia, sleep apnea syndrome,

[0042] 23

[0043] narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia, Alzheimer’s disease, obesity, insulin resistance syndrome, cardiac failure, diseases related to bone loss, sepsis, disturbance of 5 consciousness, and side effects and complications due to anesthesia.

[0026] Use according to the above-mentioned

[0024] , wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, and sleep apnea syndrome. 10

[0027] Use according to the above-mentioned

[0024] , wherein the disease or disorder is narcolepsy. [Effect of the Invention] The compound of the present invention has an orexin type 15 2 receptor agonist activity, and is useful as an agent for the prophylaxis or treatment of certain diseases, such as narcolepsy. [Detailed Description of the Invention]20The definition of each substituent used in the present specification is described in detail in the following. Unless otherwise specified, each substituent has the following definition. In the present specification, examples of the “halogen25atom” include fluorine, chlorine, bromine and iodine. In the present specification, examples of the “C1-6alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2- 30 dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl. In the present specification, examples of the “optionally halogenated C1-6alkyl group” include a C1-6alkyl group optionally having 1 to 7, preferably 1 to 5, more preferably 1 to 3, halogen atoms. Specific examples thereof 35 include methyl, chloromethyl, difluoromethyl, trichloromethyl,

[0044] 24

[0045] trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2- difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, 5 isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and 6,6,6- trifluorohexyl. In the present specification, examples of the “halo C1-6alkyl group” include “halogenated C1-6alkyl group” among the above “optionally halogenated C1-6alkyl group”. 10 In the present specification, examples of the “C2-6alkenyl group” include ethenyl, 1-propenyl, 2-propenyl, 2- methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl- 2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4- methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl. 15 In the present specification, examples of the “C2-6alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 2- methyl-1-propenyl, 1-butynyl, 2-butynyl, 3-butynyl, 3-methyl- 2-butenyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 4- methyl-3-pentenyl, 1-hexynyl, 3-hexynyl, and 5-hexynyl.20In the present specification, examples of the “C2-6alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 1- butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4- hexynyl, 5-hexynyl and 4-methyl-2-pentynyl.25In the present specification, examples of the “C3-10 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl and adamantyl. 30 In the present specification, examples of the “optionally halogenated C3-10cycloalkyl group” include a C3-10cycloalkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, 35 difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and

[0046] 25

[0047] cyclooctyl. In the present specification, examples of the “C3-10cycloalkenyl group” include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. 5 In the present specification, examples of the “C7-16aralkyl group” include benzyl, phenethyl, naphthylmethyl and phenylpropyl. In the present specification, examples of the “C1-6alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, 10 isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy. In the present specification, examples of the “optionally halogenated C1-6alkoxy group” include a C1-6alkoxy group optionally having 1 to 7, preferably 1 to 5, more preferably 1 to 3, halogen atoms. Specific examples thereof 15 include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4- trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy. In the present specification, examples of the “halo C1-620alkoxy group” include “halogenated C1-6alkoxy group” among the above “optionally halogenated C1-6alkoxy group”. In the present specification, examples of the “C3-10cycloalkyloxy group” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and25cyclooctyloxy. In the present specification, examples of the “C1-6alkylthio group” include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio. 30 In the present specification, examples of the “optionally halogenated C1-6alkylthio group” include a C1-6alkylthio group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, 35 propylthio, isopropylthio, butylthio, 4,4,4-

[0048] 26

[0049] trifluorobutylthio, pentylthio and hexylthio. In the present specification, examples of the “C1-6alkyl- carbonyl group” include acetyl, propanoyl, butanoyl, 2- methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2- 5 methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl and heptanoyl. In the present specification, examples of the “optionally halogenated C1-6alkyl-carbonyl group” include a C1-6alkyl-carbonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include acetyl, 10 chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl. In the present specification, examples of the “C1-6alkoxy-carbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, 15 butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert- butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl. In the present specification, examples of the “C6-14aryl- carbonyl group” include benzoyl, 1-naphthoyl and 2-naphthoyl. In the present specification, examples of the “C7-1620aralkyl-carbonyl group” include phenylacetyl and phenylpropionyl. In the present specification, examples of the “5- to 14- membered aromatic heterocyclylcarbonyl group” include nicotinoyl, isonicotinoyl, thenoyl and furoyl.25In the present specification, examples of the “3- to 14- membered non-aromatic heterocyclylcarbonyl group” include morpholinylcarbonyl, piperidinylcarbonyl and pyrrolidinylcarbonyl. In the present specification, examples of the “mono- or 30 di-C1-6alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and N- ethyl-N-methylcarbamoyl. In the present specification, examples of the “optionally substituted mono- or di-C1-6alkylamino group” 35 include an amino group with one or two C1-6alkyl groups. The

[0050] 27

[0051] C1-6alkyl portion of the amino group can optionally have 1 or 2 substituents selected from a C2-6alkenyl group, a C3-10cycloalkyl group, a C6-14aryl group, a C7-16aralkyl group, a C1-6alkyl-carbonyl group, a C6-14aryl-carbonyl group, a C7-165 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C1-6alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C1-6alkyl-carbamoyl group, a mono- or di-C7-1610 aralkyl-carbamoyl group, a C1-6alkylsulfonyl group and a C6-14arylsulfonyl group, each of which optionally has 1 to 3 substituents selected from Substituent group A. In the present specification, examples of the “optionally substituted amino group” include an amino group 15 optionally having “1 or 2 substituents selected from a C1-6alkyl group, a C2-6alkenyl group, a C3-10cycloalkyl group, a C6-14aryl group, a C7-16aralkyl group, a C1-6alkyl-carbonyl group, a C6-14aryl-carbonyl group, a C7-16aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to2014-membered non-aromatic heterocyclylcarbonyl group, a C1-6alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C1-6alkyl-carbamoyl group, a mono- or di-C7-16aralkyl-carbamoyl group, a C1-6alkylsulfonyl group and a C6-14arylsulfonyl group,25each of which optionally has 1 to 3 substituents selected from Substituent group A.” Preferable examples of the optionally substituted amino group include an amino group, a mono- or di-(optionally halogenated C1-6alkyl) amino group (e.g., methylamino, 30 trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), a mono- or di-C2-6alkenylamino group (e.g., diallylamino), a mono- or di-C3-10cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), a mono- or di-C6-14arylamino group (e.g., phenylamino), a mono- or di-C7-1635 aralkylamino group (e.g., benzylamino, dibenzylamino), a mono-

[0052] 28

[0053] or di-(optionally halogenated C1-6alkyl)-carbonylamino group (e.g., acetylamino, propionylamino), a mono- or di-C6-14aryl- carbonylamino group (e.g., benzoylamino), a mono- or di-C7-16aralkyl-carbonylamino group (e.g., benzylcarbonylamino), a 5 mono- or di-5- to 14-membered aromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino, isonicotinoylamino), a mono- or di-3- to 14-membered non- aromatic heterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), a mono- or di-C1-6alkoxy- 10 carbonylamino group (e.g., tert-butoxycarbonylamino), a 5- to 14-membered aromatic heterocyclylamino group (e.g., pyridylamino), a carbamoylamino group, a (mono- or di-C1-6alkyl-carbamoyl) amino group (e.g., methylcarbamoylamino), a (mono- or di-C7-16aralkyl-carbamoyl) amino group (e.g., 15 benzylcarbamoylamino), a C1-6alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino), a C6-14arylsulfonylamino group (e.g., phenylsulfonylamino), a (C1-6alkyl)(C1-6alkyl-carbonyl) amino group (e.g., N-acetyl-N- methylamino) and a (C1-6alkyl)(C6-14aryl-carbonyl) amino group20(e.g., N-benzoyl-N-methylamino). In the present specification, the “hydroxy group” refers to –OH. In the present specification, the “hydroxyl” and “hydroxy” are the same. In the present specification, examples of the “5- or 6-25membered monocyclic group” include a 5- or 6-membered monocyclic group, from among a C3-10cycloalkyl group, a C3-10cycloalkenyl group, a C6-14aryl group, and a heterocyclic group (e.g., an aromatic heterocyclic group or a non-aromatic heterocyclic group), as described herein. 30 In the present specification, examples of the “C6-14aryl group” include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2- anthryl, and 9-anthryl. In the present specification, examples of the “heterocycle” include an aromatic heterocycle and a non- 35 aromatic heterocycle, each containing, as a ring-constituting

[0054] 29

[0055] atom besides carbon atom, 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms selected from a nitrogen atom, a sulfur atom, an oxygen atom, and combinations thereof. In the present specification, examples of the “aromatic 5 heterocycle” include a 5- to 14-membered (preferably 5- to 10- membered, more preferably 5- to 6-membered) aromatic heterocycle containing, as a ring-constituting atom besides carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, an oxygen atom, and combinations thereof. 10 Examples of the “aromatic heterocycle” include 5- or 6- membered monocyclic aromatic heterocycles such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4- 15 thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, triazine and the like; and 8- to 14-membered fused polycyclic (preferably bi- or tri-cyclic) aromatic heterocycles such as benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzotriazole,20imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine,25pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathiin, indole, isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, ^-carboline, phenanthridine, acridine, phenazine, phenothiazine, 30 phenoxazine and the like. In the present specification, examples of the “non- aromatic heterocycle” include a 3- to 14-membered (preferably 4- to 10-membered, more preferably 5- to 6-membered) non- aromatic heterocycle containing, as a ring-constituting atom 35 besides carbon atom, 1 to 4 heteroatoms selected from a

[0056] 30

[0057] nitrogen atom, a sulfur atom, an oxygen atom, and combinations thereof. Examples of the “non-aromatic heterocycle” include 3- to 8-membered monocyclic non-aromatic heterocycles such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, 5 tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, 10 dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, azepane, diazepane, azepine, azocane, diazocane, oxepane and the like; and 9- to 14- membered fused polycyclic (preferably bi- or tri-cyclic) non- 15 aromatic heterocycles such as dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzisothiazole, dihydronaphtho[2,3-b]thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline, isoindoline,20tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzazepine, tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine, hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine, tetrahydroquinazoline, tetrahydrocinnoline,25tetrahydrocarbazole, tetrahydro-^-carboline, tetrahydroacridine, tetrahydrophenazine, tetrahydrothioxanthene, octahydroisoquinoline and the like. In the present specification, examples of the “4-, 5-, 6-, 7-, or 8-membered nitrogen-containing monocyclic 30 heterocyclic group” include a 4-, 5-, 6-, 7-, or 8-membered “heterocyclic group,” as described herein, containing at least one (e.g., 1, 2, 3, etc.) nitrogen atom as a ring-constituting atom. In the present specification, examples of the “acyl 35 group” include a formyl group, a carboxy group, a carbamoyl

[0058] 31

[0059] group, a thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group, each optionally having “1 or 2 substituents selected from a C1-6alkyl group, a C2-6alkenyl group, a C3-10cycloalkyl group, a C3-10cycloalkenyl 5 group, a C6-14aryl group, a C7-16aralkyl group, a 5- to 14- membered aromatic heterocyclic group and a 3- to 14-membered non-aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from a halogen atom, an optionally halogenated C1-6alkoxy group, a hydroxy group, a 10 nitro group, a cyano group, an amino group and a carbamoyl group.” Examples of the “acyl group” also include a hydrocarbon- sulfonyl group, a heterocyclylsulfonyl group, a hydrocarbon- sulfinyl group and a heterocyclylsulfinyl group. 15 Here, the hydrocarbon-sulfonyl group means a hydrocarbon group-bonded sulfonyl group, the heterocyclylsulfonyl group means a heterocyclic group-bonded sulfonyl group, the hydrocarbon-sulfinyl group means a hydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinyl group means a20heterocyclic group-bonded sulfinyl group. Examples of the “acyl group” include a formyl group, a carboxy group, a C1-6alkyl-carbonyl group, a C2-6alkenyl- carbonyl group (e.g., crotonoyl), a C3-10cycloalkyl-carbonyl group (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl,25cyclohexanecarbonyl, cycloheptanecarbonyl), a C3-10 cycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl), a C6-14aryl-carbonyl group, a C7-16aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C1-630 alkoxy-carbonyl group, a C6-14aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), a C7-16aralkyloxy- carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), a carbamoyl group, a mono- or di-C1-6alkyl-carbamoyl group, a mono- or di-C2-6alkenyl-carbamoyl35 group (e.g., diallylcarbamoyl), a mono- or di-C3-10cycloalkyl-

[0060] 32

[0061] carbamoyl group (e.g., cyclopropylcarbamoyl), a mono- or di-C6-14aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- or di- C7-16aralkyl-carbamoyl group, a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl), a 5 thiocarbamoyl group, a mono- or di-C1-6alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, N-ethyl-N- methylthiocarbamoyl), a mono- or di-C2-6alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), a mono- or di-C3-10cycloalkyl-thiocarbamoyl group (e.g., 10 cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), a mono- or di-C6-14aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), a mono- or di-C7-16aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a 5- to 14- membered aromatic heterocyclylthiocarbamoyl group (e.g., 15 pyridylthiocarbamoyl), a sulfino group, a C1-6alkylsulfinyl group (e.g., methylsulfinyl, ethylsulfinyl), a sulfo group, a C1-6alkylsulfonyl group, a C6-14arylsulfonyl group, a phosphono group and a mono- or di-C1-6alkylphosphono group (e.g., dimethylphosphono, diethylphosphono, diisopropylphosphono,20dibutylphosphono). In the present specification, examples of the “5- to 14- membered aromatic heterocyclylcarbonyl group” include nicotinoyl, isonicotinoyl, thenoyl and furoyl. In the present specification, examples of the “3- to 14-25membered non-aromatic heterocyclylcarbonyl group” include morpholinylcarbonyl, piperidinylcarbonyl and pyrrolidinylcarbonyl. In the present specification, examples of the “optionally substituted carbamoyl group” include a carbamoyl 30 group optionally having “1 or 2 substituents selected from a C1-6alkyl group, a C2-6alkenyl group, a C3-10cycloalkyl group, a C6-14aryl group, a C7-16aralkyl group, a C1-6alkyl-carbonyl group, a C6-14aryl-carbonyl group, a C7-16aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl 35 group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl

[0062] 33

[0063] group, a C1-6alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di- C1-6alkyl-carbamoyl group and a mono- or di-C7-16aralkyl- carbamoyl group, each of which optionally has 1 to 3 5 substituents selected from Substituent group A.” Preferable examples of the optionally substituted carbamoyl group include a carbamoyl group, a mono- or di-C1-6alkyl-carbamoyl group, a mono- or di-C2-6alkenyl-carbamoyl group (e.g., diallylcarbamoyl), a mono- or di-C3-10cycloalkyl- 10 carbamoyl group (e.g., cyclopropylcarbamoyl, cyclohexylcarbamoyl), a mono- or di-C6-14aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C7-16aralkyl-carbamoyl group, a mono- or di-C1-6alkyl-carbonyl-carbamoyl group (e.g., acetylcarbamoyl, propionylcarbamoyl), a mono- or di-C6-14aryl- 15 carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl). In the present specification, examples of the “optionally substituted thiocarbamoyl group” include a20thiocarbamoyl group optionally having “1 or 2 substituents selected from a C1-6alkyl group, a C2-6alkenyl group, a C3-10cycloalkyl group, a C6-14aryl group, a C7-16aralkyl group, a C1-6alkyl-carbonyl group, a C6-14aryl-carbonyl group, a C7-16aralkyl-carbonyl group, a 5- to 14-membered aromatic25heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C1-6alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C1-6alkyl-carbamoyl group and a mono- or di-C7-16aralkyl-carbamoyl group, each of which optionally has 1 to 3 30 substituents selected from Substituent group A.” Preferable examples of the optionally substituted thiocarbamoyl group include a thiocarbamoyl group, a mono- or di-C1-6alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, 35 diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), a mono-

[0064] 34

[0065] or di-C2-6alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), a mono- or di-C3-10cycloalkyl- thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), a mono- or di-C6-14aryl-thiocarbamoyl 5 group (e.g., phenylthiocarbamoyl), a mono- or di-C7-16aralkyl- thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a mono- or di-C1-6alkyl-carbonyl- thiocarbamoyl group (e.g., acetylthiocarbamoyl, propionylthiocarbamoyl), a mono- or di-C6-14aryl-carbonyl- 10 thiocarbamoyl group (e.g., benzoylthiocarbamoyl) and a 5- to 14-membered aromatic heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl). In the present specification, examples of the “optionally substituted sulfamoyl group” include a sulfamoyl 15 group optionally having “1 or 2 substituents selected from a C1-6alkyl group, a C2-6alkenyl group, a C3-10cycloalkyl group, a C6-14aryl group, a C7-16aralkyl group, a C1-6alkyl-carbonyl group, a C6-14aryl-carbonyl group, a C7-16aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl20group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C1-6alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di- C1-6alkyl-carbamoyl group and a mono- or di-C7-16aralkyl- carbamoyl group, each of which optionally has 1 to 325substituents selected from Substituent group A.” Preferable examples of the optionally substituted sulfamoyl group include a sulfamoyl group, a mono- or di-C1-6alkyl-sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N- 30 methylsulfamoyl), a mono- or di-C2-6alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), a mono- or di-C3-10cycloalkyl- sulfamoyl group (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl), a mono- or di-C6-14aryl-sulfamoyl group (e.g., phenylsulfamoyl), a mono- or di-C7-16aralkyl-sulfamoyl 35 group (e.g., benzylsulfamoyl, phenethylsulfamoyl), a mono- or

[0066] 35

[0067] di-C1-6alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl, propionylsulfamoyl), a mono- or di-C6-14aryl-carbonyl-sulfamoyl group (e.g., benzoylsulfamoyl) and a 5- to 14-membered aromatic heterocyclylsulfamoyl group (e.g., pyridylsulfamoyl). 5 In the present specification, examples of the “optionally substituted hydroxy group” include a hydroxy group optionally having “a substituent selected from a C1-6alkyl group, a C2-6alkenyl group, a C3-10cycloalkyl group, a C6-14aryl group, a C7-16aralkyl group, a C1-6alkyl-carbonyl group, a 10 C6-14aryl-carbonyl group, a C7-16aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C1-6alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C1-615 alkyl-carbamoyl group, a mono- or di-C7-16aralkyl-carbamoyl group, a C1-6alkylsulfonyl group and a C6-14arylsulfonyl group, each of which optionally has 1 to 3 substituents selected from Substituent group A.” Preferable examples of the optionally substituted20hydroxy group include a hydroxy group, a C1-6alkoxy group, a C2-6alkenyloxy group (e.g., allyloxy, 2-butenyloxy, 2- pentenyloxy, 3-hexenyloxy), a C3-10cycloalkyloxy group (e.g., cyclohexyloxy), a C6-14aryloxy group (e.g., phenoxy, naphthyloxy), a C7-16aralkyloxy group (e.g., benzyloxy,25phenethyloxy), a C1-6 alkyl-carbonyloxy group (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a C6-14aryl-carbonyloxy group (e.g., benzoyloxy), a C7-16aralkyl- carbonyloxy group (e.g., benzylcarbonyloxy), a 5- to 14- membered aromatic heterocyclylcarbonyloxy group (e.g., 30 nicotinoyloxy), a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., piperidinylcarbonyloxy), a C1-6alkoxy-carbonyloxy group (e.g., tert-butoxycarbonyloxy), a 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyridyloxy), a carbamoyloxy group, a C1-6alkyl-carbamoyloxy 35 group (e.g., methylcarbamoyloxy), a C7-16aralkyl-carbamoyloxy

[0068] 36

[0069] group (e.g., benzylcarbamoyloxy), a C1-6alkylsulfonyloxy group (e.g., methylsulfonyloxy, ethylsulfonyloxy) and a C6-14arylsulfonyloxy group (e.g., phenylsulfonyloxy). In the present specification, examples of the 5 “optionally substituted sulfanyl group” include a sulfanyl group optionally having “a substituent selected from a C1-6alkyl group, a C2-6alkenyl group, a C3-10cycloalkyl group, a C6-14aryl group, a C7-16aralkyl group, a C1-6alkyl-carbonyl group, a C6-14aryl-carbonyl group and a 5- to 14-membered aromatic 10 heterocyclic group, each of which optionally has 1 to 3 substituents selected from Substituent group A” and a halogenated sulfanyl group. Preferable examples of the optionally substituted sulfanyl group include a sulfanyl (-SH) group, a C1-6alkylthio15 group, a C2-6alkenylthio group (e.g., allylthio, 2- butenylthio, 2-pentenylthio, 3-hexenylthio), a C3-10cycloalkylthio group (e.g., cyclohexylthio), a C6-14arylthio group (e.g., phenylthio, naphthylthio), a C7-16aralkylthio group (e.g., benzylthio, phenethylthio), a C1-6alkyl-20carbonylthio group (e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), a C6-14aryl- carbonylthio group (e.g., benzoylthio), a 5- to 14-membered aromatic heterocyclylthio group (e.g., pyridylthio) and a halogenated thio group (e.g., pentafluorothio).25In the present specification, examples of the “optionally substituted silyl group” include a silyl group optionally having “1 to 3 substituents selected from a C1-6alkyl group, a C2-6alkenyl group, a C3-10cycloalkyl group, a C6-14aryl group and a C7-16aralkyl group, each of which optionally 30 has 1 to 3 substituents selected from Substituent group A.” Preferable examples of the optionally substituted silyl group include a tri-C1-6alkylsilyl group (e.g., trimethylsilyl, tert-butyl(dimethyl)silyl). In the present specification, examples of the 35 “hydrocarbon ring” include a C6-14aromatic hydrocarbon ring, C3-

[0070] 37

[0071] 10cycloalkane and C3-10cycloalkene. In the present specification, examples of the “mono- or di-C7-16aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl. 5 In the present specification, examples of the “C1-6alkylsulfonyl group” include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec- butylsulfonyl and tert-butylsulfonyl. In the present specification, examples of the 10 “optionally halogenated C1-6alkylsulfonyl group” include a C1-6alkylsulfonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, 15 isopropylsulfonyl, butylsulfonyl, 4,4,4- trifluorobutylsulfonyl, pentylsulfonyl and hexylsulfonyl. In the present specification, examples of the “C6-14arylsulfonyl group” include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.20In the present specification, examples of the “hydrocarbon group” (including “hydrocarbon group” of “optionally substituted hydrocarbon group”) include a C1-6alkyl group, a C2-6alkenyl group, a C2-6alkynyl group, a C3-10cycloalkyl group, a C3-10cycloalkenyl group, a C6-14aryl group25and a C7-16 aralkyl group. In the present specification, examples of the “heterocyclic group” (including “heterocyclic group” of “optionally substituted heterocyclic group”) include (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic 30 group and (iii) a 7- to 10-membered bridged heterocyclic group, each containing, as a ring-constituting atom besides carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. In the present specification, examples of the “aromatic 35 heterocyclic group” (including “5- to 14-membered aromatic

[0072] 38

[0073] heterocyclic group”) include a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and 5 an oxygen atom. Preferable examples of the “aromatic heterocyclic group” include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,10 pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4- thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like; and 8- to 14-membered fused polycyclic (preferably bi- or tri- cyclic) aromatic heterocyclic groups such as benzothiophenyl, 15 benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl,20thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl,25quinazolinyl, cinnolinyl, carbazolyl, ^-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like. In the present specification, examples of the “non- aromatic heterocyclic group” (including “3- to 14-membered 30 non-aromatic heterocyclic group”) include a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. 35 Preferable examples of the “non-aromatic heterocyclic

[0074] 39

[0075] group” include 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, 5 imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, 10 tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and the like; and 9- to 14-membered fused polycyclic (preferably bi- or tri- 15 cyclic) non-aromatic heterocyclic groups such as dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl,20indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl,25tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-^- carbolinyl, tetrahydroacrydinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl and the like. In the present specification, preferable examples of the “7- to 10-membered bridged heterocyclic group” include 30 quinuclidinyl and 7-azabicyclo[2.2.1]heptanyl. In the present specification, examples of the “nitrogen- containing heterocyclic group” include a “heterocyclic group” containing at least one nitrogen atom as a ring-constituting atom. 35 In the present specification, examples of the

[0076] 40

[0077] “optionally substituted heterocyclic group” include a heterocyclic group optionally having substituent(s) selected from the above-mentioned Substituent group A. The number of the substituents in the “optionally 5 substituted heterocyclic group” is, for example, 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different. In the present specification, examples of the “C6-14aromatic hydrocarbon ring” include benzene and naphthalene. 10 In the present specification, examples of the “C3-10cycloalkane” include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane. In the present specification, examples of the “C3-10cycloalkene” include cyclopropene, cyclobutene, cyclopentene, 15 cyclohexene, cycloheptene and cyclooctene. In the present specification, examples of the “nitrogen- containing heterocycle” include a heterocycle containing at least one nitrogen atom as a ring-constituting atom, from among the “heterocycle.”20In the present specification, examples of the “4- to 6- membered heterocyclic group” include an aromatic or non- aromatic 4- to 6-membered heterocyclic group. Specific examples thereof include oxetanyl, furyl, pyrazolyl, pyridyl and pyrimidinyl.25In the present specification, examples of the “ring” include “hydrocarbon ring” and “heterocycle.” In the present specification, certain moieties can be “optionally substituted,” which means that the group optionally has substituent(s) selected from the following 30 Substituent group A. [Substituent group A] (1) a halogen atom, (2) a nitro group, (3) a cyano group, 35 (4) an oxo group,

[0078] 41

[0079] (5) a hydroxy group, (6) an optionally halogenated C1-6alkoxy group, (7) a C6-14aryloxy group (e.g., phenoxy, naphthoxy), (8) a C7-16aralkyloxy group (e.g., benzyloxy), 5 (9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyridyloxy), (10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g., tetrahydropyranyloxy, morpholinyloxy, piperidinyloxy), (11) a C1-6alkyl-carbonyloxy group (e.g., acetoxy, 10 propanoyloxy), (12) a C6-14aryl-carbonyloxy group (e.g., benzoyloxy, 1- naphthoyloxy, 2-naphthoyloxy), (13) a C1-6alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy), 15 (14) a mono- or di-C1-6alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy), (15) a C6-14aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy),20(16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy), (17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy), (18) an optionally halogenated C1-6alkylsulfonyloxy group25(e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy), (19) a C6-14arylsulfonyloxy group optionally substituted by a C1-6alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy), (20) an optionally halogenated C1-6alkylthio group, (21) a 5- to 14-membered aromatic heterocyclic group, 30 (22) a 3- to 14-membered non-aromatic heterocyclic group, (23) a formyl group, (24) a carboxy group, (25) an optionally halogenated C1-6alkyl-carbonyl group, (26) a C6-14aryl-carbonyl group, 35 (27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,

[0080] 42

[0081] (28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, (29) a C1-6alkoxy-carbonyl group, (30) a C6-14aryloxy-carbonyl group (e.g., phenyloxycarbonyl, 1- 5 naphthyloxycarbonyl, 2-naphthyloxycarbonyl), (31) a C7-16aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), (32) a carbamoyl group, (33) a thiocarbamoyl group, 10 (34) a mono- or di-C1-6alkyl-carbamoyl group, (35) a C6-14aryl-carbamoyl group (e.g., phenylcarbamoyl), (36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl, thienylcarbamoyl), (37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl 15 group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl), (38) an optionally halogenated C1-6alkylsulfonyl group, (39) a C6-14arylsulfonyl group, (40) a 5- to 14-membered aromatic heterocyclylsulfonyl group (e.g., pyridylsulfonyl, thienylsulfonyl),20(41) an optionally halogenated C1-6alkylsulfinyl group, (42) a C6-14arylsulfinyl group (e.g., phenylsulfinyl, 1- naphthylsulfinyl, 2-naphthylsulfinyl), (43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g., pyridylsulfinyl, thienylsulfinyl),25(44) an amino group, (45) a mono- or di-C1-6alkylamino group (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N- ethyl-N-methylamino), 30 (46) a mono- or di-C6-14arylamino group (e.g., phenylamino), (47) a 5- to 14-membered aromatic heterocyclylamino group (e.g., pyridylamino), (48) a C7-16aralkylamino group (e.g., benzylamino), (49) a formylamino group, 35 (50) a C1-6alkyl-carbonylamino group (e.g., acetylamino,

[0082] 43

[0083] propanoylamino, butanoylamino), (51) a (C1-6alkyl)(C1-6alkyl-carbonyl) amino group (e.g., N- acetyl-N-methylamino), (52) a C6-14aryl-carbonylamino group (e.g., 5 phenylcarbonylamino, naphthylcarbonylamino), (53) a C1-6alkoxy-carbonylamino group (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert- butoxycarbonylamino), 10 (54) a C7-16aralkyloxy-carbonylamino group (e.g., benzyloxycarbonylamino), (55) a C1-6alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino), (56) a C6-14arylsulfonylamino group optionally substituted by a 15 C1-6alkyl group (e.g., phenylsulfonylamino, toluenesulfonylamino), (57) an optionally halogenated C1-6alkyl group, (58) a C2-6alkenyl group, (59) a C2-6alkynyl group,20(60) a C3-10cycloalkyl group, (61) a C3-10cycloalkenyl group, and (62) a C6-14aryl group. In some aspects, examples of the “substituent” include a halogen atom, a cyano group, a nitro group, an optionally25substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy 30 group, an optionally substituted sulfanyl (SH) group and an optionally substituted silyl group. The number of the above-mentioned substituents is, for example, 1 to 5 (e.g., 1, 2, 3, 4, or 5), preferably 1 to 3 (e.g., 1, 2, or 3). When the number of the substituents is two 35 or more, the respective substituents can be the same or

[0084] 44

[0085] different. The definition of each symbol in compound (I) is explained in detail. 5 Each is independently a single or a double bond as defined by X1, X2, X3, X4, and X5such that all valences are satisfied. X1is –CR3-, =C-, or –N-, wherein R3is a hydrogen atom, a 10 halogen atom (e.g., a fluorine atom), a hydroxy, an optionally substituted C1-6alkyl group, or an optionally substituted C1-6alkoxy group. In some aspects, X1is –CR3-, =C-, or –N-, wherein R3is a hydrogen atom. 15 In some aspects, X1is –CR3- or =C-, wherein R3is a hydrogen atom. In some aspects, X1is –CR3- wherein R3is a hydrogen atom. In some aspects, X1is =C-.20In some aspects, X1is –N-. X2is –CR4R5-, =CR4-, =N-, -NR6-, -O-, or –S-, wherein R4and R5are each independently a hydrogen atom, a halogen atom (e.g., a fluorine atom), a hydroxy, an optionally substituted25C1-6 alkyl group, an optionally substituted C1-6 alkoxy group, or an optionally substituted C3-6cycloalkyl group, and R6is a hydrogen atom or an optionally substituted C1-6alkyl group. In some aspects, X2is –CR4R5-, wherein R4and R5are each independently a hydrogen atom or a halogen atom (e.g., a 30 fluorine atom). In some aspects, R4and R5are each a hydrogen atom. In some aspects, R4and R5are each a halogen atom (e.g., a fluorine atom). In some aspects, X2is –CR4R5-, wherein R4and R5are each a hydrogen atom. 35 In some aspects, X2is -NR6-, -O-, or –S-, wherein R6is a

[0086] 45

[0087] hydrogen atom or a C1-6alkyl group (e.g., methyl). In some aspects, X2is -NR6-, wherein R6is a hydrogen atom. In some aspects, X2is –O-. 5 In some aspects, X2is –S-. X3is –CR7R8-, =CR7-, =N-, -NR9-, -O-, or –S-; wherein when X2is =N-, X3is =CR7-, -O-, or –S-; and when X3is =N-, X2is =CR4-, -O-, or –S-; and 10 when one of X2and X3is –O- or –S-, the other is not –O- or –S-, wherein R7and R8are independently a hydrogen atom, a halogen atom (e.g., a fluorine atom), a hydroxy, an optionally substituted C1-6alkyl group, an optionally substituted C1-6alkoxy group, or an optionally substituted C3-6cycloalkyl 15 group, and R9is a hydrogen atom or an optionally substituted C1-6alkyl group. In some aspects, X3is –CR7R8-, wherein R7and R8are independently a hydrogen atom, a halogen atom (e.g., a fluorine atom), or an optionally substituted C1-6alkyl group.20In some aspects, X3is –CR7R8-, wherein R7and R8are each a hydrogen atom. In some aspects, X3is -NR9-, wherein R9is a hydrogen atom or a C1-6alkyl group (e.g., methyl). In some aspects, X3is -NR9-, wherein R9is a hydrogen25atom. In some aspects, X3is =N-. In some aspects, X3is –O-. In some aspects, X3is –S-. 30 X4and X5are each =C-; or one of X4and X5is –N- and the other is =C-. In some aspects, X4and X5are each =C-. In some aspects, X4is –N- and X5is =C-. In some aspect,s X4is =C- and X5is –N-. 35

[0088] 46

[0089] X6is CR10or N, wherein R10is a hydrogen atom, a halogen atom (e.g., a fluorine atom), a hydroxy, an optionally substituted C1-6alkyl group, an optionally substituted C1-6alkoxy group, or an optionally substituted C3-6cycloalkyl 5 group. In some aspects, X6is CR10, wherein R10is a hydrogen atom, a halogen atom (e.g., a fluorine atom), or a C1-6alkyl group optionally substituted with 1 to 3 (e.g., 1, 2, 3, etc.) halogen atoms (e.g., a fluorine atom). 10 In some aspects, X6is CR10, wherein R10is a hydrogen atom. In some aspects, X6is N. X7is CR11or N, wherein R11is a hydrogen atom, a halogen 15 atom (e.g., a fluorine atom), a hydroxy, an optionally substituted C1-6alkyl group, an optionally substituted C1-6alkoxy group, or an optionally substituted C3-6cycloalkyl group. In some aspects, X7is CR11, wherein R11is a hydrogen20atom, a halogen atom (e.g., a fluorine atom, a chlorine atom, or a bromine atom), or a C1-6alkyl group (e.g, methyl). In some aspects, X7is CR11, wherein R11is a hydrogen atom. In some aspects, X7is CR11, wherein R11is a halogen atom25(e.g., a fluorine atom, a chlorine atom, or a bromine atom). In some aspects, X7is CR11, wherein R11is a C1-6alkyl group (e.g, methyl). In some aspects, X7is N. 30 X8is CR12or N, wherein R12is a hydrogen atom, a halogen atom (e.g., a fluorine atom), a hydroxy, an optionally substituted C1-6alkyl group, an optionally substituted C1-6alkoxy group, or an optionally substituted C3-6cycloalkyl group. 35 In some aspects, X8is CR12, wherein R12is a hydrogen

[0090] 47

[0091] atom, a halogen atom (e.g., a fluorine atom), or a C1-6alkyl group optionally substituted with 1 to 3 (e.g., 1, 2, 3, etc.) halogen atoms (e.g., a fluorine atom). In some aspects, X8is CR12, wherein R12is a hydrogen 5 atom. In some aspects, X8is N. R1is an optionally substituted C1-6alkyl group, an optionally substituted C3-10cycloalkyl group or an optionally 10 substituted mono- or di-C1-6alkylamino group. In some aspects, R1is (1) a C1-6alkyl group (e.g., methyl, ethyl) optionally substituted with 1 to 3 substituents independently selected from 15 (i) a halogen atom (e.g., a fluorine atom), (ii) a C1-6alkoxy group (e.g., methoxy), and (iii) a C3-6cycloalkyl group (e.g., cyclopropyl), (2) a C3-10cycloalkyl group (e.g., cyclopropyl), or (3) a mono- or di-C1-6alkylamino group (e.g., methylamino,20dimethylamino). In some aspects, R1is a C1-6alkyl group (e.g., methyl, ethyl), a C3-10cycloalkyl group (preferably a C3-6cycloalkyl group, e.g., cyclopropyl), or a di-C1-6alkylamino group (e.g., dimethylamino).25In some aspects, R1is a C1-6 alkyl group (e.g., methyl, ethyl). R2is an optionally substituted 5- or 6-membered monocyclic group. 30 In some aspects, R2is phenyl, pyrazolyl, furyl, thienyl, thiazolyl, pyridyl, or piperidyl, any of which is optionally substituted by one or more (e.g., 1, 2, 3, etc.) substituents independently selected from a C1-6alkyl group (e.g., methyl), a halogen atom (e.g., a fluorine atom, a chlorine atom), a 35 halo (C1-6) alkyl group (e.g., trifluoromethyl), and a C1-6

[0092] 48

[0093] alkoxy group (e.g., methoxy). In some aspects, R2is a phenyl group optionally substituted by 1 to 3 (e.g., 1, 2, 3, etc.) halogen atoms (e.g., a fluorine atom). 5 In some aspects, R2is a phenyl group substituted by 1 to 3 (e.g., 1, 2, 3, etc.) halogen atoms (e.g., a fluorine atom). In some aspects, R2is a phenyl group substituted by 2 or 3 fluorine atoms (e.g., 2,6- substituted, 2,4,6-substituted, or 2,5,6-substituted). 10 In some aspects, R2is a phenyl group substituted by 2 fluorine atoms (e.g., 2,6-substituted). L is a bond, -CRbRc-, -NRa-, or –O-. In some aspects, L is -NRa-. 15 Rais a hydrogen atom or an optionally substituted C1-6alkyl group. In some aspects, Rais a hydrogen atom or a C1-6alkyl group (e.g., methyl).20In some aspects, Rais a hydrogen atom. Rband Rcare each independently a hydrogen atom, a halogen atom, or an optionally substituted C1-6alkyl group. In some aspects, Rband Rcare each independently a25hydrogen atom or a C1-6 alkyl group (e.g., methyl). In some aspects, Rband Rcare each a hydrogen atom. Ring B is an optionally substituted C5-7cycloalkyl group, an optionally substituted 4-, 5-, 6-, 7-, or 8-membered 30 nitrogen-containing monocyclic heterocyclic group, and an optionally substituted 6-, 7-, or 8-membered nitrogen- containing fused heterocyclic group. In some aspects, Ring B is an C5-7cycloalkyl group optionally substituted with 1 to 3 (e.g., 1, 2, 3, etc.) 35 groups selected from halogen atoms (e.g., a fluorine atom) and

[0094] 49

[0095] and C1-6alkyl groups (e.g., methyl); or a 4-, 5-, 6-, 7-, or 8-membered nitrogen-containing monocyclic heterocyclic group optionally substituted with 1 to 3 (e.g., 1, 2, 3, etc.) groups selected from halogen atoms (e.g., a fluorine atom) and 5 and C1-6alkyl groups (e.g., methyl). In some aspects, Ring B is a 4-, 5-, 6-, 7-, or 8- membered nitrogen-containing monocyclic heterocyclic group optionally substituted with 1 to 3 (e.g., 1, 2, 3, etc.) halogen atoms (e.g., a fluorine atom). 10 In some aspects, Ring B is a 4-, 5-, 6-, 7-, or 8- membered nitrogen-containing monocyclic heterocyclic group optionally substituted with 1 to 3 (e.g., 1, 2, 3, etc.) C1-6alkyl groups (e.g., methyl). In some aspects, Ring B is a 4-, 5-, 6-, 7-, or 8- 15 membered nitrogen-containing monocyclic heterocyclic group. In some aspects, Ring B is a 4-membered nitrogen- containing monocyclic heterocyclic group. In some aspects, Ring B is a 5-membered nitrogen- containing monocyclic heterocyclic group.20In some aspects, Ring B is a 6-membered nitrogen- containing monocyclic heterocyclic group. In some aspects, Ring B is a 7-membered nitrogen- containing monocyclic heterocyclic group. In some aspects, Ring B is a 8-membered nitrogen-25containing monocyclic heterocyclic group. W is a bond and -CRdRe-. In some aspects, W is a bond. In some aspects, W is -CRdRe-. 30 Rdand Reare each independently a hydrogen atom or an optionally substituted C1-6alkyl group. In some aspects, Rdand Reare each independently a hydrogen atom or a C1-6alkyl group (e.g., methyl). In some aspects, Rdand Reare each a hydrogen atom. 35

[0096] 50

[0097] In some aspects, X6is CR10; X7is CR11; and X8is CR12. In some aspects, X1, X2, X3, X4, X5, X6, X7, and X8are selected to form a ring system selected from: i) X1is –CR3-; X2is –CR4R5-; X3is –CR7R8-; X4is =C-; X5is 5 =C-; X6is CR10; X7is CR11; and X8is CR12; ii) X1is –N-; X2is –CR4R5-; X3is –CR7R8-; X4is =C-; X5is =C-; X6is CR10; X7is CR11; and X8is CR12; iii) X1is –N-; X2is =CR4-; X3is =CR7-; X4is =C-; X5is =C-; X6is CR10; X7is CR11; and X8is CR12; 10 iv) X1is –N-; X2is =CR4-; X3is =N-; X4is =C-; X5is =C-; X6is CR10; X7is CR11; and X8is CR12; v) X1is –N-; X2is =N-; X3is =CR7-; X4is =C-; X5is =C-; X6is CR10; X7is CR11; and X8is CR12; vi) X1is =C-; X2is =CR4-; X3is =N-; X4is -N-; X5is =C-; X615 is CR10; X7is CR11; and X8is CR12; vii) X1is =C-; X2is =CR4-; X3is =N-; X4is =C-; X5is -N-; X6is CR10; X7is CR11; and X8is CR12; viii) X1is =C-; X2is =N-; X3is =CR7-; X4is -N-; X5is =C-; X6is CR10; X7is CR11; and X8is CR12;20ix) X1is =C-; X2is =N-; X3is =CR7-; X4is =C-; X5is -N-; X6is CR10; X7is CR11; and X8is CR12; x) X1is –CR3-; X2is –CR4R5-; X3is –O-; X4is =C-; X5is =C-; X6is CR10; X7is CR11; and X8is CR12; xi) X1is =C-; X2is =CR4-; X3is –O-; X4is =C-; X5is =C-; X625is CR10; X7is CR11; and X8is CR12; xii) X1is =C-; X2is =CR4-; X3is –S-; X4is =C-; X5is =C-; X6is CR10; X7is CR11; and X8is CR12; xiii) X1is =C-; X2is =N-; X3is –O-; X4is =C-; X5is =C-; X6is CR10; X7is CR11; and X8is CR12; 30 xiv) X1is =C-; X2is -O-; X3is =N-; X4is =C-; X5is =C-; X6is CR10; X7is CR11; and X8is CR12; and xv) X1is =C-; X2is =N-; X3is –S-; X4is =C-; X5is =C-; X6is CR10; X7is CR11; and X8is CR12. In some aspects, the partial structure represented by 35 the following formula:

[0098] 51

[0099] l is as defined above, is one of the partial structures represented by the following formulas: ,

[0100] 52

[0101] , w ere n eac symboa s as defined above. In these aspects, R1is selected from a C1-6alkyl group 5 (e.g., methyl, ethyl) optionally substituted with 1 to 3 (e.g., 1, 2, or 3) halogen atoms (e.g., a fluorine atom), a C3-10cycloalkyl group (e.g., cyclopropyl), and a mono- or di-C1-6alkylamino group (e.g., methylamino, dimethylamino). In some aspects, R2is a 6-membered monocyclic group 10 (e.g., phenyl) optionally substituted with 1 to 3 (e.g., 1, 2, or 3) halogen atoms (e.g., a fluorine atom, a chlorine atom, or a bromine atom). In some aspects, R3is a hydrogen atom. In some aspects, R4, R5, R7, and R8are each independently 15 a hydrogen atom, a halogen atom (e.g., a fluorine atom), or a C1-6alkyl group (e.g., methyl, ethyl). In some aspects, R10, R11, and R12are each independently a hydrogen atom, a halogen atom (e.g., a fluorine atom), or a C1-6 alkyl group (e.g., methyl, ethyl) optionally substituted with201 to 3 (e.g., 1, 2, or 3) halogen atoms (e.g., a fluorine atom). In some aspects, L is a bond, -CRbRc-, -NRa-, or –O-. In some aspects, Rais a hydrogen atom. In some aspects, Rband Rcare each independently a 25 hydrogen atom, a halogen atom (e.g., a fluorine atom), or a C1-6alkyl group (e.g., methyl, ethyl). In some aspects, Ring B is a C5-7cycloalkyl group (e.g., cyclopentyl, cyclohexyl, cycloheptyl); a 4-, 5-, 6-, or 7- membered nitrogen-containing monocyclic heterocyclic group

[0102] 54

[0103] (e.g., azetidinyl, pyrrolidinyl, piperidinyl, isoxazolinyl, morpholino, azepanyl, 1,2-oxazepanyl,1,4-oxazepanyl) optionally substituted with 1 to 3 groups (e.g., 1, 2, or 3) selected from a halogen atom (e.g., a fluorine atom), a 5 hydroxy group, a C1-6alkyl group (e.g., methyl, ethyl) optionally substituted with a C1-6alkoxy group (e.g., methoxy, ethoxy), and a halogenated C1-6alkyl group (e.g., trifluoromethyl); or a 6-, 7-, or 8-membered nitrogen- containing fused heterocyclic group (e.g., 3- 10 azabicyclo[3.2.0]heptyl, 3-azabicyclo[3.1.0]hexyl, octahydrocyclopenta[c]pyrrolyl). In some aspects, W is a bond or -CRdRe-. In some aspects, Rdand Reare each independently a hydrogen atom or a C1-6alkyl group (e.g., methyl, ethyl). 15 In some aspects, the partial structure represented by the following formula: i lowing partial structures:

[0104] 55

[0105] , 5 wherein the bond marked with “*” is attached to W. In some aspects, compound (I) is represented by the formula (Ia):

[0106] 57

[0107] ) cycloalkyl group (preferably a C3-6cycloalkyl group, e.g., cyclopropyl), or a mono- or di-C1-6alkylamino group (e.g., methylamino, dimethylamino); 10 R2is 6-membered monocyclic group (e.g, phenyl) optionally substituted with 1 to 3 (e.g., 1, 2, or 3) halogen atoms (e.g., a fluorine atom); R4, R5, R7, and R8are each a hydrogen atom; R11is a hydrogen atom, a halogen atom (e.g., a fluorine atom, 15 a chlorine atom, or a bromine atom), or a C1-6alkyl group (e.g., methyl, ethyl); and Ring B is a C5-7cycloalkyl group (e.g., cyclopentyl, cyclohexyl, cycloheptyl) or a 5-, 6-, or 7-membered nitrogen- containing monocyclic heterocyclic group (e.g., azetidinyl,20pyrrolidinyl, piperidinyl, isoxazolinyl, morpholino, azepanyl, 1,2-oxazepanyl,1,4-oxazepanyl) optionally substituted with 1 to 3 groups (e.g., 1, 2, or 3) selected from a halogen atom (e.g., a fluorine atom) and a C1-6alkyl group (e.g., methyl, ethyl);25or a salt thereof (sometimes to be referred to as compound (Ia)). In some aspects of compound (Ia), Ring B is:

[0108] 58

[0109] p p , p e represented by the following formula: l is as defined above, is one of the partial structures represented by the following formulas:

[0110] 59

[0111] 5 In some aspects of compound (Ia), R1is a C1-6alkyl group (e.g., methyl, ethyl), cyclopropyl, or a mono- or di-C1-6alkylamino group (e.g., methylamino, dimethylamino); R2is a phenyl group substituted with 1 to 3 (e.g., 1, 2,10or 3) halogen atoms (e.g., a fluorine atom); and R11is a hydrogen atom, a halogen atom (e.g., a fluorine atom, a chlorine atom, or a bromine atom), or a C1-6alkyl group (e.g., methyl, ethyl).15Exemplary examples of compound (I), including compounds (Ia), include the compounds set forth in the Examples and Table 1. In some aspects, the disclosure provides a compound selected from the group consisting of: 20 (4S)-N-[(1RS)-7-(2,6-difluorophenyl)-2,3-dihydro-1H-inden-1- yl]-4-(methanesulfonamido)azepane-1-carboxamide; (3S)-N-[(1R*)-7-(2,6-difluorophenyl)-2,3-dihydro-1H-inden-1- yl]-3-(methanesulfonamido)pyrrolidine-1-carboxamide; (4S)-N-[4-(2,6-difluorophenyl)-1-benzothiophen-3-yl]-4- 25 (methanesulfonamido)azepane-1-carboxamide;

[0112] 60

[0113] (4S)-N-[4-(2,6-difluorophenyl)-1-benzofuran-3-yl]-4- (methanesulfonamido)azepane-1-carboxamide; (5R*)-N-[4-(2,6-difluorophenyl)-1-benzofuran-3-yl]-4,4- difluoro-5-(methanesulfonamido)azepane-1-carboxamide; 5 (5R*)-N-[4-(2,6-difluorophenyl)-1-benzothiophen-3-yl]-4,4- difluoro-5-(methanesulfonamido)azepane-1-carboxamide; (4S)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-4- (methanesulfonamido)azepane-1-carboxamide; (5R*)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-4,4- 10 difluoro-5-(methanesulfonamido)azepane-1-carboxamide; (3S)-N-[4-(2,6-difluorophenyl)-6-methyl-1,2-benzoxazol-3-yl]- 3-(methanesulfonamido)pyrrolidine-1-carboxamide; (5R*)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-5- (ethanesulfonamido)-4,4-difluoroazepane-1-carboxamide; 15 (3S)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3- (dimethylsulfamamido)pyrrolidine-1-carboxamide; (2R,4S)-N-[4-(2,6-difluorophenyl)-6-methyl-1,2-benzoxazol-3- yl]-4-(methanesulfonamido)-2-methylpyrrolidine-1-carboxamide; (4R*)-N-[6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-203,3-difluoro-4-(methanesulfonamido)pyrrolidine-1-carboxamide; (4R*)-N-[6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]- 4-(ethanesulfonamido)-3,3-difluoropyrrolidine-1-carboxamide; (3S)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3- (ethanesulfonamido)pyrrolidine-1-carboxamide;25(4R*)-N-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]- 4-(ethanesulfonamido)-3,3-difluoropyrrolidine-1-carboxamide; (3S)-3-(cyclopropanesulfonamido)-N-[4-(2,6-difluorophenyl)- 1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide; (4R*)-N-[6-bromo-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]- 30 3,3-difluoro-4-(methanesulfonamido)pyrrolidine-1-carboxamide; (4S)-N-[4-(2,6-difluorophenyl)-1,2-benzothiazol-3-yl]-4- (methanesulfonamido)azepane-1-carboxamide; and (5R)-N-[4-(2,6-difluorophenyl)-1,2-benzothiazol-3-yl]-4,4- difluoro-5-(methanesulfonamido)azepane-1-carboxamide; 35 or a salt thereof.

[0114] 61

[0115] In some aspects, the disclosure provides a compound that is (4S)-N-[(1RS)-7-(2,6-difluorophenyl)-2,3-dihydro-1H-inden- 1-yl]-4-(methanesulfonamido)azepane-1-carboxamide or a salt thereof. 5 In some aspects, the disclosure provides a compound that is (3S)-N-[(1R*)-7-(2,6-difluorophenyl)-2,3-dihydro-1H-inden- 1-yl]-3-(methanesulfonamido)pyrrolidine-1-carboxamide or a salt thereof. In some aspects, the disclosure provides a compound that10 is (4S)-N-[4-(2,6-difluorophenyl)-1-benzothiophen-3-yl]-4- (methanesulfonamido)azepane-1-carboxamide or a salt thereof. In some aspects, the disclosure provides a compound that is (4S)-N-[4-(2,6-difluorophenyl)-1-benzofuran-3-yl]-4- (methanesulfonamido)azepane-1-carboxamide or a salt thereof. 15 In some aspects, the disclosure provides a compound that is (5R*)-N-[4-(2,6-difluorophenyl)-1-benzofuran-3-yl]-4,4- difluoro-5-(methanesulfonamido)azepane-1-carboxamide or a salt thereof. In some aspects, the disclosure provides a compound that20is (5R*)-N-[4-(2,6-difluorophenyl)-1-benzothiophen-3-yl]-4,4- difluoro-5-(methanesulfonamido)azepane-1-carboxamide or a salt thereof. In some aspects, the disclosure provides a compound that is (4S)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-4-25(methanesulfonamido)azepane-1-carboxamide or a salt thereof. In some aspects, the disclosure provides a compound that is (5R*)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-4,4- difluoro-5-(methanesulfonamido)azepane-1-carboxamide or a salt thereof. 30 In some aspects, the disclosure provides a compound that is (3S)-N-[4-(2,6-difluorophenyl)-6-methyl-1,2-benzoxazol-3- yl]-3-(methanesulfonamido)pyrrolidine-1-carboxamide or a salt thereof. In some aspects, the disclosure provides a compound that35 is (5R*)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-5-

[0116] 62

[0117] (ethanesulfonamido)-4,4-difluoroazepane-1-carboxamide or a salt thereof. In some aspects, the disclosure provides a compound that is (3S)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3- 5 (dimethylsulfamamido)pyrrolidine-1-carboxamide or a salt thereof. In some aspects, the disclosure provides a compound that is (2R,4S)-N-[4-(2,6-difluorophenyl)-6-methyl-1,2-benzoxazol- 3-yl]-4-(methanesulfonamido)-2-methylpyrrolidine-1-carboxamide 10 or a salt thereof. In some aspects, the disclosure provides a compound that is (4R*)-N-[6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3- yl]-3,3-difluoro-4-(methanesulfonamido)pyrrolidine-1- carboxamide or a salt thereof. 15 In some aspects, the disclosure provides a compound that is (4R*)-N-[6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3- yl]-4-(ethanesulfonamido)-3,3-difluoropyrrolidine-1- carboxamide or a salt thereof. In some aspects, the disclosure provides a compound that20is (3S)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3- (ethanesulfonamido)pyrrolidine-1-carboxamide or a salt thereof. In some aspects, the disclosure provides a compound that is (4R*)-N-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-25yl]-4-(ethanesulfonamido)-3,3-difluoropyrrolidine-1- carboxamide or a salt thereof. In some aspects, the disclosure provides a compound that is (3S)-3-(cyclopropanesulfonamido)-N-[4-(2,6-difluorophenyl)- 1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide or a salt 30 thereof. In some aspects, the disclosure provides a compound that is (4R*)-N-[6-bromo-4-(2,6-difluorophenyl)-1,2-benzoxazol-3- yl]-3,3-difluoro-4-(methanesulfonamido)pyrrolidine-1- carboxamide or a salt thereof. 35 In some aspects, the disclosure provides a compound that

[0118] 63

[0119] is (4S)-N-[4-(2,6-difluorophenyl)-1,2-benzothiazol-3-yl]-4- (methanesulfonamido)azepane-1-carboxamide or a salt thereof. In some aspects, the disclosure provides a compound that is (5R)-N-[4-(2,6-difluorophenyl)-1,2-benzothiazol-3-yl]-4,4- 5 difluoro-5-(methanesulfonamido)azepane-1-carboxamide or a salt thereof. As a salt of a compound represented by the formula (I), a pharmacologically acceptable salt is preferable, and examples of such salt include a salt with inorganic base, a 10 salt with organic base, a salt with inorganic acid, a salt with organic acid, a salt with basic or acidic amino acid and the like. Examples of the salt with inorganic base include alkali metal salts such as sodium salt, potassium salt and the like, 15 alkaline earth metal salts such as calcium salt, magnesium salt and the like, aluminum salt, ammonium salt and the like. Examples of the salt with organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine,20tromethamine[tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, benzylamine, dicyclohexylamine, N,N- dibenzylethylenediamine and the like. Examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid,25sulfuric acid, phosphoric acid and the like. Examples of the salt with organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, 30 benzenesulfonic acid, p-toluenesulfonic acid and the like. Examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like. Examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like. 35

[0120] 64

[0121] The production method of the compound of the present invention is explained below. The raw material compound and reagent used and the compound obtained in each step in the following production 5 method may be each in a form of a salt, and examples of such salt include those similar to the salts of the compound represented by the formula (I), and the like. When the compound obtained in each step is a free form, it can be converted to the objective salt according to a 10 method known per se. When the compound obtained in each step is a salt, it can be converted to the objective free form or the other salt according to a method known per se. The compound obtained in each step can be used directly as the reaction mixture or as a crude product for the next 15 reaction. Alternatively, the compound obtained in each step can be isolated and purified from a reaction mixture according to a method known per se, for example, a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation,20column chromatography and the like. When the raw material compound and reagent used in each step are commercially available, the commercially available product can also be used directly. In the reaction in each step, while the reaction time25varies depending on the kind of the reagent and solvent to be used, it is generally 1 min - 48 hr, preferably 10 min - 8 hr, unless otherwise specified. In the reaction in each step, while the reaction temperature varies depending on the kind of the reagent and30solvent to be used, it is generally -78^C - 300^C, preferably - 78^C - 150^C, unless otherwise specified. In the reaction in each step, while the pressure varies depending on the kind of the reagent and solvent to be used, it is generally 1 atm – 20 atm, preferably 1 atm – 3 atm, 35 unless otherwise specified.

[0122] 65

[0123] Microwave synthesizers such as Initiator manufactured by Biotage and the like may be used for the reaction in each step. While the reaction temperature varies depending on the kind of the reagent and solvent to be used, it is generally 5 room temperature - 300^C, preferably 50^C - 250^C, unless otherwise specified. While the reaction time varies depending on the kind of the reagent and solvent to be used, it is generally 1 min - 48 hr, preferably 1 min - 8 hr, unless otherwise specified. 10 In the reaction in each step, the reagent is used in an amount of 0.5 equivalents – 20 equivalents, preferably 0.8 equivalents – 5 equivalents, relative to the substrate, unless otherwise specified. When the reagent is used as a catalyst, the reagent is used in an amount of 0.001 equivalent – 1 15 equivalent, preferably 0.01 equivalent - 0.2 equivalent, relative to the substrate. When the reagent is used as a reaction solvent, the reagent is used in a solvent amount. Unless otherwise specified, the reaction in each step is carried out without solvent, or by dissolving or suspending20the raw material compound in a suitable solvent. Examples of the solvent include those described in Examples and the following solvents: alcohols: methanol, ethanol, tert-butyl alcohol, 2- methoxyethanol and the like;25ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane and the like; aromatic hydrocarbons: chlorobenzene, toluene, xylene and the like; saturated hydrocarbons: cyclohexane, hexane and the 30 like; amides: N,N-dimethylformamide, N-methylpyrrolidone and the like; halogenated hydrocarbons: dichloromethane, carbon tetrachloride and the like; 35 nitriles: acetonitrile and the like;

[0124] 66

[0125] sulfoxides: dimethyl sulfoxide and the like; aromatic organic bases: pyridine and the like; anhydrides: acetic anhydride and the like; organic acids: formic acid, acetic acid, trifluoroacetic 5 acid and the like; inorganic acids: hydrochloric acid, sulfuric acid and the like; esters: ethyl acetate and the like; ketones: acetone, methyl ethyl ketone and the like; and 10 water. The above-mentioned solvent can be used in a mixture of two or more kinds thereof in an appropriate ratio. When a base is used for the reaction in each step, examples thereof include those described in Examples and the 15 following bases: inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium hydrogen carbonate and the like; organic bases: triethylamine, diethylamine, pyridine, 4-20dimethylaminopyridine, N,N-dimethylaniline, 1,4- diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine and the like; metal alkoxides: sodium ethoxide, potassium tert- butoxide and the like;25alkali metal hydrides: sodium hydride and the like; metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide and the like; and organic lithiums: n-butyllithium and the like. When an acid or an acid catalyst is used for the 30 reaction in each step, examples thereof include those described in Examples and the following acids and acid catalysts: inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid and the like; 35 organic acids: acetic acid, trifluoroacetic acid, citric

[0126] 67

[0127] acid, p-toluenesulfonic acid, 10-camphorsulfonic acid and the like; Lewis acids: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc 5 chloride, anhydrous iron chloride and the like. Unless otherwise specified, the reaction in each step is carried out according to a method known per se, for example, the method described in Jikken Kagaku Kouza, 5th Edition, vol.13-19 (the Chemical Society of Japan ed.); Shin Jikken 10 Kagaku Kouza, vol.14-15 (the Chemical Society of Japan ed.); Fine Organic Chemistry, Revised 2nd Edition (L. F. Tietze, Th. Eicher, Nankodo); Organic Name Reactions, the Reaction Mechanism and Essence, Revised Edition (Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volume I-VII (John Wiley & Sons 15 Inc.); Modern Organic Synthesis in the Laboratory A Collection of Standard Experimental Procedures (Jie Jack Li, OXFORD UNIVERSITY); Comprehensive Heterocyclic Chemistry III, Vol.1 - Vol.14 (Elsevier Japan); Strategic Applications of Named Reactions in Organic Synthesis (Laszlo Kurti, Barbara Czako,20Elsevier Japan); Comprehensive Organic Transformations (VCH Publishers Inc.), 1989, or the like, or the method described in Examples. In each step, the protection or deprotection reaction of a functional group is carried out according to a method known25per se, for example, the method described in “Protective Groups in Organic Synthesis, 4th Ed”, Wiley-Interscience, Inc., 2007 (Theodora W. Greene, Peter G. M. Wuts); “Protecting Groups 3rd Ed.” Thieme, 2004 (P.J. Kocienski), or the like, or the method described in Examples. 30 Examples of the protecting group for a hydroxy group of an alcohol and the like and a phenolic hydroxy group include ether-type protecting groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, tetrahydropyranyl ether and the like; carboxylate ester-type protecting groups 35 such as acetate ester and the like; sulfonate ester-type

[0128] 68

[0129] protecting groups such as methanesulfonate ester and the like; carbonate ester-type protecting groups such as tert- butylcarbonate and the like, and the like. Examples of the protecting group for a carbonyl group of 5 an aldehyde include acetal-type protecting groups such as dimethylacetal and the like; cyclic acetal-type protecting groups such as 1,3-dioxane and the like, and the like. Examples of the protecting group for a carbonyl group of a ketone include ketal-type protecting groups such as 10 dimethylketal and the like; cyclic ketal-type protecting groups such as 1,3-dioxane and the like; oxime-type protecting groups such as O-methyloxime and the like; hydrazone-type protecting groups such as N,N-dimethylhydrazone and the like, and the like. 15 Examples of the protecting group for a carboxyl group include ester-type protecting groups such as methyl ester and the like; and amide-type protecting groups such as N,N- dimethylamide and the like. Examples of the protecting group for a thiol include20ether-type protecting groups such as benzyl thioether and the like; and ester-type protecting groups such as thioacetate ester, thiocarbonate, thiocarbamate and the like. Examples of the protecting group for an amino group and an aromatic heterocycle such as imidazole, pyrrole, indole and25the like include carbamate-type protecting groups such as benzyl carbamate and the like; amide-type protecting groups such as acetamide and the like; alkyl amine-type protecting groups such as N-triphenylmethylamine and the like; and sulfonamide-type protecting groups such as methanesulfonamide 30 and the like. The protecting groups can be removed according to a method known per se, for example, by employing a method using acid, base, ultraviolet rays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, 35 palladium acetate, trialkylsilyl halide (e.g., trimethylsilyl

[0130] 69

[0131] iodide, trimethylsilyl bromide) and the like, a reduction method, and the like. When reduction reaction is carried out in each step, examples of the reducing agent to be used include metal 5 hydrides such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, tetramethylammonium triacetoxyborohydride and the like; boranes such as borane tetrahydrofuran complex and the like; 10 Raney nickel; Raney cobalt; hydrogen; formic acid; triethylsilane and the like. When carbon-carbon double bond or triple bond is reduced, a method using a catalyst such as palladium-carbon, Lindlar’s catalyst and the like may be employed. 15 When oxidation reaction is carried out in each step, examples of the oxidizing agent to be used include peroxides such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, tert-butylhydroperoxide and the like; perchlorates such as tetrabutylammonium perchlorate and the like; chlorates such as20sodium chlorate and the like; chlorites such as sodium chlorite and the like; periodates such as sodium periodate and the like; hypervalent iodine reagents such as iodosylbenzene and the like; reagents containing manganese such as manganese dioxide, potassium permanganate and the like; leads such as25lead tetraacetate and the like; reagents containing chromium such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Jones reagent and the like; halogen compounds such as N-bromosuccinimide (NBS) and the like; oxygen; ozone; sulfur trioxide-pyridine complex; osmium tetroxide; selenium dioxide; 30 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like. When radical cyclization reaction is carried out in each step, examples of the radical initiator to be used include azo compounds such as azobisisobutyronitrile (AIBN) and the like; water-soluble radical initiators such as 4-4’-azobis-4- 35 cyanopentanoic acid (ACPA) and the like; triethylboron in the

[0132] 70

[0133] presence of air or oxygen; benzoyl peroxide and the like. Examples of the radical reagent to be used include tributylstannane, tristrimethylsilylsilane, 1,1,2,2- tetraphenyldisilane, diphenylsilane, samarium iodide and the 5 like. When Wittig reaction is carried out in each step, examples of the Wittig reagent to be used include alkylidene phosphoranes and the like. The alkylidene phosphoranes can be prepared according to a method known per se, for example, by 10 reacting a phosphonium salt with a strong base. When Horner-Emmons reaction is carried out in each step, examples of the reagent to be used include phosphonoacetates such as methyl dimethylphosphonoacetate, ethyl diethylphosphonoacetate and the like; and bases such as alkali 15 metal hydrides, organic lithiums and the like. When Friedel-Crafts reaction is carried out in each step, a combination of a Lewis acid and an acid chloride or a combination of a Lewis acid and an alkylating agent (e.g., an alkyl halide, an alcohol, an olefin etc.) is used as a20reagent. Alternatively, an organic acid or an inorganic acid can also be used instead of a Lewis acid, and an anhydride such as acetic anhydride and the like can also be used instead of an acid chloride. When aromatic nucleophilic substitution reaction is25carried out in each step, a nucleophile (e.g., an amine, imidazole etc.) and a base (e.g., an organic base etc.) are used as a reagent. When nucleophilic addition reaction by a carbo anion, nucleophilic 1,4-addition reaction (Michael addition reaction) 30 by a carbo anion or nucleophilic substitution reaction by a carbo anion is carried out in each step, and examples of the base to be used for generation of the carbo anion include organic lithiums, metal alkoxides, inorganic bases, organic bases and the like. 35 When Grignard reaction is carried out in each step,

[0134] 71

[0135] examples of the Grignard reagent to be used include arylmagnesium halides such as phenylmagnesium bromide and the like; and alkylmagnesium halides such as methylmagnesium bromide and the like. The Grignard reagent can be prepared 5 according to a method known per se, for example, by reacting an alkyl halide or an aryl halide with a metal magnesium in an ether or tetrahydrofuran as a solvent. When Knoevenagel condensation reaction is carried out in each step, a compound having an activated methylene group with 10 two electron withdrawing groups (e.g., malonic acid, diethyl malonate, malononitrile etc.) and a base (e.g., an organic base, a metal alkoxide, an inorganic base) are used as a reagent. When Vilsmeier-Haack reaction is carried out in each15 step, phosphoryl chloride and an amide derivative (e.g., N,N- dimethylformamide etc.) are used as a reagent. When azidation reaction of an alcohol, an alkyl halide or a sulfonate is carried out in each step, examples of the azidating agent to be used include diphenylphosphorylazide20(DPPA), trimethylsilylazide, sodium azide and the like. For example, for the azidation reaction of an alcohol, a method using diphenylphosphorylazide and 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), a method using trimethylsilylazide and a Lewis acid, and the like are25employed. When reductive amination reaction is carried out in each step, examples of the reducing agent to be used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid and the like. When the substrate is an amine 30 compound, examples of the carbonyl compound to be used include paraformaldehyde, aldehydes such as acetaldehyde and the like, and ketones such as cyclohexanone and the like. When the substrate is a carbonyl compound, examples of the amine to be used include ammonia, primary amines such as methylamine and 35 the like; and secondary amines such as dimethylamine and the

[0136] 72

[0137] like. When Mitsunobu reaction is carried out in each step, an azodicarboxylate (e.g., diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD) etc.) and 5 triphenylphosphine are used as a reagent. When esterification reaction, amidation reaction or urea formation reaction is carried out in each step, examples of the reagent to be used include acyl halides such as acid chlorides, acid bromides and the like; activated carboxylic 10 acids such as acid anhydrides, activated esters, sulfates and the like. Examples of the activating agent of the carboxylic acid include carbodiimide condensing agents such as 1-ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD) and the like; triazine condensing agents such as 4-(4,6-dimethoxy- 15 1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (DMT-MM) and the like; carbonate condensing agents such as 1,1-carbonyldiimidazole (CDI) and the like; diphenylphosphoryl azide (DPPA); benzotriazol-1-yloxy- trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-20methyl-pyridinium iodide (Mukaiyama reagent); thionyl chloride; lower alkyl haloformates such as ethyl chloroformate and the like; O-(7-azabenzotriazol-1-yl)-N,N,N’,N’- tetramethyluronium hexafluorophosphorate (HATU); sulfuric acid; combinations thereof and the like. When carbodiimide25condensing agent is used, an additive such as 1- hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP) and the like may be added to the reaction system. When coupling reaction is carried out in each step, 30 examples of the metal catalyst to be used include palladium compounds such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium(II), 35 tris(dibenzylideneacetone)dipalladium(0), 1,1’-

[0138] 73

[0139] bis(diphenylphosphino)ferrocene palladium(II) chloride and the like; nickel compounds such as tetrakis(triphenylphosphine)nickel(0) and the like; rhodium compounds such as tris(triphenylphosphine)rhodium(III) 5 chloride and the like; cobalt compounds; copper compounds such as copper oxide, copper(I) iodide and the like; platinum compounds and the like. In addition, a base can be added to the reaction system, and examples thereof include inorganic bases and the like. 10 When thiocarbonylation reaction is carried out in each step, phosphorus pentasulfide is typically used as the thiocarbonylating agent. Alternatively, a reagent having a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure (e.g., 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4- 15 disulfide (Lawesson reagent) etc.) can also be used instead of phosphorus pentasulfide. When Wohl-Ziegler reaction is carried out in each step, examples of the halogenating agent to be used include N- iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide20(NCS), bromine, sulfuryl chloride and the like. In addition, the reaction can be accelerated by subjecting a radical initiator such as heat, light, benzoyl peroxide, azobisisobutyronitrile and the like to the reaction system reaction.25When halogenation reaction of a hydroxy group is carried out in each step, examples of the halogenating agent to be used include hydrohalic acids and acid halides of inorganic acids, specifically, hydrochloric acid, thionyl chloride, phosphorus oxychloride and the like for chlorination, 48% 30 hydrobromic acid and the like for bromination. In addition, a method of producing an alkyl halide by reacting an alcohol with triphenylphosphine and carbon tetrachloride or carbon tetrabromide or the like can be employed. Alternatively, a method of producing an alkyl halide via two steps comprising 35 converting an alcohol to the corresponding sulfonate, and then

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[0141] reacting the sulfonate with lithium bromide, lithium chloride or sodium iodide can also be employed. When Arbuzov reaction is carried out in each step, examples of the reagent to be used include alkyl halides such 5 as ethyl bromoacetate and the like; and phosphites such as triethyl phosphite, tri(isopropyl) phosphite and the like. When sulfonate esterification reaction is carried out in each step, examples of the sulfonating agent to be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, 10 methanesulfonic anhydride, p-toluenesulfonic anhydride and the like. When hydrolysis reaction is carried out in each step, an acid or a base is used as a reagent. For acid hydrolysis reaction of tert-butyl ester, formic acid, triethylsilane and 15 the like may be added to reductively-trap tert-butyl cation which is by-produced. When dehydration reaction is carried out in each step, examples of the dehydrating agent to be used include sulfuric acid, diphosphorus pentaoxide, phosphorus oxychloride, N,N’-20dicyclohexylcarbodiimide, alumina, polyphosphoric acid and the like. Compound (4) used in the below-mentioned Scheme 3 can be produced from compound (1) according to the method shown in the following Scheme 1. As used herein, P1is a protecting25group, LG1is a leaving group, and the other symbols are as defined above. Examples of the “protecting group” for P1include those

[0142] 75

[0143] exemplified as the above-mentioned “protecting group for an amino group and an aromatic heterocycle such as imidazole, pyrrole, indole and the like”. Examples of the “leaving group” for LG1include halogen 5 atoms, optionally halogenated C1-6alkylsulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy), C6-14arylsulfonyloxy optionally substituted by C1-6alkyl (e.g., benzenesulfonyloxy, toluenesulfonyloxy) and the like. 10 Compound (1) may be commercially easily available or can be produced according to a method known per se. Compound (3) can be produced by subjecting compound (1) to a sulfonamidation reaction with compound (2). Examples of compound (2) to be used include sulfonyl chloride, sulfamoyl 15 chloride and the like. Compound (2) may be commercially easily available or can be produced according to a method known per se. Compound (7) used in the below-mentioned Scheme 3 can be produced from compound (5) according to the method shown in20the following Scheme 2. As used herein, P2is a protecting group, and the other symbols are as defined above. Examples of the “protecting group” for P2include those 25 exemplified as the above-mentioned “protecting group for a carboxyl group”. Compound (5) may be commercially easily available or can be produced according to a method known per se. Compound (6) can be produced by subjecting compound (5) 30 to a sulfonamidation reaction with compound (2). Examples of

[0144] 76

[0145] compound (2) to be used include sulfonyl chloride, sulfamoyl chloride and the like. Compound (2) may be commercially easily available or can be produced according to a method known per se. 5 Compound (I) can be produced from compound (4) or compound (7) according to the method shown in the following Scheme 3. As used herein, L1is a bond or an optionally substituted methylene group, Rfis a hydrogen atom or a substituent, and the other symbols are as defined above. to a condensation reaction with compound (8) or compound (9) or compound (10). The condensation reaction includes amidation reaction, urea formation reaction, carbamation reaction and 15 the like. Compound (8) and compound (9) and compound (10) may be commercially easily available or can be produced according to a method known per se. Compound (I) can also be produced by subjecting compound (7) to a condensation reaction with compound (8) or compound20(11). The condensation reaction includes amidation reaction, urea formation reaction, carbamation reaction and the like.

[0146] 77

[0147] Compound (8) and compound (11) may be commercially easily available or can be produced according to a method known per se. In the thus-obtained compound (I), an intramolecular 5 functional group can also be converted to an object functional group by a combination of chemical reactions known per se. Examples of the chemical reaction include oxidation reaction, reduction reaction, alkylation reaction, acylation reaction, ureation reaction, hydrolysis reaction, amination reaction, 10 esterification reaction, aryl coupling reaction, deprotection reaction and the like. In the above-mentioned production method, when a starting compound has an amino group, a carboxyl group, a hydroxy group, a carbonyl group or a mercapto group as a 15 substituent, a protecting group generally used in the peptide chemistry may be introduced into these groups, and the object compound can be obtained by removing the protecting group as necessary after the reaction. Compound (I) obtained by the above-mentioned production20method can be isolated and purified by a known means, such as solvent extraction, liquid conversion, phase transfer, crystallization, recrystallization, chromatography and the like. When compound (I) contains optical isomer, stereoisomer,25regio isomer and rotamer, these compounds are also included in compound (I), and each can be obtained as a single product by a synthesis method or a separation method known per se. For example, when an optical isomer exists in compound (I), an optical isomer resolved from the compound is also encompassed 30 in compound (I). Here, an optical isomer can be produced by a method known per se. Compound (I) may be a crystal. A crystal of compound (I) (hereinafter sometimes to be 35 abbreviated as the crystal of the present invention) can be

[0148] 78

[0149] produced by crystallizing compound (I), by applying a crystallization method known per se. In the thus-obtained compound (I), an intramolecular functional group can also be converted to an object functional 5 group by a combination of chemical reactions known per se. Examples of the chemical reaction include oxidation reaction, reduction reaction, alkylation reaction, acylation reaction, ureation reaction, hydrolysis reaction, amination reaction, esterification reaction, aryl coupling reaction, deprotection 10 reaction and the like. In the above-mentioned production method, when a starting compound has an amino group, a carboxyl group, a hydroxy group, a carbonyl group or a mercapto group as a substituent, a protecting group generally used in the peptide 15 chemistry may be introduced into these groups, and the object compound can be obtained by removing the protecting group as necessary after the reaction. Compound (I) obtained by the above-mentioned production method can be isolated and purified by a known means, such as20solvent extraction, liquid conversion, phase transfer, crystallization, recrystallization, chromatography and the like. When compound (I) contains optical isomer, stereoisomer, regio isomer and rotamer, these compounds are also included in25compound (I), and each can be obtained as a single product by a synthesis method or a separation method known per se. For example, when an optical isomer exists in compound (I), an optical isomer resolved from the compound is also encompassed in compound (I). 30 Here, an optical isomer can be produced by a method known per se. Compound (I) may be a crystal. A crystal of compound (I) (hereinafter sometimes to be abbreviated as the crystal of the present invention) can be 35 produced by crystallizing compound (I), by applying a

[0150] 79

[0151] crystallization method known per se. In the present specification, the melting point means a melting point measured, for example, by micro melting point apparatus (Yanako, MP-500D or Buchi, B-545), DSC (differential 5 scanning calorimetry analysis) apparatus (METTLER TOLEDO, DSC1) and the like. Generally, the melting point sometimes varies depending on the measurement device, measurement condition and the like. The crystal in the present specification may be a crystal 10 showing a melting point different from the values described in the present specification as long as the difference is within a general error range. The crystal of the present invention is superior in the physicochemical properties (e.g., melting point, solubility, 15 stability) and biological properties (e.g., pharmacokinetics (absorbability, distribution, metabolism, excretion), efficacy expression), and is extremely useful as a medicament. Compound (I) may be used as a prodrug. A prodrug of the compound (I) means a compound which is converted to the20compound (I) of the present invention with a reaction due to an enzyme, a gastric acid, etc. under the physiological condition in the living body, that is, a compound which is converted to the compound (I) of the present invention with oxidation, reduction, hydrolysis, etc. according to an enzyme;25a compound which is converted to the compound (I) of the present invention by hydrolysis etc. due to gastric acid, etc. A prodrug of compound (I) may be a compound obtained by subjecting an amino group in compound (I) to an acylation, alkylation or phosphorylation (e.g., a compound obtained by 30 subjecting an amino group in compound (I) to an eicosanoylation, alanylation, pentylaminocarbonylation, (5- methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation and tert-butylation, etc.); 35 a compound obtained by subjecting a hydroxy group in compound

[0152] 80

[0153] (I) to an acylation, alkylation, phosphorylation or boration (e.g., a compound obtained by subjecting a hydroxy group in compound (I) to an acetylation, palmitoylation, propanoylation, pivaloylation, succinylation, fumarylation, 5 alanylation, dimethylaminomethylcarbonylation, etc.); a compound obtained by subjecting a carboxyl group in compound (I) to an esterification or amidation (e.g., a compound obtained by subjecting a carboxyl group in compound (I) to an ethyl esterification, phenyl esterification, carboxymethyl 10 esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo- 1,3-dioxolen-4-yl)methyl esterification, cyclohexyloxycarbonylethyl esterification and methylamidation, 15 etc.) and the like. Any of these compounds can be produced from compound (I) by a method known per se. A prodrug for compound (I) may also be one which is converted into compound (I) under a physiological condition, such as those described in IYAKUHIN no KAIHATSU (Development20of Pharmaceuticals), Vol.7, Design of Molecules, p.163-198, Published by HIROKAWA SHOTEN (1990). In the present specification, a prodrug may form a salt, and as such salt, those exemplified as a salt of the compound represented by the above-mentioned formula (I) can be25mentioned. Compound (I) may be labeled with an isotope (e.g.,3H, 13C,14C,18F,35S,125I) and the like. Compound (I) labeled with or substituted by an isotope can be used, for example, as a tracer used for Positron 30 Emission Tomography (PET) (PET tracer), and is useful in the field of medical diagnosis and the like. Furthermore, compound (I) may be a hydrate or a non- hydrate, or a non-solvate (e.g., anhydride), or a solvate (e.g., hydrate). 35 Compound (I) also encompasses a deuterium conversion

[0154] 81

[0155] form wherein1H is converted to2H(D). Furthermore, compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt. The cocrystal or cocrystal salt means a crystalline substance constituted with 5 two or more special solids at room temperature, each having different physical properties (e.g., structure, melting point, melting heat, hygroscopicity, solubility and stability). The cocrystal or cocrystal salt can be produced by a cocrystallization method known per se. 10 Compound (I) or a prodrug thereof (hereinafter sometimes to be simply abbreviated as the compound of the present invention) can be used as it is or in the form of a pharmaceutical composition (also referred to as a medicament) by mixing with a pharmacologically acceptable carrier etc. to 15 mammals (e.g., human, mouse, rat, rabbit, dog, cat, bovine, horse, swine, monkey) as an agent for the prophylaxis or treatment of various diseases mentioned below. As pharmacologically acceptable carriers, various organic or inorganic carrier substances conventionally used as20preparation materials can be used. These are incorporated as excipient, lubricant, binder and disintegrant for solid preparations; or solvent, solubilizing agent, suspending agent, isotonicity agent, buffer and soothing agent for liquid preparations; and the like; and preparation additives such as25preservative, antioxidant, colorant, sweetening agent and the like can be added as necessary. Since the compound of the present invention shows low toxicity (e.g., acute toxicity, chronic toxicity, genetic 30 toxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) and less side effects, it can be used as a prophylactic or therapeutic agent, or diagnostic agent for various diseases in mammals (e.g., human, bovine, horse, dog, cat, monkey, mouse, rat). 35 The compound of the present invention has an excellent

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[0157] orexin type 2 receptor agonist activity, and can treat, prevent or ameliorate the risk of various neurological and psychiatric diseases associated with an orexin type 2 receptor. The compound of the present invention is useful as 5 an agent for the prophylaxis or treatment of various diseases, such as narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy- like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia (e.g., Kleine Levin syndrome, major depression 10 with hypersomnia, Lewy body dementia, Parkinson’s disease, progressive supranuclear paralysis, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, brain contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, acute 15 disseminated encephalomyelitis, Guillain-Barre syndrome, Rasmussen’s encephalitis, Wernicke’s encephalitis, limbic encephalitis, Hashimoto’s encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mastocytosis, exogenous obesity, hyperinsulinar obesity, hyperplasmic20obesity, hypophyseal adiposity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary obesity, hypogonadal obesity, systemic mastocytosis, simple obesity, central obesity), insulin resistance syndrome,25Alzheimer’s disease, disturbance of consciousness such as coma and the like, side effects and complications due to anesthesia, sleep disturbance, sleep problem, insomnia, Intermittent sleep, nocturnal myoclonus, REM sleep interruption, jet lag, jet lag syndrome, sleep disorder of 30 alternating worker, sleep disorder, night terror, depression, major depression, sleepwalking disease, enuresis, sleep disorder, Alzheimer’s dusk, diseases associated with circadian rhythm, fibromyalgia, condition arising from decline in the quality of sleep, overeating, obsessive compulsive eating 35 disorder, obesity-related disease, hypertension, diabetes,

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[0159] elevated plasma insulin concentration and insulin resistance, hyperlipidemia, hyperlipemia, endometrial cancer, breast cancer, prostate cancer, colorectal cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, 5 gallstones, cardiac disease, abnormal heartbeat, arrhythmia, myocardial infarction, congestive cardiac failure, cardiac failure, coronary heart disease, cardiovascular disorder, sudden death, polycysticovarian disease, craniopharingioma, Froelich’s syndrome, growth hormone deficient, normal mutant 10 short stature, Turner’s syndrome, children suffering from acute lymphoblastic leukemia, syndrome X, reproductive hormone abnormality, declining fertility, infertility, male gonadal function decline, sexual and reproductive dysfunction such as female male hirsutism, fetal defects associated with pregnant 15 women obesity, gastrointestinal motility disorders such as obesity-related gastroesophageal reflux, obesity hypoventilation syndrome (Pickwick syndrome), respiratory diseases such as dyspnea, inflammation such as systemic inflammation of the vascular system, arteriosclerosis,20hypercholesterolemia, hyperuricemia, lower back pain, gall bladder disease, gout, kidney cancer, risk of secondary outcomes of obesity such as lowering the risk of left ventricular hypertrophy, migraine pain, headache, neuropathic pain, Parkinson’s disease, psychosis, schizophrenia, facial25flushing, night sweats, diseases of the genital / urinary system, diseases related to sexual function or fertility, dysthymic disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive 30 disorder, panic attack, panic disorder, posttraumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorder, acute neurological and psychiatric disorders such as cardiac bypass surgery and post-transplant cerebral deficit, stroke, ischemic stroke, cerebral ischemia, spinal cord 35 trauma, head trauma, perinatal hypoxia, cardiac arrest,

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[0161] hypoglycemic nerve injury, Huntington’s disease, amyotrophic lateral sclerosis, multiple sclerosis, eye damage, retinopathy, cognitive impairment, muscle spasm, tremor, epilepsy, disorders associated with muscle spasticity, 5 delirium, amnestic disorder, age-related cognitive decline, schizoaffective disorder, delusional disorder, drug addiction, dyskinesia, chronic fatigue syndrome, fatigue, medication- induced Parkinsonism syndrome, Jill-do La Tourette’s syndrome, chorea, myoclonus, tic, restless legs syndrome, dystonia, 10 dyskinesia, attention deficit hyperactivity disorder (ADHD), behavior disorder, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, nerve damage, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, arthralgia, toothache, cataplexy, and 15 traumatic brain injury. Particularly, the compound of the present invention is useful as an agent for the prophylaxis or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like20symptoms, hypersomnia syndrome accompanied by daytime hypersomnia (e.g., Parkinson’s disease, Guillain-Barre syndrome and Kleine Levin syndrome), Alzheimer’s disease, obesity, insulin resistance syndrome, cardiac failure, diseases related to bone loss, sepsis, disturbance of25consciousness, such as coma and the like, side effects and complications due to anesthesia, and the like, or as an anesthetic antagonist. In some aspects, the compound of the present invention is useful as an agent for the prophylaxis or treatment of 30 narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia, Alzheimer’s disease, obesity, insulin resistance syndrome, cardiac failure, diseases related to bone loss, 35 sepsis, disturbance of consciousness, side effects and

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[0163] complications due to anesthesia. In some aspects, the compound of the present invention is useful as an agent for the prophylaxis or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, or sleep 5 apnea syndrome. In some aspects, the compound of the present invention is useful as an agent for the prophylaxis or treatment of narcolepsy. Central disorders of hypersomnolence (CDH) are 10 characterized by excessive daytime sleepiness in the absence of other sleep disorders but with the setting of adequate and regular sleep habits. Central disorders of hypersomnolence (CDH) include narcolepsy type 1, narcolepsy type 2 and idiopathic hypersomnia. Kleine-Levin syndrome as well as insufficient sleep 15 syndrome and hypersomnia caused by a medical condition, medication or substance, or psychiatric condition are also considered central orders of hypersomnolence. Evaluation of central disorders of hypersomnolence (CDH) includes sleep testing in the sleep lab (polysomnography, PSG) followed by a20multiple sleep latency test (MSLT). Symptoms that are associated with narcolepsy involve abnormal intrusions of REM sleep features into wake: for example, sleep-related hallucinations, sleep paralysis, or vivid dreams and dream-reality confusion. These symptoms can also25occur in people without a sleep disorder. Some patients with narcolepsy also experience cataplexy (narcolepsy, type 1) which is loss of muscle tone triggered by emotion, typically laughter or anticipation. Cataplexy can be generalized or partial and isn’t associated with any loss of 30 consciousness. This muscle weakness typically improves within seconds to minutes. Patients with idiopathic hypersomnia (IDH) often describe excessive daytime sleepiness, prolonged sleep duration (more than 10-11 hours of sleep nightly), and severe difficulty waking 35 up in the morning (sleep inertia). In contrast to narcolepsy,

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[0165] patients with IDH often describe long, unrefreshing daytime naps. Another common symptom of IDH is “brain fog,” a feeling of cognitive clouding during the day. Klein-Levin syndrome is a rare disorder of cyclic hypersomnia. 5 An aspect of the disclosure is a method for treating a subject having one or more central disorders of hypersomnolence (CDH), the method comprising administering to the subject a compound of the present invention. Another aspect of the disclosure is the use of a compound 10 of the present invention for the manufacture of an agent for treating one or more central disorders of hypersomnolence (CDH) in a subject. Another aspect of the disclosure is a compound of the present invention for use in treating one or more central 15 disorders of hypersomnolence (CDH) in a subject. Another aspect is a method or use of the previous aspects, wherein the subject is narcoleptic. In one aspect, the subject has been diagnosed with narcolepsy type 1. In another aspect, the subject has been diagnosed with narcolepsy type 2. In still20another aspect, the subject has been diagnosed with idiopathic hypersomnia. Another aspect is a method or use of the previous aspects, wherein administering the compound of the invention reduces daytime sleepiness, reduces instances of loss of muscle control,25and / or reduces instances of interrupted sleep in the subject. Another aspect is a method or use wherein a compound of the present invention is administered in an amount effective to reduce excessive daytime sleepiness in adults with narcolepsy. Another aspect is a method or use wherein a compound of the 30 present invention is administered in an amount effective to increase in mean sleep latency. Another aspect is a method or use wherein a compound of the present invention is administered in an amount effective to reduce cataplexy events. 35 Another aspect is a method or use wherein a compound of

[0166] 87

[0167] the present invention is administered in an amount effective to decrease disrupted nocturnal sleep in the subject. While the dose of the compound of the present invention varies depending on the subject of administration, 5 administration route, target disease, symptom, and the like, for example, when the compound of the present invention is administered orally or parenterally to an adult patient, its dose is for example, about 0.01 to 100 mg / kg body weight per dose, preferably 0.1 to 50 mg / kg body weight per dose and more 10 preferably 0.5 to 20 mg / kg body weight per dose. This amount is desirably administered in one to 3 portions daily. The compound of the present invention can be used in combination with other drugs (hereinafter to be abbreviated as a concomitant drug). 15 By combining the compound of the present invention and a concomitant drug, a superior effect can be achieved, for example, (1) the dose can be reduced as compared to single administration of the compound of the present invention or a20concomitant drug, (2) the drug to be combined with the compound of the present invention can be selected according to the condition of patients (mild case, severe case, and the like), (3) the period of treatment can be set longer by selecting a25concomitant drug having a different action and mechanism from the compound of the present invention, (4) a sustained treatment effect can be designed by selecting a concomitant drug having a different action and mechanism from the compound of the present invention, 30 (5) a synergistic effect can be afforded by a combined use of the compound of the present invention and a concomitant drug, and the like. In the present specification, the compound of the present invention and a concomitant drug used in combination 35 are referred to as the “combination agent of the present

[0168] 88

[0169] invention.” When using the combination agent of the present invention, the administration time of the compound of the present invention and the concomitant drug is not restricted, 5 and the compound of the present invention or a pharmaceutical composition thereof, or the concomitant drug or a pharmaceutical composition thereof can be administered to an administration subject simultaneously, or can be administered at different times. The dosage of the concomitant drug can be 10 determined according to the dose clinically used, and can be appropriately selected depending on an administration subject, administration route, disease, combination and the like. The administration mode of the combination agent of the present invention and the concomitant drug is not particularly 15 limited, and the compound of the present invention and the concomitant drug only need to be combined on administration. Examples of such administration mode include the following: (1) administration of a single preparation obtained by simultaneously processing the compound of the present20invention and the concomitant drug, (2) simultaneous administration of two kinds of preparations of the compound of the present invention and the concomitant drug, which have been separately produced, by the same administration route,25(3) administration of two kinds of preparations of the compound of the present invention and the concomitant drug, which have been separately produced, by the same administration route in a staggered manner, (4) simultaneous administration of two kinds of preparations 30 of the compound of the present invention and the concomitant drug, which have been separately produced, by different administration routes, (5) administration of two kinds of preparations of the compound of the present invention and the concomitant drug, 35 which have been separately produced, by different

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[0171] administration routes in a staggered manner (e.g., administration in the order of the compound of the present invention and the concomitant drug, or in the reverse order) and the like. 5 The dose of the concomitant drug can be appropriately determined based on the dose employed in clinical situations. The mixing ratio of the compound of the present invention and a concomitant drug can be appropriately determined depending on the administration subject, administration route, target 10 disease, symptom, combination and the like. For example, the content of the compound of the present invention in the combination agent of the present invention differs depending on the form of a preparation, and typically is from about 0.01 to about 100 wt%, preferably from about 0.1 15 to about 50 wt%, further preferably from about 0.5 to about 20 wt%, based on the whole preparation. The content of the concomitant drug in the combination agent of the present invention differs depending on the form of a preparation, and typically is from about 0.01 to about20100 wt%, preferably from about 0.1 to about 50 wt%, further preferably from about 0.5 to about 20 wt%, based on the whole preparation. The content of additives, such as a carrier and the like, in the combination agent of the present invention25differs depending on the form of a preparation, and typically is from about 1 to about 99.99 wt%, preferably from about 10 to about 90 wt%, based on the preparation. Similar contents can be used even when the compound of the present invention and a concomitant drug are separately 30 formulated into preparations. Examples of the concomitant drug include the following: a therapeutic drug for narcolepsy (e.g., methylphenidate, amphetamine, pemoline, phenelzine, protriptyline, sodium oxybate, modafinil, caffeine), antiobesity drug (amphetamine, 35 benzfetamine, bromocriptine, bupropion, diethylpropion,

[0172] 90

[0173] exenatide, fenfluramine, liothyronine, liraglutide, mazindol, methamphetamine, octreotide, octreotide, orlistat, phendimetrazine, phendimetrazine, phenmetrazine, phentermine, Qnexa (registered trade mark), phenylpropanolamine, 5 pramlintide, propylhexedrine, recombinant leptin, sibutramine, topiramate, zimelidine, zonisamide, Lorcaserin, metformin), acetylcholine esterase inhibitor (e.g., donepezil, rivastigmine, galanthamine, zanapezil, idebenone, tacrine), antidementia agent (e.g., memantine), inhibitor of ^ amyloid 10 protein production, secretion, accumulation, aggregation and / or deposition, ^ secretase inhibitor (e.g., 6-(4- biphenylyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6- (4-biphenylyl)methoxy-2-(N,N-dimethylamino)methyltetralin, 6- (4-biphenylyl)methoxy-2-(N,N-dipropylamino)methyltetralin, 2-15 (N,N-dimethylamino)methyl-6-(4’-methoxybiphenyl-4- yl)methoxytetralin, 6-(4-biphenylyl)methoxy-2-[2-(N,N- diethylamino)ethyl]tetralin, 2-[2-(N,N-dimethylamino)ethyl]-6- (4’-methylbiphenyl-4-yl)methoxytetralin, 2-[2-(N,N- dimethylamino)ethyl]-6-(4’-methoxybiphenyl-4-20yl)methoxytetralin, 6-(2’,4’-dimethoxybiphenyl-4-yl)methoxy-2- [2-(N,N-dimethylamino)ethyl]tetralin, 6-[4-(1,3-benzodioxol-5- yl)phenyl]methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6- (3’,4’-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N- dimethylamino)ethyl]tetralin, an optically active form25thereof, a salt thereof and a hydrate thereof, OM99-2 (WO01 / 00663)), γ secretase inhibitor, ^ amyloid protein aggregation inhibitor (e.g., PTI-00703, ALZHEMED (NC-531), PPI-368 (National Publication of International Patent Application No. 11-514333), PPI-558 (National Publication of 30 International Patent Application No. 2001-500852), SKF-74652 (Biochem. J. (1999), 340(1), 283-289)), ^ amyloid vaccine, ^ amyloid-degrading enzyme and the like, brain function enhancer (e.g., aniracetam, nicergoline), therapeutic drug for Parkinson’s disease [(e.g., dopamine receptor agonist (e.g., 35 L-DOPA, bromocriptine, pergolide, talipexole, pramipexole,

[0174] 91

[0175] cabergoline, amantadine), monoamine oxidase enzyme (MAO) inhibitor (e.g., deprenyl, selegiline, remacemide, riluzole), anticholinergic agent (e.g., trihexyphenidyl, biperiden), COMT inhibitor (e.g., entacapone)], therapeutic drug for 5 amyotrophic lateral sclerosis (e.g., riluzole etc., neurotrophic factor), therapeutic drug for abnormal behavior accompanying progress of dementia, wandering and the like (e.g., sedative, anti-anxiety drug), apoptosis inhibitor (e.g., CPI-1189, IDN-6556, CEP-1347), neuronal 10 differentiation-regenerate promoter (e.g., leteprinim, xaliproden; SR-57746-A), SB-216763, Y-128, VX-853, prosaptide, 5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3- dihydro-1-benzofuran-5-yl]isoindoline, 5,6-dimethoxy-2-[3-(4- isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-15 benzofuran-5-yl]isoindoline, 6-[3-(4-isopropylphenyl)- 2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-6,7- dihydro-5H-[1,3]dioxolo[4,5-f]isoindole and an optically active form, salt or hydrate thereof), non-steroidal antiinflammatory agents (meloxicam, tenoxicam, indomethacin,20ibuprofen, celecoxib, rofecoxib, aspirin etc.), steroid drug (dexamethasone, hexestrol, cortisone acetate etc.), disease- modifying anti-rheumatic drug (DMARDs), anti-cytokine drug (e.g., TNF inhibitor, MAP kinase inhibitor), therapeutic agent for incontinence, frequent urination (e.g., flavoxate25hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride), phosphodiesterase inhibitor (e.g., sildenafil(citrate)), dopamine agonist (e.g., apomorphine), antiarrhythmic drugs (e.g., mexiletine), sex hormone or a derivative thereof (e.g., progesterone, estradiol, estradiol 30 benzoate), therapeutic agent for osteoporosis (e.g., alfacalcidol, calcitriol, elcatonin, calcitonin salmon, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium), parathyroid hormone (PTH), calcium receptor antagonists, therapeutic drug for insomnia 35 (e.g., benzodiazepines medicament, non-benzodiazepines

[0176] 92

[0177] medicament, melatonin agonist, orexin receptor antagonists), therapeutic drug for schizophrenia (e.g., typical antipsychotic agents such as haloperidol and the like; atypical antipsychotic agents such as clozapine, olanzapine, 5 risperidone, aripiprazole and the like; medicament acting on metabotropic glutamate receptor or ion channel conjugated-type glutamate receptor; phosphodiesterase inhibitor), benzodiazepines medicament (chlordiazepoxide, diazepam, potassium clorazepate, lorazepam, clonazepam, alprazolam 10 etc.), L-type calcium channel inhibitor (pregabalin etc.), tricyclic or tetracyclic antidepressant (imipramine hydrochloride, amitriptyline hydrochloride, desipramine hydrochloride, clomipramine hydrochloride etc.), selective serotonin reuptake inhibitor (fluvoxamine maleate, fluoxetine 15 hydrochloride, citalopram hydrobromide, sertraline hydrochloride, paroxetine hydrochloride, escitalopram oxalate etc.), serotonin-noradrenaline reuptake inhibitor (venlafaxine hydrochloride, duloxetine hydrochloride, desvenlafaxine hydrochloride etc.), noradrenaline reuptake inhibitor20(reboxetine mesylate etc.), mirtazapine, trazodone hydrochloride, nefazodone hydrochloride, bupropion hydrochloride, setiptiline maleate, 5-HT1Aagonist, (buspirone hydrochloride, tandospirone citrate, osemozotan hydrochloride etc.), 5-HT2Aantagonist, 5-HT2Ainverse agonist, 5-HT325antagonist (cyamemazine etc.), heart non-selective ^ inhibitor (propranolol hydrochloride, oxprenolol hydrochloride etc.), histamine H1antagonist (hydroxyzine hydrochloride etc.), CRF antagonist, other antianxiety drug (meprobamate etc.), tachykinin antagonist (MK-869, saredutant etc.), medicament 30 that acts on metabotropic glutamate receptor, CCK antagonist, ^3 adrenaline antagonist (amibegron hydrochloride etc.), GAT-1 inhibitor (tiagabine hydrochloride etc.), N-type calcium channel inhibitor, carbonic anhydrase II inhibitor, NMDA glycine moiety agonist, NMDA antagonist (memantine etc.), 35 peripheral benzodiazepine receptor agonist, vasopressin

[0178] 93

[0179] antagonist, vasopressin V1b antagonist, vasopressin V1a antagonist, phosphodiesterase inhibitor, opioid antagonist, opioid agonist, uridine, nicotinic acid receptor agonist, thyroid hormone (T3, T4), TSH, TRH, MAO inhibitor (phenelzine 5 sulfate, tranylcypromine sulfate, moclobemide etc.), therapeutic drug for bipolar disorder (lithium carbonate, sodium valproate, lamotrigine, riluzole, felbamate etc.), cannabinoid CB1 antagonist (rimonabant etc.), FAAH inhibitor, sodium channel inhibitor, anti-ADHD drug (methylphenidate 10 hydrochloride, methamphetamine hydrochloride etc.), therapeutic drug for alcoholism, therapeutic drug for autism, therapeutic drug for chronic fatigue syndrome, therapeutic drug for spasm, therapeutic drug for fibromyalgia syndrome, therapeutic drug for headache, therapeutic drug for quitting 15 smoking, therapeutic drug for myasthenia gravis, therapeutic drug for cerebral infarction, therapeutic drug for mania, therapeutic drug for hypersomnia, therapeutic drug for pain, therapeutic drug for dysthymia, therapeutic drug for autonomic ataxia, therapeutic drug for male and female sexual20dysfunction, therapeutic drug for migraine, therapeutic drug for pathological gambler, therapeutic drug for restless legs syndrome, therapeutic drug for substance addiction, therapeutic drug for alcohol-related syndrome, therapeutic drug for irritable bowel syndrome, therapeutic drug for lipid25abnormality such as cholesterol-lowering drug (statin series (pravastatin sodium, atorvastatin, simvastatin, rosuvastatin etc.), fibrate (clofibrate etc.), squalene synthetase inhibitor), therapeutic drug for abnormal behavior or suppressant of dromomania due to dementia (sedatives, 30 antianxiety drug etc.), therapeutic drug for diabetes, therapeutic agent for diabetic complications, therapeutic drug for hypertension, therapeutic drug for hypotension, diuretic, chemotherapeutic agent, immunotherapeutic agent, antithrombotic agent, anti-cancer agent and the like. 35 Two or more kinds of the above-mentioned concomitant

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[0181] drug can be used in a mixture at an appropriate ratio. When the compound of the present invention is used for treatment of the above-mentioned diseases, it can also be used in combination with biologics (e.g., antibody drug, nucleic 5 acid or nucleic acid derivative, aptamer drug, vaccine preparation), or can be used in combination with a gene therapy method and the like, or can also be used in combination with a treatment in psychiatric field without using drugs. 10 Examples of the antibody drug and vaccine preparation include vaccine preparation against angiotensin II, vaccine preparation against CETP, CETP antibody, antibody against TNFα antibody and other cytokines, amyloid ^ vaccine preparation, vaccine for type 1 diabetes (e.g., DIAPEP-277 of Peptor), 15 anti-HIV antibody and HIV vaccine preparation, as well as antibodies or vaccine preparations against cytokines, renin- angiotensin type enzymes and products thereof, antibodies or vaccine preparations against enzymes or proteins involved in blood lipid metabolism, antibodies or vaccines relating to20enzymes and proteins involved in blood coagulation or fibrinolysis system, antibodies or vaccine preparations against proteins involved in sugar metabolism and insulin resistance, and the like. In addition, it can be used in combination with biologics relating to growth factors such as25GH, IGF and the like. Examples of the gene therapy method include a treatment method using gene relating to cytokine, renin-angiotensin type enzyme and product thereof, G protein, G protein conjugated receptor and phosphorylating enzyme thereof, a treatment 30 method using a DNA decoy such as NFκB decoy and the like, a treatment method using antisense, a treatment method using a gene relating to an enzyme or protein involved in blood lipid metabolism (e.g., a gene relating to metabolism, excretion and absorption of cholesterol or triglyceride or HDL-cholesterol 35 or blood phospholipid), a treatment method using a gene

[0182] 95

[0183] relating to an enzyme or protein involved in angiogenesis therapy for peripheral vascular obstruction and the like (e.g., growth factors such as HGF, VEGF etc.), a treatment method using a gene relating to a protein involved in glucose 5 metabolism and insulin resistance, antisense against cytokines such as TNF etc., and the like. Examples of the treatment method in the psychiatric field without using drug include modified electroconvulsive therapy, deep brain stimulation therapy, repetitive 10 transcranial magnetic stimulation therapy, psychotherapy including cognitive behavioral therapy, and the like. The compound of the present invention can also be used in combination with various organ regeneration methods, such as cardiac regeneration, renal regeneration, pancreatic 15 regeneration, revascularization and the like, cell transplantation therapy utilizing bone marrow cells (bone marrow-derived mononuclear cell, myelogenic stem cell), or artificial organ utilizing tissue engineering (e.g., artificial blood vessel, cardiomyocyte sheet).20[Examples] The present invention is explained in detail in the following by referring to Examples, Experimental Examples and Formulation Examples. However, the examples do not limit the25present invention and the examples can be modified within the scope of the present invention. The “room temperature” in the following Examples is generally about 10^C to about 35^C. The ratio for mixed solvent is, unless otherwise specified, a volume mixing ratio 30 and % means wt% unless otherwise specified. The elution by column chromatography in the Examples was performed under the observation by TLC (Thin Layer Chromatography) unless otherwise specified. In the observation by TLC, 60 F254manufactured by Merck was used as a TLC plate, 35 the solvent used as an elution solvent in column

[0184] 96

[0185] chromatography was used as an eluent, and UV detector was used for the detection. In silica gel column chromatography, the indication of NH means use of aminopropylsilane-bonded silica gel and the indication of DIOL means use of 3-(2,3- 5 dihydroxypropoxy)propylsilane-bonded silica gel. Preparative HPLC (high performance liquid chromatography) was performed under the following conditions; column: Boston Prime C18 (150 mm x 30 mm, 5 μm), Xtimate C18 (100 mm x 30 mm, 3 μm), Gemini NX C18 (150 mm x 30 mm, 5 μm), YMC Triart C18 (250 mm x 50 mm, 10 7 μm), Exsil plus C18 (150 mm x 50 mm, 5 μm), or Water Xbridge C18 (150 mm x 30 mm, 5 μm), mobile phase:aqueous ammonia / MeCN, water containing ammonia hydroxide / MeCN, water containing ammonium acetate / MeCN, water containing ammonium hydrogencarbonate / MeCN, or water containing formic acid / MeCN. 15 The indication of C18 means use of octadecyl-bonded silica gel. The ratio for elution solvent is, unless otherwise specified, a volume mixing ratio. For the analysis of1H NMR, ACD / SpecManager (trade name) software and the like were used. Peaks of a hydroxyl group, an20amino group and the like, having very mild proton peak, are not sometimes described. MS was measured by LC / MS. As the ionization method, ESI method, or APCI method was used. The data indicates actual measured value (found). While molecular ion peak is generally25observed, a fragment ion is sometimes observed. In the case of a salt, a molecular ion peak or fragment ion peak of free form is generally observed. In the following Examples, the following abbreviations are used. 30 MS: mass spectrum M: mol concentration N: normality CDCl3: deuterochloroform DMSO-d6: deuterodimethyl sulfoxide 351H NMR: proton nuclear magnetic resonance

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[0187] LC / MS: liquid chromatograph mass spectrometer ESI: electrospray ionization APCI: atmospheric pressure chemical ionization IPE: diisopropyl ether 5 NBS: N-bromosuccinimide DMF: N,N-dimethylformamide THF: tetrahydrofuran EtOAc: ethyl acetate DCM: dichloromethane 10 MeOH: methanol EtOH: ethanol MeCN: acetonitrile CPME: cyclopentyl methyl ether DME: 1,2-dimethoxyethane 15 XPhosPdG3: (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate TEA: triethylamine DPPA: diphenylphosphoryl azide20DMAP: 4-dimethylaminopyridine Pd2(dba)3: tris(dibenzylideneacetone)dipalladium(0) Example 8 N-[(4S)-1-{[7-(2,6-Difluorophenyl)-1H-indazol-1-25yl]acetyl}azepan-4-yl]methanesulfonamide A) tert-Butyl (4S)-4-(methanesulfonamido)azepane-1- carboxylate 30 To a mixture of tert-butyl (4S)-4-aminoazepane-1- carboxylate (150 mg) and TEA (142 mg) in DCM (3.0 mL) was added methanesulfonyl chloride (96 mg) at 0 °C. The mixture was stirred at 25 °C for 1 h under nitrogen atmosphere. The reaction mixture was diluted with water, and the resulting 35 mixture was extracted with DCM. The combined organic layer was

[0188] 98

[0189] washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (195 mg). 1H NMR (400 MHz, DMSO-d6) δ 1.40 (9H, s), 1.43-1.97 (6H, 5 m), 2.89 (3H, s), 3.01-3.32 (5H, m), 7.01-7.10 (1H, m). B) N-[(4S)-Azepan-4-yl]methanesulfonamide hydrochloride 4 M hydrogen chloride / CPME solution (23.1 mL) was added10 to a solution of tert-butyl (4S)-4- (methanesulfonamido)azepane-1-carboxylate (2.7 g) at 0 °C. The mixture was stirred at room temperature under a dry atmosphere for 5 h. The reaction was concentrated and the remaining gum was redissolved in hot methanol (40 mL). This solution was 15 added dropwise to 400 mL of diethyl ether at 0 °C while stirring. The precipitate was collected by filtration, washed with diethyl ether and dried under air flow to give the title compound(1.8 g). 1H NMR (300 MHz, DMSO-d6) δ 1.50-1.76 (2H, m), 1.76-1.9120(2H, m), 1.91-2.01 (1H, m), 2.01-2.15 (1H, m), 2.92 (3H, s), 2.96-3.21 (4H, m), 3.40-3.56 (1H, m), 7.21 (1H, d, J = 7.2 Hz), 8.83-9.20 (2H, m). C) Ethyl (7-bromo-1H-indazol-1-yl)acetate25Potassium carbonate (5.26 g) was added to a mixture of 7-bromo-1H-indazole (2.5 g) and ethyl 2-bromoacetate (2.39 mL) in DMF (25 mL) and the reaction was heated at 50 °C overnight. The mixture was diluted with water and extracted with EtOAc. 30 The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (0.712 g). 35 MS: [M+H]+ 282.8.

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[0191] D) Ethyl [7-(2,6-difluorophenyl)-1H-indazol-1-yl]acetate A mixture of ethyl (7-bromo-1H-indazol-1-yl)acetate (881 5 mg), (2,6-difluorophenyl)boronic acid (983 mg), XPhosPdG3 (527 mg), 1 M potassium phosphate aqueous solution (4.7 mL) in DME (15 mL) was stirred at 100 °C for 1 h. To the mixture was added (2,6-difluorophenyl)boronic acid (737 mg), and the mixture was stirred at 100 °C for 2 h. The residue was 10 purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (185 mg). MS: [M+H]+ 317.0. E) [7-(2,6-Difluorophenyl)-1H-indazol-1-yl]acetic acid 15 2 M sodium hydroxide aqueous solution (1.6 mL) was added to a mixture of ethyl [7-(2,6-difluorophenyl)-1H-indazol-1- yl]acetate (200 mg),EtOH (1.5 mL) and THF (1.5 mL) at room temperature. The reaction was stirred for 2 h, then 1 M hydrogen20chloride aqueous solution was added to pH=2-3. The precipitate obtained was filtered off and the remaining solution was extracted with EtOAc. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. This residue and the precipitate were combined25to give the title compound (175 mg). MS: [M+H]+288.9. F) N-[(4S)-1-{[7-(2,6-Difluorophenyl)-1H-indazol-1- yl]acetyl}azepan-4-yl]methanesulfonamide 30 To a mixture of [7-(2,6-difluorophenyl)-1H-indazol-1- yl]acetic acid (22 mg) and N-[(4S)-azepan-4- yl]methanesulfonamide hydrochloride (19.2 mg) in dry DMF (0.7 mL) were subsequentially added TEA (0.032 mL) and 1-

[0192] 100

[0193] [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate (43.5 mg) at room temperature. The reaction was stirred for 1 h, then poured into water and extracted with EtOAc. The combined organic layer was 5 dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: YMC-Actus Triant C18, mobile phase: water (containing 10 mM ammonium hydrogencarbonate) / MeCN) to give the title compound (25.5 mg). 101H NMR (300 MHz, DMSO-d6) δ 1.24-1.82 (6H, m), 2.81-3.06 (6H, m), 3.08-3.28 (2H, m), 4.78-5.09 (2H, m), 7.05 (1H, d, J = 7.3 Hz), 7.20-7.33 (4H, m), 7.52-7.66 (1H, m), 7.85-7.95 (1H, m), 8.18 (1H, s). 15 Example 9 N-{(4S)-1-[7-(2,6-Difluorophenyl)-2,3-dihydro-1H-indole-1- carbonyl]azepan-4-yl}methanesulfonamide A) 7-Bromo-2,3-dihydro-1H-indole20Sodium cyanotrihydroborate (2.03 g) was added to a solution of 7-bromo-1H-indole (3.0 g) in acetic acid (30 mL) at 10 °C. The reaction was stirred at room temperature overnight and then water was added slowly. The mixture was25basified with a saturated sodium hydrogencarbonate aqueous solution. The resulting mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. To the residue was added IPE and the solid was removed by filtration. The 30 solution was concentrated under reduced pressure to give the title compound (2.39 g). MS: [M+H]+198.1. B) 7-(2,6-Difluorophenyl)-2,3-dihydro-1H-indole 35

[0194] 101

[0195] To a mixture of 7-bromo-2,3-dihydro-1H-indole (500 mg), (2,6-difluorophenyl)boronic acid (797 mg) and 1 M potassium phosphate aqueous solution (7.6 mL) in DME (5.0 mL) was added XPhosPdG3(321 mg) at room temperature. The mixture was stirred 5 at 80 °C under nitrogen atmosphere for 1 h. The aqueous layer was removed and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (300 mg). 10 MS: [M+H]+232.1. C) N-{(4S)-1-[7-(2,6-Difluorophenyl)-2,3-dihydro-1H-indole-1- carbonyl]azepan-4-yl}methanesulfonamide 15 To a solution of 7-(2,6-difluorophenyl)-2,3-dihydro-1H- indole (25.3 mg) and TEA (0.055 mL) in THF (2.0 mL) was added Bis(trichloromethyl)carbonate (19.5 mg) at 0 °C and the reaction mixture was stirred for 30 min at the same temperature. Then to the mixture was added a solution of N-20[(4S)-azepan-4-yl]methanesulfonamide hydrochloride (20 mg) and TEA (0.046 mL) in THF (1.0 mL) at 0 °C and the reaction mixture was warmed to room temperature. After being stirred for 2 h at room temperature, The mixture was concentrated under reduced pressure. The residue was purified by25preparative HPLC (column: L-Column 2 ODS, mobile phase: water (containing 5 mM ammonium acetate) / MeCN) to give the title compound (28.8 mg). 1H NMR (300 MHz, DMSO-d6) δ 0.85-1.90 (6H, m), 2.90 (3H, s), 3.03-3.39 (7H, m), 3.69-3.95 (2H, m), 6.95-7.17 (5H, m), 30 7.23-7.41 (2H, m). Example 14 (4S)-N-[(1RS)-7-(2,6-Difluorophenyl)-2,3-dihydro-1H-inden-1- yl]-4-(methanesulfonamido)azepane-1-carboxamide 35

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[0197] A) tert-Butyl 4-(methanesulfonamido)azepane-1-carboxylate To a tert-butyl 4-aminoazepane-1-carboxylate (20.0 g) in DCM (180 mL) were added TEA (18.9 g) and methanesulfonyl 5 chloride (13.9 g) at 0 °C. The mixture was stirred at 20 °C for 16 h. The mixture was diluted with water and it was extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (28.5 g). 101H NMR (400 MHz, CDCl3) δ 1.45 (9H, s), 1.65-2.15 (5H, m), 2.95 (3H, s), 3.06-3.67 (6H, m), 4.64 (1H, d, J = 7.6 Hz). B) N-(Azepan-4-yl)methanesulfonamide hydrochloride 15 A mixture of tert-butyl 4-(methanesulfonamido)azepane-1- carboxylate (28.5 g) and 4 M hydrogen chloride / CPME solution (100 mL) was stirred at 20 °C for 1 h. The mixture was concentrated under reduced pressure to give the title compound (23.5 g).20 1H NMR (400 MHz, DMSO-d6) δ 1.53-2.14 (3H, m), 2.90-3.21 (3H, m), 3.35-3.52 (6H, m), 3.56 (3H, s), 7.23 (1H, d, J = 6.8 Hz), 9.16 (1H, brs). C) Benzyl (4S)-4-(methanesulfonamido)azepane-1-carboxylate25To a mixture of N-(azepan-4-yl)methanesulfonamide hydrochloride (8.00 g) in DCM (100 mL) were added TEA (7.08 g) and benzyl carbonochloridate (7.16 g) dropwise at 0 °C, and it was stirred at 20 °C for 14 h. The mixture was concentrated 30 under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) and the racemate residue was resolved by SFC (column: DAICEL CHIRALPAK IC, 250mm x 50 mm, 10 μm, mobile phase: CO2 / 0.1% ammonium hydroxide containing EtOH = 60 / 40 v / v ) to 35 give the title compound having longer retention time (4.66 g).

[0198] 103

[0199] MS: [M+H]+327.0. D) N-[(4S)-Azepan-4-yl]methanesulfonamide hydrobromide 5 To a mixture of benzyl (4S)-4- (methanesulfonamido)azepane-1-carboxylate (4.63 g) in acetic acid (40 mL) was added 40% hydrogen bromide aqueous solution (41.0 g) and it was stirred at 20 °C for 14 h. The mixture was 10 concentrated under reduced pressure to give the title compound (3.54 g). 1H NMR (400 MHz, CD3OD) δ 1.69-1.91 (2H, m), 1.93-2.06 (2H, m), 2.10-2.30 (2H, m), 2.98 (3H, s), 3.15-3.30 (3H, m), 3.32-3.40 (1H, m), 3.59-3.68 (1H, m). 15 E) 7-Bromo-2,3-dihydro-1H-inden-1-ol To a solution of 7-bromo-2,3-dihydro-1H-inden-1-one (1.00 g) in MeOH (10 mL) was added sodium borohydride (269 mg)20at 0 °C. The mixture was stirred at 25 °C for 16 h under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. Then the residue was diluted with water and then it was extracted with EtOAc. The combined organic layer was washed with brine, dried over25anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (979 mg). 1H NMR (400 MHz, CDCl3) δ 2.08-2.17 (1H, m), 2.35-2.37 (1H, m), 2.37-2.47 (1H, m), 2.84-2.94 (1H, m), 3.18-3.28 (1H, m), 5.32-5.38 (1H, m), 7.13 (1H, t, J = 8.0 Hz), 7.20 (1H, d, 30 J = 7.2 Hz), 7.35 (1H, d, J = 8.0 Hz). F) 7-Bromo-1-chloro-2,3-dihydro-1H-indene To a solution of 7-bromo-2,3-dihydro-1H-inden-1-ol (500 35 mg) in DCM (10 mL) was added thionyl chloride (558 mg). The

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[0201] mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with water and then it was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under 5 reduced pressure to give the title compound (482 mg). 1H NMR (400 MHz, CDCl3) δ 2.41-2.58 (2H, m), 2.93-3.04 (1H, m), 3.31-3.42 (1H, m), 5.47 (1H, d, J = 6.0 Hz), 7.14 (1H, t, J = 8.0 Hz), 7.22 (1H, d, J = 7.6 Hz), 7.38-7.44 (1H, m). 10 G) 7-Bromo-2,3-dihydro-1H-indene-1-carbonitrile To a solution of 7-bromo-1-chloro-2,3-dihydro-1H-indene (382 mg) in dimethylsulfoxyde (5 mL) was added sodium cyanide 15 (162 mg). The mixture was stirred at 25 °C for 16 h under nitrogen atmosphere. The reaction mixture was diluted with water and then it was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced20pressure to give a residue. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound EtOAc(140 mg). 1H NMR (400 MHz, CDCl3) δ 2.43-2.57 (2H, m), 3.03-3.14 (1H, m), 3.25-3.35 (1H, m), 4.14-4.19 (1H, m), 7.16 (1H, t, J25= 7.6 Hz), 7.22 (1H, d, J = 7.6 Hz), 7.40 (1H, d, J = 7.6 Hz). H) 7-(2,6-Difluorophenyl)-2,3-dihydro-1H-indene-1- carbonitrile 30 To a solution of 7-bromo-2,3-dihydro-1H-indene-1- carbonitrile (90.0 mg), XPhosPdG3(34.3 mg), 1 M potassium phosphate aqueous solution (258 mg) in DME (5 mL) was added (2,6-difluorophenyl)boronic acid (128 mg). The mixture was stirred at 100 °C for 16 h under nitrogen atmosphere. The 35 reaction mixture was diluted with water and then it was

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[0203] extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography 5 (EtOAc / petroleum ether) to give the title compound (49 mg). 1H NMR (400 MHz, CDCl3) δ 2.34-2.45 (1H, m), 2.54-2.64 (1H, m), 3.02-3.11 (1H, m), 3.15-3.24 (1H, m), 4.09-4.18 (1H, m), 6.96-7.10 (2H, m), 7.20-7.24 (1H, m), 7.32-7.41 (3H, m). 10 I) 7-(2,6-Difluorophenyl)-2,3-dihydro-1H-indene-1-carboxylic acid A mixture of 7-(2,6-difluorophenyl)-2,3-dihydro-1H- indene-1-carbonitrile (49.0 mg) in 25% hydrogen chloride aqueous solution (4 mL) and acetic acid (4 mL) was degassed 15 and purged with nitrogen for 3 times, and then the mixture was stirred at 100 °C for 16 h under nitrogen atmosphere. The reaction mixture was diluted with water and then it was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and 20 concentrated under reduced pressure to give the title compound (39 mg). 1H NMR (400 MHz, CDCl3) δ 2.36-2.44 (1H, m), 2.47-2.64 (1H, m), 3.01-3.11 (1H, m), 3.15-3.29 (1H, m), 4.08-4.16 (1H, m), 6.86-7.26 (4H, m), 7.32-7.38 (2H, m). 25 J) (4S)-N-[(1RS)-7-(2,6-Difluorophenyl)-2,3-dihydro-1H-inden- 1-yl]-4-(methanesulfonamido)azepane-1-carboxamide A solution of 7-(2,6-difluorophenyl)-2,3-dihydro-1H-30indene-1-carboxylic acid (30 mg), DPPA (39 mg) and TEA (66 mg) in toluene (2 mL) was stirred at 25 °C for 30 min and then at 90 °C for 1 h under nitrogen atmosphere. Then to this mixture was added N-[(4S)-azepan-4-yl]methanesulfonamide hydrobromide

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[0205] (30 mg) and the mixture was stirred at 100 °C for 1 h under nitrogen atmosphere. The reaction mixture was quenched with water and it was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium 5 sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by HPLC (column: YMC- Actus Triant C18, mobile phase: water (containing 0.05% ammonium hydroxide) / MeCN) to give the title compound (2.0 mg). 1H NMR (400 MHz, CDCl3) δ 1.39-1.52 (2H, m), 1.58-2.00 10 (5H, m), 2.56-2.67 (1H, m), 2.88-3.12 (8H, m), 3.33-3.49 (2H, m), 4.11-4.32 (2H, m), 5.33-5.43 (1H, m), 6.90-7.03 (2H, m), 7.10-7.17 (1H, m), 7.27-7.36 (3H, m). Example 15 15 (3S)-N-[(1R*)-7-(2,6-Difluorophenyl)-2,3-dihydro-1H-inden-1- yl]-3-(methanesulfonamido)pyrrolidine-1-carboxamide A) tert-Butyl (3S)-3-(methanesulfonamido)pyrrolidine-1- carboxylate20To a solution of (tert-butyl (3S)-3-aminopyrrolidine-1- carboxylate (12.0 g) in anhydrous DCM (120 mL) were added TEA (16.3 g) and methanesulfonyl chloride (8.86 g) at 0 °C, and then the mixture was stirred at 20 °C for 2 h under nitrogen25atmosphere. The reaction mixture was quenched with water and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the 30 title compound (12.8 g). 1H NMR (400 MHz, CDCl3) δ 1.44 (9H, s), 1.80-2.01 (1H, m), 2.11-2.24 (1H, m), 2.98 (3H, s), 3.16-3.54 (3H, m), 3.57-3.70 (1H, m), 3.95-4.06 (1H, m), 5.06 (1H, d, J = 7.6 Hz). 35 B) N-[(3S)-Pyrrolidin-3-yl]methanesulfonamide hydrochloride

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[0207] A solution of tert-butyl (3S)-3- (methanesulfonamido)pyrrolidine-1-carboxylate (12.8 g) in 4 M hydrogen chloride / CPME solution (150 mL) was stirred at 20 °C 5 for 2 h under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and coevaporated with EtOAc to give the title compound (9.43 g). 1H NMR (400 MHz, DMSO-d6) δ 1.82-1.95 (1H, m), 2.07-2.20 (1H, m), 2.98 (3H, s), 3.00-3.08 (1H, m), 3.10-3.27 (2H, m), 10 3.28-3.37 (1H, m), 3.95-4.09 (1H, m), 7.58 (1H, d, J = 6.4 Hz), 9.50 (2H, brs). C) 7-(2,6-difluorophenyl)-2,3-dihydro-1H-inden-1-one 15 To a stirred solution of 7-bromo-2,3-dihydro-1H-inden-1- one (2.00 g) and (2,6-difluorophenyl)boronic acid (5.99 g) in DME (60 mL) and water (20 mL) were added XPhosPdG3(802 mg) and potassium phosphate (6.03 g), and the reaction mixture was stirred at 100 °C for 16 h under nitrogen atmosphere. The20reaction mixture was poured into water and it was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (EtOAc / petroleum25ether) to give the title compound (1.11 g). 1H NMR (400 MHz, CDCl3) δ 2.43-2.80 (2H, m), 3.17 (2H, t, J = 6.4 Hz), 6.90- 7.02 (2H, m), 7.28-7.40 (2H, m), 7.54 (1H, dd, J = 8.0, 0.8 Hz), 7.64 (1H, t, J = 7.6 Hz) 30 D) 7-(2,6-Difluorophenyl)-2,3-dihydro-1H-inden-1-amine A solution of 7-(2,6-difluorophenyl)-2,3-dihydro-1H- 35 inden-1-one (569 mg), sodium cyanoborohydride (732 mg) and

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[0209] ammonium acetate (3.59 g) in isopropanol (30 mL) was stirred at 80 °C for 12 h under nitrogen atmosphere. The reaction mixture was poured into a saturated sodium hydroxide aqueous solution and it was extracted with DCM. The combined organic 5 layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (318 mg). 1H NMR (400 MHz, CDCl3) δ 2.16-2.27 (1H, m), 2.39-2.55 10 (1H, m), 2.88-3.06 (1H, m), 3.22-3.39 (1H, m), 4.62 (1H, d, J = 5.2 Hz), 7.05 (2H, q, J = 8.8 Hz), 7.19 (1H, d, J = 7.6 Hz), 7.34-7.48 (3H, m) E) (3S)-N-[(1R*)-7-(2,6-Difluorophenyl)-2,3-dihydro-1H- 15 inden-1-yl]-3-(methanesulfonamido)pyrrolidine-1-carboxamide A mixture of 7-(2,6-difluorophenyl)-2,3-dihydro-1H- inden-1-amine (77 mg), N,N-diisopropylethylamine (122 mg) and bis(trichloromethyl)carbonate (186 mg) in DCM (2 mL) was20stirred at 25 °C for 1 h under nitrogen atmosphere. The mixture was quenched with water and it was extracted with DCM. The combined organic layer was concentrated under reduced pressure to give a residue. Then to the residue were added DCM (2 mL), N-[(3S)-pyrrolidin-3-yl]methanesulfonamide25hydrochloride (76 mg) and N,N -diisopropylethylamine (122 mg), and the mixture was stirred at 25 °C for 16 h under nitrogen atmosphere. The reaction mixture was poured into water and it was extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and 30 concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Boston Prime C18, mobile phase: water (containing 0.05% ammonium hydroxide) / MeCN) The desired fraction was concentrated under reduced pressure, and the remaining solvent was removed by 35 lyophilization to give a product. Then it was further purified

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[0211] by SFC (column: DAICEL CHIRALPAK OD-H, 250 mmx 30 mm, 5 μm, mobile phase: CO2 / 0.1% ammonium hydroxide containing IPA = 60 / 40 v / v) to give the title compound having a longer retention time (17.3 mg). 51H NMR (400 MHz, CDCl3) δ 1.78-2.19 (3H, m), 2.53-2.68 (1H, m), 2.88-3.14 (8H, m), 3.21-3.35 (1H, m), 3.84-3.96 (1H, m), 4.14 (1H, d, J = 8.0 Hz), 4.37 (1H, d, J = 7.6 Hz), 5.41 (1H, q, J = 8.0 Hz), 6.93-7.02 (2H, m), 7.10-7.18 (1H, m), 7.29-7.39 (3H, m) 10 Example 24 (4S)-N-[4-(2,6-Difluorophenyl)-1-benzothiophen-3-yl]-4- (methanesulfonamido)azepane-1-carboxamide 15 A) 4-bromo-1-benzothiophene-3-carbaldehyde A mixture of 4-bromo-1-benzothiophene (2.00 g) and dichloro(methoxy)methane (1.62 g) in DCM (30 mL) was added 1 M titanium tetrachloride / DCM solution (14.1 mL) at 0 °C, and the20mixture was stirred at 25 °C for 2 h under nitrogen atmosphere. The reaction was poured into a mixture of saturated sodium hydrogencarbonate aqueous solution on an ice bath. The mixture was stirred for 30 min and then was extracted with DCM. The combined organic layer was washed with25brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (1.26 g). 1H NMR (400 MHz, CDCl3) δ 7.26-7.31 (1H, m), 7.74 (1H, dd, J = 30 7.6, 0.8 Hz), 7.89 (1H, dd, J = 8.0, 0.8 Hz), 8.53 (1H, s), 11.08 (1H, s). B) 4-(2,6-Difluorophenyl)-1-benzothiophene-3-carbaldehyde 35 To a stirred solution of 4-bromo-1-benzothiophene-3-

[0212] 110

[0213] carbaldehyde (500 mg) and (2, 6-difluorophenyl) boronic acid (982 mg) in DME (12 mL) and water (3.0 mL) were added chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′- biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (815 mg) 5 and potassium phosphate (1.32 g) and the reaction mixture was stirred at 100 °C under nitrogen atmosphere for 5 h. The mixture was diluted with water and it was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced10pressure to give a residue. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (501 mg). 1H NMR (400 MHz, CDCl3) δ 7.02-7.07 (2H, m), 7.23-7.24 (2H, m), 7.51-7.56 (1H, m), 8.00 (1H, dd, J = 8.0, 0.8 Hz), 8.47 15 (1H, s), 9.44 (1H, s). C) 4-(2,6-Difluorophenyl)-1-benzothiophene-3-carboxylic acid To a stirred solution of 4-(2,6-difluorophenyl)-1- 20 benzothiophene-3-carbaldehyde (400 mg) in acetone (10 mL) and water (5.0 mL) were added sodium dihydrogenphosphate (175 mg), 2-methylbut-2-ene (511 mg) and sodium chlorite (396 mg). The reaction mixture was stirred at 25 °C under nitrogen atmosphere for 2 h. The reaction mixture was basified to pH =259-10 with 1 M sodium hydroxide aqueous solution. Then the mixture was diluted with water and it was washed with petroleum ether / EtOAc (10:1) and the water layer was acidified with 2 M hydrogen chloride aqueous solution to pH = 3-4. The mixture was diluted with water and it was extracted with30EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound(125 mg). MS: [M+H]+291.0.

[0214] 111

[0215] D) (4S)-N-[4-(2,6-Difluorophenyl)-1-benzothiophen-3-yl]-4- (methanesulfonamido)azepane-1-carboxamide 5 A solution of 4-(2,6-difluorophenyl)-1-benzothiophene-3- carboxylic acid (50 mg), DPPA (95 mg) and TEA (87 mg) in toluene (4.0 mL) was stirred at 20 °C for 30 min and then stirred at 90 °C for 1 h. Then N-[(4S)-azepan-4- yl]methanesulfonamide hydrobromide (39 mg) was added and the 10 mixture was stirred at 90 °C for 12 h. The mixture was diluted with water and it was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC 15 (column: Phenomenex Gemini-NX C18, mobile phase: water (containing 0.05% ammonium hydroxide + 10 mM ammonium hydrogencarbonate) / MeCN)to give the title compound (1.5 mg). 1H NMR (400 MHz, CDCl3) δ 1.46-1.55 (2H, m), 1.64-1.74 (2H, m), 1.85-2.01 (2H, m), 2.77-3.49 (8H, m), 4.08-4.42 (1H,20m), 6.49 (1H, brs), 7.02-7.21 (3H, m), 7.35-7.52 (2H, m), 7.83-8.06 (2H, m). Example 42 (4S)-N-[4-(2,6-Difluorophenyl)-1-benzofuran-3-yl]-4-25(methanesulfonamido)azepane-1-carboxamide A) 2-Bromo-6-hydroxybenzaldehyde To a mixture of 2-bromo-6-hydroxybenzaldehyde (5.00 g) 30 in DCM (50 mL) was added ethoxyethane;trifluoroborane; hydrofluoride (403 mg), and then a solution of ethyl 2- diazoacetate (5.68 g) in DCM (15 mL) was added dropwise over 15 min, then the reaction mixture was stirred at 10 °C for 15 min under nitrogen atmosphere. The mixture was concentrated 35 under reduced pressure to give a residue. Then concentrated

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[0217] sulfuric acid (5.52 g) was added dropwise to the residue, and then the reaction mixture was stirred at 10 °C for 10 min. The mixture was diluted with saturated sodium hydrogencarbonate aqueous solution and extracted with EtOAc. 5 The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (4.70 g). 101H NMR (400 MHz, CDCl3) δ 1.42 (3H, t, J = 7.2 Hz), 4.41 (2H, q, J = 7.2 Hz), 7.19-7.24 (1H, m), 7.47-7.59 (2H, m), 8.22 (1H, s). B) Ethyl 4-bromo-1-benzofuran-3-carboxylate 15 To a mixture of 2-bromo-6-hydroxybenzaldehyde (1.00 g) and 2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (1.78 g) in DMF (15 mL) were added cesium carbonate (4.84 g), copper(I) chloride (368 mg), 2-20dicyclohexylphosphino-2',6'-dimethoxybiphenyl (305 mg) and palladium(II) acetate (42 mg), and then the reaction mixture was stirred at 110 °C for 10 min under nitrogen atmosphere. The mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over25anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (1.07 g). 1H NMR (400 MHz, CDCl3) δ 1.11 (3H, t, J = 7.2 Hz), 4.03 30 (2H, q, J = 7.2 Hz), 6.94-7.02 (2H, m), 7.30-7.38 (2H, m), 7.45 (1H, t, J = 7.6 Hz), 7.62 (1H, m), 8.29 (1H, s). C) Ethyl 4-(2,6-difluorophenyl)-1-benzofuran-3-carboxylate 35 To a mixture of ethyl 4-bromo-1-benzofuran-3-carboxylate

[0218] 113

[0219] (200 mg) in MeOH (3 mL) and THF (3 mL) and water (3 mL) was added sodium hydroxide (265 mg), and then the reaction mixture was stirred at 60 °C for 12 h. The mixture was acidified with 1 M hydrogen chloride aqueous solution to pH = 4, and then it 5 was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give the title compound (190 mg). 1H NMR (400 MHz, DMSO-d6) δ 7.10-7.18 (2H, m), 7.31-7.37 10 (1H, m), 7.40-7.49 (1H, m), 7.50-7.57 (1H, m), 7.78-7.88 (1H, m), 8.69 (1H, s), 12.38 (1H, brs). D) (4S)-N-[4-(2,6-Difluorophenyl)-1-benzofuran-3-yl]-4- (methanesulfonamido)azepane-1-carboxamide 15 To a mixture of ethyl 4-(2,6-difluorophenyl)-1- benzofuran-3-carboxylate (25 mg) and N-[(4S)-azepan-4- yl]methanesulfonamide (21 mg) in DMF (1.5 mL) were added 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-20b]pyridinium 3-oxide hexafluorophosphate (42 mg) and N,N- diisopropylethylamine (47 mg), and then the reaction mixture was stirred at 20 °C for 16 h under nitrogen atmosphere. The mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over25anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. The residue was purified by preparative HPLC (column: Boston Prime C18, mobile phase: water containing 0.225% formic acid / MeCN) to give the title compound (4.0 mg). 301H NMR (400 MHz, CDCl3) δ 1.46-1.58 (1H, m), 1.57-1.63 (1H, m), 1.64-1.83 (2H, m), 1.87-2.00 (2H, m), 3.86-3.56 (8H, m), 4.25-4.44 (1H, m), 6.90-7.10 (2H, m), 7.27-7.39 (2H, m), 7.43-7.50 (1H, m), 7.57-7.65 (1H, m), 7.77-7.90 (1H, m). 35 Example 66

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[0221] rel-(5R)-N-[4-(2,6-Difluorophenyl)-1-benzofuran-3-yl]-4,4- difluoro-5-(methanesulfonamido)azepane-1-carboxamide A) azepan-4-one hydrochloride 5 To a mixture of tert-butyl 4-oxoazepane-1-carboxylate (150 g) in EtOAc (300 mL) was added 4 M hydrogen chloride / EtOAc solution (750 mL) dropwise at 20 °C, and then the mixture was stirred at 20 °C for 2 h. The reaction mixture 10 was filtered and the filter cake was dried under reduced pressure to give the title compound (190 g). 1H NMR (400 MHz, DMSO-d6) δ 1.91-1.97 (2H, m), 2.60-2.63 (2H, m), 2.75-2.78 (2H, m), 3.20-3.21 (2H, m), 3.29-3.42 (2H, m), 9.47 (2H, s). 15 B) 5-Bromoazepan-4-one hydrobromide To a mixture of azepan-4-one hydrochloride (95.0 g) in acetic acid (1.12 L) was added 33.3% hydrogen bromide / acetic20acid solution(128 mL) at 20 °C，followed by bromine (101 g) in acetic acid (125 mL), and then the mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The reaction mixture was triturated with MeCN at 20 °C for 1 h, filtered and the filter25cake was dried under reduced pressure to give the title compound (330 g). MS: [M+H]+192.0, 193.9. C) Benzyl 4-bromo-5-oxoazepane-1-carboxylate 30 To a mixture of 5-bromoazepan-4-one hydrobromide (165 g) in water (1.32 L) and EtOAc (1.32 L) was added potassium carbonate (250 g), then added benzyl carbonochloridate (154 g)

[0222] 115

[0223] at 0 °C，and then the mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated 5 under reduced pressure to give the title compound (360 g). 1H NMR (400 MHz, DMSO-d6) δ 1.96-1.98 (1H, m), 2.25-2.49 (1H, m), 2.71-2.81 (2H, m), 3.59-3.65 (2H, m), 3.72-3.76 (2H, m), 5.05-5.30 (3H, m), 7.31-7.37 (5H, m). 10 D) Benzyl 4-azido-5-oxoazepane-1-carboxylate To a mixture of benzyl 4-bromo-5-oxoazepane-1- carboxylate (180 g) in DMF (1.80 L) was added sodium azide (43.0 g), and then the mixture was stirred at 20 °C for 12 h. 15 The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (EtOAc / petroleum 20 ether) to give the title compound (130 g). 1H NMR (400 MHz, CDCl3) δ 1.88-2.04 (2H, m), 2.70-2.88 (2H, m), 3.51-3.58 (2H, m), 3.81-3.85 (2H, m), 4.13-4.23 (1H, m), 5.12-5.15 (2H, m), 7.31-7.38 (5H, m).25E) Benzyl 5-azido-4,4-difluoroazepane-1-carboxylate To a mixture of benzyl 4-azido-5-oxoazepane-1- carboxylate (65.0 g) in DCM (390 mL) was added bis(2- methoxyethyl)aminosulfur trifluoride (124 g) at 0 °C, and then 30 the mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched by addition of sodium hydrogencarbonate aqueous solution at 0 °C, and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to

[0224] 116

[0225] give a residue. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (43.0 g). 1H NMR (400 MHz, CDCl3) δ 1.98-2.05 (2H, m), 2.03-2.07 5 (1H, m), 2.37-2.39 (1H, m), 3.41-3.67 (4H, m), 3.95-4.12 (1H, m), 5.16-5.17 (2H, m), 7.33-7.40 (5H, m). F) Benzyl 5-amino-4,4-difluoroazepane-1-carboxylate 10 To a mixture of benzyl 5-azido-4,4-difluoroazepane-1- carboxylate (43.0 g) in THF (650 mL) and water (150 mL) was added triphenylphosphine (36.3 g), and then the mixture was stirred at 60 °C for 12 h. The reaction solution was concentrated. EtOAc was added and the mixture was extracted 15 with 1 M hydrogen chloride aqueous solution. The acidic extracts were washed with EtOAc, basified to pH = 14 with 6 M sodium hydroxide aqueous solution, and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to20give the title compound (30.0 g). 1H NMR (400 MHz, CDCl3) δ 1.38 (2H, s), 1.83-1.87 (1H, m) 1.98-2.04 (2H, m), 2.33-2.37 (1H, m), 3.11-3.14 (1H, m), 3.45- 3.66 (4H, m), 5.15 (2H, s), 7.31-7.37 (5H, m).25G) Benzyl rac-(5R)-4,4-difluoro-5-(2,2,2- trifluoroacetamido)azepane-1-carboxylate To a mixture of benzyl 5-amino-4,4-difluoroazepane-1- carboxylate (30.0 g) in DCM (600 mL) was added N,N-30 diisopropylethylamine (16.3 g), (2,2,2-trifluoroacetyl) 2,2,2- trifluoroacetate (26.6 g) at 0 °C, and then the mixture was stirred at 20 °C for 5 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with 1 M hydrogen chloride aqueous solution, the 35 combined organic layers were washed with brine, dried over

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[0227] anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (30.0 g). 1H NMR (400 MHz, CDCl3) δ 2.02-2.07 (2H, m), 2.28-2.31 (2H, m), 3.40-3.66 (3H, m), 3.78-3.80 (1H, m), 4.39-4.44 (1H, 5 m), 5.16 (2H, s), 6.52 (1H, s), 7.34-7.40 (5H, m). H) Benzyl rel-(5R)-4,4-difluoro-5-(2,2,2- trifluoroacetamido)azepane-1-carboxylate 10 Benzyl rac-(5R)-4,4-difluoro-5-(2,2,2- trifluoroacetamido)azepane-1-carboxylate (40.0 g) was resolved by SFC (column: DAICEL CHIRALPAK AD, 250mm x 50 mm, 10 μm, mobile phase: CO2 / 0.1% ammonium hydroxide containing MeOH = 89 / 11 v / v) to give the title compound having longer retention 15 time (17.0 g). 1H NMR (400 MHz, CDCl3) δ 2.01-2.05 (2H, m), 2.20-2.38 (2H, m), 3.40-3.65 (3H, m), 3.77-3.79 (1H, m), 4.39-4.45 (1H, m), 5.13-5.21 (2H, m), 6.78 (1H, d, J = 7.6 Hz), 7.33-7.40 (5H, m).20I) Benzyl rel-(5R)-5-amino-4,4-difluoroazepane-1-carboxylate To a mixture of benzyl rel-(5R)-4,4-difluoro-5-(2,2,2- trifluoroacetamido)azepane-1-carboxylate(5.08 g), MeOH (10025mL) and water (50 mL) was added 5 M potassium carbonate aqueous solution (14 mL) at room temperature. The mixture was stirred at 50 °C overnight. After being concentrated under reduced pressure, to the mixture was added water and it was extracted with EtOAc. The organic layer was separated, washed 30 with brine, dried over anhydrous sodium sulfate. The mixture was passed through a NH silica gel pad eluting with EtOAc to give the title compound (3.77 g). MS: [M+H]+285.0. 35 J) Benzyl rel-(5R)-4,4-difluoro-5-

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[0229] (methanesulfonamido)azepane-1-carboxylate To a mixture of benzyl rel-(5R)-5-amino-4,4- difluoroazepane-1-carboxylate (1.88 g), TEA (2.0 mL), DMAP 5 (0.407 g) and THF (30 mL) was added methanesulfonic anhydride (1.8 g) at 0 °C. The mixture was stirred at room temperature under nitrogen atmosphere for 2 days. To the mixture was added water and it was extracted with EtOAc. The organic layer was separated, washed with 0.1 M hydrogen chloride aqueous 10 solution and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (2.36 g). MS: [M+Na]+385.0. 15 K) N-[rel-(4R)-5,5-Difluoroazepan-4-yl]methanesulfonamide A mixture of benzyl rel-(5R)-4,4-difluoro-5- (methanesulfonamido)azepane-1-carboxylate (2.36 g), 10% Pd on20carbon (236 mg), EtOH (40 mL), and EtOAc (20 mL) was hydrogenated under balloon pressure at room temperature overnight. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound (1.34 g).25MS: [M+H]+228.9. L) 4-Bromo-1-benzofuran-3-carboxylic acid A mixture of ethyl 4-bromo-1-benzofuran-3-carboxylate (500 mg), 2 M aqueous sodium hydroxide solution (9.3 mL), THF 30 (10 mL), and EtOH (10 mL) was stirred for 12 h at 60 °C. The reaction mixture was poured into water, neutralized with 1 M hydrogen chloride aqueous solution, and extracted with EtOAc. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to 35 give the title compound (440 mg).

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[0231] 1H NMR (400 MHz, CDCl3) δ 7.24 (1H, s), 7.53 (1H, d, J = 8.3 Hz), 7.59 (1H, d, J = 7.8 Hz), 8.38 (1H, s). M) rel-(5R)-N-(4-Bromo-1-benzofuran-3-yl)-4,4-difluoro-5- 5 (methanesulfonamido)azepane-1-carboxamide To a mixture of 4-bromo-1-benzofuran-3-carboxylic acid (127 mg) and TEA (0.244 mL) in toluene (3.0 mL) was added DPPA (0.132 mL) at room temperature. After being stirred at 100 °C10 for 1 h, N-[rel-(4R)-5,5-difluoroazepan-4- yl]methanesulfonamide (100 mg) was added to the reaction mixture. The mixture was stirred at 100 °C under nitrogen for 5 h. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (173 15 mg). MS: [M+H]+466.0. N) rel-(5R)-N-[4-(2,6-Difluorophenyl)-1-benzofuran-3-yl]-4,4- difluoro-5-(methanesulfonamido)azepane-1-carboxamide20The mixture of rel-(5R)-N-(4-bromo-1-benzofuran-3-yl)- 4,4-difluoro-5-(methanesulfonamido)azepane-1-carboxamide (173 mg), 2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (178 mg), Tris(dibenzylideneacetone)dipalladium25(0) (34.0 mg), tri-tert-butylphosphonium tetrafluoroborate (21.5 mg), potassium fluoride (64.7 mg) and DME (3.0 mL) and water (1.0 mL) was heated at 120 °C for 1 h under microwave irradiation. To the mixture was added EtOAc, then the mixture was passed through a NH silica gel pad eluting with EtOAc. 30 After being concentrated under reduced pressure, the residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (122 mg). 1H NMR (400 MHz, DMSO-d6) δ 1.67-1.88 (2H, m), 1.92-2.22 (2H, m), 2.89-3.07 (5H, m), 3.11-3.29 (2H, m), 3.63-3.80 (1H, 35 m), 7.10-7.20 (3H, m), 7.36-7.55 (3H, m), 7.60-7.74 (2H, m),

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[0233] 7.97 (1H, s). Example 71 rel-(5R)-N-[4-(2,6-Difluorophenyl)-1-benzothiophen-3-yl]-4,4- 5 difluoro-5-(methanesulfonamido)azepane-1-carboxamide A) rel-(5R)-N-[4-(2,6-Difluorophenyl)-1-benzothiophen-3-yl]- 4,4-difluoro-5-(methanesulfonamido)azepane-1-carboxamide 10 DPPA (0.028 mL) was added to a solution of 4-(2,6- difluorophenyl)-1-benzothiophene-3-carboxylic acid (30.5 mg) and TEA (0.049 mL) in toluene (1.0 mL) at room temperature. The mixture was stirred at 90 °C under nitrogen atmosphere for 1 h. N-[rel-(4R)-5,5-difluoroazepan-4-yl]methanesulfonamide 15 (20 mg) was added to the mixture at 90 °C. The mixture was stirred at 90 °C under nitrogen atmosphere for 5 h. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (15 mg). 1H NMR (300 MHz, CDCl3) δ 1.90-2.01 (2H, m), 2.08-2.33 (2H,20m), 2.48-2.64 (1H, m), 2.78-2.93 (1H, m), 3.02 (3H, s), 3.07- 3.23 (1H, m), 3.39-3.53 (1H, m), 3.58-3.82 (1H, m), 4.65-4.82 (1H, m), 6.52 (1H, s), 7.11-7.24 (3H, m), 7.37-7.57 (2H, m), 7.92 (1H, dd, J = 8.3, 1.1 Hz), 7.99 (1H, s).25Example 77 (4S)-N-[4-(2,6-Difluorophenyl)-1,2-benzoxazol-3-yl]-4- (methanesulfonamido)azepane-1-carboxamide A) 4-(2,6-Difluorophenyl)-1,2-benzoxazol-3-amine 30 The mixture of 4-bromo-1,2-benzoxazol-3-amine (500 mg), 2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.13 g), tri-tert-butylphosphonium tetrafluoroborate (136 mg), Pd2(dba)3(215 mg), potassium fluoride (409 mg) in DME (3

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[0235] mL) and water (1 mL) was heated at 120 °C for 1 h under microwave irradiation. The reaction mixture was quenched with water and extracted with EtOAc . The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and 5 concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (588 mg). MS: [M+H]+247.0. 10 B) 4-(2,6-Difluorophenyl)-3-isocyanato-1,2-benzoxazole To a solution of 4-(2,6-difluorophenyl)-1,2-benzoxazol- 3-amine (50 mg) in DCM (3 mL) was added bis(trichloromethyl)carbonate (60.3 mg) at 0 °C. Then pyridine 15 (48.2 mg) was added slowly. The reaction mixture was stirred at 20 °C for 1 h. The mixture was diluted with water and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give the title compound20(60 mg). MS: [M+H]+272.9. C) (4S)-N-[4-(2,6-Difluorophenyl)-1,2-benzoxazol-3-yl]-4- (methanesulfonamido)azepane-1-carboxamide25To a mixture of N-[(4S)-azepan-4-yl]methanesulfonamide hydrobromide (30.0 mg) and 4-(2,6-difluorophenyl)-3- isocyanato-1,2-benzoxazole (58.0 mg) in DCM (3 mL) was added TEA (33.3 mg), and then the mixture was stirred at 20 °C for 30 14 h under nitrogen atmosphere. The mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Boston Prime C18, mobile 35 phase: water containing 0.05% ammonium hydroxide / MeCN) to give

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[0237] the title compound (1.9 mg). 1H NMR (400 MHz, CDCl3) δ 1.41-1.52 (2H, m), 1.65-2.12 (4H, m), 2.78-2.96 (4H, m), 3.03-3.53 (4H, m), 4.62 (1H, brs), 6.73- 7.20 (3H, m), 7.30-7.74 (4H, m). 5 Example 83 rel-(5R)-N-[4-(2,6-Difluorophenyl)-1,2-benzoxazol-3-yl]-4,4- difluoro-5-(methanesulfonamido)azepane-1-carboxamide 10 A) rel-(5R)-N-[4-(2,6-Difluorophenyl)-1,2-benzoxazol-3-yl]- 4,4-difluoro-5-(methanesulfonamido)azepane-1-carboxamide To a mixture of 4-(2,6-difluorophenyl)-3-isocyanato-1,2- benzoxazole (68.1 mg) and DCM (2.5 ml) was added N-[rel-(4R)- 5,5-difluoroazepan-4-yl]methanesulfonamide (57.1 mg) and TEA 15 (0.105 ml) at room temperature. The mixture was stirred at room temperature under nitrogen atmosphere overnight and then at 40 °C for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by by silica gel column chromatography (EtOAc / hexane) to give the title compound(45 mg).20 1H NMR (400 MHz, DMSO-d6) δ 1.65-2.28 (4H, m), 2.90-3.20 (5H, m), 3.25-3.40 (2H, m), 3.63-3.81 (1H, m), 7.09-7.22 (2H, m), 7.28-7.35 (1H, m), 7.44-7.55 (1H, m), 7.66-7.76 (2H, m), 7.77-7.83 (1H, m), 9.26 (1H, s).25Example 84 (3S)-N-[4-(2,6-Difluorophenyl)-6-methyl-1,2-benzoxazol-3-yl]- 3-(methanesulfonamido)pyrrolidine-1-carboxamide A) 4-Bromo-6-methyl-1,2-benzoxazol-3-amine 30 To a solution of N-hydroxyacetamide (879 mg) in DMF (15 mL) was added 1 M potassium tert-butoxide / THF solution (11.7 mL) was stirred at 20 °C for 30 min then 2-bromo-6-fluoro-4- methylbenzonitrile (835 mg) in DMF (10 mL) was added. The 35 reaction mixture was stirred at 20 °C for 14 h. The combined

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[0239] reaction mixture was diluted with water (50 mL) and extracted with EtOAc. The organic layer was washed with brine and dried by anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography 5 (EtOAc / hexane) to give the title compound (384 mg). 1H NMR (400 MHz, CDCl3) δ 2.47 (3H, s), 4.42-5.15 (2H, m), 7.17 (1H, s), 7.20 (1H, s). B) 4-(2,6-Difluorophenyl)-6-methyl-1,2-benzoxazol-3-amine 10 The mixture of 4-bromo-6-methyl-1,2-benzoxazol-3-amine (73.0 mg), 2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (154 mg), tri-tert-butylphosphonium tetrafluoroborate (18 mg), Pd2(dba)3(29 mg) and potassium fluoride (56.0 mg) in DME (3 mL) and water (1 mL) was heated 15 at 115 °C for 1 h under microwave irradiation. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column20chromatography (EtOAc / hexane) to give the title compound (103 mg). 1H NMR (400 MHz, CDCl3) δ 2.50-2.59 (3H, m), 3.68-4.10 (2H, m), 7.01 (1H, s), 7.04-7.12 (2H, m), 7.30 (1H, s), 7.39- 7.51 (1H, m).25C) (3S)-N-[4-(2,6-Difluorophenyl)-6-methyl-1,2-benzoxazol-3- yl]-3-(methanesulfonamido)pyrrolidine-1-carboxamide To a solution of 4-(2,6-difluorophenyl)-6-methyl-1,2- 30 benzoxazol-3-amine (100 mg) in DCM (3 mL) was added pyridine (122 mg) at 0 °C, then bis(trichloromethyl)carbonate (228 mg) was added, the reaction mixture was stirred at 20 °C for 2 h under nitrogen atmosphere. The reaction mixture was diluted with water and it was extracted with DCM. The combined organic 35 layer was washed with brine, dried over anhydrous sodium

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[0241] sulfate and concentrated under reduced pressure. Then the mixture was diluted with DCM (3 mL), TEA (117 mg) and N-[(3S)- pyrrolidin-3-yl]methanesulfonamide hydrochloride (77.1 mg) were added, the reaction mixture was warmed to 20 °C for 16 h 5 under nitrogen atmosphere. The reaction mixture was diluted with water and it was extracted with EtOAc. The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC 10 (column: Boston Prime C18-1, mobile phase: water containing ammonium hydroxide / MeCN) to give the title compound (10.4 mg). 1H NMR (400 MHz, CDCl3) δ 1.84-2.03 (2H, m), 2.54 (3H, s), 2.89 (3H, s), 2.99-3.30 (4H, m), 3.76-4.08 (1H, m), 5.45 (1H, d, J = 7.6 Hz), 6.97-7.06 (3H, m), 7.09 (1H, s), 7.34-7.46 15 (2H, m). Example 86 rel-(5R)-N-[4-(2,6-Difluorophenyl)-1,2-benzoxazol-3-yl]-5- (ethanesulfonamido)-4,4-difluoroazepane-1-carboxamide20A) Benzyl rel-(5R)-5-(ethanesulfonamido)-4,4-difluoroazepane- 1-carboxylate To a mixture of benzyl rel-(5R)-5-amino-4,4-25difluoroazepane-1-carboxylate (2.24 g), TEA (2.19 mL), DMAP (0.406 g) and THF (36 mL) was added ethanesulfonyl chloride (1.12 mL) at 0 °C. The mixture was stirred at room temperature under nitrogen atmosphere overnight. To the mixture was added water and extracted with EtOAc. The organic layer was 30 separated, washed with 0.1 M hydrogen chloride aqueous solution and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (2.73 g). 35 MS: [M+H]+377.0.

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[0243] B) N-[rel-(4R)-5,5-Difluoroazepan-4-yl]ethanesulfonamide A mixture of benzyl rel-(5R)-5-(ethanesulfonamido)-4,4- 5 difluoroazepane-1-carboxylate (2.73 g), 10% Pd on carbon (273 mg), EtOH (48 mL) and EtOAc (24 mL) was hydrogenated under balloon pressure at room temperature overnight. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound (1.64 g). 10 MS: [M+H]+243.0. C) rel-(5R)-N-[4-(2,6-Difluorophenyl)-1,2-benzoxazol-3-yl]-5- (ethanesulfonamido)-4,4-difluoroazepane-1-carboxamide 15 To a solution of 4-(2,6-difluorophenyl)-1,2-benzoxazol- 3- (200 mg) in DCM (15 mL) was added pyridine (0.200 mL) at 0 °C, then to the mixture was added bis(trichloromethyl)carbonate (366 mg) at 0 °C, the reaction mixture was stirred at 20 °C for 1 h under nitrogen atmosphere20then the solvent was removed under reduced pressure. The residue was redissolved in THF (15 mL) , TEA (0.258 mL) and N- [rel-(4R)-5,5-difluoroazepan-4-yl]ethanesulfonamide (150 mg) were added, and the reaction mixture was stirred at 50 °C overnight under nitrogen atmosphere. The reaction mixture was25poured into water and it was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) and recrystallized from 30 EtOAc / Heptane at 80 °C to give the title compound (160 mg). 1H NMR (400 MHz, DMSO-d6) δ 1.22 (3H, t, J = 7.3 Hz), 1.66-2.29 (4H, m), 2.87-3.23 (5H, m), 3.25-3.41 (1H, m), 3.58- 3.74 (1H, m), 7.10-7.21 (2H, m), 7.31 (1H, d, J = 7.0 Hz), 7.44-7.54 (1H, m), 7.65-7.76 (2H, m), 7.76-7.83 (1H, m), 9.26 35 (1H, s).

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[0245] Example 87 (3S)-N-[4-(2,6-Difluorophenyl)-1,2-benzoxazol-3-yl]-3- (dimethylsulfamamido)pyrrolidine-1-carboxamide 5 A) tert-Butyl [(3S)-1-{[4-(2,6-difluorophenyl)-1,2- benzoxazol-3-yl]carbamoyl}pyrrolidin-3-yl]carbamate To a solution of 4-(2,6-difluorophenyl)-1,2-benzoxazol- 10 3-amine (20 mg) in dry THF (1.5 mL) was added pyridine (0.02 mL) at 0 °C, then to the mixture was added bis(trichloromethyl)carbonate (36.6 mg) at 0 °C , the reaction mixture was stirred at 20 °C for 2 h under nitrogen atmosphere. The reaction mixture was poured into water and it 15 was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Then the mixture was diluted with THF (1.5 mL), TEA (0.026 mL) and tert-butyl (3S)- pyrrolidin-3-ylcarbamate (18.4 mg) were added, and the20reaction mixture was stirred at 20 °C for 12 h under nitrogen atmosphere. The volatiles were evaporated under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (12.7 mg).25 1H NMR (400 MHz, DMSO-d6) δ 1.41 (9H, d, J = 4.3 Hz), 1.51-1.70 (1H, m), 1.74-1.96 (1H, m), 2.70-3.22 (3H, m), 3.33- 3.58 (1H, m), 3.66-3.97 (1H, m), 7.14 (2H, t, J = 8.5 Hz), 7.31 (1H, d, J = 7.2 Hz), 7.46-7.55 (1H, m), 7.69-7.81 (2H, m), 9.09 (1H, s). 30 B) (3S)-3-Amino-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3- yl]pyrrolidine-1-carboxamide hydrochloride tert-Butyl [(3S)-1-{[4-(2,6-difluorophenyl)-1,2- 35 benzoxazol-3-yl]carbamoyl}pyrrolidin-3-yl]carbamate (223 mg)

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[0247] was dissolved in 4 M hydrogen chloride / CPME solution (2 mL) at room temperature. The mixture was stirred at the same temperature for 1h. The volatiles were evaporated under reduced pressure to give the title compound (189 mg). 5 MS: [M+H]+359.0. C) (3S)-N-[4-(2,6-Difluorophenyl)-1,2-benzoxazol-3-yl]-3- (dimethylsulfamamido)pyrrolidine-1-carboxamide 10 To a solution of (3S)-3-amino-N-[4-(2,6-difluorophenyl)- 1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide hydrochloride (21.9 mg) and TEA (0.034 mL) in DME (0.5 mL) were added dimethylsulfamoyl chloride (0.013 mL) and DMAP (3.7 mg) at 0 °C. The mixture was stirred at 60 °C for 6 h. The solvent 15 was removed under reduced pressure and the residue was purified by HPLC (column: YMC-Actus Triant C18, mobile phase: water(containing 10 mM ammonium hydrogencarbonate) / MeCN) to give the title compound (14.6 mg). 1H NMR (400 MHz, DMSO-d6) δ 1.55-2.02 (2H, m), 2.64-2.7520(6H, m), 2.82-3.38 (4H, m), 3.53-3.70 (1H, m), 7.07-7.23 (2H, m), 7.31 (1H, d, J = 7.2 Hz), 7.42-7.55 (2H, m), 7.68-7.83 (2H, m), 9.17 (1H, s). Example 8825(2R,4S)-N-[4-(2,6-Difluorophenyl)-6-methyl-1,2-benzoxazol-3- yl]-4-(methanesulfonamido)-2-methylpyrrolidine-1-carboxamide A) tert-Butyl (2R,4S)-4-(methanesulfonamido)-2- methylpyrrolidine-1-carboxylate 30 To a mixture of tert-butyl (2R,4S)-4-amino-2- methylpyrrolidine-1-carboxylate (100 mg) in DCM (8.0 mL) were added TEA (101 mg) and methanesulfonyl chloride (86 mg) dropwise at 0 °C, and it was stirred at 20 °C for 12 h. The 35 reaction mixture was poured into water and it was extracted

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[0249] with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. the residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to 5 give the title compound (138 mg). 1H NMR (400 MHz, CDCl3) δ 1.32 (3H, d, J = 6.0 Hz), 1.47 (9H, s), 1.51-1.58 (1H, m,), 2.46-2.57 (1H, m), 3.00 (3H, s), 3.08-3.18 (1H, m), 3.80-3.98 (3H, m), 4.49 (1H, brs). 10 B) N-[(3S,5R)-5-Methylpyrrolidin-3-yl]methanesulfonamide hydrochloride To a mixture of tert-butyl (2R,4S)-4- (methanesulfonamido)-2-methylpyrrolidine-1-carboxylate (138 15 mg) in dioxane (1 mL) was added 4 M hydrogen chloride / dioxane solution (1 mL), and it was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure to give the title compound (123 mg). 1H NMR (400 MHz, DMSO-d6) δ 1.32 (3H, d, J = 6.4 Hz),201.46-1.58 (1H, m), 2.39-2.45 (1H, m,), 2.95-3.08 (4H, m), 3.47-3.53 (1H, m), 3.64-3.77 (1H, m), 3.98-4.09 (1H, m), 7.30- 7.60 (1H, m), 9.00 (1H, brs), 9.35 (1H, brs). C) (2R,4S)-N-[4-(2,6-Difluorophenyl)-6-methyl-1,2-benzoxazol-253-yl]-4-(methanesulfonamido)-2-methylpyrrolidine-1-carboxamide To a solution of 4-(2,6-difluorophenyl)-6-methyl-1,2- benzoxazol-3-amine (50 mg) in DCM (3.0 mL) was added pyridine (61 mg) at 0 °C, then to the mixture was added 30 bis(trichloromethyl)carbonate (114 mg) at 0 °C, the reaction mixture was stirred at 20 °C for 2 h under nitrogen atmosphere. The reaction mixture was poured into water and it was extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and 35 concentrated under reduced pressure. Then the mixture was

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[0251] diluted with DCM (3 mL), then TEA (58 mg) and N-[(3S,5R)-5- methylpyrrolidin-3-yl]methanesulfonamide hydrochloride (54 mg) were added, and the reaction mixture was warmed to 20 °C for 12 h under nitrogen atmosphere. The reaction mixture was 5 poured into water and it was extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Boston Prime C18, mobile phase: water (containing 0.05% ammonium 10 hydroxide) / MeCN). The desired fraction was concentrated under reduced pressure and the remaining solvent was removed by lyophilization to give the title compound (5.1 mg). 1H NMR (400 MHz, CDCl3) δ 1.18 (3H, d, J = 6.0 Hz), 1.42- 1.52 (1H, m), 2.32-2.42 (1H, m), 2.55 (3H, s), 2.97-3.07 (4H, 15 m), 3.52-3.68 (2H, m), 3.75-3.87 (1H, m), 4.82 (1H, brs), 6.75 (1H, brs), 7.00-7.11 (3H, m), 7.35-7.47 (2H, m). Example 90 rel-(4R)-N-[6-Chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-20yl]-3,3-difluoro-4-(methanesulfonamido)pyrrolidine-1- carboxamide A) tert-Butyl rac-(4R)-4-{[(benzyloxy)carbonyl]amino}-3,3- difluoropyrrolidine-1-carboxylate25To a solution of tert-butyl 4-amino-3,3- difluoropyrrolidine-1-carboxylate (10.0 g) in DCM (100 mL) were added N,N-diisopropylethylamine (8.72 g) and benzyl carbonochloridate (8.44 g) at 0 °C. The mixture was stirred at 30 20 °C for 16 h. The mixture was quenched with water and it was extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. The residue was purified by silica gel column chromatography 35 (EtOAc / petroleum ether) to give the title compound (14.5 g).

[0252] 130

[0253] MS: [M+H-Boc]+257.1. B) tert-Butyl rel-(4R)-4-{[(benzyloxy)carbonyl]amino}-3,3- difluoropyrrolidine-1-carboxylate 5 tert-butyl rac-(4R)-4-{[(benzyloxy)carbonyl]amino}-3,3- difluoropyrrolidine-1-carboxylate (21.9 g) was purified by SFC (column: DAICEL CHIRALCEL OD, 250mm x 50 mm, 10 μm, mobile phase: CO2 / 0.1% ammonium hydroxide containing EtOH = 89 / 15 10 v / v ) to give the title compound having longer retention time (8.30 g). MS: [M+H-t-Bu]+301.0. C) tert-Butyl rel-(4R)-4-amino-3,3-difluoropyrrolidine-1- 15 carboxylate A mixture of tert-butyl rel-(4R)-4- {[(benzyloxy)carbonyl]amino}-3,3-difluoropyrrolidine-1- carboxylate (3.12 g) and 10% Pd on carbon (0.332 g) in EtOAc20(30 mL) and EtOH (15 mL) was hydrogenated under balloon pressure at room temperature overnight. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound (1.99 g) 1H NMR (400 MHz, CDCl3) δ 1.35 (2H,d, J = 6.0 Hz), 1.4625(9H, s), 3.05-3.20 (1H, m), 3.48-3.89 (4H, m). D) tert-Butyl rel-(4R)-3,3-difluoro-4- (methanesulfonamido)pyrrolidine-1-carboxylate To a mixture of tert-butyl rel-(4R)-4-amino-3,3- 30 difluoropyrrolidine-1-carboxylate (656 mg), TEA (899 mg) and THF (14 mL) was added a mixture of methanesulfonic anhydride (778 mg) and THF (7.0 mL) at 0 °C. The mixture was stirred at room temperature under nitrogen atmosphere overnight. To the mixture was added a saturated aqueous sodium hydrogencarbonate 35 solution at 0 °C and extracted with EtOAc. The organic layer

[0254] 131

[0255] was separated, washed with water and brine, dried over anhydrous sodium sulfate, passed through a plug of silica gel and NH silica gel eluting with EtOAc, and concentrated under reduced pressure to give the title compound (794 mg). 51H NMR (400 MHz, DMSO-d6) δ 1.41 (9H, s), 2.99 (3H, s), 3.08-3.22 (1H, m), 3.60-3.75 (2H, m), 3.80 (1H, t, J = 9.7 Hz), 4.24-4.43 (1H, m), 7.93 (1H, d, J = 8.9 Hz). E) rel-N-[(3R)-4,4-Difluoropyrrolidin-3- 10 yl]methanesulfonamide hydrochloride To a mixture tert-butyl rel-(4R)-3,3-difluoro-4- (methanesulfonamido)pyrrolidine-1-carboxylate (794 mg) and CPME (5.0 mL) was added 4 M hydrogen chloride / CPME solution (10 mL) 15 at 0 °C. The mixture was stirred at room temperature under nitrogen atmosphere overnight. To the mixture was added a mixture of EtOAc / hexane. The insoluble material was collected by filtration, washed with EtOAc / hexane to give the title compound (569 mg). 201H NMR (400 MHz, DMSO-d6) δ 3.02 (3H, s), 3.13 (1H, t, J = 11.1 Hz), 3.64-3.85 (3H, m), 4.33-4.50 (1H, m), 8.11 (1H, d, J = 9.0 Hz), 9.92 (2H, br s). F) 5-Chloro-2',3,6'-trifluoro[1,1'-biphenyl]-2-amine25To a mixture of 2-bromo-4-chloro-6-fluoroaniline (3.00 g), (2,6-difluorophenyl)boronic acid (3.20 g), potassium fluoride (2.41 g), tri-tert-butylphosphonium tetrafluoroborate (0.194 g), water (3.0 mL) and THF (18 mL) was added Pd2(dba)330 (0.245 g) at room temperature. The mixture was stirred at room temperature under nitrogen atmosphere for 3 h. To the mixture was added EtOAc, then the mixture was passed through an NH silica gel pad eluted with EtOAc. After being concentrated under reduced pressure, the residue was purified by silica gel

[0256] 132

[0257] column chromatography (EtOAc / hexane) to give the title compound (2.50 g). MS: [M+H]+258.0. 5 G) 5-Chloro-2',3,6'-trifluoro[1,1'-biphenyl]-2-carbonitrile To a mixture of 5-chloro-2',3,6'-trifluoro[1,1'- biphenyl]-2-amine (510 mg) and 6 M hydrogen chloride aqueous solution (2.0 mL) was added a mixture of sodium nitrite (167 10 mg) and water (0.50 mL) at 0 °C. After being stirred at 0 °C for 30 min, to the mixture was slowly added sodium bicarbonate (831 mg) at 0 °C. The mixture was added to a mixture of potassium cyanide (380 mg), cuprous cyanide (270 mg) and water (2.0 mL) at 70 °C. After addition of toluene (1.0 mL), the 15 mixture was stirred at 70 °C for 30 min. To the mixture was added toluene at room temperature and it was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel20column chromatography (EtOAc / hexane) to give the title compound (146 mg). 1H NMR (400 MHz, DMSO-d6) δ 7.32-7.42 (2H, m), 7.64-7.74 (1H, m), 7.82 (1H, s), 8.03 (1H, dd, J = 9.4, 1.9 Hz).25H) 6-Chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-amine To a mixture of N-(propan-2-ylidene)hydroxylamine (46.9 mg) and DMF (6.0 mL) was added 1 M potassium tert-butoxide / THF solution (0.65 mL) at room temperature. The mixture was 30 stirred at room temperature under nitrogen atmosphere for 20 min. To the mixture was added a solution of 5-chloro-2',3,6'- trifluoro[1,1'-biphenyl]-2-carbonitrile (143 mg) and DMF (2.0 mL) at 0 °C. The mixture was stirred at 0 °C under nitrogen atmosphere for 5 min. To the mixture was added saturated 35 ammonium chloride aqueous solution at 0 °C and extracted with

[0258] 133

[0259] EtOAc. The organic layer was separated, washed with water, and concentrated under reduced pressure. The residue was diluted with EtOH (2.0 mL), water (1.0 mL), and 6 M hydrogen chloride aqueous solution (1.0 mL). The mixture was stirred at 80 °C 5 under nitrogen atmosphere overnight. After cooling to room temperature, to the mixture was added EtOH and 6 M hydrogen chloride aqueous solution. The mixture was stirred at 70 °C under nitrogen atmosphere for 2 h. To the mixture was added saturated sodium hydrogencarbonate aqueous solution at 0 °C 10 and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (EtOAc / hexane) to give the title compound (43.6 mg). 15 MS: [M+H]+280.9. I) rel-(4R)-N-[6-Chloro-4-(2,6-difluorophenyl)-1,2- benzoxazol-3-yl]-3,3-difluoro-4- (methanesulfonamido)pyrrolidine-1-carboxamide20To a mixture of 6-chloro-4-(2,6-difluorophenyl)-1,2- benzoxazol-3-amine (20 mg), pyridine (23 mg) and DCM (1.5 mL) was added a mixture of bis(trichloromethyl)carbonate (42 mg) and DCM (0.5 mL) at 0 °C. The mixture was stirred at room25temperature under nitrogen atmosphere for 2 h. After being concentrated under reduced pressure, to the residue was added DCM (1.5 mL), rel-N-[(3R)-4,4-difluoropyrrolidin-3- yl]methanesulfonamide hydrochloride (16.9 mg), and TEA (0.030 mL) at room temperature. The mixture was stirred at room 30 temperature under nitrogen atmosphere for 3 h. After being concentrated under reduced pressure, the residue was diluted with THF (1.5 mL), and TEA (0.030 mL) was added. The mixture was stirred at 50 °C under nitrogen atmosphere overnight. The mixture was diluted with EtOAc, and passed through a silica 35 gel pad eluted with EtOAc, and concentrated under reduced

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[0261] pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) then recrystallized from EtOAc- heptane to give the title compound (20.9 mg). 1H NMR (400 MHz, DMSO-d6) δ 2.77-3.11 (4H, m), 3.29 (1H, 5 s), 3.35-3.77 (2H, m), 4.08-4.28 (1H, m), 7.11-7.23 (2H, m), 7.42-7.56 (2H, m), 7.81-8.19 (2H, m), 9.44-9.67 (1H, m). Example 91 rel-(4R)-N-[6-Chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-10 yl]-4-(ethanesulfonamido)-3,3-difluoropyrrolidine-1- carboxamide A) tert-Butyl rel-(4R)-4-(ethanesulfonamido)-3,3- difluoropyrrolidine-1-carboxylate 15 To a solution of tert-butyl rel-(4R)-4-amino-3,3- difluoropyrrolidine-1-carboxylate (660 mg) and TEA (2.1 mL) in DME (9.9 mL) was added ethanesulfonyl chloride (394 µL) at 5 °C. The mixture was stirred at room temperature for 2 h. The20mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (870 mg). MS: [M+H-Boc]+215.0.25B) rel-N-[(3R)-4,4-Difluoropyrrolidin-3-yl]ethanesulfonamide hydrochloride 4 M hydrogen chloride / EtOAc solution (4.15 mL) was added to tert-butyl rel-(4R)-4-(ethanesulfonamido)-3,3- 30 difluoropyrrolidine-1-carboxylate (870 mg) at room temperature. The mixture was stirred at room temperature under a dry atmosphere overnight. An insoluble material was collected by filtration and washed with EtOAc to give the title compound (632 mg). 35 MS: [M+H]+215.0.

[0262] 135

[0263] C) rel-(4R)-N-[6-Chloro-4-(2,6-difluorophenyl)-1,2- benzoxazol-3-yl]-4-(ethanesulfonamido)-3,3- difluoropyrrolidine-1-carboxamide 5 To a mixture of 6-chloro-4-(2,6-difluorophenyl)-1,2- benzoxazol-3-amine (200 mg), pyridine (0.231 mL) and DCM (10 mL) was added bis(trichloromethyl)carbonate (423 mg) at 0 °C. The mixture was stirred at room temperature under nitrogen 10 atmosphere for 1 h. The mixture was concentrated under reduced pressure to give a residue. A solution of the residue in THF (1.0 mL) was added to a mixture of rel-N-[(3R)-4,4- difluoropyrrolidin-3-yl]ethanesulfonamide hydrochloride (178 mg), TEA (0.592 mL) and THF (1.0 mL) at room temperature. The 15 mixture was stirred at 50 °C overnight. The mixture was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (155 mg). 1H NMR (400 MHz, CDCl3) δ 1.42 (3H, t, J = 7.3 Hz), 3.00- 3.22 (3H, m), 3.41-3.73 (3H, m), 4.06-4.21 (1H, m), 4.82-4.9120(1H, m), 6.79-6.89 (1H, m),7.02-7.11 (2H, m), 7.29-7.31 (1H, m), 7.43-7.53 (1H, m), 7.62-7.65 (1H, m). Example 92 (3S)-N-[4-(2,6-Difluorophenyl)-1,2-benzoxazol-3-yl]-3-25(ethanesulfonamido)pyrrolidine-1-carboxamide A) (3S)-N-[4-(2,6-Difluorophenyl)-1,2-benzoxazol-3-yl]-3- (ethanesulfonamido)pyrrolidine-1-carboxamide 30 To a mixture of (3S)-3-amino-N-[4-(2,6-difluorophenyl)- 1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide hydrochloride (30 mg), TEA (0.032 mL), DMAP (4.6 mg) and THF (1 mL) was added ethanesulfonyl chloride (11 µL) at 0 °C. The mixture was stirred at room temperature under nitrogen atmosphere 35 overnight. To the mixture was added water and it was extracted

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[0265] with EtOAc. The organic layer was separated, washed with 0.1 M hydrogen chloride aqueous solution and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC 5 (column: YMC-Actus Triant C18, mobile phase: water (containing 10 mM ammonium hydrogencarbonate) / MeCN) to give the title compound (15.7 mg). 1H NMR (400 MHz, DMSO-d6) δ 1.22 (3H, t, J = 7.3 Hz), 1.57-1.78 (1H, m), 1.88-2.05 (1H, m), 2.71-3.35 (6H, m), 3.59- 10 3.80 (1H, m), 7.10-7.22 (2H, m), 7.32 (1H, d, J = 7.1 Hz), 7.36-7.44 (1H, m), 7.46-7.56 (1H, m), 7.69-7.75 (1H, m), 7.76- 7.83 (1H, m), 9.16 (1H, s). Example 93 15 rel-(4R)-N-[4-(2,6-Difluorophenyl)-6-fluoro-1,2-benzoxazol-3- yl]-4-(ethanesulfonamido)-3,3-difluoropyrrolidine-1- carboxamide A) 2,4-Difluoro-6-iodobenzonitrile20A mixture of 2,4-difluorobenzonitrile (3 g), N- iodosuccinimide (5.34 g), 4-methylbenzenesulfonic acid hydrate (2.05 g) and palladium(II) acetate (0.242 g) in DMF (45 mL) was heated to 70 °C in an oil bath for 6 h. After cooling to25room temperature the mixture was poured into water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the 30 title compound (1.62 g). 1H NMR (400 MHz, DMSO-d6) δ 7.63-7.80 (1H, m), 7.91-7.98 (1H, m). B) 6-Fluoro-4-iodo-1,2-benzoxazol-3-amine 35

[0266] 137

[0267] 1 M potassium tert-butoxide / THF solution (1.62 mL) was added to a solution of N-(propan-2-ylidene)hydroxylamine (118 mg) in DMF (16 mL) at room temperature. The mixture was stirred at room temperature under nitrogen atmosphere for 30 min. Then this 5 mixture was added dropwise to a solution of 2,4-difluoro-6- iodobenzonitrile (428 mg) in DMF (5.3 mL) at 0 °C. The mixture was stirred at 0 °C under nitrogen atmosphere for 5 min. The mixture was quenched with saturated ammonium chloride aqueous solution at 0 °C and extracted with EtOAc. The organic layer was 10 separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was diluted with EtOH (17.8 mL) and 6 M hydrogen chloride aqueous solution (8.9 mL) and the mixture was stirred at 80 °C under nitrogen atmosphere for 5 h. The mixture was concentrated in vacuo and 15 then was neutralized with saturated aqueous sodium hydrogencarbonate at 0 °C and extracted with EtOAc. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (EtOAc / hexane)20to give the title compound (180 mg). MS: [M+H]+278.9. C) 4-(2,6-Difluorophenyl)-6-fluoro-1,2-benzoxazol-3-amine25To a mixture of 6-fluoro-4-iodo-1,2-benzoxazol-3-amine (115 mg), 2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (596 mg), potassium fluoride (72.1 mg), tri- tert-butylphosphonium tetrafluoroborate (24.0 mg), water (1 mL) and DME (5 mL) was added Pd2(dba)3(37.9 mg) at room 30 temperature. The mixture was stirred at 120 °C for 1 h under microwave irradiation. The water layer was removed and the solvent was evaporated under reduced pressure. Then the mixture was passed through a NH silica gel pad eluted with EtOAc. After being concentrated under reduced pressure, The 35 residue was purified by silica gel column chromatography

[0268] 138

[0269] (EtOAc / hexane) to give the title compound (103 mg). MS: [M+H]+265.0. D) 4-(2,6-Difluorophenyl)-6-fluoro-3-isocyanato-1,2- 5 benzoxazole To a mixture of 4-(2,6-difluorophenyl)-6-fluoro-1,2- benzoxazol-3-amine (36 mg), pyridine (0.044 mL) and toluene (4.5 mL) was added bis(trichloromethyl)carbonate (81 mg) at 10 0 °C. The mixture was stirred at 0 °C under nitrogen atmosphere for 1 h. The mixture was diluted with diethyl ether / hexane and filtered over a celite pad. The filtrate was concentrated under reduced pressure to give the title compound (29 mg). 15 MS: [M+H]+290.9. E) rel-(4R)-N-[4-(2,6-Difluorophenyl)-6-fluoro-1,2- benzoxazol-3-yl]-4-(ethanesulfonamido)-3,3- difluoropyrrolidine-1-carboxamide20To a mixture of rel-N-[(3R)-4,4-difluoropyrrolidin-3- yl]ethanesulfonamide hydrochloride (12.4 mg) and THF (1.5 mL) was added 4-(2,6-difluorophenyl)-6-fluoro-3-isocyanato-1,2- benzoxazole (12 mg) at room temperature. The mixture was25stirred at room temperature for 15 min. To the mixture was added TEA (0.023 mL) at room temperature, the mixture was stirred at room temperature for 15 min, then at 50 °C overnight. After being concentrated under reduced pressure, the residue was purified by silica gel column chromatography 30 (EtOAc / hexane) to give the title compound (2.8 mg). 1H NMR (400 MHz, DMSO-d6) δ 1.19-1.52 (5H, m), 1.93-2.08 (1H, m), 2.83-3.40 (4H, m), 4.04-4.25 (1H, m), 7.13-7.23 (1H, m), 7.39 (1H, dd, J = 9.8, 1.9 Hz), 7.44-7.57 (1H, m), 7.79-7.89 (1H, m), 7.95-8.06 (1H, m), 9.46-9.57 (1H, m). 35

[0270] 139

[0271] Example 96 (3S)-3-(Cyclopropanesulfonamido)-N-[4-(2,6-difluorophenyl)- 1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide 5 A) (3S)-3-(Cyclopropanesulfonamido)-N-[4-(2,6- difluorophenyl)-1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide To a solution of (3S)-3-amino-N-[4-(2,6-difluorophenyl)- 1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide hydrochloride 10 (30 mg) and TEA (31 µL) in dry THF (1.00 mL) was added dropwise cyclopropanesulfonyl chloride (11 µL) at 25 °C. The mixture was stirred at room temperature for 2 h then the solvent was removed under reduced pressure and the crude was directly purified by preparative HPLC (column: YMC-Actus 15 Triant C18, mobile phase: water (containing 10 mM ammonium hydrogencarbonate) / MeCN) followed by NH silica gel column chromatography (EtOAc / hexane) to give the title compound (15.3 mg). 1H NMR (400 MHz, DMSO-d6) δ 0.88-1.06 (4H, m), 1.59-1.8120(1H, m), 1.92-2.05 (1H, m), 2.54-2.63 (1H, m), 2.70-3.38 (4H, m), 3.66-3.85 (1H, m), 7.10-7.23 (2H, m), 7.32 (1H, d, J = 7.1 Hz), 7.35-7.45 (1H, m), 7.46-7.56 (1H, m), 7.69-7.76 (1H, m), 7.77-7.82 (1H, m), 9.13-9.19 (1H, m).25Example 97 rel-(4R)-N-[6-Bromo-4-(2,6-difluorophenyl)-1,2-benzoxazol-3- yl]-3,3-difluoro-4-(methanesulfonamido)pyrrolidine-1- carboxamide 30 A) 2',3,6'-Trifluoro[1,1'-biphenyl]-2-amine To a mixture of 2-bromo-6-fluoroaniline (5.51 g), (2,6- difluorophenyl)boronic acid (6.87 g), potassium fluoride (5.05 g), tri-tert-butylphosphonium tetrafluoroborate (0.841 g), 35 water (6 mL) and THF (30 mL) was added palladium(II) acetate

[0272] 140

[0273] (0.326 g) at room temperature. The mixture was stirred at room temperature under nitrogen overnight. To the mixture was added EtOAc, then the mixture was passed through a NH silica gel pad eluted with EtOAc. After being concentrated under reduced 5 pressure, the residue was purified by NH silica gel column chromatography (EtOAc / hexane) to give the title compound (5.62 g). MS: [M+H]+224.0. 10 B) 5-Bromo-2',3,6'-trifluoro[1,1'-biphenyl]-2-amine To a mixture of 2',3,6'-trifluoro[1,1'-biphenyl]-2-amine (5.62 g) and MeCN (120 mL) was added N-bromosuccinimide (4.93 g) at room temperature. The mixture was stirred at room 15 temperature for 10 min. To the mixture was added sodium thiosulfate aqueous solution and it was extracted with EtOAc. The organic layer was separated, washed with saturated sodium hydrogencarbonate aqueous solution and brine, dried over anhydrous sodium sulfate and concentrated under reduced20pressure. The residue was purified by NH silica gel column chromatography (EtOAc / hexane) to give the title compound (6.73 g). MS: [M+H]+301.9.25C) 5-Bromo-2',3,6'-trifluoro[1,1'-biphenyl]-2-amine To a mixture of 5-bromo-2',3,6'-trifluoro[1,1'- biphenyl]-2-amine (3.00 g) and 6 M hydrogen chloride aqueous solution (15 mL) was added a solution of sodium nitrite (0.82 30 g) in water (3.0 mL) at 0 °C. After being stirred at 0 °C for 30 min, to the mixture was slowly added sodium hydrogencarbonate (6.51 g) at 0 °C. The mixture was added to a mixture of potassium cyanide (1.98 g), cuprous cyanide (1.35 g), toluene (6.0 mL) and water (15 mL) at 70 °C. The mixture 35 was stirred at 70 °C for 30 min. Toluene was added at room

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[0275] temperature and the mixture was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel 5 column chromatography (EtOAc / hexane) to give the title compound (0.819 g). 1H NMR (400 MHz, DMSO-d6) δ 7.32-7.41 (2H, m), 7.63-7.74 (1H, m), 7.93 (1H, s), 8.14 (1H, dd, J = 9.0, 1.7 Hz). 10 D) 6-Bromo-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-amine To a mixture of N-(propan-2-ylidene)hydroxylamine (230 mg) and DMF (27 mL) was added 1 M potassium tert-butoxide / THF solution (3.2 mL) at room temperature. The mixture was stirred 15 at room temperature under nitrogen atmosphere for 10 min. To the mixture was added a mixture of 6-bromo-4-(2,6- difluorophenyl)-1,2-benzoxazol-3-amine (819 mg) and DMF (9.0 mL) at 0 °C. The mixture was stirred at 0 °C under nitrogen atmosphere for 5 min. To the mixture was added saturated20ammonium chloride aqueous solution at 0 °C and extracted with EtOAc. The organic layer was separated, washed with water, and concentrated under reduced pressure. The residue was diluted with EtOH (30 mL), and 6 M hydrogen chloride aqueous solution (15 mL). The mixture was stirred at 80 °C under nitrogen25atmosphere overnight. After being concentrated under reduced pressure, to the residue was added saturated sodium hydrogencarbonate aqueous solution at 0 °C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate and concentrated 30 under reduced pressure. The residue was purified by NH silica gel column chromatography (EtOAc / hexane) to give the title compound (515 mg). MS: [M+H]+324.9. 35 E) rel-(4R)-N-[6-Bromo-4-(2,6-difluorophenyl)-1,2-benzoxazol-

[0276] 142

[0277] 3-yl]-3,3-difluoro-4-(methanesulfonamido)pyrrolidine-1- carboxamide To a mixture of 6-bromo-4-(2,6-difluorophenyl)-1,2- 5 benzoxazol-3-amine (20 mg), pyridine (0.020 mL) and DCM (1.0 mL) was added a mixture of bis(trichloromethyl)carbonate (36.5 mg) at 0 °C. The mixture was stirred at room temperature under nitrogen atmosphere for 4 h. The mixture was concentrated under reduced pressure to give a residue. To a mixture of rel- 10 N-[(3R)-4,4-difluoropyrrolidin-3-yl]methanesulfonamide hydrochloride (14.2 mg), TEA (0.050 mL) and THF (0.5 mL) was added a solution of the above described residue in THF (0.5 mL) at room temperature. The mixture was stirred at 50 °C overnight. The mixture was purified by NH silica gel column 15 chromatography (EtOAc / hexane) to give the title compound (6.0 mg). 1H NMR (400 MHz, CD3OD) δ 2.91-3.10 (4H, m), 3.39-3.77 (3H, m), 4.17-4.33 (1H, m), 7.12 (2H, t, J = 8.4 Hz), 7.49 (1H, s), 7.50-7.59 (1H, m), 7.97 (1H, d, J = 1.3 Hz).20Example 98 (4S)-N-[4-(2,6-Difluorophenyl)-1,2-benzothiazol-3-yl]-4- (methanesulfonamido)azepane-1-carboxamide25A) 4-Nitrophenyl (4S)-4-(methanesulfonamido)azepane-1- carboxylate To a mixture of N-[(4S)-azepan-4-yl]methanesulfonamide hydrobromide (300 mg) and TEA (333 mg) in THF (10 mL) was 30 added 4-nitrophenyl carbonochloridate (266 mg) at 0 °C, then the mixture was stirred at 25 °C for 12 h. It was diluted with water and extracted with EtOAc, dried over anhydrous sodium sulfate. The combined organic layer was concentrated under reduced pressure. The residue was purified by NH silica gel

[0278] 143

[0279] column chromatography (EtOAc / hexane) to give the title compound (190 mg) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.62-1.89 (3H, m), 1.91-2.12 (2H, m), 2.15-2.32 (1H, m), 2.95-3.02 (3H, m), 3.29-3.48 (1H, 5 m), 3.51-3.89 (4H, m), 4.32-4.44 (1H, m), 7.28-7.35 (2H, m), 8.22-8.29 (2H, m). B) 4-Bromo-1,2-benzothiazol-3-amine 10 To a solution of 2-bromo-6-fluorobenzonitrile (800 mg) in DMSO (8 mL) was added sodium sulfide (312 mg). The mixture was stirred at 70 °C under nitrogen atmosphere for 16 h. Then the reaction was cooled to 0 °C. 25% ammonium hydroxide aqueous solution (2.62 g) and 10% sodium hypochlorite aqueous 15 solution (4.85 g) were added to the mixture dropwise. Then the final mixture was stirred at 20 °C for 5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (182 mg).20 1H NMR (400 MHz, CDCl3) δ 5.74 (2H, brs), 7.26-7.32 (1H, m,), 7.49-7.56 (1H, m), 7.69-7.76 (1H, m). C) 4-(2,6-Difluorophenyl)-1,2-benzothiazol-3-amine25The mixture of 4-bromo-1,2-benzothiazol-3-amine (206 mg), 2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (431 mg), tert-butylphosphonium tetrafluoroborate (26.1 mg), Pd2(dba)3(166 mg) and potassium fluoride (157 mg) in DME (4.5 mL) and water (1.5 mL) was 30 heated at 120 °C for 1 h under microwave. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica 35 gel column chromatography (EtOAc / hexane) to give the title

[0280] 144

[0281] compound (176 mg) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 4.55 (2H, brs), 7.05-7.14 (2H, m), 7.22-7.26 (1H, m), 7.43-7.53 (1H, m), 7.53-7.61 (1H, m), 7.84-7.90 (1H, m). 5 D) (4S)-N-[4-(2,6-Difluorophenyl)-1,2-benzothiazol-3-yl]-4- (methanesulfonamido)azepane-1-carboxamide A solution of 4-(2,6-difluorophenyl)-1,2-benzothiazol-3- 10 amine (30.0 mg) in THF (1.5 mL) was degassed and purged with nitrogen atmosphere, and cooled to -78 °C, then 1 M Lithium bis(trimethylsilyl)amide / THF solution (0.229 mL) was added dropwise, then to the mixture was added a solution of 4- nitrophenyl (4S)-4-(methanesulfonamido)azepane-1-carboxylate 15 (40.9 mg) in THF (1 mL) dropwise. Then the mixture was stirred at 25 °C for 14 h under nitrogen atmosphere. The reaction mixture was quenched by saturated ammonium chloride aqueous solution, and then extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium20sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give (column: YMC-Actus Triant C18, mobile phase: water (containing ammonium hydroxide) / MeCN) to give the title compound (10.0 mg).25 1H NMR (400 MHz, DMSO-d6) δ 1.22-1.49 (3H, m), 1.63-1.83 (3H, m), 2.64-3.19 (8H, m), 7.01-7.19 (3H, m), 7.33 (1H, d, J = 6.8 Hz), 7.46-7.77 (2H, m), 8.23 (1H, d, J = 8.0 Hz), 8.87 (1H, brs). The compounds of Examples are shown in the following 30 tables. MS in the tables means actual measured value. The compounds of Examples 1-7, 10-13, 16-23, 25-41, 43-65, 67-70, 72-76, 78-82, 85, 89, 94, 95, 99-109 in the following tables were produced according to the methods described in the above- mentioned Examples, or methods analogous thereto. 35

[0282] 145

[0283] Table 1-1 Ex. IUPAC Name Strctre MS

[0284] 146

[0285] Table 1-2 Ex. IUPAC Name Strctre MS

[0286] 147

[0287] Table 1-3 Ex. IUPAC Name Strctre MS

[0288] 148

[0289] Table 1-4 Ex. IUPAC Name Strctre MS

[0290] 149

[0291] Table 1-5 Ex. IUPAC Name Strctre MS

[0292] 150

[0293] Table 1-6 Ex. IUPAC Name Strctre MS

[0294] 151

[0295] Table 1-7 Ex. IUPAC Name Strctre MS

[0296] 152

[0297] Table 1-8 Ex. IUPAC Name Strctre MS

[0298] 153

[0299] Table 1-9 Ex. IUPAC Name Strctre MS

[0300] 154

[0301] Table 1-10 Ex. IUPAC Name Strctre MS

[0302] 155 Table 1-11 Ex. IUPAC Name Strctre MS

[0303] Table 1-12 Ex. IUPAC Name Strctre MS

[0304] 157

[0305] Table 1-13 Ex. IUPAC Name Strctre MS

[0306] 158 Table 1-14 Ex. IUPAC Name Strctre MS Table 1-15 Ex. IUPAC Name Strctre MS

[0307] Table 1-16 Ex. IUPAC Name Strctre MS

[0308] 161

[0309] Table 1-17 Ex. IUPAC Name Strctre MS

[0310] 162

[0311] Table 1-18 Ex. IUPAC Name Strctre MS

[0312] 163

[0313] Table 1-19 Ex. IUPAC Name Strctre MS

[0314] 164

[0315] Experimental Example 1: Obtainment of cell stably expressing human orexin type 2 receptor (hOX2R) To obtain a cell clone stably expressing human orexin type 2 receptor, human orexin type 2 receptor cDNA was 5 inserted into pcDNA3.1(+) plasmid vector (Invitrogen), and a plasmid DNA for expression of human orexin type 2 receptor (pcDNA3.1(+) / hOX2R) was cloned. The plasmid DNA was introduced into CHO-K1 cell by an electroporation method, and human orexin type 2 receptor expressing clone cells were obtained by 10 limiting dilution method by using G418 drug resistance as a selection marker. Experimental Example 2: Measurement of orexin type 2 receptor agonist activity 15 CHO cells forcibly expressing human OX2 receptor were seeded in each well of 384 well black transparent bottom plate (BD Falcon) at 10,000 cells / well, and cultured for one day in a 5% CO2incubator at 37^C. After removal of the medium in the cell plate, assay buffer A containing a calcium indicator20(HBSS (Thermo Fisher Scientific), 20 mM HEPES (Thermo Fisher Scientific), 0.1% BSA (Sigma-Aldrich), 2.5 μg / mL Fluo-4 AM (DOJINDO Chemical), 0.08% Pluronic F127 (DOJINDO Chemical), 1.25 mM probenecid (DOJINDO Chemical)) was added at 30 μL / well. The plate was stood for 30 min in a 5% CO2incubator25at 37^C, and further stood at room temperature for 30 min. A test compound prepared by diluting with assay buffer B (HBSS, 20 mM HEPES, 0.1 % BSA) was added at 10 μL / well, and the fluorescence value was measured by FDSSμCELL (Hamamatsu Photonics K.K.) every one sec for 1 min, and thereafter every 30 two sec for 1 min 40 sec. The activity (%) of the test compound was calculated assuming that variation in the fluorescence value when DMSO was added instead of the test compound was 0%, and variation in the fluorescence value when orexin A (human) (PEPTIDE INSTITUTE, INC.) was added at the 35 final concentration of 10 nM was 100%. The activity of each

[0316] 165 compound at the concentration of 3 μM was shown in Tables 2-1. As is clear from the results, the compound of the present invention was shown to have an agonist activity on human orexin type 2 receptor. 5 Table 2-1 Example No. OX2R agonist activity (3 μM, %)

[0317] 91 102 Formulation Example 1 (production of capsule) 1) compound of Example 1 30 mg 2) crystalline cellulose 10 mg 5 3) lactose 19 mg 4) magnesium stearate 1 mg total 60 mg 1), 2), 3) and 4) are mixed and filled in a gelatin capsule.10Formulation Example 2 (production of tablet) 1) compound of Example 1 30 g 2) lactose 50 g 3) cornstarch 15 g 15 4) calcium carboxymethylcellulose 44 g 5) magnesium stearate 1 g 1000 tablets 140 g in total The total amount of 1), 2), 3) and 30 g of 4) are kneaded with water, vacuum dried and sieved. The sieved powder 20 is mixed with 14 g of 4) and 1 g of 5), and the mixture is punched by a tableting machine. In this way, 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained. 25 [Industrial Applicability] The compound of the present invention has an orexin type

[0318] 167

[0319] 2 receptor agonist activity, and is useful as an agent for the prophylaxis or treatment of narcolepsy.

[0320] 168

Claims

[Document] CLAIMS

1. A compound represented by the formula (I): )each is independently a single or a double bond as defined by X1, X2, X3, X4, and X5such that all valences are satisfied; X1is selected from –CR3-, =C-, and –N-; 10 X2is selected from –CR4R5-, =CR4-, =N-, -NR6-, -O-, and –S-; and X3is selected from –CR7R8-, =CR7-, =N-, -NR9-, -O-, and –S-; wherein when X2is =N-, X3is selected from =CR7-, -O-, and –S-; and when X3is =N-, X2is selected from =CR4-, -O-, and –S-; and 15 when one of X2and X3is –O- or –S-, the other is not –O- or –S-; X4and X5are each =C-; or one of X4and X5is –N- and the other is =C-; X6is selected from CR10and N;20X7is selected from CR11and N; X8is selected from CR12and N; R1is selected from an optionally substituted C1-6alkyl group, an optionally substituted C3-10cycloalkyl group and an optionally substituted mono- or di-C1-6alkylamino group; 25 R2is an optionally substituted 5- or 6-membered monocyclic group; R3is selected from a hydrogen atom, a halogen atom, a hydroxy, an optionally substituted C1-6alkyl group, and an optionally substituted C1-6alkoxy group;169R4, R5, R7, and R8are independently selected from a hydrogen atom, a halogen atom, a hydroxy, an optionally substituted C1-6alkyl group, an optionally substituted C1-6alkoxy group, and an optionally substituted C3-6cycloalkyl group; 5 R6and R9are independently selected from a hydrogen atom and an optionally substituted C1-6alkyl group; R10, R11, and R12are independently selected from a hydrogen atom, a halogen atom, a hydroxy, an optionally substituted C1-6alkyl group, an optionally substituted C1-6alkoxy group, and an 10 optionally substituted C3-6cycloalkyl group; L is selected from a bond, -CRbRc-, -NRa-, and –O-; Rais selected from a hydrogen atom and an optionally substituted C1-6alkyl group; Rband Rcare independently selected from a hydrogen atom, a 15 halogen atom, and an optionally substituted C1-6alkyl group; Ring B is selected from an optionally substituted C5-7cycloalkyl group, an optionally substituted 4-, 5-, 6-, 7-, or 8-membered nitrogen-containing monocyclic heterocyclic group, and an optionally substituted 6-, 7-, or 8-membered nitrogen-containing20fused heterocyclic group; W is selected from a bond and -CRdRe-; and Rdand Reare independently selected from a hydrogen atom and an optionally substituted C1-6alkyl group; or a salt thereof.25

2. The compound of claim 1, wherein: X6is CR10; X7is CR11; and 30 X8is CR12; or a salt thereof.

3. The compound of claim 1, wherein:170171-6alkyl group optionally substituted with 1 to 3 halogen atoms, a C3-10cycloalkyl group, and a mono- or di-C1-6alkylamino group; 5 R2is a 6-membered monocyclic group optionally substituted with 1 to 3 halogen atoms; R3is a hydrogen atom; R4, R5, R7, and R8are independently selected from a hydrogen atom, a halogen atom, and a C1-6alkyl group; 10 R10, R11, and R12are independently selected from a hydrogen atom, a halogen atom, and a C1-6alkyl group optionally substituted with 1 to 3 halogen atoms; L is selected from a bond, -CRbRc-, -NRa-, and –O-; Rais a hydrogen atom; 15 Rband Rcare independently selected from a hydrogen atom, a halogen atom, and a C1-6alkyl group; Ring B is selected from: a C5-7cycloalkyl group; a 4-, 5-, 6-, or 7-membered nitrogen-containing monocyclic20heterocyclic group optionally substituted with 1 to 3 groups selected from a halogen atom, a hydroxy group, a C1-6alkyl group optionally substituted with a C1-6alkoxy group, and a halogenated C1-6alkyl group; and a 6-, 7-, or 8-membered nitrogen-containing fused 25 heterocyclic group; W is selected from a bond and -CRdRe-; and Rdand Reare independently selected from a hydrogen atom and a C1-6alkyl group; or a salt thereof.173

4. The compound of claim 1, wherein Ring B is selected from:174,wherein the bond marked with “*” is attached to W; or a salt thereof. 5

5. The compound of claim 1 represented by the formula (Ia): ) were n: X2is selected from –CR4R5-, =CR4-, and =N-; and 10 X3is selected from –CR7R8-, -O-, and –S-; wherein when X2is =N-, X3is selected from –O- and –S-; R1is selected from a C1-6alkyl group, a C3-10cycloalkyl group, and a mono- or di-C1-6alkylamino group; R2is 6-membered monocyclic group optionally substituted with 1 to 15 3 halogen atoms; R4, R5, R7, and R8are each a hydrogen atom; R11is selected from a hydrogen atom, a halogen atom, and a C1-6alkyl group; and Ring B is selected from:20a C5-7cycloalkyl group; and a 5-, 6-, or 7-membered nitrogen-containing monocyclic176heterocyclic group optionally substituted with 1 to 3 groups selected from a halogen atom and a C1-6alkyl group; or a salt thereof. 5

6. The compound of claim 5, wherein Ring B is selected from: , oa sa e eo . 10

7. The compound of claim 5, wherein:elected from the group consisting of:177-C1-65 alkylamino group; R2is a phenyl group substituted with 1 to 3 halogen atoms; and R11is a hydrogen atom, a halogen atom, or a C1-6alkyl group; or a salt thereof.10

8. The compound of claim 1, wherein the compound is selected from the group consisting of: (4S)-N-[(1RS)-7-(2,6-difluorophenyl)-2,3-dihydro-1H-inden-1- yl]-4-(methanesulfonamido)azepane-1-carboxamide; 15 (3S)-N-[(1R*)-7-(2,6-difluorophenyl)-2,3-dihydro-1H-inden-1- yl]-3-(methanesulfonamido)pyrrolidine-1-carboxamide; (4S)-N-[4-(2,6-difluorophenyl)-1-benzothiophen-3-yl]-4- (methanesulfonamido)azepane-1-carboxamide; (4S)-N-[4-(2,6-difluorophenyl)-1-benzofuran-3-yl]-4- 20 (methanesulfonamido)azepane-1-carboxamide;178(5R*)-N-[4-(2,6-difluorophenyl)-1-benzofuran-3-yl]-4,4- difluoro-5-(methanesulfonamido)azepane-1-carboxamide; (5R*)-N-[4-(2,6-difluorophenyl)-1-benzothiophen-3-yl]-4,4- difluoro-5-(methanesulfonamido)azepane-1-carboxamide; 5 (4S)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-4- (methanesulfonamido)azepane-1-carboxamide; (5R*)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-4,4- difluoro-5-(methanesulfonamido)azepane-1-carboxamide; (3S)-N-[4-(2,6-difluorophenyl)-6-methyl-1,2-benzoxazol-3-yl]- 10 3-(methanesulfonamido)pyrrolidine-1-carboxamide; (5R*)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-5- (ethanesulfonamido)-4,4-difluoroazepane-1-carboxamide; (3S)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3- (dimethylsulfamamido)pyrrolidine-1-carboxamide; 15 (2R,4S)-N-[4-(2,6-difluorophenyl)-6-methyl-1,2-benzoxazol-3- yl]-4-(methanesulfonamido)-2-methylpyrrolidine-1-carboxamide; (4R*)-N-[6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]- 3,3-difluoro-4-(methanesulfonamido)pyrrolidine-1-carboxamide; (4R*)-N-[6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-204-(ethanesulfonamido)-3,3-difluoropyrrolidine-1-carboxamide; (3S)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3- (ethanesulfonamido)pyrrolidine-1-carboxamide; (4R*)-N-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]- 4-(ethanesulfonamido)-3,3-difluoropyrrolidine-1-carboxamide;25(3S)-3-(cyclopropanesulfonamido)-N-[4-(2,6-difluorophenyl)- 1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide; (4R*)-N-[6-bromo-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]- 3,3-difluoro-4-(methanesulfonamido)pyrrolidine-1-carboxamide; (4S)-N-[4-(2,6-difluorophenyl)-1,2-benzothiazol-3-yl]-4- 30 (methanesulfonamido)azepane-1-carboxamide; and (5R)-N-[4-(2,6-difluorophenyl)-1,2-benzothiazol-3-yl]-4,4- difluoro-5-(methanesulfonamido)azepane-1-carboxamide; or a salt thereof. 35

9. 179A pharmaceutical composition comprising the compound as defined in any one of claims 1 to 8 or a salt thereof, and a pharmacologically acceptable carrier. 5

10. A medicament comprising the compound as defined in any one of claims 1 to 8 or a salt thereof.

11. 10 The medicament according to claim 10, which is an orexin type 2 receptor agonist.

12. The medicament according to claim 10, which is an agent for the 15 prophylaxis or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia, Alzheimer’s disease, obesity, insulin resistance syndrome, cardiac failure, diseases related to bone20loss, sepsis, disturbance of consciousness, or side effects and complications due to anesthesia.

13. The medicament according to claim 10, which is an agent for the25prophylaxis or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, or sleep apnea syndrome.

14. The medicament according to claim 10, which is an agent for the 30 prophylaxis or treatment of narcolepsy.

15. A method for the prophylaxis or treatment of a disease or disorder associated with an orexin type 2 receptor in a mammal in need 35 thereof comprising administering to the mammal a therapeutically180effective amount of the compound as defined in any one of claims 1 to 8 or a salt thereof.

16. 5 The method according to claim 15, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia, Alzheimer’s disease, 10 obesity, insulin resistance syndrome, cardiac failure, diseases related to bone loss, sepsis, disturbance of consciousness, and side effects and complications due to anesthesia.

17. 15 The method according to claim 15, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, and sleep apnea syndrome.

18. 20The method according to claim 15, wherein the disease or disorder is narcolepsy.

19. The compound as defined in any one of claims 1 to 8, or a salt25thereof, for use in therapy.

20. The compound or salt according to claim 19, wherein the therapy comprises treatment of a disease or disorder associated with an 30 orexin type 2 receptor.

21. The compound or salt according to claim 20, wherein the disease or disorder is selected from the group consisting of narcolepsy, 35 idiopathic hypersomnia, hypersomnia, sleep apnea syndrome,181narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia, Alzheimer’s disease, obesity, insulin resistance syndrome, cardiac failure, diseases related to bone loss, sepsis, disturbance of 5 consciousness, and side effects and complications due to anesthesia.

22. The compound or salt according to claim 20, wherein the disease 10 or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, and sleep apnea syndrome.

23. The compound or salt according to claim 20, wherein the disease 15 or disorder is narcolepsy.

24. Use of the compound as defined in any one of claims 1 to 8 or a salt thereof, in the manufacture of a medicament for the treatment20of a disease or disorder associated with an orexin type 2 receptor.

25. Use according to claim 24, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic25hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime hypersomnia, Alzheimer’s disease, obesity, insulin resistance syndrome, cardiac failure, diseases related to bone loss, sepsis, disturbance of consciousness, and 30 side effects and complications due to anesthesia.

26. Use according to claim 24, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic 35 hypersomnia, hypersomnia, and sleep apnea syndrome.182

27. Use according to claim 24, wherein the disease or disorder is narcolepsy. 5183

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